Tissue engineered vascular grafts: A quarter century journey of courage, challenge and persistence
M Emmert, M Generali, P Zilla and S Hoerstrup
JACC (2025) Editorial Comment
https://doi.org/10.1016/j.jacbts.2025.04.008
 

Mechanical valve replacement for patients with rheumatic heart disease: the reality of INR control in Africa and beyond
P Zilla, P Human and T Pennel
Front Cardiovasc Med (2024) 11(1347838
10.3389/fcvm.2024.1347838

The majority of patients requiring heart valve replacement in low- to middle-income countries (LMICs) need it for rheumatic heart disease (RHD). While the young age of such patients largely prescribes replacement with mechanical prostheses, reliable anticoagulation management is often unattainable under the prevailing socioeconomic circumstances. Cases of patients with clotted valves presenting for emergency surgery as a consequence of poor adherence to anticoagulation control are frequent. The operative mortality rates of reoperations for thrombosed mechanical valves are several times higher than those for tissue valves, and long-term results are also disappointing. Under-anticoagulation prevails in these regions that has clearly been linked to poor international normalised ratio (INR) monitoring. In industrialised countries, safe anticoagulation is defined as >60%-70% of the time in the therapeutic range (TTR). In LMICs, the TTR has been found to be in the range of twenty to forty percent. In this study, we analysed >20,000 INR test results of 552 consecutive patients receiving a mechanical valve for RHD. Only 27% of these test results were in the therapeutic range, with the vast majority (61%) being sub-therapeutic. Interestingly, the post-operative frequency of INR tests of one every 3-4 weeks in year 1 had dropped to less than 1 per year by year 7. LMICs need to use clinical judgement and assess the probability of insufficient INR monitoring prior to uncritically applying Western guidelines predominantly based on chronological age. The process of identification of high-risk subgroups in terms of non-adherence to anticoagulation control should take into account both the adherence history of >50% of patients with RHD who were in chronic atrial fibrillation prior to surgery as well as geographic and socioeconomic circumstances.

 

A case of cytomegalovirus cystic lung disease and review of literature
SM Wordui, S Singh, T Pillay, M Zampoli, A Daniels, A Brooks, A Vanker and D Gray
Respirol Case Rep (2024) 12(10): e70054
10.1002/rcr2.70054

A 31-week gestation male infant with respiratory distress since day of delivery had lobectomy at 8 weeks of age for symptomatic, suspected congenital pulmonary airway malformation (CPAM). Histology of resected lung showed cytomegalovirus (CMV) inclusion bodies and emphysematous changes. The infant was treated with antiviral therapy with improvement in symptoms. CMV infection of the lung should be considered in any neonate presenting with lung cysts.

 

Analysis of morphological properties of fibrous electrospun polyurethane grafts using image segmentation
J Ochola, C Hume and D Bezuidenhout
J Mech Behav Biomed Mater (2024) 155(106573
10.1016/j.jmbbm.2024.106573

The concentration of the polymer in the electrospinning solution greatly influences the mechanical behaviour of electrospun vascular grafts due to the influence on scaffold morphology. The scaffold morphology (fiber diameter, fiber orientation and inter-fiber voids) of the grafts plays an important role in their behaviour during use. Even though manual methods and complex algorithms have been used so far for characterisation of the morphology of electrospun architecture, they still have several drawbacks that limit their reliability. This study therefore uses conventional, statistical region merging and a hybrid image segmentation algorithm, to characterise the morphology of the electrospun vascular grafts. Consequently, vascular grafts were fabricated using an in-house electrospinning equipment using three polymer material concentration levels (14%, 16% and 18%) of medical-grade thermoplastic polyurethane (Pellethane(R)). The image thresholding and segementation algorithms were then used for segmentation of SEM images extracted from the polymer grafts and then morphological parameters were investigated in terms of fiber diameter, fiber orientation, and interfiber spaces (pore area and porosity). The results indicate that electrospun image segmentation was "best" when the hybrid algorithm and the conventional algorithm was used, which implied that fiber property values computed from the hybrid algorithm were closed to the manually measurements especially for the 14% PU with fiber diameter 2.2%, fiber orientation 7.6% and porosity at 1.9%. However there was higher disperity between the manual and hybrid algorithm. This suggests more fiber uniformity in the 14%PU potentially affected the accuracy of the hybrid algorithm.

 

In silico Mechanics of Stem Cells Intramyocardially Transplanted with a Biomaterial Injectate for Treatment of Myocardial Infarction
YD Motchon, KL Sack, MS Sirry, NJ Nchejane, T Abdalrahman, J Nagawa, M Kruger, E Pauwels, D Van Loo, A De Muynck, L Van Hoorebeke, NH Davies and T Franz
Cardiovasc Eng Technol (2024) 15(5): 594-605
10.1007/s13239-024-00734-1

PURPOSE: Biomaterial and stem cell delivery are promising approaches to treating myocardial infarction. However, the mechanical and biochemical mechanisms underlying the therapeutic benefits require further clarification. This study aimed to assess the deformation of stem cells injected with the biomaterial into the infarcted heart. METHODS: A microstructural finite element model of a mid-wall infarcted myocardial region was developed from ex vivo microcomputed tomography data of a rat heart with left ventricular infarct and intramyocardial biomaterial injectate. Nine cells were numerically seeded in the injectate of the microstructural model. The microstructural and a previously developed biventricular finite element model of the same rat heart were used to quantify the deformation of the cells during a cardiac cycle for a biomaterial elastic modulus (E(inj)) ranging between 4.1 and 405,900 kPa. RESULTS: The transplanted cells' deformation was largest for E(inj) = 7.4 kPa, matching that of the cells, and decreased for an increase and decrease in E(inj). The cell deformation was more sensitive to E(inj) changes for softer (E(inj) </= 738 kPa) than stiffer biomaterials. CONCLUSIONS: Combining the microstructural and biventricular finite element models enables quantifying micromechanics of transplanted cells in the heart. The approach offers a broader scope for in silico investigations of biomaterial and cell therapies for myocardial infarction and other cardiac pathologies.

 

Common Arterial Trunk Repair at the Red Cross War Memorial Hospital, Cape Town: A 20-Year Review of Surgical Practice and Outcomes
A Moodley, HM Meyer, S Salie, P Human, LJ Zuhlke and A Brooks
World J Pediatr Congenit Heart Surg (2024) 15(6): 766-773
10.1177/21501351241256582

BACKGROUND: This study describes the 20-year experience of managing common arterial trunk (CAT) in a low-and-middle-income country and compares the early and medium-term outcomes following the transition from conduit to nonconduit repair at the Red Cross War Memorial Children's Hospital. METHODS: Single-center retrospective study of consecutive patients aged less than 18 years who underwent repair of CAT from January 1999 to December 2018 at the Red Cross War Memorial Children's Hospital. Patients with interrupted aortic arch or previous pulmonary artery banding were excluded. RESULTS: Fifty-four patients had CAT repair during the study period. Thirty-four (63.0%) patients had a conduit repair, and 20 (37.0%) patients had a nonconduit repair. There were two intraoperative deaths. Thirty-day in-hospital mortality was 22.2% (12/54). Overall, in-hospital mortality was 29.6% (16/54). Eight (21.1%) late mortalities were observed. The actuarial survival for the conduit group was 77.5%, 53.4%, and 44.5% at 6, 12, and 27 months, respectively, and the nonconduit group was 58.6% at six months. The overall freedom from reoperation between the conduit group and nonconduit group was 66.2% versus 86.5%, 66.2% versus 76.9%, and 29.8% versus 64.1% at 1, 2, and 8 years, respectively. CONCLUSIONS: The outcomes following the transition to nonconduit repair for CAT in a low- and middle-income setting appear to be encouraging. There was no difference in mortality between conduit and nonconduit repairs, and importantly the results suggest a trend toward lower reintervention rates.

 

In-home TB Testing Using GeneXpert Edge is Acceptable, Feasible, and Improves the Proportion of Symptomatic Household Contacts Tested for TB: A Proof-of-Concept Study
A Medina-Marino, D Bezuidenhout, C Bezuidenhout, SN Facente, B Fourie, SS Shin, A Penn-Nicholson and G Theron
Open Forum Infect Dis (2024) 11(6): ofae279
10.1093/ofid/ofae279

BACKGROUND: Household contact investigations are effective for finding tuberculosis (TB) cases but are hindered by low referral uptake for clinic-based evaluation and testing. We assessed the acceptability and feasibility of in-home testing of household contacts (HHC) using the GeneXpert Edge platform. METHODS: We conducted a 2-arm, randomized study in Eastern Cape, South Africa. HHCs were verbally assessed using the World Health Organization-recommended 4-symptom screen. Households with >/=1 eligible symptomatic contact were randomized. Intervention households received in-home GeneXpert MTB/RIF molecular testing. GeneXpert-positive HHCs were referred for clinic-based treatment. Standard-of-care households were referred for clinic-based sputum collection and testing. We defined acceptability as agreeing to in-home testing and feasibility as generation of valid Xpert MTB/RIF results. The proportion and timeliness of test results received was compared between groups. RESULTS: Eighty-four households were randomized (n = 42 per arm). Of 100 eligible HHCs identified, 98/100 (98%) provided consent. Of 51 HHCs allocated to the intervention arm, all accepted in-home testing; of those, 24/51 (47%) were sputum productive and 23/24 (96%) received their test results. Of 47 HCCs allocated to standard-of-care, 7 (15%) presented for clinic-based TB evaluation, 6/47 (13%) were tested, and 4/6 (67%) returned for their results. The median (interquartile range) number of days from screening to receiving test results was 0 (0) and 16.5 (11-15) in the intervention and standard-of-care arms, respectively. CONCLUSIONS: In-home testing for TB was acceptable, feasible, and increased HHCs with a molecular test result. In-home testing mitigates a major limitation of household contact investigations (dependency on clinic-based referral), revealing new strategies for enhancing early case detection.

 

Missed opportunities for hand hygiene at the patient's bedside: a pilot descriptive study
O Mbamalu, C Bonaconsa, S Surendran, V Nampoothiri, T Pennel, A Boutall, N Papavarnavas, S Singh, A Holmes, E Charani and M Mendelson
J Hosp Infect (2024) 147(216-218
10.1016/j.jhin.2023.11.011

 

Two decades of recipient and donor referrals for heart transplantation to Groote Schuur Hospital, Cape Town, South Africa: A retrospective study
R Kanyongo, G Calligaro, B Cupido, J Scherman, A Brooks, C Ofoegbu, N Da Silva, A Ryan, M Mofamadi, K Seele, P Human, J Brink, P Zilla and T Pennel
S Afr Med J (2024) 114(3b): e1371
10.7196/SAMJ.2024.v114i3b.1371

BACKGROUND: Heart transplantation in South Africa faces numerous challenges related to organ scarcity and unequal access to advanced heart therapy. There is an urgent need to analyse the current transplant referral pathway to optimise equitable access to transplantation. OBJECTIVES: To provide an audit of heart transplant referrals to Groote Schuur Hospital, Cape Town, over a 23-year period, focusing on patient demographics, indications for referral, waiting-list dynamics, and transplant referral outcomes. METHODS: The study utilised a retrospective patient folder review for the period 1 January 1997 - 31 December 2019 and audited the trends in heart transplant referrals and associated outcomes of the referral at a tertiary academic hospital. RESULTS: A total of 625 recipients were referred for heart transplantation, with the majority being male (n=412; 65.9%), while gender was undocumented for 69 cases (11.0%). The mean age was 38.1 (14.6) years, and 153 (24.5%) were listed for transplant, while 215 (34.4%) were deemed ineligible for listing. Contraindications for listing included social (n=106; 49.3%), medical (n=83; 38.6%) and psychological (n=26; 12.0%) factors, while 134 patients (21.4%) were considered too well. Poor social circumstances (n=38; 39.6%), poor insight (n=28; 29.2%) and poor compliance (n=21; 21.9%) were the most common non-medical reasons for not listing recipients, while obesity (n=30; 31.3%) and smoking (n=23; 24.0%) were notable medical contraindications. Forty-nine patients (7.8%) died during work-up, while 130 (85.0%) of the listed patients received a heart transplant. Of the 429 donor referrals, 139 (32.4%) were accepted for organ procurement. Reasons for declining donors included unsuitability for transplantation (30.3%), lack of capacity (1.8%), and recipient-donor mismatch (66.9%). CONCLUSION: Three-quarters of the referred patients were deemed unsuitable for heart transplantation for medical and/or social reasons. The ratio of referral to listing has decreased over time. However, once listed, the likelihood of receiving a transplant was high.

 

Cardioprotection with Intralipid During Coronary Artery Bypass Grafting Surgery on Cardiopulmonary Bypass: A Randomized Clinical Trial
N Hadebe, M Cour, A Imamdin, T Petersen, T Pennel, J Scherman, J Snowball, M Ntsekhe, P Zilla, J Swanevelder and S Lecour
Cardiovasc Drugs Ther (2024) 10.1007/s10557-024-07594-w

PURPOSE: Coronary artery bypass grafting (CABG) on cardiopulmonary bypass (CPB) is associated with myocardial ischemia-reperfusion injury (IRI), which may limit the benefit of the surgery. Both experimental and clinical studies suggest that Intralipid, a lipid emulsion commonly used for parenteral nutrition, can limit myocardial IRI. We therefore aimed to investigate whether Intralipid administered at reperfusion can reduce myocardial IRI in patients undergoing CABG on CPB. METHODS: We conducted a randomized, double-blind, pilot trial in which 29 adult patients scheduled for CABG were randomly assigned (on a 1:1 basis) to receive either 1.5 ml/kg Intralipid 20% or Ringer's Lactate 3 min before aortic cross unclamping. The primary endpoint was the 72-h area under the curve (AUC) for troponin I. RESULTS: Of the 29 patients randomized, 26 were included in the study (two withdrew consent and one was excluded before surgery). The 72-h AUC for troponin I did not significantly differ between the control and Intralipid group (546437 +/- 205518 versus 487561 +/- 115724 arbitrary units, respectively; P = 0.804). Other outcomes (including 72-h AUC for CK-MB, C-reactive protein, need for defibrillation, time to extubation, length of ICU and hospital stay, and serious adverse events) were similar between the two groups. CONCLUSION: In patients undergoing CABG on CPB, Intralipid did not limit myocardial IRI compared to placebo. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02807727 (registration date: 16 June 2016).

 

Outcomes Following Neonatal Cardiac Surgery in Cape Town, South Africa
D du Toit, LC Swanson, S Salie, S Perkins, W Basera, JB Lawrenson, T Aldersley, A Brooks and LJ Zuhlke
World J Pediatr Congenit Heart Surg (2024) 15(6): 774-782
10.1177/21501351241268559

BACKGROUND: Neonatal Cardiac Surgery has developed significantly since its advent, with improved outcomes, survival, and physiological repair. Limited programs offer neonatal cardiac surgery in emerging economies. We report our experience with neonates undergoing cardiac surgery in our cardiac surgery program. METHODS: We performed a secondary data analysis on all neonates aged </= 30 days undergoing congenital cardiac surgery from April 1, 2017 to March 31, 2020, including outcomes up to 30-days post-surgery. RESULTS: A total of 859 patients underwent cardiac surgery at our center, of these 81 (9.4%) were neonates. The proportion of neonates increased annually (8.7%, 9.6%, and 10.2%). There were 49 (60%) male patients, and 32 (40%) had surgery in the second week of life. Fourteen (17%) were premature, four (5%) had a major chromosomal abnormality, five (6%) a major medical illness, and eight (10%) a major noncardiac structural anomaly. The Risk Adjustment for Congenital Heart Surgery (RACHS) categorization of surgery was predominantly RACHS 3; n = 28 (35%) and 4; n = 23 (29%). Hours in the intensive care unit (ICU) were extensive; median 189 [interquartile range (IQR): 114-286] as were hours of ventilation; median 95 [IQR 45-163]. Almost 60% (n = 48) of procedures were complicated by sepsis, as defined in our database. The in-hospital mortality rate was 16% (n = 13); the 30-day mortality rate was 19.8% (n = 16). CONCLUSION: The proportion of neonates in our service increased over the period. Focused strategies to shorten prolonged ICU stay and decrease rates of bacterial sepsis in neonates are needed. A multidisciplinary, collaborative heart-team approach is crucial for best outcomes.

 

Making a difference: 5 years of Cardiac Surgery Intersociety Alliance (CSIA)
RM Bolman, P Zilla, F Beyersdorf, P Boateng, J Bavaria, J Dearani, J Pomar, S Kumar, T Chotivatanapong, K Sliwa, JL Eisele, Z Enumah, B Podesser, EA Farkas, T Kofidis, LJ Zuhlke and R Higgins
Asian Cardiovasc Thorac Ann (2024) 32(5): 271-284
10.1177/02184923241259191

Informed by the almost unimaginable unmet need for cardiac surgery in the developing regions of the world, leading surgeons, cardiologists, editors in chief of the major cardiothoracic journals as well as representatives of medical industry and government convened in December 2017 to address this unacceptable disparity in access to care. The ensuing "Cape Town Declaration" constituted a clarion call to cardiac surgical societies to jointly advocate the strengthening of sustainable, local cardiac surgical capacity in the developing world. The Cardiac Surgery Intersociety Alliance (CSIA) was thus created, comprising The Society of Thoracic Surgeons (STS), the American Association for Thoracic Surgery (AATS), the Asian Society for Cardiovascular and Thoracic Surgery (ASCVTS), the European Association for Cardio-Thoracic Surgery (EACTS) and the World Heart Federation (WHF). The guiding principle was advocacy for sustainable cardiac surgical capacity in low-income countries. As a first step, a global needs assessment confirmed rheumatic heart disease as the overwhelming pathology requiring cardiac surgery in these regions. Subsequently, CSIA published a request for proposals to support fledgling programmes that could demonstrate the backing by their governments and health care institution. Out of 11 applicants, and following an evaluation of the sites, including site visits to the 3 finalists, Mozambique and Rwanda were selected as the first Pilot Sites. Subsequently, a mentorship and training agreement was completed between Mozambique and the University of Cape Town, a middle-income country with a comparable burden of rheumatic heart disease. The agreement entails regular video calls between the heart teams, targeted training across all aspects of cardiac surgery, as well as on-site presence of mentoring teams for complex cases with the strict observance of 'assisting only'. In Rwanda, Team Heart, a US and Rwanda-based non-governmental organization (NGO) that has been performing cardiac surgery in Rwanda and helping to train the cardiac surgery workforce since 2008, has agreed to continue providing mentorship for the local team and to assist in the establishment of independent cardiac surgery with all that entails. This involves intermittent virtual conferences between Rwandan and US cardiologists for surgical case selection. Five years after CSIA was founded, it's 'Seal of Approval' for the sustainability of endorsed programmes in Mozambique and Rwanda has resulted in higher case numbers, a stronger government commitment, significant upgrades of infrastructure, the nurturing of generous consumable donations by industry and the commencement of negotiations with global donors for major grants. Extending the CSIA Seal to additional deserving programmes could further align the international cardiac surgical community with the principle of local cardiac surgery capacity-building in developing countries.

 

Transcatheter or Surgical Treatment of Aortic-Valve Stenosis
S Blankenberg, M Seiffert, R Vonthein, H Baumgartner, S Bleiziffer, MA Borger, YH Choi, P Clemmensen, J Cremer, M Czerny, N Diercks, I Eitel, S Ensminger, D Frank, N Frey, A Hagendorff, C Hagl, C Hamm, U Kappert, M Karck, WK Kim, IR Konig, M Krane, U Landmesser, A Linke, LS Maier, S Massberg, FJ Neumann, H Reichenspurner, TK Rudolph, C Schmid, H Thiele, R Twerenbold, T Walther, D Westermann, E Xhepa, A Ziegler, V Falk and D-DT Investigators
N Engl J Med (2024) 390(17): 1572-1583
10.1056/NEJMoa2400685

BACKGROUND: Among low-risk patients with severe, symptomatic aortic stenosis who are eligible for both transcatheter aortic-valve implantation (TAVI) and surgical aortic-valve replacement (SAVR), data are lacking on the appropriate treatment strategy in routine clinical practice. METHODS: In this randomized noninferiority trial conducted at 38 sites in Germany, we assigned patients with severe aortic stenosis who were at low or intermediate surgical risk to undergo either TAVI or SAVR. Percutaneous- and surgical-valve prostheses were selected according to operator discretion. The primary outcome was a composite of death from any cause or fatal or nonfatal stroke at 1 year. RESULTS: A total of 1414 patients underwent randomization (701 to the TAVI group and 713 to the SAVR group). The mean (+/-SD) age of the patients was 74+/-4 years; 57% were men, and the median Society of Thoracic Surgeons risk score was 1.8% (low surgical risk). The Kaplan-Meier estimate of the primary outcome at 1 year was 5.4% in the TAVI group and 10.0% in the SAVR group (hazard ratio for death or stroke, 0.53; 95% confidence interval [CI], 0.35 to 0.79; P<0.001 for noninferiority). The incidence of death from any cause was 2.6% in the TAVI group and 6.2% in the SAVR group (hazard ratio, 0.43; 95% CI, 0.24 to 0.73); the incidence of stroke was 2.9% and 4.7%, respectively (hazard ratio, 0.61; 95% CI, 0.35 to 1.06). Procedural complications occurred in 1.5% and 1.0% of patients in the TAVI and SAVR groups, respectively. CONCLUSIONS: Among patients with severe aortic stenosis at low or intermediate surgical risk, TAVI was noninferior to SAVR with respect to death from any cause or stroke at 1 year. (Funded by the German Center for Cardiovascular Research and the German Heart Foundation; DEDICATE-DZHK6 ClinicalTrials.gov number, NCT03112980.).

 

Immunotherapy in the Context of Aortic Valve Diseases
F Bartoli-Leonard, T Pennel and M Caputo
Cardiovasc Drugs Ther (2024) 38(6): 1173-1185
10.1007/s10557-024-07608-7

PURPOSE: Aortic valve disease (AVD) affects millions of people around the world, with no pharmacological intervention available. Widely considered a multi-faceted disease comprising both regurgitative pathogenesis, in which retrograde blood flows back through to the left ventricle, and aortic valve stenosis, which is characterized by the thickening, fibrosis, and subsequent mineralization of the aortic valve leaflets, limiting the anterograde flow through the valve, surgical intervention is still the main treatment, which incurs considerable risk to the patient. RESULTS: Though originally thought of as a passive degeneration of the valve or a congenital malformation that has occurred before birth, the paradigm of AVD is shifting, and research into the inflammatory drivers of valve disease as a potential mechanism to modulate the pathobiology of this life-limiting pathology is taking center stage. Following limited success in mainstay therapeutics such as statins and mineralisation inhibitors, immunomodulatory strategies are being developed. Immune cell therapy has begun to be adopted in the cancer field, in which T cells (chimeric antigen receptor (CAR) T cells) are isolated from the patient, programmed to attack the cancer, and then re-administered to the patient. Within cardiac research, a novel T cell-based therapeutic approach has been developed to target lipid nanoparticles responsible for increasing cardiac fibrosis in a failing heart. With clonally expanded T-cell populations recently identified within the diseased valve, their unique epitope presentation may serve to identify novel targets for the treatment of valve disease. CONCLUSION: Taken together, targeted T-cell therapy may hold promise as a therapeutic platform to target a multitude of diseases with an autoimmune aspect, and this review aims to frame this in the context of cardiovascular disease, delineating what is currently known in the field, both clinically and translationally.

 

Farewell to a pioneer of Austrian cardiovascular surgery: Univ. Prof. Dr. Manfred Deutsch (1939-2023)
P Zilla, M Grimm, N Bonaros and T Fischlein
Wien Klin Wochenschr (2023) 135(11-12): 316-317
10.1007/s00508-023-02201-8

 

Farewell to a pioneer in Cardiovascular Surgery
P Zilla and T Fischlein
Wiener Med Wochenschrift (2023) 135(316-317

 

Mucoepidermoid carcinoma of the bronchus in two children: Case reports
SM Wordui, A Lakhan, J Eze, Z Nowalaza, S Makate, A Brooks, R De Decker, E Banderker, K Pillay, S Singh, M Hendricks, D Gray, M Zampoli and A Vanker
Respir Med Case Rep (2023) 43(101858
10.1016/j.rmcr.2023.101858

Childhood mucoepidermoid carcinomas (MEC) of the bronchus are rare. They present with non-specific symptoms and signs making diagnosis delayed. We present two children with bronchial MEC managed in a tertiary children's hospital in Cape Town, South Africa. The first was a 11-year male with recurrent haemoptysis and the second child was a 6-year female with recurrent unifocal pneumonia. Chest CT scan and bronchoscopy with biopsy confirmed the diagnosis. Both patients underwent treatment, including surgery and are doing well. It is important to exclude endobronchial lesions when children present with recurrent respiratory symptoms, since early diagnosis will enable lung-sparing treatment.

 

Vaginal changes after ovariectomy in ewes: A large animal model for genitourinary syndrome of menopause
EV Vodegel, Z Guler, L Ras, K Mackova, A Groeneveld, D Bezuidenhout, J Deprest, ST Jeffery and JWR Roovers
Int J Gynaecol Obstet (2023) 162(3): 1042-1049
10.1002/ijgo.14816

OBJECTIVE: To evaluate the effect of iatrogenic menopause on the physiology of the vagina of the ewe and to evaluate if vaginal changes in ewes can be translated to women with genitourinary syndrome of menopause (GSM). METHODS: Preclinical research with Dohne Merino ewes. Iatrogenic menopause was induced by bilateral ovariectomy (OVX). Animals were randomized for surgery, blinded for allocation and outcome assessment. Differences between groups were determined by linear regression analyses at 5 months after OVX. Outcome measures were vaginal epithelial thickness, pH, vaginal maturation value, vaginal maturation index, epithelial glycogen accumulation, content of elastin fibers, collagen, and vascularity. RESULTS: OVX ewes (n = 20) showed epithelial thinning of the vaginal wall from 146 mum to 47 mum (mean, P < 0.001). Furthermore, epithelial glycogen accumulation and vascularity of the vaginal wall significantly decreased (43% and 23%, respectively) as compared with the control group (no intervention; n = 5). No significant differences were found for other outcome measures. CONCLUSION: This study established the ewe as a suitable large animal model for GSM. Furthermore, the similar relevant outcomes in humans and ewes hold great value for future translational research for the evaluation and optimization of different treatment modalities for GSM.

 

Awareness of infection care terms among outpatients and carers in a public health facility: a cross-sectional survey
ER Useh, B Mfeketo, O Mbengo, I Karangwa, T Pennel, A Boutall, S Maswime, L Pohl, E Charani, M Mendelson and O Mbamalu
Wellcome Open Res (2023) 8(574
10.12688/wellcomeopenres.20162.2

BACKGROUND: As healthcare recipients and individuals affected by antimicrobial resistance (AMR), patients and their carers can be engaged in infection prevention and control (IPC) and antimicrobial stewardship (AMS) initiatives to manage AMR. To effectively participate in these initiatives, patients and carers need to understand general terms used in infection care. We explored awareness of commonly used infection-related terms among patients and carers in the surgical out-patient of a tertiary academic hospital. METHODS: Self-administered paper survey distributed among out-patients from August to September 2022. Categorical variables were analysed using Chi squared test. Significance was set as p-value of < 0.05. Content analysis identified terms commonly used by patients when talking about infections. RESULTS: Overall, 896 out of 1,269 respondents (response rate 70.6%), with a 1:3 male to female ratio were included. Most respondents were patients (75%), with a minimum of high school education (91.2%) and a surgical history (60.3%). Surgical wound infection was the most familiar term to participants. While many respondents had not heard of Methicillin-resistant Staphylococcus aureus ( MRSA) (92.3%, n=754) or antimicrobial resistance (92.8%, n=755), significantly more were aware of the descriptions provided for these terms (13.7% and 33.0%, respectively; p<0.001). Participants considered antibiotic resistance to be a condition in which the body rejects, resists, or does not respond to antibiotics. CONCLUSIONS: Findings show dissonance between patients' awareness of and healthcare workers' use of infection-care terms, highlighting the need for relatable and accessible terms in infection-care engagement initiatives. More than half of respondents acknowledged that patient engagement responsibility is everyone's, underscoring the need for contextually fit and relevant communication strategies to advance patient engagement and infection awareness.

 

Transcatheter aortic valve implantation versus surgical aortic valve replacement in patients at low to intermediate surgical risk: rationale and design of the randomised DEDICATE Trial
M Seiffert, R Vonthein, H Baumgartner, MA Borger, YH Choi, V Falk, N Frey, A Hagendorff, C Hagl, C Hamm, IR Konig, U Landmesser, S Massberg, H Reichenspurner, H Thiele, R Twerenbold, M Vens, T Walther, A Ziegler, J Cremer and S Blankenberg
EuroIntervention (2023) 19(8): 652-658
10.4244/EIJ-D-23-00232

Transcatheter aortic valve implantation (TAVI) has become the preferred treatment option for patients with severe aortic stenosis at increased risk for surgical aortic valve replacement (SAVR) and for older patients irrespective of risk. However, in younger, low-risk patients for whom both therapeutic options, TAVI and SAVR, are applicable, the optimal treatment strategy remains controversial, as data on long-term outcomes remain limited. The DEDICATE-DZHK6 Trial is an investigator-initiated, industry-independent, prospective, multicentre, randomised controlled trial investigating the efficacy and safety of TAVI compared to SAVR in low- to intermediate-risk patients aged 65 years or older. To evaluate both treatment strategies, approximately 1,404 patients determined eligible for both TAVI and SAVR by the interdisciplinary Heart Team were randomised to TAVI or SAVR. Broad inclusion and strict exclusion criteria targeted an all-comers patient population. Procedures were performed according to local best practice with contemporary routine medical devices. The primary endpoints are a composite of mortality or stroke at 1 year and 5 years in order to incorporate midterm efficacy results and complement early safety data. Primary outcomes will be tested sequentially for non-inferiority and superiority. The DEDICATE-DZHK6 Trial has been designed to mirror clinical reality for the treatment of severe aortic stenosis and provide unique information on overall outcomes after TAVI and SAVR that can be directly applied to clinical routines. Its results will help further define optimal treatment strategies for low- to intermediate-risk patients in whom both TAVI and SAVR are currently advisable.

 

Modified fibrin hydrogel for sustained delivery of RNAi lipopolyplexes in skeletal muscle
E Ngarande, E Doubell, O Tamgue, M Mano, P Human, M Giacca and NH Davies
Regen Biomater (2023) 10(rbac101
10.1093/rb/rbac101

RNA interference is a promising therapeutical approach presently hindered by delivery concerns such as rapid RNA degradation and targeting of individual tissues. Injectable hydrogels are one potentially simple and direct route towards overcoming these barriers. Here we report on the utility of a combination of a mildly modified form of the clinically utilised fibrin hydrogel with Invivofectamine((R)) 3.0, a lipid nonviral transfection vector, for local and sustained release. PEGylation of fibrin allowed for controlled release of small interfering RNA (siRNA)-lipopolyplexes for at least 10 days and greatly increased the stability of fibrin in vitro and in vivo. A 3D cell culture model and a release study showed transfection efficacy of siRNA-lipopolyplexes was retained for a minimum of 7 days. Injection in conjunction with PEGylated-fibrinogen significantly increased retention of siRNA-lipopolyplexes in mouse skeletal muscle and enhanced knockdown of myostatin mRNA that correlated with muscle growth. Thus, the increased efficacy observed here for the combination of a lipid nanoparticle, the only type of nonviral vector approved for the clinic, with fibrin, might allow for more rapid translation of injectable hydrogel-based RNA interference.

 

Correlations between the alpha-Gal antigen, antibody response and calcification of cardiac valve bioprostheses: experimental evidence obtained using an alpha-Gal knockout mouse animal model
F Naso, A Colli, P Zilla, AM Calafiore, C Lotan, MA Padalino, G Sturaro, A Gandaglia and M Spina
Front Immunol (2023) 14(1210098
10.3389/fimmu.2023.1210098

INTRODUCTION: Preformed antibodies against alphaGal in the human and the presence of alphaGal antigens on the tissue constituting the commercial bioprosthetic heart valves (BHVs, mainly bovine or porcine pericardium), lead to opsonization of the implanted BHV, leading to deterioration and calcification. Murine subcutaneous implantation of BHVs leaflets has been widely used for testing the efficacy of anti-calcification treatments. Unfortunately, commercial BHVs leaflets implanted into a murine model will not be able to elicit an alphaGal immune response because such antigen is expressed in the recipient and therefore immunologically tolerated. METHODS: This study evaluates the calcium deposition on commercial BHV using a new humanized murine alphaGal knockout (KO) animal model. Furtherly, the anti-calcification efficacy of a polyphenol-based treatment was deeply investigated. By using CRISPR/Cas9 approach an alphaGal KO mouse was created and adopted for the evaluation of the calcific propensity of original and polyphenols treated BHV by subcutaneous implantation. The calcium quantification was carried out by plasma analysis; the immune response evaluation was performed by histology and immunological assays. Anti-alphaGal antibodies level in KO mice increases at least double after 2 months of implantation of original commercial BHV compared to WT mice, conversely, the polyphenols-based treatment seems to effectively mask the antigen to the KO mice's immune system. RESULTS: Commercial leaflets explanted after 1 month from KO mice showed a four-time increased calcium deposition than what was observed on that explanted from WT. Polyphenol treatment prevents calcium deposition by over 99% in both KO and WT animals. The implantation of commercial BHV leaflets significantly stimulates the KO mouse immune system resulting in massive production of anti-Gal antibodies and the exacerbation of the alphaGal-related calcific effect if compared with the WT mouse. DISCUSSION: The polyphenol-based treatment applied in this investigation showed an unexpected ability to inhibit the recognition of BHV xenoantigens by circulating antibodies almost completely preventing calcific depositions compared to the untreated counterpart.

 

The elephant in the room: Exploring the influence and participation of patients in infection-related care across surgical pathways in South Africa and India
V Nampoothiri, O Mbamalu, S Surendran, C Bonaconsa, T Pennel, A Boutall, K Gopal, E Castro Sanchez, P Dhar, A Holmes, S Singh, M Mendelson, C Tarrant, E Charani and A Co-Investigators
Health Expect (2023) 26(2): 892-904
10.1111/hex.13715

OBJECTIVE: The irrational use of antibiotics is a leading contributor to antibiotic resistance. Antibiotic stewardship (AS) interventions predominantly focus on prescribers. This study investigated the influence and participation of inpatients in infection-related care, including antibiotic decision-making, within and across two tertiary hospitals in South Africa (Cape Town) and India (Kerala). METHODS: Through ethnographic enquiry of clinical practice in surgical pathways, including direct nonparticipant observation of clinical practices, healthcare worker (HCW), patient and carer interactions in surgical ward rounds and face-to-face interviews with participants (HCWs and patients), we sought to capture the implicit and explicit influence that patients and carers have in infection-related care. Field notes and interview transcripts were thematically coded, aided by NVivo 12(R) Pro software. RESULTS: Whilst observational data revealed the nuanced roles that patients/carers play in antibiotic decision-making, HCWs did not recognize these roles. Patients and carers, though invested in patient care, are not routinely involved, nor are they aware of the opportunities for engagement in infection-related decision-making. Patients associated clinical improvement with antibiotic use and did not consider hospitalization to be associated with infection acquisition or transmission, highlighting a lack of understanding of the threat of infection and antibiotic resistance. Patients' economic and cultural positionalities may influence their infection-related behaviours. In the study site in India, cultural norms mean that carers play widespread but unrecognized roles in inpatient care, participating in infection prevention activities. CONCLUSION: For patients to have a valuable role in AS and make informed decisions regarding their infection-related care, a mutual understanding of their role in this process among HCWs and patients is crucial. The observed differences between the two study sites indicate the critical need for understanding and addressing the contextual drivers that impact effective patient-centred healthcare delivery. PATIENT OR PUBLIC CONTRIBUTION: Ethnographic observations and interviews conducted in this study involved patients as participants. Patients were recruited for interviews after obtaining signed informed consent forms. Patients' identities were completely anonymized when presenting the study findings.

 

Evaluating Calcification in Tissue-Engineered Heart Valves: Much More Complicated Than Expected?
SE Motta, CK Breuer, P Zilla, SP Hoerstrup and MY Emmert
JACC Basic Transl Sci (2023) 8(5): 592-593
10.1016/j.jacbts.2023.02.020

 

Effect of biomaterial stiffness on cardiac mechanics in a biventricular infarcted rat heart model with microstructural representation of in situ intramyocardial injectate
YD Motchon, KL Sack, MS Sirry, M Kruger, E Pauwels, D Van Loo, A De Muynck, L Van Hoorebeke, NH Davies and T Franz
Int J Numer Method Biomed Eng (2023) 39(5): e3693
10.1002/cnm.3693

Intramyocardial delivery of biomaterials is a promising concept for treating myocardial infarction. The delivered biomaterial provides mechanical support and attenuates wall thinning and elevated wall stress in the infarct region. This study aimed at developing a biventricular finite element model of an infarcted rat heart with a microstructural representation of an in situ biomaterial injectate, and a parametric investigation of the effect of the injectate stiffness on the cardiac mechanics. A three-dimensional subject-specific biventricular finite element model of a rat heart with left ventricular infarct and microstructurally dispersed biomaterial delivered 1 week after infarct induction was developed from ex vivo microcomputed tomography data. The volumetric mesh density varied between 303 mm(-3) in the myocardium and 3852 mm(-3) in the injectate region due to the microstructural intramyocardial dispersion. Parametric simulations were conducted with the injectate's elastic modulus varying from 4.1 to 405,900 kPa, and myocardial and injectate strains were recorded. With increasing injectate stiffness, the end-diastolic median myocardial fibre and cross-fibre strain decreased in magnitude from 3.6% to 1.1% and from -6.0% to -2.9%, respectively. At end-systole, the myocardial fibre and cross-fibre strain decreased in magnitude from -20.4% to -11.8% and from 6.5% to 4.6%, respectively. In the injectate, the maximum and minimum principal strains decreased in magnitude from 5.4% to 0.001% and from -5.4% to -0.001%, respectively, at end-diastole and from 38.5% to 0.06% and from -39.0% to -0.06%, respectively, at end-systole. With the microstructural injectate geometry, the developed subject-specific cardiac finite element model offers potential for extension to cellular injectates and in silico studies of mechanotransduction and therapeutic signalling in the infarcted heart with an infarct animal model extensively used in preclinical research.

 

Preventing extrinsic mechanisms of bioprosthetic degeneration using polyphenols
RJ Melder, F Naso, F Nicotra, L Russo, I Vesely, SR Tuladhar, AM Calafiore, P Zilla, A Gandaglia and S Korossis
Eur J Cardiothorac Surg (2023) 63(4): 10.1093/ejcts/ezac583

OBJECTIVES: The purpose of this study was to evaluate the impact of a polyphenols-based treatment on the extrinsic mechanisms responsible for early bioprosthetic heart valve (BHV) degeneration. Structural degeneration can be driven by both extrinsic and intrinsic mechanisms. While intrinsic mechanisms have been associated with inherent biocompatibility characteristics of the BHV, the extrinsic ones have been reported to involve external causes, such as chemical, mechanical and hydrodynamic, responsible to facilitate graft damage. METHODS: The chemical interaction and the stability degree between polyphenols and pericardial tissue were carefully evaluated. The detoxification of glutaraldehyde in commercial BHVs models and the protective effect from in vivo calcification were taken into relevant consideration. Finally, the hydrodynamic and biomechanical features of the polyphenols-treated pericardial tissue were deeply investigated by pulse duplicator and stress-strain analysis. RESULTS: The study demonstrated the durability of the polyphenols-based treatment on pericardial tissue and the stability of the bound polyphenols. The treatment improves glutaraldehyde stabilization's current degree, demonstrating a surprising in vivo anti-calcific effect. It is able to make the pericardial tissue more pliable while maintaining the correct hydrodynamic characteristics. CONCLUSIONS: The polyphenols treatment has proved to be a promising approach capable of acting simultaneously on several factors related to the premature degeneration of cardiac valve substitutes by extrinsic mechanisms.

 

Mechanical reinforcement of amniotic membranes for vesicovaginal fistula repair
LP Maljaars, Z Guler, JWR Roovers and D Bezuidenhout
J Mech Behav Biomed Mater (2023) 139(105680
10.1016/j.jmbbm.2023.105680

INTRODUCTION: Amniotic membranes (AM) have shown its great potential in reconstructive surgery due to their regenerative capacity. However, AM is regarded to be relatively weak when applied for load-bearing purposes. This study aims to produce an AM-based scaffold that can withstand the mechanical loads applied in vesicovaginal fistula repair. Different strategies are investigated to improve the mechanical characteristics of AM. METHODS: Single and multilayered AM, and composite constructs of AM with electrospun poly-4-hydroxybutyrate (P4HB) or bovine pericardial tissue combined with the use of fibrin glue, were mechanically tested in this study. Suture retention strength and mechanical characteristics (tensile stress, elongation, tangent modulus and maximum load) were assessed by uniaxial testing. The effect of degradation of the composite constructs on the mechanical characteristics was determined by uniaxial testing after 4 and 8 weeks. RESULTS: Single and multilayered AM could not provide the mechanical requirements needed for surgical implantation (>2N load). AM was combined successfully with electrospun P4HB and bovine pericardium with the use of fibrin glue and were able to exceed the 2N load. CONCLUSION: The composite constructs with AM showed sufficient mechanical characteristics for surgical implantation. Electrospun P4HB combined with AM seemed the most promising candidate since the mechanical characteristics of P4HB can be further modified to meet the requirements of the application site and the degradation of the P4HB allows a gradual transfer of load. Eventhough the scaffold is intended for fistula repair, it can potentially be applied in surgical reconstruction of other hollow organs by modifying the mechanical characteristics.

 

Prevalence and Impact of HIV Infections in Patients with Rheumatic Heart Disease: A Systematic Review and Meta-Analysis
EN Lumngwena, D Mokaila, O Aremu, PD Katoto, J Blackburn, P Zilla, CS Wiysonge and N Ntusi
Glob Heart (2023) 18(1): 49
10.5334/gh.1265

Socioeconomic factors such as poor health and poor nutrition in low- and middle-income countries (LMICs) may favour inflammatory reactions, thus contributing to the recurrence of rheumatic fever (RF) and thereby modifying trends in rheumatic heart disease (RHD). Apart from epidemiological studies, studies of HIV infections in RHD patients are limited. This systematic review synthesises data on the prevalence and impact of HIV infections or AIDS on RHD from PubMed, Scopus, Web of Science databases up to April 2021. The outcomes were managed using PRISMA guidelines. Of a total of 15 studies found, 10 were eligible for meta-analyses. Meta-analysis found that 17% (95 % CI 8-33, I(2) = 91%) of adults in cardiovascular disease (CVD) cohorts in Southern Africa are HIV positive. The proportion of RHD diagnosed among people living with HIV was 4% (95% CI 2-8, I(2) = 79%) for adults but lower [2% (95% CI 1-4, I(2) = 87%)] among perinatally infected children. Despite limited reporting, HIV-infected patients with RHD are prone to other infections that may enhance cardiac complications due to poor immunological control. PROSPERO registration number: CRD42021237046.

 

Pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension in Cape Town, South Africa
SA Davies-van Es, TC Pennel, J Brink, GJ Symons and GL Calligaro
Afr J Thorac Crit Care Med (2023) 29(3): 10.7196/AJTCCM.2023.v29i3.294

BACKGROUND: Pulmonary endarterectomy (PEA) is the only definitive and potentially curative therapy for chronic thromboembolic pulmonary hypertension (CTEPH), associated with impressive improvements in symptoms and haemodynamics. However, it is only offered at a few centres in South Africa. The characteristics and outcomes of patients undergoing PEA in Cape Town have not been reported previously. OBJECTIVES: To assess the difference in World Health Organization functional class (WHO-FC) before and at least 6 weeks after surgery. METHODS: We interrogated the adult cardiothoracic surgery database at the University of Cape Town between December 2005 and April 2021 for patients undergoing PEA at Groote Schuur Hospital and a private hospital. RESULTS: A total of 32 patients underwent PEA, of whom 8 were excluded from the final analysis owing to incomplete data or a histological diagnosis other than CTEPH. The work-up of these patients for surgery was variable: all had a computed tomography pulmonary angiogram, 7 (29%) had a ventilation/perfusion scan, 5 (21%) underwent right heart catheterisation, and none had a pulmonary angiogram. The perioperative mortality was 4/24 (17%): 1 patient (4%) had a cardiac arrest on induction of anaesthesia, 2 patients (8%) died of postoperative pulmonary haemorrhage, and 1 patient (4%) died of septic complications in the intensive care unit. Among the survivors, the median (interquartile range) improvement in WHO-FC was 2 (1 - 3) classes (p=0.0004); 10/16 patients (63%) returned to a normal baseline (WHO-FC I). CONCLUSION: Even in a low-volume centre, PEA is associated with significant improvements in WHO-FC and a return to a normal baseline in survivors. STUDY SYNOPSIS: What the study adds. South African patients undergoing pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH) have a marked improvement in functional status, with many returning to a normal functional baseline. However, the small number of patients included in this study indicates that PEA is probably underutilised. Pre- and postoperative assessment is inconsistent, despite availability of established guidelines.Implications of the findings. More patients should be referred to specialist centres for assessment for this potentially curative procedure. Use of guidelines to standardise investigations and monitoring of patients with CTEPH may improve patient selection for surgery.

 

"I know why I am taking this pill": Young women navigation of disclosure and support for PrEP uptake and adherence in Eastern Cape Province, South Africa
J Daniels, L De Vos, D Bezuidenhout, M Atujuna, C Celum, S Hosek, LG Bekker and A Medina-Marino
PLOS Glob Public Health (2023) 3(1): e0000636
10.1371/journal.pgph.0000636

There is limited understanding of the dynamic interplay between adolescent girl's and young women's (AGYW) disclosure and social support for using oral pre-exposure prophylaxis (PrEP) and adherence. Towards this, we conducted interviews with 42 AGYW enrolled in The Community PrEP Study who exhibited either high or low blood concentrations of tenofovir-diphosphate (TFV-DP) in dried blood spots. Guided by Theories of Practice, interviews and analysis focused on AGYW perspectives and experiences with PrEP disclosure, support and adherence. AGYW with high TFV-DP blood concentrations described larger social support networks and disclosure events. In contrast, those with low TFV-DP blood concentrations described disclosing to fewer people, resulting in limited social support. Participants discussed partner support, however, this support was not described as consequential to adherence, irrespective of TFV-DP levels. Those with high levels of TFV-DP in their blood described the ability to navigate social scrutiny and changes in social support, while those with low levels of TFV-DP in their blood were more likely to question their own continued use of PrEP. To facilitate AGYW's prevention-effective use of PrEP, expanded skill-building for disclosure and resiliency against changes to social support should be examined as part of PrEP services.

 

Outcomes of patients undergoing lung resection for drug-resistant TB and the prognostic significance of pre-operative positron emission tomography/computed tomography (PET/CT) in predicting treatment failure
GL Calligaro, N Singh, TC Pennel, R Steyn, A Brink, A Esmail, L Mottay, S Oelofse, BL Mastrapa, W Basera, K Manning, C Ofoegbu, A Linegar and K Dheda
EClinicalMedicine (2023) 55(101728
10.1016/j.eclinm.2022.101728

BACKGROUND: Surgery remains an adjunctive treatment for drug-resistant tuberculosis (DR-TB) treatment failure despite the use of bedaquiline. However, there are few data about the role of surgery when combined with newer drugs. There are no outcome data from TB endemic countries, and the prognostic significance of pre-operative PET-CT remains unknown. METHODS: We performed a prospective observational study of 57 DR-TB patients referred for surgery at Groote Schuur Hospital between 2010 and 2016. PET-CT was performed if there was nodal disease or disease outside the area of planned resection but did not influence treatment decisions. 24-month treatment success post-surgery (cure or treatment completion), including all-cause mortality, was determined. FINDINGS: 35/57 (61.4%) patients (median age 40 years; 26% HIV-infected) underwent surgery and 22/57 (38.6%) did not (11 patients were deemed unsuitable due to bilateral cavitary disease and 11 patients declined surgery). Treatment failure was significantly lower in those who underwent surgery compared to those eligible but declined surgery [15/35 (43%) versus 11/11 (100%); relative risk 0.57 (0.42-0.76); p < 0.01). In patients treated with surgery, a post-operative regimen containing bedaquiline was associated with a lower odds of treatment failure [OR (95%CI) 0.06 (0.00-0.48); p = 0.007]. Pre-operative PET-CT (n = 25) did not predict treatment outcome. INTERPRETATION: Resectional surgery for DR-TB combined with chemotherapy was associated with significantly better outcomes than chemotherapy alone. A post-operative bedaquiline-containing regimen was associated with improved outcome; however, this finding may have been confounded by higher use of bedaquiline and less loss to follow-up in the surgical group. However, PET-CT had no prognostic value. These data inform clinical practice in TB-endemic settings. FUNDING: This work was supported by the South African MRC (RFA-EMU-02-2017) and the EDCTP (TMA-2015SF-1043 & TMA- 1051-TESAII).

 

The impact of COVID-19 on a South African pediatric cardiac service: implications and insights into service capacity
T Aldersley, A Brooks, P Human, J Lawrenson, G Comitis, R De Decker, B Fourie, R Manganyi, H Pribut, S Salie, L Swanson and L Zuhlke
Front Public Health (2023) 11(1177365
10.3389/fpubh.2023.1177365

BACKGROUND AND OBJECTIVES: The Western Cape public pediatric cardiac service is under-resourced. COVID-19 regulations are likely to have long-term effects on patient care but may provide insight into service capacity requirements. As such, we aimed to quantify the impact of COVID-19 regulations on this service. METHODS: An uncontrolled retrospective pre-post study of all presenting patients over two, one-year periods; the pre-COVID-19 period (01/03/2019-29/02/2020) and the peri-COVID-19 period (01/03/2020-28/02/2021). RESULTS: Admissions decreased by 39% (624 to 378) and cardiac surgeries decreased by 29% (293 to 208) in the peri-COVID-19 period, with an increase in urgent cases (PR:5.99, 95%CI:3.58-10.02, p < 0.001). Age at surgery was lower in the peri-COVID-19 period, 7.2 (2.4-20.4) vs. 10.8 (4.8-49.2) months (p < 0.05), likewise, age at surgery for transposition of the great arteries (TGA) was lower peri-COVID-19, 15 (IQR:11.2-25.5) vs. 46 (IQR:11-62.5) days (p < 0.05). Length of stay 6 (IQR:2-14) vs. 3 days (IQR:1-9) (p < 0.001), complications (PR:1.21, 95%CI:1.01-1.43, p < 0.05), and age-adjusted delayed-sternal-closure rates (PR:3.20, 95%CI:1.09-9.33, p < 0.05) increased peri-COVID-19. CONCLUSION: Cardiac procedures were significantly reduced in the peri-COVID-19 period which will have implications on an overburdened service and ultimately, patient outcomes. COVID-19 restrictions on elective procedures freed capacity for urgent cases, demonstrated by the absolute increase in urgent cases and significant decrease in age at TGA-surgery. This facilitated intervention at the point of physiological need, albeit at the expense of elective procedures, and also revealed insights into capacity requirements of the Western Cape. These data emphasize the need for an informed strategy to increase capacity and reduce backlog whilst ensuring minimal morbidity and mortality.Graphical Abstract.

 

Mathematical model of mechano-sensing and mechanically induced collective motility of cells on planar elastic substrates
RK Ahmed, T Abdalrahman, NH Davies, F Vermolen and T Franz
Biomech Model Mechanobiol (2023) 22(3): 809-824
10.1007/s10237-022-01682-2

Cells mechanically interact with their environment to sense, for example, topography, elasticity and mechanical cues from other cells. Mechano-sensing has profound effects on cellular behaviour, including motility. The current study aims to develop a mathematical model of cellular mechano-sensing on planar elastic substrates and demonstrate the model's predictive capabilities for the motility of individual cells in a colony. In the model, a cell is assumed to transmit an adhesion force, derived from a dynamic focal adhesion integrin density, that locally deforms a substrate, and to sense substrate deformation originating from neighbouring cells. The substrate deformation from multiple cells is expressed as total strain energy density with a spatially varying gradient. The magnitude and direction of the gradient at the cell location define the cell motion. Cell-substrate friction, partial motion randomness, and cell death and division are included. The substrate deformation by a single cell and the motility of two cells are presented for several substrate elasticities and thicknesses. The collective motility of 25 cells on a uniform substrate mimicking the closure of a circular wound of 200 microm is predicted for deterministic and random motion. Cell motility on substrates with varying elasticity and thickness is explored for four cells and 15 cells, the latter again mimicking wound closure. Wound closure by 45 cells is used to demonstrate the simulation of cell death and division during migration. The mathematical model can adequately simulate the mechanically induced collective cell motility on planar elastic substrates. The model is suitable for extension to other cell and substrates shapes and the inclusion of chemotactic cues, offering the potential to complement in vitro and in vivo studies.

 

Absorbable Electrospun Poly-4-hydroxybutyrate Scaffolds as a Potential Solution for Pelvic Organ Prolapse Surgery
K Verhorstert, A Gudde, C Weitsz, D Bezuidenhout, JP Roovers and Z Guler
ACS Appl Bio Mater (2022) 5(11): 5270-5280
10.1021/acsabm.2c00691

Women with pelvic organ prolapse (POP) have bothersome complaints that significantly affect their quality of life. While native tissue repair is associated with high recurrence rates, polypropylene knitted implants have caused specific implant-related adverse events that have detrimental, often irreversible, effects. We hypothesize that surgical outcome can be improved with a tissue-engineered solution using an absorbable implant that mimics the natural extracellular matrix (ECM) structure, releases estrogen, and activates collagen metabolism by fibroblasts as the main regulators of wound healing. To this aim, we produced electrospun poly-4-hydroxybutyrate (P4HB) scaffolds and biofunctionalized them with estradiol (E2). The cell-implant interactions relevant for POP repair were assessed by seeding primary POP vaginal fibroblasts isolated from patients on electrospun P4HB scaffolds with 1%, 2%, or 5% E2 and without E2. To test our hypothesis on whether ECM mimicking structures should improve regeneration, electrospun P4HB was compared to knitted P4HB implants. We evaluated vaginal fibroblast proliferation, ECM deposition, and metabolism by quantification of collagen, elastin, and matrix metalloproteinases and by gene expression analysis for 28 days. We established effective E2 drug loading with a steady release over time. Significantly higher cell proliferation, collagen-, and elastin deposition were observed on electrospun P4HB scaffolds as compared to knitted P4HB. For this study, physical properties of the scaffolds were more determinant on the cell response than the release of E2. These results indicate that making these electrospun P4HB scaffolds E2-releasing appears to be technically feasible. In addition, electrospun P4HB scaffolds promote the cellular response of vaginal fibroblasts and further studies are merited to assess if their use results in improved surgical outcomes in case of POP repair.

 

Investigation of Copy Number Variation in South African Patients With Congenital Heart Defects
NA Saacks, J Eales, TF Spracklen, T Aldersley, P Human, M Verryn, J Lawrenson, B Cupido, G Comitis, R De Decker, B Fourie, L Swanson, A Joachim, A Brooks, R Ramesar, G Shaboodien, BD Keavney and LJ Zuhlke
Circ Genom Precis Med (2022) 15(6): e003510
10.1161/CIRCGEN.121.003510

BACKGROUND: Congenital heart disease (CHD) is a leading non-infectious cause of pediatric morbidity and mortality worldwide. Although the etiology of CHD is poorly understood, genetic factors including copy number variants (CNVs) contribute to the risk of CHD in individuals of European ancestry. The presence of rare CNVs in African CHD populations is unknown. This study aimed to identify pathogenic and likely pathogenic CNVs in South African patients with CHD. METHODS: Genotyping was performed on 90 patients with nonsyndromic CHD using the Affymetrix CytoScan HD platform. These data were used to identify large, rare CNVs in known CHD-associated genes and candidate genes. RESULTS: We identified eight CNVs overlapping known CHD-associated genes (GATA4, CRKL, TBX1, FLT4, B3GAT3, NSD1) in six patients. The analysis also revealed CNVs encompassing five candidate genes likely to play a role in the development of CHD (DGCR8, KDM2A, JARID2, FSTL1, CYFIP1) in five patients. One patient was found to have 47, XXY karyotype. We report a total discovery yield of 6.7%, with 5.6% of the cohort carrying pathogenic or likely pathogenic CNVs expected to cause the observed phenotypes. CONCLUSIONS: In this study, we show that chromosomal microarray is an effective technique for identifying CNVs in African patients diagnosed with CHD and have demonstrated results similar to previous CHD genetic studies in Europeans. Novel potential CHD genes were also identified, indicating the value of genetic studies of CHD in ancestrally diverse populations.

 

Polyphenols could be Effective in Exerting a Disinfectant-Like Action on Bioprosthetic Heart Valves, Counteracting Bacterial Adhesiveness
F Naso, AM Calafiore, M Gaudino, P Zilla, A Haverich, A Colli, RJ Melder and A Gandaglia
Cardiol Cardiovasc Med (2022) 6(5): 487-492
10.26502/fccm.92920287

BACKGROUND: The incidence of infective endocarditis in patients with bioprosthetic heart valves is over 100 times that of the general population with S. aureus recognized as the causative organism in approximately 1/3 of cases. In this study, (1) the microbicidal and virucidal effect of a polyphenolic solution was carefully evaluated. The same solution was then adopted for the treatment of a commercial bioprosthetic heart valve model for (2) the assessment of inhibition of S. aureus adhesiveness. METHODS: (1) the viability of 9 microorganisms strains (colony-forming units) and the infectivity degree of 3 viral strains (cellular infection capacity) were evaluated after suspension in the polyphenolic solution. (2) Leaflets from a treated and untreated commercial surgical valve model were incubated with a known concentration of S. aureus. After incubation, the leaflets were homogenized and placed in specific culture media to quantify the bacterial load. RESULTS: (1) The polyphenolic solution proved to be effective in eliminating microorganisms strains guaranteeing the killing of at least 99.9%. The effectiveness is particularly relevant against M. chelonae (99.999%). (2) The polyphenol-based treatment resulted in the inhibition of the S. aureus adhesiveness by 96% concerning untreated samples. CONCLUSIONS: The data suggest an interesting protective effect against infections and bacterial adhesiveness by a polyphenolic-based solution. Further studies will plan to extend the panel of microorganisms for the evaluation of the anti-adhesive effect; however, the use of optimized polyphenolic blends could lead to the development of new treatments capable to make transcatheter-valve substitutes more resistant to infection.

 

Outcomes After Bidirectional Glenn Shunt in a Tertiary-Care Pediatric Hospital in South Africa
HM Meyer, D Marange-Chikuni, M Anaesthesia, L Zuhlke, B Roussow, P Human and A Brooks
J Cardiothorac Vasc Anesth (2022) 36(6): 1573-1581
10.1053/j.jvca.2022.01.003

OBJECTIVES: Large data sets have been published on short- and long-term outcomes following bidirectional Glenn surgery (BDG), or partial cavopulmonary connection, in high-income countries. Data from low-income and middle-income countries are few and often limited to the immediate postoperative period. The primary outcome was any in-hospital postoperative complication, assessed according to predefined criteria, in children who underwent BDG surgery at Red Cross War Memorial Children's Hospital. DESIGN: A retrospective cohort study. SETTING: A tertiary teaching hospital. PARTICIPANTS: The study authors identified 61 children (<18 years of age) who underwent BDG over 8 years. The median age of patients undergoing BDG was 2.5 years (interquartile range, 1.4-5.5 years). INTERVENTIONS: BDG surgery. MEASUREMENTS AND MAIN RESULTS: Thirty-five patients (57.4%) had a postoperative complication, with some patients (17 of 61, 27.9%) having more than 1 complication. The most frequent complications were infective (29.5%). Univariate analysis found that postoperative complications were associated with the use of nitric oxide (p = 0.004) and a longer duration of anesthesia (p = 0.045) and surgery (p = 0.004). Patients with complications spent longer in the pediatric intensive care unit (ICU) (p < 0.001) and in the hospital (p < 0.012). On multivariate analysis, a priori risk factors based on previous studies were not found to be statistically significant. A total of 37.3% of patients completed their single-ventricle palliation, and 30.5% of patients were lost to follow-up. CONCLUSIONS: Important findings were the older age at which the BDG was performed compared to high-income countries, an acceptable mortality rate of 3.3%, infection being the most common complication, the association of a complication with increased ICU and hospital lengths of stay, and the high rate of patients lost to follow-up.

 

Acceptability and feasibility of leveraging community-based HIV counselling and testing platforms for same-day oral PrEP initiation among adolescent girls and young women in Eastern Cape, South Africa
A Medina-Marino, D Bezuidenhout, P Ngwepe, C Bezuidenhout, SN Facente, S Mabandla, S Hosek, F Little, CL Celum and LG Bekker
J Int AIDS Soc (2022) 25(7): e25968
10.1002/jia2.25968

INTRODUCTION: Community-based delivery of HIV pre-exposure prophylaxis (PrEP) to South African adolescent girls and young women's (AGYW) could increase access but needs evaluation. We integrated PrEP services via home-based services and pop-up tents into existing community-based HIV testing services (CB-HTS) in Eastern Cape Province, South Africa. METHODS: After accessing CB-HTS via a "pop-up" tent or home-based services, HIV-negative AGYW aged 16-25 years were invited to complete a baseline questionnaire and referred for PrEP services at a community-based PrEP site co-located with pop-up HTS tents. A 30-day supply of PrEP was dispensed. PrEP uptake, time-to-initiation, cohort characteristics and first medication refill within 90 days were measured using descriptive statistics. RESULTS: Of the 1164 AGYW who tested for HIV, 825 (74.3%) completed a questionnaire and 806 (97.7%) were referred for community-based PrEP. Of those, 624 (77.4%) presented for PrEP (482/483 [99.8%] from pop-up HTS and 142/323 [44.0%] from home-based HTS), of which 603 (96.6%) initiated PrEP. Of those initiating PrEP following home-based HTS, 59.1% initiated within 0-3 days, 25.6% within 4-14 days and 15.3% took >/=15 days to initiate; 100% of AGYW who used pop-up HTS initiated PrEP the same day. Among AGWY initiating PrEP, 37.5% had a detectable sexually transmitted infection (STI). Although AGYW reported a low self-perception of HIV risk, post-hoc application of HIV risk assessment measures to available data classified most study participants as high risk for HIV acquisition. Cumulatively, 329 (54.6%) AGYW presented for a first medication refill within 90 days of accepting their first bottle of PrEP. CONCLUSIONS: Leveraging CB-HTS platforms to provide same-day PrEP initiation and refill services was acceptable to AGYW. A higher proportion of AGYW initiated PrEP when co-located with CB-HTS sites compared to those referred following home-based HTS, suggesting that proximity of CB-HTS and PrEP services facilitates PrEP uptake among AGYW. The high prevalence of STIs among those initiating PrEP necessitates the integration of STI and HIV prevention programs for AGYW. Eligibility for PrEP initiation should not be required among AHYW in high HIV burden communities. Community-based service delivery will be crucial to maintaining access to PrEP services during the COVID-19 pandemic and future health and humanitarian emergencies.

 

Qualitative Identification of Intervention Preferences to Support Men's Engagement and Retention in TB Care in South Africa
A Medina-Marino, D Bezuidenhout, N Ngcelwane, M Cornell, M Wainberg, C Beyrer, LG Bekker and J Daniels
Am J Mens Health (2022) 16(5): 15579883221129349
10.1177/15579883221129349

Globally and in South African specifically, men account for 56% and 62% of all tuberculosis (TB) cases, respectively. Men are at increased risk of not accessing TB testing or treatment, and having poor treatment outcomes. Unfortunately, no interventions exist to address these issues. Toward the development of targeted, patient-centered TB care and support interventions, we used semistructured interviews to explored men's social network composition, TB testing behaviors, disclosure and treatment support, clinical experiences, and TB's influence on daily living. Data were analyzed using a thematic approach guided by the Network Individual Resource Model to identify mental and tangible resources influential and preferred during engagement in TB treatment. Men emphasized the desire for peer-to-peer support to navigate TB-related stigma and unhealthy masculinity norms. Men advocated for awareness events to educate communities about their challenges with TB. Men strongly suggested that interventions be delivered in familiar locations where men congregate. Since 2022, no TB treatment support interventions have included the preferred components or delivery modes described by men in our study. To improve men's TB-related health outcomes, the global TB community must identify and address men's unique challenges when designing interventions.

 

Validation of an ovine vesicovaginal fistula model
LP Maljaars, ST Jeffery, M Scholten, L Kaestner, K Jere, D Bezuidenhout, Z Guler and JWR Roovers
Int Urogynecol J (2022) 33(11): 3185-3193
10.1007/s00192-022-05342-y

INTRODUCTION AND HYPOTHESIS: A representative, large animal model of vesicovaginal fistulas is needed for the training of surgeons and for the development of new surgical techniques and materials for obstetric fistula repair. METHODS: The safety, feasibility, and reproducibility of vesicovaginal fistula creation were studied in 4 adult female sheep. A 1-cm fistula was created between the vagina and the bladder through a transvaginal approach. The defect was allowed to heal for 8 weeks and the animals were then euthanized. The primary outcome was the fistula patency. Secondary outcomes were fistula size, urogenital dimensions, urodynamic evaluation, histology (inflammation, vascularization, collagen deposition) and biomechanical characteristics of the fistula edge (stress at break, maximum elongation, and stiffness). RESULTS: The transvaginal creation of a vesicovaginal fistula was safe. All animals survived the surgical procedure and follow-up period, without complications. Three of the four animals demonstrated a patent vesicovaginal fistula after 8 weeks. Baseline data are provided of the urogenital dimensions and the urodynamic, histological, and biomechanical characteristics of the model. CONCLUSIONS: The ewe is a safe, feasible, and reproducible model for vesicovaginal fistulas. The model can help to study new techniques and materials to boost surgical innovation for vesicovaginal fistula repair.

 

Effect of paclitaxel treatment on cellular mechanics and morphology of human oesophageal squamous cell carcinoma in 2D and 3D environments
M Kiwanuka, G Higgins, S Ngcobo, J Nagawa, DM Lang, MH Zaman, NH Davies and T Franz
Integr Biol (Camb) (2022) 14(6): 137-49
10.1093/intbio/zyac013

During chemotherapy, structural and mechanical changes in malignant cells have been observed in several cancers, including leukaemia and pancreatic and prostate cancer. Such cellular changes may act as physical biomarkers for chemoresistance and cancer recurrence. This study aimed to determine how exposure to paclitaxel affects the intracellular stiffness of human oesophageal cancer of South African origin in vitro. A human oesophageal squamous cell carcinoma cell line WHCO1 was cultured on glass substrates (2D) and in collagen gels (3D) and exposed to paclitaxel for up to 48 h. Cellular morphology and stiffness were assessed with confocal microscopy, visually aided morpho-phenotyping image recognition and mitochondrial particle tracking microrheology at 24 and 48 h. In the 2D environment, the intracellular stiffness was higher for the paclitaxel-treated than for untreated cells at 24 and 48 h. In the 3D environment, the paclitaxel-treated cells were stiffer than the untreated cells at 24 h, but no statistically significant differences in stiffness were observed at 48 h. In 2D, paclitaxel-treated cells were significantly larger at 24 and 48 h and more circular at 24 but not at 48 h than the untreated controls. In 3D, there were no significant morphological differences between treated and untreated cells. The distribution of cell shapes was not significantly different across the different treatment conditions in 2D and 3D environments. Future studies with patient-derived primary cancer cells and prolonged drug exposure will help identify physical cellular biomarkers to detect chemoresistance onset and assess therapy effectiveness in oesophageal cancer patients.

 

PROSE: Prospective Randomized Trial of the On-X Mechanical Prosthesis and the St Jude Medical Mechanical Prosthesis Evaluation: Part 2: Study results-prostheses, positions, and economic development
WRE Jamieson, JL Ely, J Brink, T Pennel, P Bannon, J Patel, RK Gupta, PS Mohan Rao, D Agrawal, L Wiklund, AP Kappetein, R Haaverstad, T Geisner, T Doenst, C Schlensak, S Nair, C Brown, M Siepe, RJ Damiano, Y Langlois, KM Cherian, H Azar, JC Chen, JE Bavaria, LM Fedoruk, NA Munfakh, V Sridhar, PM Scholz, TA Pfeffer and J Ye
JTCVS Open (2022) 12(51-70
10.1016/j.xjon.2022.07.011

OBJECTIVES: The Prospective Randomized On-X Mechanical Prosthesis Versus St Jude Medical Mechanical Prosthesis Evaluation (PROSE) trial purpose was to investigate whether a current-generation mechanical prosthesis (On-X; On-X Life Technologies/Artivion Inc) reduced the incidence of thromboembolic-related complications compared with a previous-generation mechanical prosthesis (St Jude Medical Mechanical Prosthesis; Abbott/St Jude Medical). This second report documents the valve-related complications by individual prostheses and by Western and Developing populations. METHODS: The PROSE trial study was conducted in 28 worldwide centers and incorporated 855 subjects randomized between 2003 and 2016. The study enrollment was discontinued on August 31, 2016. The study protocol, and analyses of 10 demographic variables and 24 risk factors were published in detail in 2021. RESULTS: The total patient population (N = 855) included patients receiving an On-X valve (n = 462) and a St Jude Medical valve (n = 393). The overall freedom evaluation showed no differences at 5 years between the prostheses for thromboembolism or for valve thrombosis. There were also no differences in mortality. There were several differences between Developing and Western populations. The freedom relations at 5 years for mortality favored Western over Developing populations. Valve thrombosis was differentiated by position and site: aortic < mitral (P = .007) and Western < Developing (P = .005). In the mitral position there were no cases in Western populations, whereas there were 8 in Developing populations (P = .217). CONCLUSIONS: The On-X valve and St Jude Medical valve performed equally well in the study with no differences found. The only differentiation occurred with valve thrombosis in the mitral position more than the aortic position and occurring in Developing more than Western populations. The occurrence of valve thrombosis was also related to a younger population possibly due to anticoagulation compliance based on record review.

 

2022 SASCI/SCTSSA joint consensus statement and guideline on transcatheter aortic valve implantation (TAVI) in South Africa
J Hitzeroth, H Weich and J Scherman
Cardiovasc J Afr (2022) 33(5): 267-269
10.5830/CVJA-2022-049

Patients with severe symptomatic aortic stenosis (AS) have traditionally been treated with surgical aortic valve replacement (sAVR). Transcatheter aortic valve implantation is a percutaneous option that has been shown to be at least as effective as sAVR in numerous subgroups of patients with severe AS. This is an update on the previous joint consensus statement and guideline on transcatheter aortic valve implantation (TAVI) in South Africa, published in 2016. It provides guidance on which patients should preferably be offered TAVI over sAVR, with special consideration of the resource-constrained environment in South Africa.

 

Blue Turns to Gray: Paleogenomic Insights into the Evolutionary History and Extinction of the Blue Antelope (Hippotragus leucophaeus)
E Hempel, F Bibi, JT Faith, KP Koepfli, AM Klittich, DA Duchene, JS Brink, DC Kalthoff, L Dalen, M Hofreiter and MV Westbury
Mol Biol Evol (2022) 39(12): 10.1093/molbev/msac241

The blue antelope (Hippotragus leucophaeus) is the only large African mammal species to have become extinct in historical times, yet no nuclear genomic information is available for this species. A recent study showed that many alleged blue antelope museum specimens are either roan (Hippotragus equinus) or sable (Hippotragus niger) antelopes, further reducing the possibilities for obtaining genomic information for this extinct species. While the blue antelope has a rich fossil record from South Africa, climatic conditions in the region are generally unfavorable to the preservation of ancient DNA. Nevertheless, we recovered two blue antelope draft genomes, one at 3.4x mean coverage from a historical specimen ( approximately 200 years old) and one at 2.1x mean coverage from a fossil specimen dating to 9,800-9,300 cal years BP, making it currently the oldest paleogenome from Africa. Phylogenomic analyses show that blue and sable antelope are sister species, confirming previous mitogenomic results, and demonstrate ancient gene flow from roan into blue antelope. We show that blue antelope genomic diversity was much lower than in roan and sable antelope, indicative of a low population size since at least the early Holocene. This supports observations from the fossil record documenting major decreases in the abundance of blue antelope after the Pleistocene-Holocene transition. Finally, the persistence of this species throughout the Holocene despite low population size suggests that colonial-era human impact was likely the decisive factor in the blue antelope's extinction.

 

Combining 3D-Printing and Electrospinning to Manufacture Biomimetic Heart Valve Leaflets
B Freystetter, M Grab, L Grefen, L Bischof, L Isert, P Mela, D Bezuidenhout, C Hagl and N Thierfelder
J Vis Exp (2022) 181): 10.3791/63604

Electrospinning has become a widely used technique in cardiovascular tissue engineering as it offers the possibility to create (micro-)fibrous scaffolds with adjustable properties. The aim of this study was to create multilayered scaffolds mimicking the architectural fiber characteristics of human heart valve leaflets using conductive 3D-printed collectors. Models of aortic valve cusps were created using commercial computer-aided design (CAD) software. Conductive polylactic acid was used to fabricate 3D-printed leaflet templates. These cusp negatives were integrated into a specifically designed, rotating electrospinning mandrel. Three layers of polyurethane were spun onto the collector, mimicking the fiber orientation of human heart valves. Surface and fiber structure was assessed with a scanning electron microscope (SEM). The application of fluorescent dye additionally permitted the microscopic visualization of the multilayered fiber structure. Tensile testing was performed to assess the biomechanical properties of the scaffolds. 3D-printing of essential parts for the electrospinning rig was possible in a short time for a low budget. The aortic valve cusps created following this protocol were three-layered, with a fiber diameter of 4.1 +/- 1.6 microm. SEM imaging revealed an even distribution of fibers. Fluorescence microscopy revealed individual layers with differently aligned fibers, with each layer precisely reaching the desired fiber configuration. The produced scaffolds showed high tensile strength, especially along the direction of alignment. The printing files for the different collectors are available as Supplemental File 1, Supplemental File 2, Supplemental File 3, Supplemental File 4, and Supplemental File 5. With a highly specialized setup and workflow protocol, it is possible to mimic tissues with complex fiber structures over multiple layers. Spinning directly on 3D-printed collectors creates considerable flexibility in manufacturing 3D shapes at low production costs.

 

Reasons for missed opportunities to screen and test for TB in healthcare facilities
L de Vos, E Mazinyo, D Bezuidenhout, N Ngcelwane, DS Mandell, SH Schriger, J Daniels and A Medina-Marino
Public Health Action (2022) 12(4): 171-173
10.5588/pha.22.0042

Missed opportunities for TB screening and/or passive testing in clinics continues to contribute to the number of missed cases. To understand reasons for these missed opportunities, we conducted focus group discussions with clinic-based nurses. Nurses described low indices of suspicion, prioritization of seemingly more urgent ailments and clinic operational challenges as barriers to TB screening and testing. To improve TB screening and testing in clinics, standard patients should be used to identify real-time factors that impact nurses' clinical decision-making and engage in real-time feedback and discussion with nurses to help optimize opportunities for TB screening and testing.

 

Blood derived extracellular vesicles as regenerative medicine therapeutics
C de Boer and NH Davies
Biochimie (2022) 196(203-215
10.1016/j.biochi.2021.10.009

The regenerative promise of nanosized extracellular vesicles (EVs) secreted by cells is widely explored. Recently, the capacity of EVs purified from blood to elicit regenerative effect has begun to be evaluated. Blood might be a readily available source of EVs, avoiding need for extensive cell culturing, but there are specific issues that complicate use of the biofluid in this area. We assess the evidence for blood containing regenerative material, progress made towards delivering blood derived EVs as regenerative therapeutics, difficulties that relate to the complexity of blood and the promise of hydrogel-based delivery of EVs.

 

Discovery of a radio emitting neutron star with an ultra-long spin period of 76 seconds
M Caleb, I Heywood, K Rajwade, M Malenta, B Stappers, E Barr, W Chen, V Morello, S Sanidas, J van den Eijnden, M Kramer, D Buckley, J Brink, SE Motta, P Woudt, P Weltevrede, F Jankowski, M Surnis, S Buchner, MC Bezuidenhout, LN Driessen and R Fender
Nat Astron (2022) 6(7): 828-836
10.1038/s41550-022-01688-x

The radio-emitting neutron star population encompasses objects with spin periods ranging from milliseconds to tens of seconds. As they age and spin more slowly, their radio emission is expected to cease. We present the discovery of an ultra-long period radio-emitting neutron star, PSR J0901-4046, with spin properties distinct from the known spin and magnetic-decay powered neutron stars. With a spin-period of 75.88 s, a characteristic age of 5.3 Myr, and a narrow pulse duty-cycle, it is uncertain how radio emission is generated and challenges our current understanding of how these systems evolve. The radio emission has unique spectro-temporal properties such as quasi-periodicity and partial nulling that provide important clues to the emission mechanism. Detecting similar sources is observationally challenging, which implies a larger undetected population. Our discovery establishes the existence of ultra-long period neutron stars, suggesting a possible connection to the evolution of highly magnetized neutron stars, ultra-long period magnetars, and fast radio bursts.

 

Immunoreaction to xenogenic tissue in cardiac surgery: alpha-Gal and beyond
AM Calafiore, A Haverich, M Gaudino, M Di Mauro, K Fattouch, S Prapas and P Zilla
Eur J Cardiothorac Surg (2022) 62(1): 10.1093/ejcts/ezac115

 

The Technological Basis of a Balloon-Expandable TAVR System: Non-occlusive Deployment, Anchorage in the Absence of Calcification and Polymer Leaflets
H Appa, K Park, D Bezuidenhout, B van Breda, B de Jongh, J de Villiers, R Chacko, J Scherman, C Ofoegbu, J Swanevelder, M Cousins, P Human, R Smith, F Vogt, BK Podesser, C Schmitz, L Conradi, H Treede, H Schrofel, T Fischlein, M Grabenwoger, X Luo, H Coombes, S Matskeplishvili, DF Williams and P Zilla
Front Cardiovasc Med (2022) 9(791949
10.3389/fcvm.2022.791949

Leaflet durability and costs restrict contemporary trans-catheter aortic valve replacement (TAVR) largely to elderly patients in affluent countries. TAVR that are easily deployable, avoid secondary procedures and are also suitable for younger patients and non-calcific aortic regurgitation (AR) would significantly expand their global reach. Recognizing the reduced need for post-implantation pacemakers in balloon-expandable (BE) TAVR and the recent advances with potentially superior leaflet materials, a trans-catheter BE-system was developed that allows tactile, non-occlusive deployment without rapid pacing, direct attachment of both bioprosthetic and polymer leaflets onto a shape-stabilized scallop and anchorage achieved by plastic deformation even in the absence of calcification. Three sizes were developed from nickel-cobalt-chromium MP35N alloy tubes: Small/23 mm, Medium/26 mm and Large/29 mm. Crimp-diameters of valves with both bioprosthetic (sandwich-crosslinked decellularized pericardium) and polymer leaflets (triblock polyurethane combining siloxane and carbonate segments) match those of modern clinically used BE TAVR. Balloon expansion favors the wing-structures of the stent thereby creating supra-annular anchors whose diameter exceeds the outer diameter at the waist level by a quarter. In the pulse duplicator, polymer and bioprosthetic TAVR showed equivalent fluid dynamics with excellent EOA, pressure gradients and regurgitation volumes. Post-deployment fatigue resistance surpassed ISO requirements. The radial force of the helical deployment balloon at different filling pressures resulted in a fully developed anchorage profile of the valves from two thirds of their maximum deployment diameter onwards. By combining a unique balloon-expandable TAVR system that also caters for non-calcific AR with polymer leaflets, a powerful, potentially disruptive technology for heart valve disease has been incorporated into a TAVR that addresses global needs. While fulfilling key prerequisites for expanding the scope of TAVR to the vast number of patients of low- to middle income countries living with rheumatic heart disease the system may eventually also bring hope to patients of high-income countries presently excluded from TAVR for being too young.

 

TAVR for Patients With Rheumatic Heart Disease: Opening the Door for the Many?
P Zilla, DF Williams and D Bezuidenhout
J Am Coll Cardiol (2021) 77(14): 1714-1716
10.1016/j.jacc.2021.02.044

 

Long-Term Stability and Biocompatibility of Pericardial Bioprosthetic Heart Valves
DF Williams, D Bezuidenhout, J de Villiers, P Human and P Zilla
Front Cardiovasc Med (2021) 8(728577
10.3389/fcvm.2021.728577

The use of bioprostheses for heart valve therapy has gradually evolved over several decades and both surgical and transcatheter devices are now highly successful. The rapid expansion of the transcatheter concept has clearly placed a significant onus on the need for improved production methods, particularly the pre-treatment of bovine pericardium. Two of the difficulties associated with the biocompatibility of bioprosthetic valves are the possibilities of immune responses and calcification, which have led to either catastrophic failure or slow dystrophic changes. These have been addressed by evolutionary trends in cross-linking and decellularization techniques and, over the last two decades, the improvements have resulted in somewhat greater durability. However, as the need to consider the use of bioprosthetic valves in younger patients has become an important clinical and sociological issue, the requirement for even greater longevity and safety is now paramount. This is especially true with respect to potential therapies for young people who are afflicted by rheumatic heart disease, mostly in low- to middle-income countries, for whom no clinically acceptable and cost-effective treatments currently exist. To extend longevity to this new level, it has been necessary to evaluate the mechanisms of pericardium biocompatibility, with special emphasis on the interplay between cross-linking, decellularization and anti-immunogenicity processes. These mechanisms are reviewed in this paper. On the basis of a better understanding of these mechanisms, a few alternative treatment protocols have been developed in the last few years. The most promising protocol here is based on a carefully designed combination of phases of tissue-protective decellularization with a finely-titrated cross-linking sequence. Such refined protocols offer considerable potential in the progress toward superior longevity of pericardial heart valves and introduce a scientific dimension beyond the largely disappointing 'anti-calcification' treatments of past decades.

 

Investigating infection management and antimicrobial stewardship in surgery: a qualitative study from India and South Africa
S Singh, M Mendelson, S Surendran, C Bonaconsa, O Mbamalu, V Nampoothiri, A Boutall, M Hampton, P Dhar, T Pennel, C Tarrant, A Leather, A Holmes, E Charani and A co-investigators
Clin Microbiol Infect (2021) 27(10): 1455-1464
10.1016/j.cmi.2020.12.013

OBJECTIVES: To investigate the drivers for infection management and antimicrobial stewardship (AMS) across high-infection-risk surgical pathways. METHODS: A qualitative study-ethnographic observation of clinical practices, patient case studies, and face-to-face interviews with healthcare professionals (HCPs) and patients-was conducted across cardiovascular and thoracic and gastrointestinal surgical pathways in South Africa (SA) and India. Aided by Nvivo 11 software, data were coded and analysed until saturation was reached. The multiple modes of enquiry enabled cross-validation and triangulation of findings. RESULTS: Between July 2018 and August 2019, data were gathered from 190 hours of non-participant observations (138 India, 72 SA), interviews with HCPs (44 India, 61 SA), patients (six India, eight SA), and case studies (four India, two SA). Across the surgical pathway, multiple barriers impede effective infection management and AMS. The existing implicit roles of HCPs (including nurses and senior surgeons) are overlooked as interventions target junior doctors, bypassing the opportunity for integrating infection-related care across the surgical team. Critically, the ownership of decisions remains with the operating surgeons, and entrenched hierarchies restrict the inclusion of other HCPs in decision-making. The structural foundations to enable staff to change their behaviours and participate in infection-related surgical care are lacking. CONCLUSIONS: Identifying the implicit existing HCP roles in infection management is critical and will facilitate the development of effective and transparent processes across the surgical team for optimized care. Applying a framework approach that includes nurse leadership, empowering pharmacists and engaging surgical leads, is essential for integrated AMS and infection-related care.

 

Neurologic recovery after ten minutes of absent cerebral blood flow at normothermia
T Pennel, F Beyersdorf, E Gates and P Zilla
Perfusion (2021) 36(4): 432-434
10.1177/0267659120951091

Prolonged normothermic cardiac arrest is associated with a high incidence of neurological morbidity and mortality. Whole body temperature-controlled perfusion has been applied to limit reperfusion injury and minimize ischemia. We describe the full recovery of a patient after the application of rapid hypothermia following an intraoperative aortic rupture with ten minutes of absent cerebral blood flow.

 

"How I do it": Novel non-occlusive balloon dilation in paediatric airway stenosis: A paradigm shift (with video)
S Peer, A Brooks and J McGuire
Eur Ann Otorhinolaryngol Head Neck Dis (2021) 138 Suppl 1(21-22
10.1016/j.anorl.2021.05.020

 

Experience of cardiac implantable electronic device lead removal from a South African tertiary referral centre
P Mkoko, NX Mdakane, G Govender, J Scherman and A Chin
Cardiovasc J Afr (2021) 32(4): 193-197
10.5830/CVJA-2021-010

BACKGROUND: The rate of cardiac implantable electronic device (CIED) implantation in low- and middle-income countries is increasing. Patients recieving these devices are frequently older and with multiple co-morbidities, which may later lead to complications requiring CIED removal. CIED removals are associated with life-threatening complications. However, high sucesss rates are reported in high-income countries. The purpose of this study was to report on the experience of CIED removal in a resource-constrained setting. METHODS: In this retrospective study, we included consecutive adult patients admitted to Groote Schuur Hospital and the University of Cape Town Private Academic Hospital for CIED removal from 1 January 2008 to 31 December 2019. RESULTS: During the study period, 53 patients underwent CIED removal (26 extractions and 27 explants). The patients had a mean (standard deviation) age of 59.1 (16.0) years. A history of systemic hypertension was present in 50.9% of patients, diabetes mellitus in 30.2% and dilated cardiomyopathy in 47.2%. Complete heart block was the leading indication for CIED implantation (37.7%), and device infection was the leading indication for removal (69.2%). CIEDs were removed after a median (interquantile range) of 243 (53-831) days. There were 40 leads extracted and 35 explants. Lead extractions were perfomed in the cardiac catheterisation laboratory under general anaesthesia via a percutaneous transvenous superior approach. There was one major and one minor complication related to lead extraction. CONCLUSIONS: CIED infections were the primary indication for CIED removal in a tertiary referral centre in South Africa. Despite being a low-volume centre, we report a high percutaneous transvenous extraction success rate with low complication rate; results which are comparable to high-volume centres.

 

"I got tested at home, the help came to me": acceptability and feasibility of home-based TB testing of household contacts using portable molecular diagnostics in South Africa
A Medina-Marino, L de Vos, D Bezuidenhout, CM Denkinger, SG Schumacher, SS Shin, W Stevens, G Theron, M van der Walt and J Daniels
Trop Med Int Health (2021) 26(3): 343-354
10.1111/tmi.13533

OBJECTIVE: The effectiveness of household contact investigations is limited by low referral uptake for clinic-based TB testing by symptomatic household contacts. We qualitatively investigated the acceptability and perceived benefits of home-based TB testing using a portable GeneXpert-I instrument (GX-I) in an urban South African township. METHODS: In-depth interviews were conducted with household contacts tested and those that observed testing. Semi-structured interviews explored household contact's understanding of TB, perceptions of the GX-I device and testing procedures, confidentiality, willingness to refer others, and views on home- vs. clinic-based testing. Focus group discussions with home-based TB testing implementing staff assessed operational considerations for scale-up. Data were analysed using a constant comparison approach to qualitatively evaluate the acceptability and feasibility of home-based TB testing. RESULTS: Thirty in-depth interviews and two focus group discussions were conducted. Observing one's own sputum being tested resulted in an emergent trust in home-based TB testing, the GX-I device and one's test results. Home-based TB testing was considered convenient, helped to overcome apathy towards testing and mitigated barriers to clinic-based testing. Perceptions that home-based TB testing contributes to improved household and community health resulted in an emergent theme of alleviation of health insecurities. Operational concerns regarding inadvertent disclosure of one's diagnosis to household members and time spent in people's homes were identified. CONCLUSIONS: Home-based TB testing was acceptable and feasible. Individuals expressed belief in the machine by being able to witness the testing process. Though most themes mirrored qualitative studies of home-based HIV testing, the alleviation of health insecurities theme is unique to home-based TB testing. Future research must evaluate the impact of home-based TB testing on case finding yield, time-to-treatment initiation and household outcomes.

 

Outcomes from a multimodal, at-scale community-based HIV counselling and testing programme in twelve high HIV burden districts in South Africa
A Medina-Marino, J Daniels, D Bezuidenhout, R Peters, T Farirai, J Slabbert, G Guloba, S Johnson, LG Bekker and N Nkhwashu
J Int AIDS Soc (2021) 24(3): e25678
10.1002/jia2.25678

INTRODUCTION: Facility-based HIV testing services (HTS) have been less acceptable and accessible by adolescents, men and key populations in South Africa. Community-based HIV counselling and testing (CBCT) modalities, including mobile unit and home-based testing, have been proposed to decrease barriers to HIV testing uptake. CBCT modalities and approaches may be differentially acceptable to men and women based on age. Implementation of multimodal CBCT services may improve HIV testing rates among adolescents and men, and support the roll-out of prevention services. METHODS: A cross-sectional analysis was conducted using aggregate, routine programmatic data collected from 1 October 2015 through 31 March 2017 from a multimodal, at-scale CBCT programme implemented in 12 high-burden districts throughout South Africa. Data collection tools were aligned to reporting standards for the National Department of Health and donor requirements. HIV testing rates (i.e. number of tests performed per 100,000 population using South African census data) and testing proportions by modality were stratified by sex, age groups and heath districts. Descriptive statistics were performed using STATA 13.0. RESULTS: Overall, 944,487 tests were performed during the 1.5-year testing period reported. More tests were conducted among females than males (53.6% vs. 46.4%). Overall, 8206 tests per 100,000 population (95% CI: 8190.2 to 8221.9) were performed; female-to-male (F:M) testing ratio was 1.11. Testing rates were highest among young women age 20 to 24 years (16,328.4; 95% CI: 16,237.9 to 16,419.1) and adolescent girls aged 15 to 19 years (12,817.0; 95% CI: 12,727.9 to 12,906.6). Home-based testing accounted for 61.3% of HIV tests, followed by near-home mobile unit testing (30.2%) and workplace mobile unit testing (4.7%). More women received HTS via home-based testing (F:M ratio = 1.29), whereas more men accessed work-place mobile testing (M:F ratio = 1.35). No sex differential was observed among those accessing near-home mobile testing (F:M ratio = 0.98). CONCLUSIONS: Concurrent implementation of multiple, targeted CBCT modalities can reduce sex disparities in HIV testing in South Africa. Given the acceptability and accessibility of these CBCT services to adolescent girls and young women, evident from their high testing rates, leveraging community-based services delivery platforms to increase access to HIV prevention services, including pre-exposure prophylaxis (PrEP), should be considered.

 

The Community PrEP Study: a randomized control trial leveraging community-based platforms to improve access and adherence to pre-exposure prophylaxis to prevent HIV among adolescent girls and young women in South Africa-study protocol
A Medina-Marino, D Bezuidenhout, S Hosek, RV Barnabas, M Atujuna, C Bezuidenhout, P Ngwepe, RPH Peters, F Little, CL Celum, J Daniels and LG Bekker
Trials (2021) 22(1): 489
10.1186/s13063-021-05402-6

BACKGROUND: HIV incidence among South African adolescent girls and young women (AGYW) remains high, but could be reduced by highly effective pre-exposure prophylaxis (PrEP). Unfortunately, AGYW report significant barriers to clinic-based sexual and reproductive health services. Even when AGYW access PrEP as an HIV prevention method, poor prevention-effective use was a serious barrier to achieving its optimal HIV prevention benefits. Determining the acceptability and feasibility of community-based platforms to increase AGYW's access to PrEP, and evaluating behavioural interventions to improve prevention-effective use of PrEP are needed. METHODS: We propose a mixed-methods study among AGYW aged 16-25 years in Eastern Cape Province, South Africa. In the first component, a cross-sectional study will assess the acceptability and feasibility of leveraging community-based HIV counselling and testing (CBCT) platforms to refer HIV-negative, at-risk AGYW to non-clinic-based, same-day PrEP initiation services. In the second component, we will enrol 480 AGYW initiating PrEP via our CBCT platforms into a three-armed (1:1:1) randomized control trial (RCT) that will evaluate the effectiveness of adherence support interventions to improve the prevention-effective use of PrEP. Adherence will be measured over 24 months via tenofovir-diphosphate blood concentration levels. Qualitative investigations will explore participant, staff, and community experiences associated with community-based PrEP services, adherence support activities, study implementation, and community awareness. Costs and scalability of service platforms and interventions will be evaluated. DISCUSSION: This will be the first study to assess the acceptability and feasibility of leveraging CBCT platforms to identify and refer at-risk AGYW to community-based, same-day PrEP initiation services. It will also provide quantitative and qualitative results to inform adherence support activities and services that promote the prevention-effective use of PrEP among AGYW. By applying principles of implementation science, behavioural science, and health economics research, we aim to inform strategies to improve access to and prevention-effective use of PrEP by AGYW. TRIAL REGISTRATION: ClinicalTrials.gov NCT03977181 . Registered on 6 June 2019-retrospectively registered.

 

Patient understanding of and participation in infection-related care across surgical pathways: a scoping review
O Mbamalu, C Bonaconsa, V Nampoothiri, S Surendran, P Veepanattu, S Singh, P Dhar, V Carter, A Boutall, T Pennel, M Hampton, A Holmes, M Mendelson and E Charani
Int J Infect Dis (2021) 110(123-134
10.1016/j.ijid.2021.07.039

OBJECTIVE: To explore the existing evidence on patient understanding of and/or participation in infection-related care in surgical specialties. METHOD: A scoping review of the literature was conducted. PubMed, Web of Science, Scopus, and grey literature sources were searched using predefined search criteria for policies, guidelines, and studies in the English language. Data synthesis was done through content and thematic analysis to identify key themes in the included studies. RESULTS: The initial search identified 604 studies, of which 41 (36 from high-income and five from low- and middle-income countries) were included in the final review. Most of the included studies focused on measures to engage patients in infection prevention and control (IPC) activities, with few examples of antimicrobial stewardship (AMS) engagement strategies. While patient engagement interventions in infection-related care varied depending on study goals, surgical wound management was the most common intervention. AMS engagement was primarily limited to needs assessment, without follow-up to address such needs. CONCLUSION: Existing evidence highlights a gap in patient participation in infection-related care in the surgical pathway. Standardization of patient engagement strategies is challenging, particularly in the context of surgery, where several factors influence how the patient can engage and retain information. Infection-related patient engagement and participation strategies in surgery need to be inclusive and contextually fit.

 

Early detection of SARS-CoV-2 and other infections in solid organ transplant recipients and household members using wearable devices
BJ Keating, EH Mukhtar, ED Elftmann, FR Eweje, H Gao, LI Ibrahim, RG Kathawate, AC Lee, EH Li, KA Moore, N Nair, V Chaluvadi, J Reason, F Zanoni, AT Honkala, AK Al-Ali, F Abdullah Alrubaish, M Ahmad Al-Mozaini, FA Al-Muhanna, K Al-Romaih, SB Goldfarb, R Kellogg, K Kiryluk, SJ Kizilbash, TJ Kohut, J Kumar, MJ O'Connor, EB Rand, RR Redfield, B Rolnik, J Rossano, PG Sanchez, A Alavi, A Bahmani, GK Bogu, AW Brooks, AA Metwally, T Mishra, SD Marks, RA Montgomery, JA Fishman, S Amaral, PA Jacobson, M Wang and MP Snyder
Transpl Int (2021) 34(6): 1019-1031
10.1111/tri.13860

The increasing global prevalence of SARS-CoV-2 and the resulting COVID-19 disease pandemic pose significant concerns for clinical management of solid organ transplant recipients (SOTR). Wearable devices that can measure physiologic changes in biometrics including heart rate, heart rate variability, body temperature, respiratory, activity (such as steps taken per day) and sleep patterns, and blood oxygen saturation show utility for the early detection of infection before clinical presentation of symptoms. Recent algorithms developed using preliminary wearable datasets show that SARS-CoV-2 is detectable before clinical symptoms in >80% of adults. Early detection of SARS-CoV-2, influenza, and other pathogens in SOTR, and their household members, could facilitate early interventions such as self-isolation and early clinical management of relevant infection(s). Ongoing studies testing the utility of wearable devices such as smartwatches for early detection of SARS-CoV-2 and other infections in the general population are reviewed here, along with the practical challenges to implementing these processes at scale in pediatric and adult SOTR, and their household members. The resources and logistics, including transplant-specific analyses pipelines to account for confounders such as polypharmacy and comorbidities, required in studies of pediatric and adult SOTR for the robust early detection of SARS-CoV-2, and other infections are also reviewed.

 

PROSE: Prospective Randomized Trial of the On-X Mechanical Prosthesis and the St Jude Medical Mechanical Prosthesis Evaluation : Part 1(Patient Dynamics): Preoperative demographics and preoperative and operative risk factors
WRE Jamieson, JL Ely, J Brink, T Pennel, P Bannon, J Patel, R Kumar Gupta, PS Mohan Rao, D Agrawal, L Wiklund, AP Kappetein, R Haaverstad, T Geisner, T Doenst, C Schlensak, S Nair, C Brown, M Siepe, RJ Damiano, Y Langlois, KM Cherian, H Azar, JC Chen, JE Bavaria, LM Fedoruk, NA Munfakh, V Sridhar, PM Scholz, TA Pfeffer and J Ye
J Cardiothorac Surg (2021) 16(1): 323
10.1186/s13019-021-01632-6

OBJECTIVES: The PROSE trial purpose is to investigate whether the incidence of thromboembolic-related complications is reduced with a current generation mechanical prosthesis (On-X Life Technologies/CryoLife Inc.-On-X) compared with a previous generation mechanical prosthesis (St Jude Medical-SJM). The primary purpose of the initial report is to document the preoperative demographics, and the preoperative and operative risk factors by individual prosthesis and by Western and Developing populations. METHODS: The PROSE study was conducted in 28 worldwide centres and incorporated 855 subjects randomized between 2003 and 2016. The study enrollment was discontinued on August 31, 2016. The preoperative demographics incorporated age, gender, functional class, etiology, prosthetic degeneration, primary rhythm, primary valve lesion, weight, height, BSA and BMI. The preoperative and operative evaluation incorporated 24 risk factors. RESULTS: The total patient population (855) incorporated On-X population (462) and the St Jude Medical population (393). There was no significant difference of any of the preoperative demographics between the On-X and SJM groups. The preoperative and operative risk factors evaluation showed there was no significant difference between the On-X and St Jude Medical populations. The preoperative and operative risk factors by valve position (aortic and mitral) also documented no differentiation. The dominant preoperative demographics of the Western world population were older age, male gender, sinus rhythm, aortic stenosis, congenital aortic lesion, and mitral regurgitation. The dominant demographics of the Developing world population were rheumatic etiology, atrial fibrillation, aortic regurgitation, mixed aortic lesions, mitral stenosis and mixed mitral lesions. The Developing world group had only one significant risk factor, congestive heart failure. The majority of the preoperative and operative risk factors were significant in the Western world population. CONCLUSIONS: The preoperative demographics do not differentiate the prostheses but do differentiate the Western and Developing world populations. The preoperative and operative risk factors do not differentiate the prostheses BUT do differentiate the Western and Developing world populations.

 

Residual Bioprosthetic Valve Immunogenicity: Forgotten, Not Lost
P Human, D Bezuidenhout, E Aikawa and P Zilla
Front Cardiovasc Med (2021) 8(760635
10.3389/fcvm.2021.760635

Despite early realization of the need to control inherent immunogenicity of bioprosthetic replacement heart valves and thereby mitigate the ensuing host response and its associated pathology, including dystrophic calcification, the problem remains unresolved to this day. Concerns over mechanical stiffness associated with prerequisite high cross-link density to effect abrogation of this response, together with the insinuated role of leaching glutaraldehyde monomer in subsequent dystrophic mineralization, have understandably introduced compromises. These have become so entrenched as a benchmark standard that residual immunogenicity of the extracellular matrix has seemingly been relegated to a very subordinate role. Instead, focus has shifted toward the removal of cellular compartment antigens renowned for their implication in the failure of vascularized organ xenotransplants. While decellularization certainly offers advantages, this review aims to refocus attention on the unresolved matter of the host response to the extracellular matrix. Furthermore, by implicating remnant immune and inflammatory processes to bioprosthetic valve pathology, including pannus overgrowth and mineralization, the validity of a preeminent focus on decellularization, in the context of inefficient antigen and possible residual microbial remnant removal, is questioned.

 

Tendon-like tether formation for tongue-base advancement in an ovine model using a novel implant device intended for the surgical management of obstructive sleep apnoea
R Hendricks, E Hofmann, J Peres, S Prince, J Hille, NH Davies and D Bezuidenhout
J Biomed Mater Res B Appl Biomater (2021) 109(7): 1005-1016
10.1002/jbm.b.34765

Obstructive sleep apnoea (OSA) is a serious debilitating condition with significant morbidity and mortality affecting almost one billion adults globally. The current gold standard in the non-surgical management of airway collapse is continuous positive airway pressure (CPAP). However, non-compliance leads to a high abandon rate (27-46%). While there are multiple sites of airway obstruction during sleep, the tongue base is recognized as the key player in the pathogenesis of OSA. Poor outcomes of current tongue suspension devices are due to fracture, slippage or migration of devices. Three tongue tethering device groups, namely a polydioxanone/polyurethane combination (PDO + PU) treatment group, a PDO analytical control group, and a polypropylene (PP) descriptive control group, were implanted into 22 sheep (75-85 kg) in a two-phased study. After implant times of 8, 16, and 32 weeks, sheep were serially euthanized to allow for explantation of their tongues and chins. The PDO + PU devices remodeled during the 32-week implant period into a hybrid biological tendon-like tether through the process of gradual degradation of the PDO and collagen deposition as shown by electrophoresis, histology and mechanical testing. The control PDO device degraded completely after 32 weeks and the PP devices remained intact. The hybrid biological tendon-like tether exhibited a break-strength of 60 N, thus exceeding the maximum force to overcome upper airway collapse.

 

Identifying the true number of specimens of the extinct blue antelope (Hippotragus leucophaeus)
E Hempel, F Bibi, JT Faith, JS Brink, DC Kalthoff, P Kamminga, JLA Paijmans, MV Westbury, M Hofreiter and FE Zachos
Sci Rep (2021) 11(1): 2100
10.1038/s41598-020-80142-2

Native to southern Africa, the blue antelope (Hippotragus leucophaeus) is the only large African mammal species known to have become extinct in historical times. However, it was poorly documented prior to its extinction 
 1800 AD, and many of the small number of museum specimens attributed to it are taxonomically contentious. This places limitations on our understanding of its morphology, ecology, and the mechanisms responsible for its demise. We retrieved genetic information from ten of the sixteen putative blue antelope museum specimens using both shotgun sequencing and mitochondrial genome target capture in an attempt to resolve the uncertainty surrounding the identification of these specimens. We found that only four of the ten investigated specimens, and not a single skull, represent the blue antelope. This indicates that the true number of historical museum specimens of the blue antelope is even smaller than previously thought, and therefore hardly any reference material is available for morphometric, comparative and genetic studies. Our study highlights how genetics can be used to identify rare species in natural history collections where other methods may fail or when records are scarce. Additionally, we present an improved mitochondrial reference genome for the blue antelope as well as one complete and two partial mitochondrial genomes. A first analysis of these mitochondrial genomes indicates low levels of maternal genetic diversity in the 'museum population', possibly confirming previous results that blue antelope population size was already low at the time of the European colonization of South Africa.

 

A Novel Hybrid Membrane VAD as First Step Toward Hemocompatible Blood Propulsion
A Ferrari, C Giampietro, B Bachmann, L Bernardi, D Bezuidenhhout, P Ermanni, R Hopf, S Kitz, G Kress, C Loosli, V Marina, M Meboldt, G Pellegrini, D Poulikakos, M Rebholz, M Schmid Daners, T Schmidt, C Starck, G Stefopoulos, S Sundermann, B Thamsen, P Zilla, E Potapov, V Falk and E Mazza
Ann Biomed Eng (2021) 49(2): 716-731
10.1007/s10439-020-02590-1

Heart failure is a raising cause of mortality. Heart transplantation and ventricular assist device (VAD) support represent the only available lifelines for end stage disease. In the context of donor organ shortage, the future role of VAD as destination therapy is emerging. Yet, major drawbacks are connected to the long-term implantation of current devices. Poor VAD hemocompatibility exposes the patient to life-threatening events, including haemorrhagic syndromes and thrombosis. Here, we introduce a new concept of artificial support, the Hybrid Membrane VAD, as a first-of-its-kind pump prototype enabling physiological blood propulsion through the cyclic actuation of a hyperelastic membrane, enabling the protection from the thrombogenic interaction between blood and the implant materials. The centre of the luminal membrane surface displays a rationally-developed surface topography interfering with flow to support a living endothelium. The precast cell layer survives to a range of dynamically changing pump actuating conditions i.e., actuation frequency from 1 to 4 Hz, stroke volume from 12 to 30 mL, and support duration up to 313 min, which are tested both in vitro and in vivo, ensuring the full retention of tissue integrity and connectivity under challenging conditions. In summary, the presented results constitute a proof of principle for the Hybrid Membrane VAD concept and represent the basis for its future development towards clinical validation.

 

United in earnest: First pilot sites for increased surgical capacity for rheumatic heart disease announced by Cardiac Surgery Intersociety Alliance
ZO Enumah, RM Bolman, P Zilla, P Boateng, B Wilson, AS Kumar, T Chotivatanapong, F Beyersdorf, J Pomar, K Sliwa, JL Eisele, J Dearani and R Higgins
Asian Cardiovasc Thorac Ann (2021) 29(8): 729-734
10.1177/02184923211005667

BACKGROUND: Rheumatic heart disease affects more than 33,000,000 individuals, mostly from low- and middle-income countries. The Cape Town Declaration on Access to Cardiac Surgery in the Developing World was published in August 2018, signaling the commitment of the global cardiac surgery and cardiology communities to improving care for rheumatic heart disease patients. METHODS: As the Cape Town Declaration formed the basis for which the Cardiac Surgery Intersociety Alliance was formed, the purpose of this article is to describe the history of the Cardiac Surgery Intersociety Alliance, its formation, ongoing activities, and future directions, including the announcement of selected pilot sites. RESULTS: The Cardiac Surgery Intersociety Alliance is an international alliance consisting of representatives from major cardiothoracic surgical societies and the World Heart Federation. Activities have included meetings at annual conferences, exhibit hall participation for advertisement and recruitment, and publication of selection criteria for cardiac surgery centers to apply for Cardiac Surgery Intersociety Alliance support. Criteria focused on local operating capacity, local championing, governmental and facility support, appropriate identification of a specific gap in care and desire to engage in future research. Eleven applications were received for which three finalist sites were selected and site visits conducted. The two selected sites were Hospital Central Maputo (Mozambique) and King Faisal Hospital Kigali (Rwanda). CONCLUSIONS: Substantial progress has been made since the passing of the Cape Town Declaration and the formation of the Cardiac Surgery Intersociety Alliance, but ongoing efforts with collaboration of all committed parties-cardiac surgery, cardiology, industry, and government-will be necessary to improve access to life-saving cardiac surgery for rheumatic heart disease patients.

 

United in earnest: first pilot sites for increased surgical capacity for rheumatic heart disease announced by cardiac surgery intersociety alliance
ZO Enumah, RM Bolman, P Zilla, P Boateng, B Wilson, AS Kumar, T Chotivatanapong, F Beyersdorf, J Pomar, K Sliwa, JL Eisele, J Dearani and R Higgins
Eur J Cardiothorac Surg (2021) 59(6): 1139-1143
10.1093/ejcts/ezab145

OBJECTIVES: Rheumatic heart disease (RHD) affects >33 000 000 individuals, mostly from low- and middle-income countries. The Cape Town Declaration on Access to Cardiac Surgery in the Developing World was published in August 2018, signalling the commitment of the global cardiac surgery and cardiology communities to improving care for patients with RHD. METHODS: As the Cape Town Declaration formed the basis for which the Cardiac Surgery Intersociety Alliance (CSIA) was formed, the purpose of this article is to describe the history of the CSIA, its formation, ongoing activities and future directions, including the announcement of selected pilot sites. RESULTS: The CSIA is an international alliance consisting of representatives from major cardiothoracic surgical societies and the World Heart Federation. Activities have included meetings at annual conferences, exhibit hall participation for advertisement and recruitment and publication of selection criteria for cardiac surgery centres to apply for CSIA support. Criteria focused on local operating capacity, local championing, governmental and facility support, appropriate identification of a specific gap in care and desire to engage in future research. Eleven applications were received for which 3 finalist sites were selected and site visits conducted. The 2 selected sites were Hospital Central Maputo (Mozambique) and King Faisal Hospital Kigali (Rwanda). CONCLUSIONS: Substantial progress has been made since the passing of the Cape Town Declaration and the formation of the CSIA, but ongoing efforts with collaboration of all committed parties-cardiac surgery, cardiology, industry and government-will be necessary to improve access to life-saving cardiac surgery for patients with RHD.

 

United in Earnest: First Pilot Sites for Increased Surgical Capacity for Rheumatic Heart Disease Announced by Cardiac Surgery Intersociety Alliance
ZO Enumah, RM Bolman, P Zilla, P Boateng, B Wilson, AS Kumar, T Chotivatanapong, F Beyersdorf, J Pomar, K Sliwa, JL Eisele, J Dearani and R Higgins
Ann Thorac Surg (2021) 111(6): 1931-1936
10.1016/j.athoracsur.2020.11.043

BACKGROUND: Rheumatic heart disease (RHD) affects more than 33,000,000 individuals, mostly from low- and middle-income countries. The Cape Town Declaration On Access to Cardiac Surgery in the Developing World was published in August 2018, signaling the commitment of the global cardiac surgery and cardiology communities to improving care for RHD patients. METHODS: As the Cape Town Declaration formed the basis for which the Cardiac Surgery Intersociety Alliance (CSIA) was formed, the purpose of this article is to describe the history of the CSIA, its formation, ongoing activities, and future directions, including the announcement of selected pilot sites. RESULTS: The CSIA is an international alliance consisting of representatives from major cardiothoracic surgical societies and the World Heart Federation. Activities have included meetings at annual conferences, exhibit hall participation for advertisement and recruitment, and publication of selection criteria for cardiac surgery centers to apply for CSIA support. Criteria focused on local operating capacity, local championing, governmental and facility support, appropriate identification of a specific gap in care, and desire to engage in future research. Eleven applications were received for which three finalist sites were selected and site visits conducted. The two selected sites were Hospital Central Maputo (Mozambique) and King Faisal Hospital Kigali (Rwanda). CONCLUSIONS: Substantial progress has been made since the passing of the Cape Town Declaration and the formation of the CSIA, but ongoing efforts with collaboration of all committed parties-cardiac surgery, cardiology, industry, and government-will be necessary to improve access to life-saving cardiac surgery for RHD patients.

 

United in earnest: First pilot sites for increased surgical capacity for rheumatic heart disease announced by Cardiac Surgery Intersociety Alliance
ZO Enumah, RM Bolman, P Zilla, P Boateng, B Wilson, AS Kumar, T Chotivatanapong, F Beyersdorf, J Pomar, K Sliwa, JL Eisele, J Dearani and R Higgins
J Thorac Cardiovasc Surg (2021) 161(6): 2108-2113
10.1016/j.jtcvs.2020.11.183

BACKGROUND: Rheumatic heart disease (RHD) affects more than 33,000,000 individuals, mostly from low- and middle-income countries. The Cape Town Declaration On Access to Cardiac Surgery in the Developing World was published in August 2018, signaling the commitment of the global cardiac surgery and cardiology communities to improving care for RHD patients. METHODS: As the Cape Town Declaration formed the basis for which the Cardiac Surgery Intersociety Alliance (CSIA) was formed, the purpose of this article is to describe the history of the CSIA, its formation, ongoing activities, and future directions, including the announcement of selected pilot sites. RESULTS: The CSIA is an international alliance consisting of representatives from major cardiothoracic surgical societies and the World Heart Federation. Activities have included meetings at annual conferences, exhibit hall participation for advertisement and recruitment, and publication of selection criteria for cardiac surgery centers to apply for CSIA support. Criteria focused on local operating capacity, local championing, governmental and facility support, appropriate identification of a specific gap in care, and desire to engage in future research. Eleven applications were received for which three finalist sites were selected and site visits conducted. The two selected sites were Hospital Central Maputo (Mozambique) and King Faisal Hospital Kigali (Rwanda). CONCLUSIONS: Substantial progress has been made since the passing of the Cape Town Declaration and the formation of the CSIA, but ongoing efforts with collaboration of all committed parties-cardiac surgery, cardiology, industry, and government-will be necessary to improve access to life-saving cardiac surgery for RHD patients.

 

Erratum to: 'United in earnest: first pilot sites for increased surgical capacity for rheumatic heart disease announced by cardiac surgery intersociety alliance' [Eur J Cardiothorac Surg 2021;59:1139-43]
ZO Enumah, RM Bolman, P Zilla, P Boateng, B Wilson, AS Kumar, T Chotivatanapong, F Beyersdorf, J Pomar, K Sliwa, JL Eisele, J Dearani and R Higgins
Eur J Cardiothorac Surg (2021) 60(6): 1480
10.1093/ejcts/ezab414

 

Societies of Futures Past: Examining the History and Potential of International Society Collaborations in Addressing the Burden of Rheumatic Heart Disease in the Developing World
ZO Enumah, P Boateng, RM Bolman, F Beyersdorf, L Zuhlke, M Musoni, A Tivane and P Zilla
Front Cardiovasc Med (2021) 8(740745
10.3389/fcvm.2021.740745

This paper explores the role and place of national, regional, and international society collaborations in addressing the major global burden of rheumatic heart disease (RHD). On the same order of HIV, RHD affects over 40 million people worldwide. In this article, we will outline the background and current therapeutic landscape for cardiac surgery in low- and middle-income countries (LMICs) including the resource-constrained settings within which RHD surgery often occurs. This creates numerous challenges to delivering adequate surgical care and post-operative management for RHD patients, and thus provides some context for a growing movement for and applicability of structural heart approaches, innovative valve replacement technologies, and minimally invasive techniques in this setting. Intertwined and building from this context will be the remainder of the paper which elaborates how national, regional, and international societies have collaborated to address rheumatic heart disease in the past (e.g., Drakensberg Declaration, World Heart Federation Working Group on RHD) with a focus on primary and secondary prevention. We then provide the recent history and context of the growing movement for how surgery has become front and center in the discussion of addressing RHD through the passing of the Cape Town Declaration.

 

Analysis of the regenerative capacity of human serum exosomes after a simple multistep separation from lipoproteins
C de Boer, B Calder, D Blackhurst, D Marais, J Blackburn, M Steinmaurer, NJ Woudberg, S Lecour, J Lovett, K Myburgh, D Bezuidenhout, P Human and NH Davies
J Tissue Eng Regen Med (2021) 15(1): 63-77
10.1002/term.3155

Due to the abundance of lipoproteins in blood, it is challenging to characterize the biological functions and components of blood-derived extracellular vesicles. The aim of this study was to develop a multiple-step purification protocol to separate serum exosomes from serum proteins and lipoproteins and assess their regenerative potential. Exosomes were isolated by concentrating them in human serum using ultracentrifugation (UC), followed sequentially by density gradient (DG) UC and size exclusion chromatography (SEC). Purity and characterization were assessed by western blots, Lipoprint(R), enzyme-linked immunosorbent assay, electron microscopy, mass spectrometry, and nanoparticle tracking analysis. Functionality was assessed by cell proliferation analysis and with an in vivo subcutaneous angiogenesis model. SEC alone isolated nano-sized vesicles possessing vesicle markers TSG101 and CD9, but there was a substantial presence of apolipoprotein B, predominantly derived from very-low- and intermediate-density lipoprotein particles. This was reduced to an undetectable level using the combined UC DG SEC approach. Mass spectrometry identified 224 proteins in UC DG SEC isolates relative to the 135 from SEC, with considerable increases in exosome-related proteins and reductions in lipoproteins. A consistent but limited increase in human dermal fibroblast proliferation and evidence of neovascularization enhancement were observed after exposure to UC DG SEC exosomes. An UC DG SEC purification protocol considerably improved the removal of lipoproteins during isolation of serum exosomes. The purified exosomes stimulated cell proliferation and potentially increased an in vivo angiogenic response. This multistep purification allows for more accurate identification of serum exosome functional activity and composition.

 

The role of lipid droplets in microbial pathogenesis
JTR Brink, R Fourie, O Sebolai, J Albertyn and CH Pohl
J Med Microbiol (2021) 70(6): 10.1099/jmm.0.001383

The nonpolar lipids present in cells are mainly triacylglycerols and steryl esters. When cells are provided with an abundance of nutrients, these storage lipids accumulate. As large quantities of nonpolar lipids cannot be integrated into membranes, they are isolated from the cytosolic environment in lipid droplets. As specialized, inducible cytoplasmic organelles, lipid droplets have functions beyond the regulation of lipid metabolism, in cell signalling and activation, membrane trafficking and control of inflammatory mediator synthesis and secretion. Pathogens, including fungi, viruses, parasites, or intracellular bacteria can induce and may benefit from lipid droplets in infected cells. Here we review biogenesis of lipid droplets as well as the role of lipid droplets in the pathogenesis of selected viruses, bacteria, protists and yeasts.

 

Visual mapping of team dynamics and communication patterns on surgical ward rounds: an ethnographic study
C Bonaconsa, O Mbamalu, M Mendelson, A Boutall, C Warden, S Rayamajhi, T Pennel, M Hampton, I Joubert, C Tarrant, A Holmes, E Charani, S Groote Schuur Hospital Antimicrobial and G Surgical Study
BMJ Qual Saf (2021) 30(10): 812-824
10.1136/bmjqs-2020-012372

BACKGROUND: The effect of team dynamics on infection management and antimicrobial stewardship (AMS) behaviours is not well understood. Using innovative visual mapping, alongside traditional qualitative methods, we studied how surgical team dynamics and communication patterns influence infection-related decision making. MATERIALS/METHODS: Between May and November 2019, data were gathered through direct observations of ward rounds and face-to-face interviews with ward round participants in three high infection risk surgical specialties at a tertiary hospital in South Africa. Sociograms, a visual mapping method, mapped content and flow of communication and the social links between participants. Data were analysed using a grounded theory approach. RESULTS: Data were gathered from 70 hours of ward round observations, including 1024 individual patient discussions, 60 sociograms and face-to-face interviews with 61 healthcare professionals. AMS and infection-related discussions on ward rounds vary across specialties and are affected by the content and structure of the clinical update provided, consultant leadership styles and competing priorities at the bedside. Registrars and consultants dominate the discussions, limiting the input of other team members with recognised roles in AMS and infection management. Team hierarchies also manifest where staff position themselves, and this influences their contribution to active participation in patient care. Leadership styles affect ward-round dynamics, determining whether nurses and patients are actively engaged in discussions on infection management and antibiotic therapy and whether actions are assigned to identified persons. CONCLUSIONS: The surgical bedside ward round remains a medium of communication between registrars and consultants, with little interaction with the patient or other healthcare professionals. A team-focused and inclusive approach could result in more effective decision making about infection management and AMS.

 

PROTEA, A Southern African Multicenter Congenital Heart Disease Registry and Biorepository: Rationale, Design, and Initial Results
T Aldersley, J Lawrenson, P Human, G Shaboodien, B Cupido, G Comitis, R De Decker, B Fourie, L Swanson, A Joachim, P Magadla, M Ngoepe, L Swanson, A Revell, R Ramesar, A Brooks, N Saacks, B De Koning, K Sliwa, J Anthony, A Osman, B Keavney and L Zuhlke
Front Pediatr (2021) 9(763060
10.3389/fped.2021.763060

Objectives: The PartneRships in cOngeniTal hEart disease (PROTEA) project aims to establish a densely phenotyped and genotyped Congenital Heart Disease (CHD) cohort for southern Africa. This will facilitate research into the epidemiology and genetic determinants of CHD in the region. This paper introduces the PROTEA project, characterizes its initial cohort, from the Western Cape Province of South Africa, and compares the proportion or "cohort-prevalences" of CHD-subtypes with international findings. Methods: PROTEA is a prospective multicenter CHD registry and biorepository. The initial cohort was recruited from seven hospitals in the Western Cape Province of South Africa from 1 April 2017 to 31 March 2019. All patients with structural CHD were eligible for inclusion. Descriptive data for the preliminary cohort are presented. In addition, cohort-prevalences (i.e., the proportion of patients within the cohort with a specific CHD-subtype) of 26 CHD-subtypes in PROTEA's pediatric cohort were compared with the cohort-prevalences of CHD-subtypes in two global birth-prevalence studies. Results: The study enrolled 1,473 participants over 2 years, median age was 1.9 (IQR 0.4-7.1) years. Predominant subtypes included ventricular septal defect (VSD) (339, 20%), atrial septal defect (ASD) (174, 11%), patent ductus arteriosus (185, 11%), atrioventricular septal defect (AVSD) (124, 7%), and tetralogy of Fallot (121, 7%). VSDs were 1.8 (95% CI, 1.6-2.0) times and ASDs 1.4 (95% CI, 1.2-1.6) times more common in global prevalence estimates than in PROTEA's pediatric cohort. AVSDs were 2.1 (95% CI, 1.7-2.5) times more common in PROTEA and pulmonary stenosis and double outlet right ventricle were also significantly more common compared to global estimates. Median maternal age at delivery was 28 (IQR 23-34) years. Eighty-two percent (347/425) of mothers used no pre-conception supplementation and 42% (105/250) used no first trimester supplements. Conclusions: The cohort-prevalence of certain mild CHD subtypes is lower than for international estimates and the cohort-prevalence of certain severe subtypes is higher. PROTEA is not a prevalence study, and these inconsistencies are unlikely the result of true differences in prevalence. However, these findings may indicate under-diagnosis of mild to moderate CHD and differences in CHD management and outcomes. This reemphasizes the need for robust CHD epidemiological research in the region.

 

In silico stress fibre content affects peak strain in cytoplasm and nucleus but not in the membrane for uniaxial substrate stretch
T Abdalrahman, NH Davies and T Franz
Med Biol Eng Comput (2021) 59(9): 1933-1944
10.1007/s11517-021-02393-z

Existing in silico models for single cell mechanics feature limited representations of cytoskeletal structures that contribute substantially to the mechanics of a cell. We propose a micromechanical hierarchical approach to capture the mechanical contribution of actin stress fibres. For a cell-specific fibroblast geometry with membrane, cytoplasm and nucleus, the Mori-Tanaka homogenization method was employed to describe cytoplasmic inhomogeneities and constitutive contribution of actin stress fibres. The homogenization was implemented in a finite element model of the fibroblast attached to a substrate through focal adhesions. Strain in cell membrane, cytoplasm and nucleus due to uniaxial substrate stretch was assessed for different stress fibre volume fractions and different elastic modulus of the substrate. A considerable decrease of the peak strain with increasing stress fibre content was observed in cytoplasm and nucleus but not the membrane, whereas the peak strain in cytoplasm, nucleus and membrane increased for increasing elastic modulus of the substrate. Finite element mesh of reconstructed human fibroblast and intracellular strain distribution in cell subjected to substrate stretch.

 

Progressive Reinvention or Destination Lost? Half a Century of Cardiovascular Tissue Engineering
P Zilla, M Deutsch, D Bezuidenhout, NH Davies and T Pennel
Front Cardiovasc Med (2020) 7(159
10.3389/fcvm.2020.00159

The concept of tissue engineering evolved long before the phrase was forged, driven by the thromboembolic complications associated with the early total artificial heart programs of the 1960s. Yet more than half a century of dedicated research has not fulfilled the promise of successful broad clinical implementation. A historical account outlines reasons for this scientific impasse. For one, there was a disconnect between distinct eras each characterized by different clinical needs and different advocates. Initiated by the pioneers of cardiac surgery attempting to create neointimas on total artificial hearts, tissue engineering became fashionable when vascular surgeons pursued the endothelialisation of vascular grafts in the late 1970s. A decade later, it were cardiac surgeons again who strived to improve the longevity of tissue heart valves, and lastly, cardiologists entered the fray pursuing myocardial regeneration. Each of these disciplines and eras started with immense enthusiasm but were only remotely aware of the preceding efforts. Over the decades, the growing complexity of cellular and molecular biology as well as polymer sciences have led to surgeons gradually being replaced by scientists as the champions of tissue engineering. Together with a widening chasm between clinical purpose, human pathobiology and laboratory-based solutions, clinical implementation increasingly faded away as the singular endpoint of all strategies. Moreover, a loss of insight into the healing of cardiovascular prostheses in humans resulted in the acceptance of misleading animal models compromising the translation from laboratory to clinical reality. This was most evident in vascular graft healing, where the two main impediments to the in-situ generation of functional tissue in humans remained unheeded-the trans-anastomotic outgrowth stoppage of endothelium and the build-up of an impenetrable surface thrombus. To overcome this dead-lock, research focus needs to shift from a biologically possible tissue regeneration response to one that is feasible at the intended site and in the intended host environment of patients. Equipped with an impressive toolbox of modern biomaterials and deep insight into cues for facilitated healing, reconnecting to the "user needs" of patients would bring one of the most exciting concepts of cardiovascular medicine closer to clinical reality.

 

A glimpse of hope: cardiac surgery in low- and middle-income countries (LMICs)
P Zilla, RM Bolman, 3rd, P Boateng and K Sliwa
Cardiovasc Diagn Ther (2020) 10(2): 336-349
10.21037/cdt.2019.11.03

Currently, more than five times more people live in low- and middle-income countries (LMICs) than in high-income countries (HICs). As such, the downward trend in cardiac surgical needs in HICs reflects only the situation of one sixth of the world population while the vast majority living in LMICs has still no or limited access to life saving heart operations. In these countries, rheumatic heart disease (RHD) still accounts for a significant proportion of cardiac surgical needs. In low- and lower-middle income countries it remains the single most common cardiovascular disease in young adult and adolescent patients in need of heart surgery outweighing other indications such as congenital cardiac defects almost 4-fold. Compared to HICs with their predominance of calcific aortic stenosis in the elderly mitral valve surgery is required in >90% of the largely young patients with RHD in low-income countries (LICs) and still in 70% of the often middle aged patients in middle-income countries (MICs). Although recent government initiatives in LICs led to the establishment of local, independent cardiac surgical services gradually replacing fly-in missions, these centers still only cover less than 2% of the needs of their populations. In MICs, cardiac surgical needs continually grow with the emergence of degenerative diseases. As such, in spite of the concomitant growth of cardiac surgical capacity, significantly less than half the estimated patients in need have access. Capacities in LICs range from 0.5 to 7 cardiac operations/million population; 100-481/million in MICs and >1,200/million in HICs such as the USA and Germany. While a new level of awareness of the scope and magnitude of the problem has begun to emerge in LICs and the establishment of local cardiac surgical capacity has given rise to a glimpse of hope, the challenges of expanding these fledgling services to a significant proportion of the population still seem insurmountable. Challenges in MICs are on the other hand the widening gap between private cardiac medicine for the affluent few and overwhelmed public services for the many and the rural urban divide with the underappreciation of the ongoing dominance of RHD in the rural and indigent population on the other. Overshadowing all LMICs is the low level of valve-repair skills associated with insufficient cardiac surgical capacity and the unavailability of suitable replacement valves which address the young age of the patients and the difficulties of anticoagulation in a socioeconomic environment distinctly different from the elderly patients of HICs.

 

A Patient-Specific CFD Pipeline Using Doppler Echocardiography for Application in Coarctation of the Aorta in a Limited Resource Clinical Context
L Swanson, B Owen, A Keshmiri, A Deyranlou, T Aldersley, J Lawrenson, P Human, R De Decker, B Fourie, G Comitis, ME Engel, B Keavney, L Zuhlke, M Ngoepe and A Revell
Front Bioeng Biotechnol (2020) 8(409
10.3389/fbioe.2020.00409

Congenital heart disease (CHD) is the most common birth defect globally and coarctation of the aorta (CoA) is one of the commoner CHD conditions, affecting around 1/1800 live births. CoA is considered a CHD of critical severity. Unfortunately, the prognosis for a child born in a low and lower-middle income country (LLMICs) with CoA is far worse than in a high-income country. Reduced diagnostic and interventional capacities of specialists in these regions lead to delayed diagnosis and treatment, which in turn lead to more cases presenting at an advanced stage. Computational fluid dynamics (CFD) is an important tool in this context since it can provide additional diagnostic data in the form of hemodynamic parameters. It also provides an in silico framework, both to test potential procedures and to assess the risk of further complications arising post-repair. Although this concept is already in practice in high income countries, the clinical infrastructure in LLMICs can be sparse, and access to advanced imaging modalities such as phase contrast magnetic resonance imaging (PC-MRI) is limited, if not impossible. In this study, a pipeline was developed in conjunction with clinicians at the Red Cross War Memorial Children's Hospital, Cape Town and was applied to perform a patient-specific CFD study of CoA. The pipeline uses data acquired from CT angiography and Doppler transthoracic echocardiography (both much more clinically available than MRI in LLMICs), while segmentation is conducted via SimVascular and simulation is realized using OpenFOAM. The reduction in cost through use of open-source software and the use of broadly available imaging modalities makes the methodology clinically feasible and repeatable within resource-constrained environments. The project identifies the key role of Doppler echocardiography, despite its disadvantages, as an intrinsic component of the pipeline if it is to be used routinely in LLMICs.

 

Poorly suited heart valve prostheses heighten the plight of patients with rheumatic heart disease
J Scherman and P Zilla
Int J Cardiol (2020) 318(104-114
10.1016/j.ijcard.2020.05.073

Rheumatic heart disease (RHD) still affects more patients globally than degenerative valve disease. The vast majority of these patients live in low- to middle-income countries. Once symptomatic, they will need heart valve surgery. Unfortunately, prosthetic valves perform poorly in these patients given their young age, the high incidence of multi-valve disease, late diagnoses and often challenging socio-economic circumstances. Notwithstanding the fact that better valve designs would ideally be available, ill-informed decision making processes between bioprosthetic and mechanical valves are contributing to the poor results. In the absence of multicentred, randomised clinical trials, comparing the current generations of bioprostheses with mechanical valves across all age groups Western guidelines tend to be uncritically applied. As a consequence, mechanical valves are being implanted into patients who are often not able to deal with anticoagulation while bioprosthetic valves may be overly shunned for fear of reoperations. Almost sixty years after the advent of cardiac surgery heart valve prostheses have eventually undergone improvements and several potentially disruptive developments are on the horizon. Until they materialise, however, choices between contemporary valve prostheses need to be made on the basis of individual risk and life-expectancy rather than an uncritical implementation of guidelines that were derived for very different patients and under distinctly different conditions. Given the fast expansion of cardiac surgery in middle-income countries and a growing number of independently operating centres in low-income countries a critical appraisal of facts underlying the choice of heart valve prostheses for patients with RHD seems opportune.

 

Intra-myocardial alginate hydrogel injection acts as a left ventricular mid-wall constraint in swine
KL Sack, E Aliotta, JS Choy, DB Ennis, NH Davies, T Franz, GS Kassab and JM Guccione
Acta Biomater (2020) 111(170-180
10.1016/j.actbio.2020.04.033

Despite positive initial outcomes emerging from preclinical and early clinical investigation of alginate hydrogel injection therapy as a treatment for heart failure, the lack of knowledge about the mechanism of action remains a major shortcoming that limits the efficacy of treatment design. To identify the mechanism of action, we examined previously unobtainable measurements of cardiac function from in vivo, ex vivo, and in silico states of clinically relevant heart failure (HF) in large animals. High-resolution ex vivo magnetic resonance imaging and histological data were used along with state-of-the-art subject-specific computational model simulations. Ex vivo data were incorporated in detailed geometric computational models for swine hearts in health (n = 5), ischemic HF (n = 5), and ischemic HF treated with alginate hydrogel injection therapy (n = 5). Hydrogel injection therapy mitigated elongation of sarcomere lengths (1.68 +/- 0.10mum [treated] vs. 1.78 +/- 0.15mum [untreated], p<0.001). Systolic contractility in treated animals improved substantially (ejection fraction = 43.9 +/- 2.8% [treated] vs. 34.7 +/- 2.7% [untreated], p<0.01). The in silico models realistically simulated in vivo function with >99% accuracy and predicted small myofiber strain in the vicinity of the solidified hydrogel that was sustained for up to 13 mm away from the implant. These findings suggest that the solidified alginate hydrogel material acts as an LV mid-wall constraint that significantly reduces adverse LV remodeling compared to untreated HF controls without causing negative secondary outcomes to cardiac function. STATEMENT OF SIGNIFICANCE: Heart failure is considered a growing epidemic and hence an important health problem in the US and worldwide. Its high prevalence (5.8 million and 23 million, respectively) is expected to increase by 25% in the US alone by 2030. Heart failure is associated with high morbidity and mortality, has a 5-year mortality rate of 50%, and contributes considerably to the overall cost of health care ($53.1 billion in the US by 2030). Despite positive initial outcomes emerging from preclinical and early clinical investigation of alginate hydrogel injection therapy as a treatment for heart failure, the lack of knowledge concerning the mechanism of action remains a major shortcoming that limits the efficacy of treatment design. To understand the mechanism of action, we combined high-resolution ex vivo magnetic resonance imaging and histological data in swine with state-of-the-art subject-specific computational model simulations. The in silico models realistically simulated in vivo function with >99% accuracy and predicted small myofiber strain in the vicinity of the solidified hydrogel that was sustained for up to 13 mm away from the implant. These findings suggest that the solidified alginate hydrogel material acts as a left ventricular mid-wall constraint that significantly reduces adverse LV remodeling compared to untreated heart failure controls without causing negative secondary outcomes to cardiac function. Moreover, if the hydrogel can be delivered percutaneously rather than via the currently used open-chest procedure, this therapy may become routine for heart failure treatment. A minimally invasive procedure would be in the best interest of this patient population; i.e., one that cannot tolerate general anesthesia and surgery, and it would be significantly more cost-effective than surgery.

 

COVID-19 and cardiothoracic surgery:A risk-adjusted approach in the context of a global pandemic
BD Reddy, R Kleinloog, J Jansen, R Manganyi, J Brink and P Zilla
SA Heart (2020) 17(346-350
In the face of the novel coronavirus pandemic, the impact of COVID-19 infection has disrupted cardio- thoracic surgical services globally. A risk-adjusted approach to restructuring the delivery of cardiothoracic surgical services has been proposed in accordance with international guidance to ensure that the surgical standard of care is maintained in the practice of adult and paediatric cardiac surgery, as well as thoracic surgery.The potential influx of COVID-19 patients with cardio-respiratory complications requiring intensive care management and associated surgical procedures falling within the gamut of the thoracic surgeon, is con- sidered. Finally, the protection of healthcare workers, in particular the surgical team exposed to aerosolising procedures, is outlined.

 

Transesophageal echocardiography in minimally invasive cardiac surgery
ABA Prempeh, J Scherman and JL Swanevelder
Curr Opin Anaesthesiol (2020) 33(1): 83-91
10.1097/ACO.0000000000000807

PURPOSE OF REVIEW: Transesophageal echocardiography (TEE) has made its way into the cardiac surgery realm and spurred the development of many interventions. In the domain of minimally invasive cardiac surgery (MICS), TEE has become central to reducing cardiovascular complications. RECENT FINDINGS: Real-time three-dimensional TEE is a key contributor to the safe and precise deployment of the PASCAL mitral valve repair system, which is showing great potential in ongoing studies. The current data on outcomes of transcatheter aortic valve replacement show that preprocedural three-dimensional TEE and multidetector computed tomography (CT) perform similarly in aortic root assessment. Three-dimensional color Doppler TEE has been suggested to be more appropriate in quantifying residual mitral regurgitation and evaluating the success of surgical or percutaneous closure. A three-dimensional TEE-derived aortomitral angle may be valuable in predicting and detecting dynamic left ventricular outflow tract obstruction, thereby enhancing the safety of transcatheter mitral valve replacement. SUMMARY: Advanced imaging modalities are essential for the sustained growth of MICS, particularly with the evolution of novel transcatheter systems. These techniques rely on exceptional imaging quality at all stages of the perioperative period to modify surgical-risk and improve patient outcomes. TEE has the additional benefit of providing real-time information on intrathoracic structures to guide intraoperative management.

 

Transcatheter valve-in-valve implantation in degenerated aortic bioprostheses: are patients with small surgical bioprostheses at higher risk for unfavourable mid-term outcomes?
C Pingpoh, H Schroefel, T Franz, M Czerny, M Kreibich, M Moser, C Bode, F Beyersdorf, FJ Neumann, W Hochholzer and M Siepe
Ann Cardiothorac Surg (2020) 9(6): 478-486
10.21037/acs-2020-av-fs-0124

BACKGROUND: To examine outcomes of valve-in-valve (ViV) transcatheter aortic valve implantation (TAVI) according to the inner diameter (ID) of the degenerated aortic valve bioprosthesis. METHODS: We analyzed survival, stroke, permanent pacemaker (PPM) implantation, paravalvular (PV) leakage, acute kidney injury and vascular complications in fifty-nine patients during a ten-year period. Patients were stratified according to the ID of the indwelling degenerated biological aortic valve (true ID </= and >20 mm). Differences in post-procedural transvalvular gradients and hospital re-admissions were analyzed. RESULTS: The median age of the small diameter group and large diameter group was eighty-one and eighty years, respectively. Median logistic EuroSCORE I was 23.9% and 26.2% and median Society of Thoracic Surgeons (STS) score was 5.7% and 7.8% for the small and large groups, respectively. Survival, stroke, PPM implantation, PV leakage, acute kidney injury and vascular complications did not reach any statistically significant difference between both groups. Postprocedural transvalvular gradients differed significantly according to the true ID of the degenerated bioprosthetic valve and consequently of the respective TAVI valve. There was a significant difference with regard to hospital readmissions according to the true ID. CONCLUSIONS: TAVI ViV implantation for aortic bioprostheses with small true IDs of </=20 mm is associated with comparable mid-term mortality and periprocedural stroke rate compared to implantation into larger bioprostheses. However, the periprocedural and mid-term transvalvular gradients, as well as hospital re-admission rates are significantly higher in the small diameter group.

 

Raising awareness for rheumatic mitral valve disease
LSA Passos, MCP Nunes, P Zilla, MH Yacoub and E Aikawa
Glob Cardiol Sci Pract (2020) 2020(2): e202026
10.21542/gcsp.2020.26

Rheumatic heart disease (RHD) is a major burden in low- to mid-income countries, where each year it accounts for over a million premature deaths associated with severe valve disease. Life-saving valve replacement procedures are not available to the majority of affected RHD patients, contributing to an increased risk of death in young adults and creating a devastating impact. In December 2017, a group of representatives of major cardiothoracic societies and industry, discussed the plight of the millions of patients who suffer from RHD. A comprehensive solution based on this global partnership was outlined in "The Cape Town Declaration on Access to Cardiac Surgery in the Developing World". The key challenge in controlling RHD is related to identification and removal of barriers to the translation of existing knowledge into policy, programs, and practice to provide high-quality care for patients with RHD. This review provides an overview on RHD by emphasizing the disease medical and economic burdens worldwide, risk factors, recent advance for early disease detection, and overall preventive strategies.

 

Haemoptysis secondary to a complicated hydatid cyst of the lung: A case report
R Manganyi, A Moodley, T Pennel, C Ofoegbu and A Linegar
Afr J Thorac Crit Care Med (2020) 26(2): 10.7196/AJTCCM.2020.v26i2.029

Pulmonary hydatid disease is almost exclusively caused by the infestation of the larval stage of Echinococcus granulosus. Humans are infected, accidentally, through the faeco-oral route by the ingestion of food and milk, contaminated by dog faeces containing the ova of parasites or direct contact with dogs. We describe an unusual cause of massive haemoptysis in a young male who had bilateral lung hydatid cysts as well as a large splenic hydatic cyst. He underwent bilateral thoracotomies for cyst excision for relief of haemoptysis.

 

Cardiac Surgery Publications in Africa Over the Last 20 years: A Literature Review
Y Lin, B Till, S Yi, J Dahm, K Taylor, N Lu, P Zilla and RM Bolman
S Afr J Sci (2020) 16(1-6
https://doi.org/10.17159/sajs.2020/6359

 

Tissue Ingrowth Markedly Reduces Mechanical Anisotropy and Stiffness in Fibre Direction of Highly Aligned Electrospun Polyurethane Scaffolds
H Krynauw, J Buescher, J Koehne, L Verrijt, G Limbert, NH Davies, D Bezuidenhout and T Franz
Cardiovasc Eng Technol (2020) 11(4): 456-468
10.1007/s13239-020-00475-x

PURPOSE: The lack of long-term patency of synthetic vascular grafts currently available on the market has directed research towards improving the performance of small diameter grafts. Improved radial compliance matching and tissue ingrowth into the graft scaffold are amongst the main goals for an ideal vascular graft. METHODS: Biostable polyurethane scaffolds were manufactured by electrospinning and implanted in subcutaneous and circulatory positions in the rat for 7, 14 and 28 days. Scaffold morphology, tissue ingrowth, and mechanical properties of the scaffolds were assessed before implantation and after retrieval. RESULTS: Tissue ingrowth after 24 days was 96.5 +/- 2.3% in the subcutaneous implants and 77.8 +/- 5.4% in the circulatory implants. Over the 24 days implantation, the elastic modulus at 12% strain decreased by 59% in direction of the fibre alignment whereas it increased by 1379% transverse to the fibre alignment of the highly aligned scaffold of the subcutaneous implants. The lesser aligned scaffold of the circulatory graft implants exhibited an increase of the elastic modulus at 12% strain by 77% in circumferential direction. CONCLUSION: Based on the observations, it is proposed that the mechanism underlying the softening of the highly aligned scaffold in the predominant fibre direction is associated with scaffold compaction and local displacement of fibres by the newly formed tissue. The stiffening of the scaffold, observed transverse to highly aligned fibres and for more a random fibre distribution, represents the actual mechanical contribution of the tissue that developed in the scaffold.

 

Decellularization and engineered crosslinking: a promising dual approach towards bioprosthetic heart valve longevity
P Human, C Ofoegbu, H Ilsley, D Bezuidenhout, J de Villiers, DF Williams and P Zilla
Eur J Cardiothorac Surg (2020) 58(6): 1192-1200
10.1093/ejcts/ezaa257

OBJECTIVES: While decellularization has previously significantly improved the durability of bioprosthetic tissue, remnant immunogenicity may yet necessitate masking through crosslinking. To alleviate the fears of reintroducing the risk of calcific degeneration, we investigated the application of rationally designed crosslinking chemistry, capable of abrogating mineralization in isolation, in decellularized tissue. METHODS: Bovine and porcine pericardium were decellularized using the standard Triton X/sodium deoxycholate/DNAse/RNAse methodology and thereafter combined incrementally with components of a four-stage high-density dialdehyde-based fixation regimen. Mechanical properties prior to, and calcium levels following, subcutaneous implantation for 6 and 10 weeks in rats were assessed. RESULTS: Enhanced four-stage crosslinking, independent of decellularization, or decellularization followed by any of the crosslinking regimens, achieved sustained, near-elimination of tissue calcification. Decellularization additionally resulted in significantly lower tissue stiffness and higher fatigue resistance in all groups compared to their non-decellularized counterparts. CONCLUSIONS: The dual approach of combining decellularization with enhanced crosslinking chemistry in xenogeneic pericardial tissue offers much promise in extending bioprosthetic heart valve longevity.

 

Customized stent-grafts for endovascular aneurysm repair with challenging necks: A numerical proof of concept
A Hemmler, A Lin, N Thierfelder, T Franz, MW Gee and D Bezuidenhout
Int J Numer Method Biomed Eng (2020) 36(4): e3316
10.1002/cnm.3316

Endovascular aortic repair (EVAR) is a challenging intervention whose long-term success strongly depends on the appropriate stent-graft (SG) selection and sizing. Most off-the-shelf SGs are straight and cylindrical. Especially in challenging vessel morphologies, the morphology of off-the-shelf SGs is not able to meet the patient-specific demands. Advanced manufacturing technologies facilitate the development of highly customized SGs. Customized SGs that have the same morphology as the luminal vessel surface could considerably improve the quality of the EVAR outcome with reduced likelihoods of EVAR related complications such as endoleaks type I and SG migration. In this contribution, we use an in silico EVAR methodology that approximates the deployed state of the elastically deformable SG in a hyperelastic, anisotropic vessel. The in silico EVAR results of off-the-shelf SGs and customized SGs are compared qualitatively and quantitatively in terms of mechanical and geometrical parameters such as stent stresses, contact tractions, SG fixation forces and the SG-vessel attachment. In a numerical proof of concept, eight different vessel morphologies, such as a conical vessel, a barrel shaped vessel and a curved vessel, are used to demonstrate the added value of customized SGs compared to off-the-shelf SGs. The numerical investigation has shown large benefits of the highly customized SGs compared to off-the-shelf SGs with respect to a better SG-vessel attachment and a considerable increase in SG fixation forces of up to 50% which indicate decreased likelihoods of EVAR related complications. Hence, this numerical proof of concept motivates further research and development of highly customized SGs for the use in challenging vessel morphologies.

 

Multimodal soft tissue markers for bridging high-resolution diagnostic imaging with therapeutic intervention
AE Hansen, JR Henriksen, RI Jolck, FP Fliedner, LM Bruun, J Scherman, AI Jensen, P Munck Af Rosenschold, L Moorman, S Kurbegovic, SR de Blanck, KR Larsen, PF Clementsen, AN Christensen, MH Clausen, W Wang, P Kempen, M Christensen, NE Viby, G Persson, R Larsen, K Conradsen, FJ McEvoy, A Kjaer, T Eriksen and TL Andresen
Sci Adv (2020) 6(34): eabb5353
10.1126/sciadv.abb5353

Diagnostic imaging often outperforms the surgeon's ability to identify small structures during therapeutic procedures. Smart soft tissue markers that translate the sensitivity of diagnostic imaging into optimal therapeutic intervention are therefore highly warranted. This paper presents a unique adaptable liquid soft tissue marker system based on functionalized carbohydrates (Carbo-gel). The liquid state of these markers allows for high-precision placement under image guidance using thin needles. Based on step-by-step modifications, the image features and mechanical properties of markers can be optimized to bridge diagnostic imaging and specific therapeutic interventions. The performance of Carbo-gel is demonstrated for markers that (i) have radiographic, magnetic resonance, and ultrasound visibility; (ii) are palpable and visible; and (iii) are localizable by near-infrared fluorescence and radio guidance. The study demonstrates encouraging proof of concept for the liquid marker system as a well-tolerated multimodal imaging marker that can improve image-guided radiotherapy and surgical interventions, including robotic surgery.

 

Dating the skull from Broken Hill, Zambia, and its position in human evolution
R Grun, A Pike, F McDermott, S Eggins, G Mortimer, M Aubert, L Kinsley, R Joannes-Boyau, M Rumsey, C Denys, J Brink, T Clark and C Stringer
Nature (2020) 580(7803): 372-375
10.1038/s41586-020-2165-4

The cranium from Broken Hill (Kabwe) was recovered from cave deposits in 1921, during metal ore mining in what is now Zambia(1). It is one of the best-preserved skulls of a fossil hominin, and was initially designated as the type specimen of Homo rhodesiensis, but recently it has often been included in the taxon Homo heidelbergensis(2-4). However, the original site has since been completely quarried away, and-although the cranium is often estimated to be around 500 thousand years old(5-7)-its unsystematic recovery impedes its accurate dating and placement in human evolution. Here we carried out analyses directly on the skull and found a best age estimate of 299 +/- 25 thousand years (mean +/- 2sigma). The result suggests that later Middle Pleistocene Africa contained multiple contemporaneous hominin lineages (that is, Homo sapiens(8,9), H. heidelbergensis/H. rhodesiensis and Homo naledi(10,11)), similar to Eurasia, where Homo neanderthalensis, the Denisovans, Homo floresiensis, Homo luzonensis and perhaps also Homo heidelbergensis and Homo erectus(12) were found contemporaneously. The age estimate also raises further questions about the mode of evolution of H. sapiens in Africa and whether H. heidelbergensis/H. rhodesiensis was a direct ancestor of our species(13,14).

 

Waking Up Safer? An Anesthesiologist’s Record, Berend Mets
P Zilla, J Brink and J Swanevelder
South African Medical Journal (2019) 109(4): https://hdl.handle.net/10520/EJC-14d88da11f

The unique and exciting life story of Berend Mets is the backdrop to a book that gives us an unusual insight into anaesthesia. Sometimes underappreciated, this highly scientific medical specialty enabled the phenomenal advances of surgery over the past 150 years. The book provides the historical background to a discipline that was closely linked to the unprecedented technological and scientific advances of the nineteenth century. The tour through the emergence of anaesthesia could not better contrast it with that of its sister discipline, surgery. While the urge to cut open an infection or amputate a crushed limb has been around for millennia, the controlled management of pain and the resultant ability to perform major operations had to await the innovative medical discoveries of the nineteenth century. Mets recounts the history of the pioneers of anaesthesia with the ease and skill of a seasoned writer. He shows that a daring pioneering spirit was needed to open the door to painless surgery, but argues that meticulous attention to detail and continued improvement of algorithms of care are the modern-day trademarks that allow us to wake up safely after an operation. He uses numbers to illustrate the astounding evolution of this discipline, with mortality rates decreasing from 1 in 1 500 in 1954 to 1 in 140 000 in 2014. Mets maintains that this is still far from the safety record of air transportation, with one fatal incident in 2 300 000 flights. As such, he proposes that aviation protocols should guide us in the even more rigorous implementation of safety measures for yet better outcomes in anaesthesia.

 

Reply to D. Vervoort
P Zilla
Eur J Cardiothorac Surg (2019) 55(5): 1023
10.1093/ejcts/ezy320

 

Preclinical evaluation of a transcatheter aortic valve replacement system for patients with rheumatic heart disease
J Scherman, C Ofoegbu, A Myburgh, J Swanevelder, B van Breda, H Appa, P Human, D Williams, D Bezuidenhout and P Zilla
EuroIntervention (2019) 15(11): e975-e982
10.4244/EIJ-D-18-01052

AIMS: Cardiac surgery in middle-income countries differs significantly from that in high-income countries regarding prevailing heart valve pathologies and access to cardiac surgery. Typically, rheumatic aortic regurgitation in the absence of calcification by far outweighs stenosis. As such, entirely different transcatheter aortic valve implantation (TAVI) concepts are required for these regions. The aim of the study was to evaluate the five-month performance of the SAT (Strait Access Technologies, Cape Town, South Africa) pericardial TAVI system in the orthotopic aortic position of juvenile sheep. METHODS AND RESULTS: A self-homing, non-occlusive balloon-expandable TAVI system comprising a hollow balloon, stabilising locator trunks, a scalloped CoCr stent with elevating anchorage arms and decellularised, sandwich-crosslinked pericardium was compared with control surgical valves (Edwards PERIMOUNT) in sheep. The implantation period was five months. The tactile placement of the TAVI valves was accomplished without the need for rapid pacing. At termination, no structural degeneration was observed in either group. The TAVIs were well healed with the stent struts largely embedded in tissue. Correlating with sheep growth (weight gain of 40.4+/-13.0%) during the implantation period, mean transvalvular gradients increased from 3.08+/-1.95 mmHg to 8.50+/-5.38 mmHg (p=0.044) after five months. CONCLUSIONS: A single-stage, balloon-expandable, easy to place TAVI system with antigen-depleted and antigen-masked bioprosthetic leaflets promises to address the distinct needs of low- and middle-income countries with regard to TAVI better than conventional systems.

 

Isolated mechanical aortic valve replacement in rheumatic patients in a low- to middle-income country
J Scherman, R Manganyi, P Human, T Pennel, A Brooks, J Brink and P Zilla
J Thorac Cardiovasc Surg (2019) 157(3): 886-893
10.1016/j.jtcvs.2018.06.083

OBJECTIVE: Although the results of aortic valve replacement are well documented for industrialized countries, the outcome in patients with rheumatic aortic valve disease in low- to middle-income countries is less well explored. The aim of this study was to determine the long-term survival and clinical outcomes after isolated aortic valve replacement in patients with rheumatic heart disease in a Sub-Saharan country where follow-up of indigent patients is often challenging. METHODS: A retrospective review of 969 aortic valve replacements performed between 2003 and 2013 was conducted at Cape Town's Groote Schuur Hospital. Patients who underwent concomitant procedures (n = 664) or had nonrheumatic valve pathology (n = 185) were excluded. The mean age of the rheumatic cohort (n = 121) was 43.1 +/- 11.6 years with a mean follow-up period of 6.14 +/- 3.44 years. The primary end points were survival and valve-related complications. RESULTS: A 15% cardiac- or valve-related 10-year mortality after receiving a mechanical prosthesis corresponded with a significantly higher mortality rate than that of a matched population. Overall cumulative survival at 1, 5, and 10 years was 93.5% (87.0-96.9), 86.4% (78.4-91.8), and 78.1% (67.5-86.0), respectively, and the corresponding cumulative freedom from combined thromboembolism and bleeding was 94.4% (88.2-97.5), 87.4% (79.4-92.5), and 86.1% (77.9-91.6), respectively. CONCLUSIONS: In low- to middle-income countries, with their unique mix of indigent and "First World" patients, rheumatic heart disease still accounts for a significant proportion of patients requiring isolated aortic valve replacement. Although mechanical prostheses are often selected in these young adults, survival remains suboptimal. Major bleeding and thromboembolic events account for the majority (77%) of the reported valve-related complications.

 

Kinematic boundary conditions substantially impact in silico ventricular function
M Peirlinck, KL Sack, P De Backer, P Morais, P Segers, T Franz and M De Beule
Int J Numer Method Biomed Eng (2019) 35(1): e3151
10.1002/cnm.3151

Computational cardiac mechanical models, individualized to the patient, have the potential to elucidate the fundamentals of cardiac (patho-)physiology, enable non-invasive quantification of clinically significant metrics (eg, stiffness, active contraction, work), and anticipate the potential efficacy of therapeutic cardiovascular intervention. In a clinical setting, however, the available imaging resolution is often limited, which limits cardiac models to focus on the ventricles, without including the atria, valves, and proximal arteries and veins. In such models, the absence of surrounding structures needs to be accounted for by imposing realistic kinematic boundary conditions, which, for prognostic purposes, are preferably generic and thus non-image derived. Unfortunately, the literature on cardiac models shows no consistent approach to kinematically constrain the myocardium. The impact of different approaches (eg, fully constrained base, constrained epi-ring) on the predictive capacity of cardiac mechanical models has not been thoroughly studied. For that reason, this study first gives an overview of current approaches to kinematically constrain (bi) ventricular models. Next, we developed a patient-specific in silico biventricular model that compares well with literature and in vivo recorded strains. Alternative constraints were introduced to assess the influence of commonly used mechanical boundary conditions on both the predicted global functional behavior of the in-silico heart (cavity volumes, stroke volume, ejection fraction) and local strain distributions. Meaningful differences in global functioning were found between different kinematic anchoring strategies, which brought forward the importance of selecting appropriate boundary conditions for biventricular models that, in the near future, may inform clinical intervention. However, whilst statistically significant differences were also found in local strain distributions, these differences were minor and mostly confined to the region close to the applied boundary conditions.

 

TAVI for rheumatic aortic stenosis - The next frontier?
M Ntsekhe and J Scherman
Int J Cardiol (2019) 280(51-52
10.1016/j.ijcard.2019.01.015

 

A Preliminary Computational Investigation Into the Flow of PEG in Rat Myocardial Tissue for Regenerative Therapy
M Ngoepe, A Passos, S Balabani, J King, A Lynn, J Moodley, L Swanson, D Bezuidenhout, NH Davies and T Franz
Front Cardiovasc Med (2019) 6(104
10.3389/fcvm.2019.00104

Myocardial infarction (MI), a type of cardiovascular disease, affects a significant proportion of people around the world. Traditionally, non-communicable chronic diseases were largely associated with aging populations in higher income countries. It is now evident that low- to middle-income countries are also affected and in these settings, younger individuals are at high risk. Currently, interventions for MI prolong the time to heart failure. Regenerative medicine and stem cell therapy have the potential to mitigate the effects of MI and to significantly improve the quality of life for patients. The main drawback with these therapies is that many of the injected cells are lost due to the vigorous motion of the heart. Great effort has been directed toward the development of scaffolds which can be injected alongside stem cells, in an attempt to improve retention and cell engraftment. In some cases, the scaffold alone has been seen to improve heart function. This study focuses on a synthetic polyethylene glycol (PEG) based hydrogel which is injected into the heart to improve left ventricular function following MI. Many studies in literature characterize PEG as a Newtonian fluid within a specified shear rate range, on the macroscale. The aim of the study is to characterize the flow of a 20 kDa PEG on the microscale, where the behavior is likely to deviate from macroscale flow patterns. Micro particle image velocimetry (muPIV) is used to observe flow behavior in microchannels, representing the gaps in myocardial tissue. The fluid exhibits non-Newtonian, shear-thinning behavior at this scale. Idealized two-dimensional computational fluid dynamics (CFD) models of PEG flow in microchannels are then developed and validated using the muPIV study. The validated computational model is applied to a realistic, microscopy-derived myocardial tissue model. From the realistic tissue reconstruction, it is evident that the myocardial flow region plays an important role in the distribution of PEG, and therefore, in the retention of material.

 

Acute cellular rejection in lung transplantation
F Manyeruke, T Pennel, R Roberts and GL Calligaro
Afr J Thorac Crit Care Med (2019) 25(2): 10.7196/AJTCCM.2019.v25i2.010

Lung transplantation is an important therapy for end-stage respiratory failure in patients who have exhausted other therapeutic options. The lung is unique among solid-organ transplants in that it is exposed to the outside environment, and undergoes continuous stimulation from infectious and non-infectious agents, which may play a part in upregulating the immune response to the allograft. Despite induction immunosuppression and the use of aggressive maintenance regimens, acute allograft rejection is still a major problem, especially in the first year after transplant, with important diagnostic and therapeutic challenges. As well as being responsible for early graft failure and death, acute rejection also initiates alloimmune responses that predispose patients to chronic lung allograft dysfunction, in particular bronchiolitis obliterans syndrome. Cellular responses to human leukocyte antigens (HLAs) on the allograft have traditionally been considered the main mechanism of acute rejection, although the influence of humoral immunity is increasingly recognised. Here, we present two cases of acute cellular rejection (ACR) in the early post-transplant period and review the pathophysiology, diagnosis, clinical presentation and treatment of ACR.

 

Suitability of developed composite materials for meniscal replacement: Mechanical, friction and wear evaluation
AO Inyang, T Abdalrahman, D Bezuidenhout, J Bowen and CL Vaughan
J Mech Behav Biomed Mater (2019) 89(217-226
10.1016/j.jmbbm.2018.09.025

The meniscus is a complex and frequently damaged tissue which requires a substitute capable of reproducing similar biomechanical functions. This study aims to develop a synthetic meniscal substitute that can mimic the function of the native meniscus. Medical grade silicones reinforced with nylon were fabricated using compression moulding and evaluated for mechanical and tribological properties. The optimal properties were obtained with tensile modulus increased considerably from 10.7 +/- 2.9 MPa to 114.6 +/- 20.9 MPa while compressive modulus was found to reduce from 2.5 +/- 0.6 MPa to 0.7 +/- 0.3 MPa. Using a tribometer, the coefficient of friction of 0.08 +/- 0.02 was measured at the end of the 100,000 cycles. The developed composite could be an auspicious substitute for the native meniscus and the knowledge gained from this study is useful as it enhances the understanding of a potentially suitable material for meniscal implants.

 

After 50 Years of Heart Transplants: What Does the Next 50 Years Hold for Cardiovascular Medicine? A Perspective From the International Society for Applied Cardiovascular Biology
JD Hutcheson, CJ Goergen, FJ Schoen, M Aikawa, P Zilla, E Aikawa and GR Gaudette
Front Cardiovasc Med (2019) 6(8
10.3389/fcvm.2019.00008

The first successful heart transplant 50 years ago by Dr.Christiaan Barnard in Cape Town, South Africa revolutionized cardiovascular medicine and research. Following this procedure, numerous other advances have reduced many contributors to cardiovascular morbidity and mortality; yet, cardiovascular disease remains the leading cause of death globally. Various unmet needs in cardiovascular medicine affect developing and underserved communities, where access to state-of-the-art advances remain out of reach. Addressing the remaining challenges in cardiovascular medicine in both developed and developing nations will require collaborative efforts from basic science researchers, engineers, industry, and clinicians. In this perspective, we discuss the advancements made in cardiovascular medicine since Dr. Barnard's groundbreaking procedure and ongoing research efforts to address these medical issues. Particular focus is given to the mission of the International Society for Applied Cardiovascular Biology (ISACB), which was founded in Cape Town during the 20th celebration of the first heart transplant in order to promote collaborative and translational research in the field of cardiovascular medicine.

 

Tracheoesophageal fistula following button battery ingestion in an infant : Airway management considerations
R Hofmeyr, K Bester, A Willms, J Hewitson and C Byhahn
Anaesthesist (2019) 68(11): 777-779
10.1007/s00101-019-00679-4

A 13-month-old infant was admitted to hospital approximately 3 weeks after ingestion of a button battery, which was lodged in the esophagus and had caused a tracheoesophageal fistula requiring mechanical ventilation. Since the battery had partially penetrated into the tracheal lumen just above the carina and also was in direct contact with the pulmonary artery, extensive considerations regarding airway and circulatory management were required preoperatively, which are presented and discussed in this case report.

 

Performance analysis of the transcatheter aortic valve implantation on blood flow hemodynamics: An optical imaging-based in vitro study
U Gulan, H Appa, P Corso, C Templin, D Bezuidenhout, P Zilla, F Duru and M Holzner
Artif Organs (2019) 43(10): E282-E293
10.1111/aor.13504

Cardiac implants may have a strong influence on the hemodynamics of the circulatory system. In this study, we aimed at investigating the impact of transcatheter aortic valve implantation (TAVI) devices on blood flow patterns that develop in the ascending aorta under physiological flow conditions in vitro. For this purpose, a noninvasive optical measurement tool, three-dimensional particle tracking velocimetry (3D-PTV), was used in a realistic compliant silicone aortic model. The performance and the influence of two TAVIs and one surgical valve on the aortic flow were investigated. Our results showed that valve design and materials may have a distinct influence on relevant hemodynamic properties, namely kinetic energy, production of turbulence, and shear stresses in the ascending aorta. All properties varied considerably between the different valve models. We found that the total aortic regurgitation composed of the closing volume, transvalvular and paravalvular leakages varied for the three valves investigated. Furthermore, peak mean kinetic energy (MKE) ranged from 61 to 116 J/m(3) , whereas peak turbulent kinetic energy (TKE) ranged from 23 to 36 J/m(3) . The analysis of shear showed that all the three studied devices had minimal overall risk for thrombus formation. We conclude that the characteristics and material designs of TAVI devices have strong influences on the hemodynamics in the ascending aorta.

 

Enamel pearls: Their occurrence in recent human populations and earliest manifestation in the modern human lineage
FE Grine, S Holt, JS Brink and A du Plessis
Arch Oral Biol (2019) 101(147-155
10.1016/j.archoralbio.2019.03.004

OBJECTIVE: To document and describe the occurrence of an enamel pearl on the distal root surface of the maxillary M3 of the fossil hominin specimen from Florisbad, South Africa that is dated to ca. 259,000 years B.P., and is an early representative of Homo sapiens or as a member of the evolutionary line that was directly ancestral to modern humans. DESIGN: The molar was examined macroscopically and by micro-computed tomography (muCT) to enable accurate measurement and visualization of the structure of the enamel pearl. RESULTS: The single pearl has a diameter of 0.97 mm; it is a Type 2 "composite" pearl comprising an enamel cap and dentine core without pulp chamber involvement. The size of the Florisbad pearl falls within or just below the size ranges of this anomaly in modern human samples. Type 2 pearls are most commonly encountered in recent human populations, and the location of the pearl on the distal root surface of the Florisbad M(3) is consistent with its most frequent location in recent humans. Pearls in recent human populations affect between 0.2-4.8% of individuals, and 1.7-6.8% of permanent molars. Pearls have been documented in several prehistoric human dentitions, and all examples are less than 4000 years old. CONCLUSIONS: Enamel pearls have been associated with periodontal disease, but it is not possible to relate its presence to the advanced periodontal inflammation and alveolar bone loss in the Florisbad fossil. Florisbad presents the earliest evidence of this anomaly in the fossil record pertaining to modern humans.

 

A truly non-occlusive stent-graft moulding balloon for thoracic endovascular aortic repair
R Gottardi, T Mudge, M Czerny, R Seitelberger, DF Williams, J Scherman, D Bezuidenhout and P Zilla
Interact Cardiovasc Thorac Surg (2019) 29(3): 352-354
10.1093/icvts/ivz098

Endovascular treatment of thoracic aortic pathologies has recently progressed towards more proximal pathologies, including those of the aortic arch and ascending aorta where there is a higher risk for stent-graft migration during the deployment or the moulding procedure due to the beating and ejecting heart. Typical measures to prevent dislodgement of the balloon or the stent-graft during the procedure are rapid pacing or pharmacologically induced hypotension. We present a circular and fully non-occlusive stent-graft moulding balloon that does not require any reduction of cardiac output or hypotension during inflation, moulding and deflation of the balloon.

 

Early HIV treatment and labour outcomes: A case study of mining workers in South Africa
D French, J Brink and T Barnighausen
Health Econ (2019) 28(2): 204-218
10.1002/hec.3837

This study examines whether labour outcomes of HIV-infected workers treated with antiretrovirals are associated with the stage of the disease when commencing therapy. We use data on employment separation and absenteeism from the workplace health programme of South Africa's largest coal mining company over the period of January 2009 to March 2017 in a Cox proportional hazards model. When treatment was initiated at a CD4(+) T cell count above 350 cells/mul, the risk of separating from the company was 37% lower and the risk of absence was 20%t lower than initiating at a CD4 count below 200 cells/mul, and these differences persist over time. Also, we find that workers initiating antiretroviral therapy at CD4 >/= 350 have an 8% lower risk of absence prior to treatment. Although many companies and the South African government have adopted universal test-and-treat policies aiming to initiate all HIV-infected people as early as possible, most HIV patients still start treatment late in the disease course when their CD4 counts have fallen to low levels. Our results indicate early HIV detection and treatment could have large productivity gains.

 

Making cardiac surgery feasible in African countries: Experience from Namibia, Uganda, and Zambia
J Forcillo, DA Watkins, A Brooks, C Hugo-Hamman, L Chikoya, M Oketcho, VH Thourani, L Zuhlke, Z contributors from Namibia and Uganda
J Thorac Cardiovasc Surg (2019) 158(5): 1384-1393
10.1016/j.jtcvs.2019.01.054

OBJECTIVES: Few African countries have the resources to provide optimal cardiac surgery care. We explored needs at cardiac surgery centers in Namibia, Zambia, and Uganda. Our objectives were (1) to determine the key variables to be included in a cardiac surgery needs assessment tool and (2) to highlight the current initiatives, challenges and opportunities, and future goals for cardiac surgery in these 3 countries. METHODS: We conducted in-depth interviews with stakeholders in each country as well as surveys of surgical facilities. We synthesized our findings using a health systems conceptual framework. Each program's current capacity was compared with a standardized definition of "adequate" surgical capacity. On the basis of these findings, we developed a formal needs assessment questionnaire for use in resource-constrained countries. RESULTS: Although each of these countries has adequate facilities and surgical expertise, they still lack key support staff and material resources. Training and mentorship programs are being built, and the sites participate in cardiovascular research. Yet a comprehensive, multidisciplinary approach-including palliative care and rehabilitation-is lacking, and patients in remote areas are not being served. These observations allowed us to define the variables in our needs assessment tool. CONCLUSIONS: Our study demonstrates the great potential that exists to expand cardiac surgery in Africa and highlights some of the major resource bottlenecks that may hinder the scale-up of surgical programs. Our needs assessment questionnaire will assist ministries of health in building sustainable cardiac surgery programs using innovative Afro-centric solutions.

 

Spatial Network Mapping of Pulmonary Multidrug-Resistant Tuberculosis Cavities Using RNA Sequencing
K Dheda, L Lenders, S Srivastava, G Magombedze, H Wainwright, P Raj, SJ Bush, G Pollara, R Steyn, M Davids, A Pooran, T Pennel, A Linegar, R McNerney, L Moodley, JG Pasipanodya, CT Turner, M Noursadeghi, RM Warren, E Wakeland and T Gumbo
Am J Respir Crit Care Med (2019) 200(3): 370-380
10.1164/rccm.201807-1361OC

Rationale: There is poor understanding about protective immunity and the pathogenesis of cavitation in patients with tuberculosis.Objectives: To map pathophysiological pathways at anatomically distinct positions within the human tuberculosis cavity.Methods: Biopsies were obtained from eight predetermined locations within lung cavities of patients with multidrug-resistant tuberculosis undergoing therapeutic surgical resection (n = 14) and healthy lung tissue from control subjects without tuberculosis (n = 10). RNA sequencing, immunohistochemistry, and bacterial load determination were performed at each cavity position. Differentially expressed genes were normalized to control subjects without tuberculosis, and ontologically mapped to identify a spatially compartmentalized pathophysiological map of the cavity. In silico perturbation using a novel distance-dependent dynamical sink model was used to investigate interactions between immune networks and bacterial burden, and to integrate these identified pathways.Measurements and Main Results: The median (range) lung cavity volume on positron emission tomography/computed tomography scans was 50 cm(3) (15-389 cm(3)). RNA sequence reads (31% splice variants) mapped to 19,049 annotated human genes. Multiple proinflammatory pathways were upregulated in the cavity wall, whereas a downregulation "sink" in the central caseum-fluid interface characterized 53% of pathways including neuroendocrine signaling, calcium signaling, triggering receptor expressed on myeloid cells-1, reactive oxygen and nitrogen species production, retinoic acid-mediated apoptosis, and RIG-I-like receptor signaling. The mathematical model demonstrated that neuroendocrine, protein kinase C-theta, and triggering receptor expressed on myeloid cells-1 pathways, and macrophage and neutrophil numbers, had the highest correlation with bacterial burden (r > 0.6), whereas T-helper effector systems did not.Conclusions: These data provide novel insights into host immunity to Mycobacterium tuberculosis-related cavitation. The pathways defined may serve as useful targets for the design of host-directed therapies, and transmission prevention interventions.

 

Bioinspired Heart Valve Prosthesis Made by Silicone Additive Manufacturing
FB Coulter, M Schaffner, JA Faber, A Rafsanjani, R Smith, H Appa, P Zilla, D Bezuidenhhout and AR Studart
Matter (2019) 1(1): 266-279
https://doi.org/10.1016/j.matt.2019.05.013

Current heart valve solutions are expensive and labor intensive to manufacture, have relatively short life spans, contain animal-derived tissue or metallic elements that require immunosuppression or antithrombogenic drugs, and tend not to fit perfectly into the patient's aorta. As such, the number of patients who can receive such replacements is limited. Heart valves customized to fit the anatomy of the patient, match the softness of surrounding tissue, and adapt to the pathology and growth of diseased host tissue represent the next frontier in treatment. Using silicone valves as a model system, we additively manufactured patient-specific, bioinspired designs, effective for in vitro disease modeling and physical simulators. Furthermore, the technology we demonstrate offers a unique potential to create tissue-engineered constructs that closely resemble the architecture and functionality of their biological counterparts, providing mechanical cues to induce the controlled growth of cells.

 

Tuning Tissue Ingrowth into Proangiogenic Hydrogels via Dual Modality Degradation
C Chokoza, CA Gustafsson, KP Goetsch, P Zilla, N Thierfelder, F Pisano, M Mura, M Gnecchi, D Bezuidenhhout and NH Davies
ACS Biomater Sci Eng (2019) 5(10): 5430-5438
doi: 10.1021/acsbiomaterials.9b01220. Epub 2019 Oct 2.

The potential to control the rate of replacement of a biodegradable implant by a tissue would be advantageous. Here, we demonstrate that tissue invasion can be tuned through the novel approach of overlaying an enzymatically degradable hydrogel with an increasingly hydrolytically degradable environment. Poly(ethylene glycol) (PEG) hydrogels were formed from varying proportions of PEG-vinyl sulfone and PEG-acrylate (PEG-AC) monomers via a Michael-type addition reaction with a dithiol-containing matrix-metalloproteinase-susceptible peptide cross-linker. Swelling studies showed that PEG hydrogels with similar initial stiffnesses degraded more rapidly as the PEG-AC content increased. The replacement of subcutaneously implanted PEG hydrogels was also found to be proportional to their PEG-AC content. In addition, it would in many instances be desirable that these materials have the ability to stimulate their neovascularization. These hydrogels contained covalently bound heparin, and it was shown that a formulation of the hydrogel that allowed tissue replacement to occur over 1 month could trap and release growth factors and increase neovascularization by 50% over that time.

 

Cardiac Surgery for the Forgotten Millions: The Way Forward. Cardiac Surgery Intersociety Alliance (CSIA) Site Selection Criteria
P Boateng, RM Bolman, 3rd, P Zilla and Csia
Ann Thorac Surg (2019) 108(3): 653
10.1016/j.athoracsur.2019.06.006

 

Cardiac surgery for the forgotten millions: the way forward - CSIA site selection criteria
P Boateng, RM Bolman, 3rd and P Zilla
Asian Cardiovasc Thorac Ann (2019) 27(5): 338
10.1177/0218492319854930

 

Cardiac surgery for the forgotten millions: the way forward. Cardiac Surgery Intersociety Alliance (CSIA) Site Selection Criteria
P Boateng, RM Bolman and P Zilla
Eur J Cardiothorac Surg (2019) 56(2): 217
10.1093/ejcts/ezz192

 

The African context of the Cape Town Declaration
P Zilla, L Zuhlke, K Sliwa and P Commerford
Cardiovasc J Afr (2018) 29(4): 204

 

Global Unmet Needs in Cardiac Surgery
P Zilla, M Yacoub, L Zuhlke, F Beyersdorf, K Sliwa, G Khubulava, A Bouzid, AO Mocumbi, D Velayoudam, D Shetty, C Ofoegbu, A Geldenhuys, J Brink, J Scherman, H du Toit, S Hosseini, H Zhang, XJ Luo, W Wang, J Mejia, T Kofidis, RSD Higgins, J Pomar, RM Bolman, BM Mayosi, R Madansein, J Bavaria, AA Yanes-Quintana, AS Kumar, O Adeoye, RF Chauke and DF Williams
Glob Heart (2018) 13(4): 293-303
10.1016/j.gheart.2018.08.002

More than 6 billion people live outside industrialized countries and have insufficient access to cardiac surgery. Given the recently confirmed high prevailing mortality for rheumatic heart disease in many of these countries together with increasing numbers of patients needing interventions for lifestyle diseases due to an accelerating epidemiological transition, a significant need for cardiac surgery could be assumed. Yet, need estimates were largely based on extrapolated screening studies while true service levels remained unknown. A multi-author effort representing 16 high-, middle-, and low-income countries was undertaken to narrow the need assessment for cardiac surgery including rheumatic and lifestyle cardiac diseases as well as congenital heart disease on the basis of existing data deduction. Actual levels of cardiac surgery were determined in each of these countries on the basis of questionnaires, national databases, or annual reports of national societies. Need estimates range from 200 operations per million in low-income countries that are nonendemic for rheumatic heart disease to >1,000 operations per million in high-income countries representing the end of the epidemiological transition. Actually provided levels of cardiac surgery range from 0.5 per million in the assessed low- and lower-middle income countries (average 107 +/- 113 per million; representing a population of 1.6 billion) to 500 in the upper-middle-income countries (average 270 +/- 163 per million representing a population of 1.9 billion). By combining need estimates with the assessment of de facto provided levels of cardiac surgery, it emerged that a significant degree of underdelivery of often lifesaving open heart surgery does not only prevail in low-income countries but is also disturbingly high in middle-income countries.

 

Celebrating 50 years of heart transplant surgery: A missed opportunity to honour Hamilton Naki
P Zilla, J Brink and T Pennel
S Afr Med J (2018) 108(4): 12270
10.7196/SAMJ.2017.v108i4.13242

Reply to Mankahla N, Dlamini S, Taunyane IC, Maqungo S, Cairncross L, Chiliza B. Celebrating 50 years of heart transplant surgery: A missed opportunity to honour Hamilton Naki. S Afr Med J 2018;108(3):151. https://doi.org/10.7196/SAMJ.2018.v108i3.13114.

 

The Cape Town Declaration on Access to Cardiac Surgery in the Developing World
P Zilla, RM Bolman, MH Yacoub, F Beyersdorf, K Sliwa, L Zuhlke, RSD Higgins, B Mayosi, A Carpentier and D Williams
Ann Thorac Surg (2018) 106(3): 930-933
10.1016/j.athoracsur.2018.05.020

 

The Cape Town Declaration on access to cardiac surgery in the developing world
P Zilla, RM Bolman, MH Yacoub, F Beyersdorf, K Sliwa, L Zuhlke, RSD Higgins, B Mayosi, A Carpentier and D Williams
J Thorac Cardiovasc Surg (2018) 156(6): 2206-2209
10.1016/j.jtcvs.2018.06.002

 

The Cape Town declaration on access to cardiac surgery in the developing world
P Zilla, RM Bolman, MH Yacoub, F Beyersdorf, K Sliwa, L Zuhlke, RSD Higgins, B Mayosi, A Carpentier and D Williams
Eur J Cardiothorac Surg (2018) 54(3): 407-410
10.1093/ejcts/ezy272

 

The Cape Town Declaration on Access to Cardiac Surgery in the Developing World
P Zilla, RM Bolman, MH Yacoub, F Beyersdorf, K Sliwa, L Zuhlke, RSD Higgins, B Mayosi, A Carpentier and D Williams
S Afr Med J (2018) 108(9): 702-704
10.7196/SAMJ.2018.v108i9.13102

Twelve years after cardiologists and cardiac surgeons from all over the world issued the 'Drakensberg Declaration on the Control of Rheumatic Fever and Rheumatic Heart Disease in Africa', calling on the world community to address the prevention and treatment of rheumatic heart disease (RHD) through improving living conditions, to develop pilot programmes at selected sites for control of rheumatic fever and RHD, and to periodically review progress made and challenges that remain, RHD still accounts for a major proportion of cardiovascular diseases in children and young adults in low- and middle-income countries, where more than 80% of the world population live. Globally equal in prevalence to human immunodeficiency virus infection, RHD affects 33 million people worldwide. Prevention efforts have been important but have failed to eradicate the disease. At the present time, the only effective treatment for symptomatic RHD is open heart surgery, yet that life-saving cardiac surgery is woefully absent in many endemic regions. In this declaration, we propose a framework structure to create a co-ordinated and transparent international alliance to address this inequality.

 

The Cape Town Declaration on Access to Cardiac Surgery in the Developing World
P Zilla, RM Bolman, MH Yacoub, F Beyersdorf, K Sliwa, L Zuhlke, RS Higgins, BM Mayosi, A Carpentier and D Williams
Cardiovasc J Afr (2018) 29(4): 256-259
10.5830/CVJA-2018-046

to urge all relevant entities within the international cardiac surgery, industry and government sectors to commit to develop and implement an effective strategy to address the scourge of rheumatic heart disease in the developing world through increased access to life-saving cardiac surgery.

 

The Cape Town Declaration on Access to Cardiac Surgery in the Developing World
P Zilla, RM Bolman, MH Yacoub, F Beyersdorf, K Sliwa, L Zuhlke, RS Higgins, B Mayosi, A Carpentier and D Williams
Asian Cardiovasc Thorac Ann (2018) 26(7): 535-539
10.1177/0218492318791359

 

Fifty Years: Reflections Since the First Successful Heart Transplant
JLC Swanevelder, PC Gordon, JG Brink, JT Gutsche, RA Dyer and JG Augoustides
J Cardiothorac Vasc Anesth (2018) 32(1): 14-18
10.1053/j.jvca.2017.10.028

 

Momentum builds for a global response to rheumatic heart disease
K Sliwa, A White, P Milan, A Olga Mocumbi, P Zilla and D Wood
Eur Heart J (2018) 39(48): 4229-4232
10.1093/eurheartj/ehy763

 

Transcatheter valve with a hollow balloon for aortic valve insufficiency
J Scherman, B van Breda, H Appa, C Heerden, C Ofoegbu, D Bezuidenhout and P Zilla
Multimed Man Cardiothorac Surg (2018) 2018(10.1510/mmcts.2018.012

During the past decade transcatheter aortic valve implantation (TAVI) has revolutionized our approach to heart valve disease. Although largely applied to patients with calcific aortic valve stenosis, there is an unmet clinical need to also treat patients with aortic valve insufficiency in patients with non-calcific aortic valve disorders. The following Techno-College tutorial demonstrates our pre-clinical experience with a novel non-occlusive, self-homing TAVI system, developed with Strait Access Technologies, that we hope will improve outcomes for treatment of non-calcific aortic valve insufficiency.

 

Pedunculated aortic thrombus propagating from the right coronary artery in a patient with IgA nephropathy
J Scherman, N da Silva, A Myburgh and T Pennel
Eur Heart J (2018) 39(34): 3000
10.1093/eurheartj/ehy282

 

Investigating the Role of Interventricular Interdependence in Development of Right Heart Dysfunction During LVAD Support: A Patient-Specific Methods-Based Approach
KL Sack, Y Dabiri, T Franz, SD Solomon, D Burkhoff and JM Guccione
Front Physiol (2018) 9(520
10.3389/fphys.2018.00520

Predictive computation models offer the potential to uncover the mechanisms of treatments whose actions cannot be easily determined by experimental or imaging techniques. This is particularly relevant for investigating left ventricular mechanical assistance, a therapy for end-stage heart failure, which is increasingly used as more than just a bridge-to-transplant therapy. The high incidence of right ventricular failure following left ventricular assistance reflects an undesired consequence of treatment, which has been hypothesized to be related to the mechanical interdependence between the two ventricles. To investigate the implication of this interdependence specifically in the setting of left ventricular assistance device (LVAD) support, we introduce a patient-specific finite-element model of dilated chronic heart failure. The model geometry and material parameters were calibrated using patient-specific clinical data, producing a mechanical surrogate of the failing in vivo heart that models its dynamic strain and stress throughout the cardiac cycle. The model of the heart was coupled to lumped-parameter circulatory systems to simulate realistic ventricular loading conditions. Finally, the impact of ventricular assistance was investigated by incorporating a pump with pressure-flow characteristics of an LVAD (HeartMate II operating between 8 and 12 k RPM) in parallel to the left ventricle. This allowed us to investigate the mechanical impact of acute left ventricular assistance at multiple operating-speeds on right ventricular mechanics and septal wall motion. Our findings show that left ventricular assistance reduces myofiber stress in the left ventricle and, to a lesser extent, right ventricle free wall, while increasing leftward septal-shift with increased operating-speeds. These effects were achieved with secondary, potentially negative effects on the interventricular septum which showed that support from LVADs, introduces unnatural bending of the septum and with it, increased localized stress regions. Left ventricular assistance unloads the left ventricle significantly and shifts the right ventricular pressure-volume-loop toward larger volumes and higher pressures; a consequence of left-to-right ventricular interactions and a leftward septal shift. The methods and results described in the present study are a meaningful advancement of computational efforts to investigate heart-failure therapies in silico and illustrate the potential of computational models to aid understanding of complex mechanical and hemodynamic effects of new therapies.

 

Transmural capillary ingrowth is essential for confluent vascular graft healing
T Pennel, D Bezuidenhout, J Koehne, NH Davies and P Zilla
Acta Biomater (2018) 65(237-247
10.1016/j.actbio.2017.10.038

Spontaneous endothelialization of synthetic vascular grafts may occur via three independent or concurrent modalities: transanastomotic (TA) outgrowth, transmural (TM) ingrowth or fallout (FO) from the blood. The limited TA and FO endothelialization, which occurs in humans, results in poor long-term patency in the small diameter position, where TM ingrowth may offer a clinically relevant alternative. To achieve sequential analysis of each mode of healing, loop grafts comprising anastomotically isolated angiopermissive polyurethane control grafts were abluminally sealed using either ePTFE wraps or solid polyurethane skins and implanted in the rat infrarenal aortic loop model for twelve weeks. Positive control grafts showed improved endothelialization and patency compared to the abluminally isolated mid-grafts. Furthermore, the mid-graft healing was accelerated with surface heparin and heparin-growth factor (VEGF, PDGF) modification in a three-week sub-study. We are thus able to distinguish between the three vascular graft endothelialization modes, and conclude that fallout plays a secondary role to TM healing. The increased endothelialisation for growth factor presenting grafts indicates the promise of this simple approach but further optimization is required. STATEMENT OF SIGNIFICANCE: In addition to the full elucidation of, and differentiation between, the three healing/endothelialisation modes of vascular grafts, the significance of the work relates to the near-complete lack of endothelialisation of small diameter vascular grafts in humans (1-2 cm transanastomotic outgrowth on a graft that may be 60 cm long) even after decades of implantation. The concomitant retained midgraft thrombogenicity leads, together with anastomotic hyperplastic responses, to poor long-term outcomes. The large impact of successful translation of the current research to the achievement of full endothelialisation of long peripheral grafts in humans via transmural ingrowth (half a millimetre distance; thickness of the graft wall), is evident, and supported by the large improvements in clinical patencies achievable in by pre-seeding of ePTFE grafts with confluent endothelia.

 

Long term outcome and EuroSCORE II validation in native valve surgery for active infective endocarditis in a South African cohort
JJ Koshy, ME Engel, H Carrara, J Brink and P Zilla
South African Heart Journal (2018) 15(2): 116-126
https://doi.org/10.24170/15-2-3045

Objectives: To evaluate the major risk factors for adverse short and long term outcomes in patients with active native valve infective endocarditis needing cardiac surgery and to validate the EuroSCORE II in our cohort of patients.

 

 

 

Methods: We retrospectively studied 149 patients who underwent native valve surgery for infective endocarditis in June 2000 - May 2011 at our referral centre. Ninety-six patients met the inclusion criteria for the study: 29 aortic valve replacements (AVR), 27 mitral valve replacements (MVR), 28 aortic/mitral (double) valve replacements (DVR) and 12 mitral valve repairs (MV Repair).

 

 

 

Results: Mechanical valves were implanted in 68 patients (70.8%), bioprosthetic valves in 16 (16.7%) and mitral annuloplasty rings in 12 (12.5%). The Cox proportional hazard model showed that the most important risk factors for early 30-day mortality were: critical preoperative state, emergency surgery, EuroSCORE II >12%, low cardiac output state (LCOS), HIV positive status, preoperative embolic episodes, vegetation size >1cm and postoperative ventilation >24 hours. The EuroSCORE II underestimated early mortality for the entire cohort. The discriminatory ability was evaluated with the receiver operating characteristic (ROC) curve with an area under the curve of 0.796. The discriminatory ability in the subgroup analysis showed that the AUROC curve was poorer for MVR (0.696), 0.837 for DVR and better for AVR group (0.92).

 

 

 

Conclusions: The EuroSCORE II underestimated mortality in the highest risk groups and overestimated mortality in the lowest risk groups. The discriminatory ability and model fit were evaluated to be good and a EuroSCORE II >12% predicted a signifi cantly higher early and medium term mortality.

 

Challenges to paediatric cardiac services in South Africa
J Hewitson and P Zilla
Lancet Child Adolesc Health (2018) 2(8): e15
10.1016/S2352-4642(18)30185-8

 

The palaeoecological context of the Oldowan-Acheulean in southern Africa
M Ecker, JS Brink, L Rossouw, M Chazan, LK Horwitz and JA Lee-Thorp
Nat Ecol Evol (2018) 2(7): 1080-1086
10.1038/s41559-018-0560-0

The influence of climatic and environmental change on human evolution in the Pleistocene epoch is understood largely from extensive East African stable isotope records. These records show increasing proportions of C(4) plants in the Early Pleistocene. We know far less about the expansion of C(4) grasses at higher latitudes, which were also occupied by early Homo but are more marginal for C(4) plants. Here we show that both C(3) and C(4) grasses and prolonged wetlands remained major components of Early Pleistocene environments in the central interior of southern Africa, based on enamel stable carbon and oxygen isotope data and associated faunal abundance and phytolith evidence from the site of Wonderwerk Cave. Vegetation contexts associated with Oldowan and early Acheulean lithic industries, in which climate is driven by an interplay of regional rainfall seasonality together with global CO(2) levels, develop along a regional distinct trajectory compared to eastern South Africa and East Africa.

 

Drug-Penetration Gradients Associated with Acquired Drug Resistance in Patients with Tuberculosis
K Dheda, L Lenders, G Magombedze, S Srivastava, P Raj, E Arning, P Ashcraft, T Bottiglieri, H Wainwright, T Pennel, A Linegar, L Moodley, A Pooran, JG Pasipanodya, FA Sirgel, PD van Helden, E Wakeland, RM Warren and T Gumbo
Am J Respir Crit Care Med (2018) 198(9): 1208-1219
10.1164/rccm.201711-2333OC

RATIONALE: Acquired resistance is an important driver of multidrug-resistant tuberculosis (TB), even with good treatment adherence. However, exactly what initiates the resistance and how it arises remain poorly understood. OBJECTIVES: To identify the relationship between drug concentrations and drug susceptibility readouts (minimum inhibitory concentrations [MICs]) in the TB cavity. METHODS: We recruited patients with medically incurable TB who were undergoing therapeutic lung resection while on treatment with a cocktail of second-line anti-TB drugs. On the day of surgery, antibiotic concentrations were measured in the blood and at seven prespecified biopsy sites within each cavity. Mycobacterium tuberculosis was grown from each biopsy site, MICs of each drug identified, and whole-genome sequencing performed. Spearman correlation coefficients between drug concentration and MIC were calculated. MEASUREMENTS AND MAIN RESULTS: Fourteen patients treated for a median of 13 months (range, 5-31 mo) were recruited. MICs and drug resistance-associated single-nucleotide variants differed between the different geospatial locations within each cavity, and with pretreatment and serial sputum isolates, consistent with ongoing acquisition of resistance. However, pretreatment sputum MIC had an accuracy of only 49.48% in predicting cavitary MICs. There were large concentration-distance gradients for each antibiotic. The location-specific concentrations inversely correlated with MICs (P < 0.05) and therefore acquired resistance. Moreover, pharmacokinetic/pharmacodynamic exposures known to amplify drug-resistant subpopulations were encountered in all positions. CONCLUSIONS: These data inform interventional strategies relevant to drug delivery, dosing, and diagnostics to prevent the development of acquired resistance. The role of high intracavitary penetration as a biomarker of antibiotic efficacy, when assessing new regimens, requires clarification.

 

Sinus of Valsalva-right atrial tunnel causing heart failure in a 38-year-old
SL Dellis, T Pennel, Q Said-Hartley and P Zilla
J Thorac Cardiovasc Surg (2018) 155(1): e51-e53
10.1016/j.jtcvs.2017.06.005

 

Surgical management and outcomes of 12 cases of Wilms tumour with intracardiac extension from a single centre
SG Cox, A Davidson, J Thomas, A Brooks, J Hewitson, A Numanoglu and AJW Millar
Pediatr Surg Int (2018) 34(2): 227-235
10.1007/s00383-017-4197-x

PURPOSE: To review demographics, effect of preoperative chemotherapy on tumour thrombus, imaging, operative strategy, and outcomes of 12 patients presenting with intracardiac extension of Wilms tumour thrombus. METHODS: A retrospective audit was undertaken on patients with intracardiac extension of Wilms tumour. Patients were identified from the oncology database and information obtained on clinical presentation, stage, preoperative treatment, surgical procedures and complications, histology, and survival status. Ethics approval was obtained from the University of Cape Town Human Research Ethics Committee. RESULTS: From 1984 to 2016, 337 children with Wilms tumour were treated. Twelve (3.6%) had intracardiac extension of tumour thrombus, nine into the right atrium, and three into the right ventricle. Ultrasound, computerized tomography, magnetic resonance imaging, and echocardiograms were used to assess thrombus level. Patients were staged as stage III(8) and IV(4). All patients received preoperative chemotherapy. Thrombus retracted from the heart in two cases. One patient died preoperatively. Eleven underwent laparotomy, median sternotomy, and cardiopulmonary bypass (CPB). Four underwent cavectomy. Five required cavoatrial patches. Thrombus extending into the hepatic veins was extracted in five patients. There was one intraoperative complication and one perioperative death. Thrombus histology showed viable tumour in 9 of 11 patients. Three patients died of progressive disease. Seven patients are currently disease free. CONCLUSION: A combination of imaging is required to determine thrombus extent, and this facilitates surgical planning. Preoperative chemotherapy may cause thrombus regression, thus avoiding CPB. CPB offers appropriate conditions for safe tumour thrombus excision. Full management in centres with appropriately experienced staff and facilities for CPB is recommended.

 

Synthetic extracellular matrix mimic hydrogel improves efficacy of mesenchymal stromal cell therapy for ischemic cardiomyopathy
MC Ciuffreda, G Malpasso, C Chokoza, D Bezuidenhout, KP Goetsch, M Mura, F Pisano, NH Davies and M Gnecchi
Acta Biomater (2018) 70(71-83
10.1016/j.actbio.2018.01.005

BACKGROUND: Mesenchymal stromal cells (MSC) repair infarcted hearts mainly through paracrine mechanisms. Low cell engraftment limits the release of soluble paracrine factors (SF) over time and, consequently, MSC efficacy. We tested whether a synthetic extracellular matrix mimic, a hydrogel containing heparin (H-HG), could ameliorate MSC engraftment and binding/release of SF, thus improving MSC therapy efficacy. METHODS AND RESULTS: In vitro, rat bone-marrow MSC (rBM-MSC) were seeded and grown into H-HG. Under normoxia, the hydrogel did not affect cell survival (rBM-MSC survival >90% at each time point tested); vice versa, under hypoxia the biomaterial resulted to be protective for the cells (p < .001 vs rBM-MSC alone). H-HG or control PEG hydrogels (HG) were incubated with VEGF or bFGF for binding/release quantification. Data showed significantly higher amount of VEGF and bFGF bound by H-HG compared with HG (p < .05) and a constant release over time. In vivo, myocardial infarction (MI) was induced in female Sprague Dawley rats by permanent coronary ligation. One week later, saline, rBM-MSC, H-HG or rBM-MSC/H-HG were injected in the infarct zone. The co-injection of rBM-MSC/H-HG into infarcted hearts significantly increased cardiac function. Importantly, we observed a significant gain in MSC engraftment, reduction of ventricular remodeling and stimulation of neo-vasculogenesis. We also documented higher amounts of several pro-angiogenic factors in hearts treated with rBM-MSC/H-HG. CONCLUSIONS: Our data show that H-HG increases MSC engraftment, efficiently fine tunes the paracrine MSC actions and improves cardiac function in infarcted rat hearts. STATEMENT OF SIGNIFICANCE: Transplantation of MSC is a promising treatment for ischemic heart disease, but low cell engraftment has so far limited its efficacy. The enzymatically degradable H-HG that we developed is able to increase MSC retention/engraftment and, at the same time, to fine-tune the paracrine effects mediated by the cells. Most importantly, the co-transplantation of MSC and H-HG in a rat model of ischemic cardiomyopathy improved heart function through a significant reduction in ventricular remodeling/scarring and amelioration in neo-vasculogenesis/endogenous cardiac regeneration. These beneficial effects are comparable to those obtained by others using a much greater number of cells, strengthening the efficacy of the biomaterial used in increasing the therapeutic effects of MSC. Given its efficacy and safety, documented by the absence of immunoreaction, our strategy appears readily translatable to clinical scenarios.

 

Lung transplantation in South Africa: Indications, outcomes and disease-specific referral guidelines
GL Calligaro, J Brink, P Williams, A Geldenhuys, M Sussman and T Pennel
Afr J Thorac Crit Care Med (2018) 24(3): 10.7196/SARJ.2018.v24i3.217

Lung transplantation (LT) is a robust therapy for advanced lung disease, which offers recipients extended and good-quality survival. In South Africa (SA), patients have historically had limited access to this therapy, particularly if unfunded. LT has been used as a successful therapeutic intervention for a wide variety of end-stage pulmonary parenchymal and vascular diseases, but the most common diseases that lead to LT are chronic obstructive pulmonary disease, interstitial lung disease, cystic fibrosis, alpha-1-antitrypsin deficiency and pulmonary arterial hypertension. Timing of referral for LT can be challenging and is disease specific, influenced by the rate of progression of the disease, the development of associated comorbidities, and access and response to advanced therapies. Advances in recipient and donor selection, surgical technique and postoperative management have improved early survival, but mortality remains higher than for other solid organ transplants. Rejection and infection remain major causes of early posttransplant death, while chronic rejection is the major cause of death after the first year. Survival is heavily influenced by the underlying lung disease. In this review, we summarise the indications and contraindications for LT, remind pulmonologists of the availability of this therapy in SA and offer guidelines for the timely referral of suitable candidates.

 

Group A Streptococcus, Acute Rheumatic Fever and Rheumatic Heart Disease: Epidemiology and Clinical Considerations
LJ Zuhlke, A Beaton, ME Engel, CT Hugo-Hamman, G Karthikeyan, JM Katzenellenbogen, N Ntusi, AP Ralph, A Saxena, PR Smeesters, D Watkins, P Zilla and J Carapetis
Curr Treat Options Cardiovasc Med (2017) 19(2): 15
10.1007/s11936-017-0513-y

Early recognition of group A streptococcal pharyngitis and appropriate management with benzathine penicillin using local clinical prediction rules together with validated rapi-strep testing when available should be incorporated in primary health care. A directed approach to the differential diagnosis of acute rheumatic fever now includes the concept of low-risk versus medium-to-high risk populations. Initiation of secondary prophylaxis and the establishment of early medium to long-term care plans is a key aspect of the management of ARF. It is a requirement to identify high-risk individuals with RHD such as those with heart failure, pregnant women, and those with severe disease and multiple valve involvement. As penicillin is the mainstay of primary and secondary prevention, further research into penicillin supply chains, alternate preparations and modes of delivery is required.

 

Rapidly Recoverable Thixotropic Hydrogels from the Racemate of Chiral OFm Monosubstituted Cyclo(Glu-Glu) Derivatives
L Wang, X Jin, L Ye, AY Zhang, D Bezuidenhout and ZG Feng
Langmuir (2017) 33(48): 13821-13827
10.1021/acs.langmuir.7b03527

Both chiral OFm monosubstituted cyclo(l-Glu-l-Glu) and cyclo(d-Glu-d-Glu) display a robust gelation ability in a variety of organic solvents and water. In contrast to an individual enantiomer, their racemate can form rapidly recoverable thixotropic hydrogels with a remarkably shorter thixotropic recovery time. This unexpected thixotropic behavior is induced by the random arrangement of d- and l-enantiomers in the cell units, leading to the formation of "pseudoracemate", noncrystalline self-assemblies in the resulting 3D fibrous network.

 

Dual electrospinning with sacrificial fibers for engineered porosity and enhancement of tissue ingrowth
J Voorneveld, A Oosthuysen, T Franz, P Zilla and D Bezuidenhout
J Biomed Mater Res B Appl Biomater (2017) 105(6): 1559-1572
10.1002/jbm.b.33695

Porosity, pore size and pore interconnectivity are critical factors for cellular infiltration into electrospun scaffolds. This study utilized dual electrospinning with sacrificial fiber extraction to produce scaffolds with engineered porosity and mechanical properties. Subsequently, scaffolds were covalently grafted with heparin, a known anti-coagulant with growth-factor binding properties. We hypothesized that the tissue ingrowth would correlate positively with the porosity of the scaffolds. Pellethane(R) (PU) was spun simultaneously with poly(ethylene oxide) (PEO, subsequently extracted). Low, medium and high porosity scaffolds and heparinized versions of each were characterized and implanted in vivo for evaluation of cellular infiltration and inflammation subcutaneously in male Wistar rats (7,14 and 28 days, n = 6). Average pore-size for low (76 +/- 0.2%), medium (83 +/- 0.5%) and high (90 +/- 1.0%) porosity scaffolds was 4.0 +/- 2.3 microm, 9.9 +/- 4.2 microm and 11.1 +/- 5.5 microm (p < 0.0001). Heparinization resulted in increased fiber diameter (3.6 +/- 1.1 microm vs. 1.8 +/- 0.8 microm, p < 0.0001) but influenced neither pore-size (p = 0.67) nor porosity (p = 0.27). Cellular infiltration for low, medium and high porosity scaffolds reached 33 +/- 7%, 77 +/- 20% and 98 +/- 1% of scaffold width, respectively, by day 28 of implantation (p < 0001); heparinization did not affect infiltration (p = 0.89). The ultimate tensile strength (UTS) and Young's modulus (E(y) ) of the constructs increased linearly with increasing PU fiber fraction (UTS: r(2) = 0.97, p < 0.0001, E(y) : r(2) = 0.76, p < 0.0001) and heparinization resulted in decreased strength but increased stiffness compared to non-heparinized scaffolds. Increased PEO to PU fraction in the scaffold resulted in predictable losses to mechanical strength and improvements to cellular infiltration, which could make PEO to PU fraction a useful optimization parameter for small diameter vascular grafts. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1559-1572, 2017.

 

50th Anniversary of the first Human Heart Transplant-How is it seen today?
K Sliwa and P Zilla
Eur Heart J (2017) 38(46): 3402-3404
10.1093/eurheartj/ehx695

 

TAVI for low to middle income countries
J Scherman, D Bezuidenhhout, C Ofoegbu, DF Williams and P Zilla
European Heart Journal (2017) 38(16): 1182–1184
https://doi.org/10.1093/eurheartj/ehx169

 

Point-of-care testing improves diabetes management in a primary care clinic in South Africa
LA Motta, MDS Shephard, J Brink, S Lawson and P Rheeder
Prim Care Diabetes (2017) 11(3): 248-253
10.1016/j.pcd.2016.09.008

INTRODUCTION: Diabetes is a major health problem in South Africa. DiabCare Africa found just 47% of diabetes patients had a hemoglobin A1c (HbA1c) test for their management in the previous year. METHODS: Patients attending an urban diabetes clinic near Johannesburg, run by Project HOPE, accessed HbA1c (and urine albumin:creatinine ratio) point-of-care testing (POCT) as part of a quality-assured international program called ACE (Analytical and Clinical Excellence). Patients who had two or more HbA1c POC tests from 2012 to 2014 were assessed to determine their change in glycaemic control. RESULTS: The mean (+/-SD) HbA1c in this group of diabetes patients (n=131) fell significantly from 9.7%+/-2.4 (83mmol/mol) at their first POCT measurement to 8.4%+/-2.4 (68mmol/mmol/mol) at their most recent POCT measurement (paired t-test p<0.01). The average time between first and most recent HbA1c test was 15 months. The number of diabetes patients achieving optimal glycaemic control (HbA1c</=6.5-7.5% [48-58mmol/mol) increased by 125%, while the number with very poor glycaemic control (HbA1c>10% [86mmol/mol]) halved. An association was observed between degree of glycaemic control and increasing albuminuria in this cohort. DISCUSSION: POCT has promoted change in clinical practice by facilitating greater accessibility to HbA1c testing.

 

High heparin content surface-modified polyurethane discs promote rapid and stable angiogenesis in full thickness skin defects through VEGF immobilization
M McLuckie, CA Schmidt, A Oosthuysen, N Sanchez-Macedo, H Merker, D Bezuidenhout, SP Hoerstrup and N Lindenblatt
J Biomed Mater Res A (2017) 105(9): 2543-2550
10.1002/jbm.a.36108

Three-dimensional scaffolds have the capacity to serve as an architectural framework to guide and promote tissue regeneration. Parameters such as the type of material, growth factors, and pore dimensions are therefore critical in the scaffold's success. In this study, heparin has been covalently bound to the surface of macroporous polyurethane (PU) discs via two different loading methods to determine if the amount of heparin content had an influence on the therapeutic affinity loading and release of (VEGF(165) ) in full thickness skin defects. PU discs (5.4 mm diameter, 300 microm thickness, and interconnected pore size of 150 microm) were produced with either a low (2.5 mg/g) or high (6.6 mg/g) heparin content (LC and HC respectively), and were implanted into the modified dorsal skin chamber (MDSC) of C57BL/6 J mice with and without VEGF. Both low- and high-content discs with immobilized VEGF(165) (LCV and HCV, respectively) presented accelerated neovascularization and tissue repair in comparison to heparin discs alone. However, the highest angiogenetic peak was on day 7 with subsequent stabilization for HCV, whereas other groups displayed a delayed peak on day 14. We therefore attribute the superior performance of HCV due to its ability to hold more VEGF(165,) based on its increased heparin surface coverage, as also demonstrated in VEGF elution dynamics. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2543-2550, 2017.

 

Improved vascularization of porous scaffolds through growth factor delivery from heparinized polyethylene glycol hydrogels
A Janse van Rensburg, NH Davies, A Oosthuysen, C Chokoza, P Zilla and D Bezuidenhout
Acta Biomater (2017) 49(89-100
10.1016/j.actbio.2016.11.036

Surface modification with heparin has previously been shown to increase vascularization of porous scaffolds. In order to determine its efficacy with sustained release, heparin (Hep) was covalently incorporated into degradable (Type D) and non-degradable (Type N) polyethylene glycol (PEG) hydrogels. After in vitro characterization of their physicochemical properties, growth factor (GF) loaded, heparinised Type D gels were formed within the pores of porous polyurethane disks, which were then implanted and evaluated in a subcutaneous model. Type N gels formed faster (3.1+/-0.1 vs. 7.2+/-0.2min), were stiffer (10.0+/-0.5kPa vs. 7.1+/-1.2kPa) and more stable than degradable gels (>6month stability vs. disintegration ⩽22d in vitro; all p<0.001). Sustained release of covalently incorporated (CI) heparin from Type N (56days; first order kinetics) and Type D (21days; zero order kinetics) was achieved, as opposed to non-covalently incorporated (NI) heparin that eluted in a burst release within the first 2days. While Type D gels initially impeded tissue ingrowth into the porous scaffolds, they were completely degraded and replaced by ingrown tissue after 28days in vivo. At the latter timepoint disks containing gels without Hep or with non-covalently incorporated Hep were less vascularized than empty (no gel) controls. In contrast, the incorporation of covalently heparinized (no GF) and GF containing gels (no Hep) resulted in a 50% and 42% (p<0.05) improvement in vascularization, while an increase of 119% (p<0.001) was achieved with a combination of covalently attached Hep and GF. These gels thus provide a sustained release system for heparin and GF that extends the duration of their action to local tissue ingrowth. STATEMENT OF SIGNIFICANCE: The paper describes the modification and covalent incorporation of heparin into degradable and non-degradable polyethylene glycol hydrogels in a way that provides for the hydrolytic cleavage of the linker for the release of the heparin in original and active form, and in an extended (21-56d) controlled (zero and first order respectively) manner. The successful use of these gels as growth-factor containing and releasing matrices for the improvement of in vivo vascularization holds promise for many potential uses in tissue engineering and regenerative medicine applications, such as vascular grafts and myocardial infarction therapy, where the antithrombotic and/or growth factor binding/potentiating properties are required.

 

The Neglected Villain of Bioprosthetic Degeneration: Inflammatory and Immune Processes
P Human and P Zilla
J Long Term Eff Med Implants (2017) 27(2-4): 159-180
10.1615/JLongTermEffMedImplants.v27.i2-4.50

In an attempt to avoid the destructive process of bioprosthetic heart-valve calcification associated with the use of glutaraldehyde, valves are today prepared using low concentrations of the crosslinking reagent. In this review, we summarize our findings and those of others that confirm that the immunogenicity of such tissue is not sufficiently masked and that a defined humoral response is indeed mounted against a repertoire of antigens unrelated to those associated with vascularized and non—cross-linked xenograft organs. We demonstrate the need for increased cross-linking of tissue to satisfactorily mitigate that response; furthermore, we examine the impact of increased cross-link density on the macrophage as antigen presenting cell with respect to its involvement in both tissue erosion and pannus overgrowth. Finally we present evidence for a role of circulating antibodies in bioprosthesis calcification.

 

Status and Challenges of Care in Africa for Adults With Congenital Heart Defects
F Edwin, L Zuhlke, H Farouk, AO Mocumbi, K Entsua-Mensah, D Delsol-Gyan, F Bode-Thomas, A Brooks, B Cupido, M Tettey, E Aniteye, MM Tamatey, KB Gyan, JCT Tchoumi and MA Elgamal
World J Pediatr Congenit Heart Surg (2017) 8(4): 495-501
10.1177/2150135117706340

The 54 countries in Africa have an estimated total annual congenital heart defect (CHD) birth prevalence of 300,486 cases. More than half (51.4%) of the continental birth prevalence occurs in only seven countries. Congenital heart disease remains primarily a pediatric health issue in Africa because of the deficient health-care systems: the adults with CHD made up just 10% of patients with CHD in Ghana, and 13.7% of patients with CHD presenting for surgery in Mozambique. With Africa's population projected to double in the next 35 years, the already deficient health systems for CHD care will suffer unbearable strain unless determined and courageous action is undertaken by the African leaders.

 

The world's first human-to-human heart transplant at Groote Schuur Hospital: 50 years later
J Brink, T Pennel, K Seele and P Zilla
S Afr Med J (2017) 107(12): 1035-1036
10.7196/SAMJ.2017.v107i12.12960

 

Cellular mechanosensitivity to substrate stiffness decreases with increasing dissimilarity to cell stiffness
T Abdalrahman, L Dubuis, J Green, N Davies and T Franz
Biomech Model Mechanobiol (2017) 16(6): 2063-2075
10.1007/s10237-017-0938-y

Computational modelling has received increasing attention to investigate multi-scale coupled problems in micro-heterogeneous biological structures such as cells. In the current study, we investigated for a single cell the effects of (1) different cell-substrate attachment (2) and different substrate modulus [Formula: see text] on intracellular deformations. A fibroblast was geometrically reconstructed from confocal micrographs. Finite element models of the cell on a planar substrate were developed. Intracellular deformations due to substrate stretch of [Formula: see text], were assessed for: (1) cell-substrate attachment implemented as full basal contact (FC) and 124 focal adhesions (FA), respectively, and [Formula: see text]140 KPa and (2) [Formula: see text], 140, 1000, and 10,000 KPa, respectively, and FA attachment. The largest strains in cytosol, nucleus and cell membrane were higher for FC (1.35[Formula: see text], 0.235[Formula: see text] and 0.6[Formula: see text]) than for FA attachment (0.0952[Formula: see text], 0.0472[Formula: see text] and 0.05[Formula: see text]). For increasing [Formula: see text], the largest maximum principal strain was 4.4[Formula: see text], 5[Formula: see text], 5.3[Formula: see text] and 5.3[Formula: see text] in the membrane, 9.5[Formula: see text], 1.1[Formula: see text], 1.2[Formula: see text] and 1.2[Formula: see text] in the cytosol, and 4.5[Formula: see text], 5.3[Formula: see text], 5.7[Formula: see text] and 5.7[Formula: see text] in the nucleus. The results show (1) the importance of representing FA in cell models and (2) higher cellular mechanical sensitivity for substrate stiffness changes in the range of cell stiffness. The latter indicates that matching substrate stiffness to cell stiffness, and moderate variation of the former is very effective for controlled variation of cell deformation. The developed methodology is useful for parametric studies on cellular mechanics to obtain quantitative data of subcellular strains and stresses that cannot easily be measured experimentally.

 

Excessive volume of hydrogel injectates may compromise the efficacy for the treatment of acute myocardial infarction
P Wise, NH Davies, MS Sirry, J Kortsmit, L Dubuis, CK Chai, FP Baaijens and T Franz
Int J Numer Method Biomed Eng (2016) 32(12): 10.1002/cnm.2772

Biomaterial injectates are promising as a therapy for myocardial infarction to inhibit the adverse ventricular remodeling. The current study explored interrelated effects of injectate volume and infarct size on treatment efficacy. A finite element model of a rat heart was utilized to represent ischemic infarcts of 10%, 20%, and 38% of left ventricular wall volume and polyethylene glycol hydrogel injectates of 25%, 50%, and 75% of the infarct volume. Ejection fraction was 49.7% in the healthy left ventricle and 44.9%, 46.4%, 47.4%, and 47.3% in the untreated 10% infarct and treated with 25%, 50%, and 75% injectate, respectively. Maximum end-systolic infarct fiber stress was 41.6, 53.4, 44.7, 44.0, and 45.3 kPa in the healthy heart, the untreated 10% infarct, and when treated with the three injectate volumes, respectively. Treating the 10% and 38% infarcts with the 25% injectate volume reduced the maximum end-systolic fiber stress by 16.3% and 34.7% and the associated strain by 30.2% and 9.8%, respectively. The results indicate the existence of a threshold for injectate volume above which efficacy does not further increase but may decrease. The efficacy of an injectate in reducing infarct stress and strain changes with infarct size. Copyright (c) 2016 John Wiley & Sons, Ltd.

 

Cast Tube Assay: A 3-D in vitro assay for visualization and quantification of horizontal chemotaxis and cellular invasion
BC Whitehead, D Bezuidenhout, C Chokoza, NH Davies and KP Goetsch
Biotechniques (2016) 61(2): 66-72
10.2144/000114442

Directed cell motility, as controlled by soluble factors, is crucial for many biological processes, including development, cancer progression, and wound healing. The use of directed cell motility also shows promise for applications in regenerative medicine such as therapeutic angiogenesis. Unfortunately, current in vitro 3-D migration and invasion models limit our understanding and application of these processes. Here, we present a novel and cost-effective 3-D chemotaxis assay for assessing the invasive response of cells to a chemoattractant extracellular matrix (ECM). Our system takes advantage of a custom-casting chamber to set two gels in contact with each other along a defined front, one containing a suitable chemoattractant and the other the cells. Rotation of the chamber allows easy visualization of invasion across the interface. The effectiveness of the assay was demonstrated by studying the invasion of both human dermal fibroblasts (FBs) and smooth muscle cells (SMCs) into a polyethylene glycol (PEG) hydrogel containing basic fibroblast growth factor (bFGF). Incorporation of bFGF resulted in significantly increased and directional invasion for both cell groups.

 

Characterisation of the mechanical properties of infarcted myocardium in the rat under biaxial tension and uniaxial compression
MS Sirry, JR Butler, SS Patnaik, B Brazile, R Bertucci, A Claude, R McLaughlin, NH Davies, J Liao and T Franz
J Mech Behav Biomed Mater (2016) 63(252-264
10.1016/j.jmbbm.2016.06.029

Understanding the passive mechanical properties of infarcted tissue at different healing stages is essential to explore the emerging biomaterial injection-based therapy for myocardial infarction (MI). Although rats have been widely used as animal models in such investigations, the data in literature that quantify the passive mechanical properties of rat heart infarcts is very limited. MI was induced in rats and hearts were harvested immediately (0 day), 7, 14 and 28 days after infarction onset. Left ventricle anterioapical samples were cut and underwent equibiaxial and non equibiaxial tension followed by uniaxial compression mechanical tests. Histological analysis was conducted to confirm MI and to quantify the size of the induced infarcts. Infarcts maintained anisotropy and the nonlinear biaxial and compressive mechanical behaviour throughout the healing phases with the circumferential direction being stiffer than the longitudinal direction. Mechanical coupling was observed between the two axes in all infarct groups. The 0, 7, 14 and 28 days infarcts showed 438, 693, 1048 and 1218kPa circumferential tensile moduli. The 28 day infarct group showed a significantly higher compressive modulus compared to the other infarct groups (p=0.0060, 0.0293, and 0.0268 for 0, 7 and 14 days groups). Collagen fibres were found to align in a preferred direction for all infarct groups supporting the observed mechanical anisotropy. The presented data are useful for developing material models for healing infarcts and for setting a baseline for future assessment of emerging mechanical-based MI therapies.

 

Infarcted rat myocardium: Data from biaxial tensile and uniaxial compressive testing and analysis of collagen fibre orientation
MS Sirry, JR Butler, SS Patnaik, B Brazile, R Bertucci, A Claude, R McLaughlin, NH Davies, J Liao and T Franz
Data Brief (2016) 8(1338-43
10.1016/j.dib.2016.08.005

Myocardial infarction was experimentally induced in rat hearts and harvested immediately, 7, 14 and 28 days after the infarction induction. Anterior wall infarct samples underwent biaxial tensile and uniaxial compressive testing. Orientation of collagen fibres was analysed following mechanical testing. In this paper, we present the tensile and compressive stress-strain raw data, the calculated tensile and compressive moduli and the measured angles of collagen orientation. The presented data is associated with the research article titled "Characterisation of the mechanical properties of infarcted myocardium in the rat under biaxial tension and uniaxial compression" (Sirry et al., 2016) [1].

 

SASCI/SCTSSA joint consensus statement and guidelines on transcatheter aortic valve implantation (TAVI) in South Africa
J Scherman and H Weich
Cardiovasc J Afr (2016) 27(6): 399-400
10.5830/CVJA-2016-092

 

Personalised computational cardiology: Patient-specific modelling in cardiac mechanics and biomaterial injection therapies for myocardial infarction
KL Sack, NH Davies, JM Guccione and T Franz
Heart Fail Rev (2016) 21(6): 815-826
10.1007/s10741-016-9528-9

Predictive computational modelling in biomedical research offers the potential to integrate diverse data, uncover biological mechanisms that are not easily accessible through experimental methods and expose gaps in knowledge requiring further research. Recent developments in computing and diagnostic technologies have initiated the advancement of computational models in terms of complexity and specificity. Consequently, computational modelling can increasingly be utilised as enabling and complementing modality in the clinic-with medical decisions and interventions being personalised. Myocardial infarction and heart failure are amongst the leading causes of death globally despite optimal modern treatment. The development of novel MI therapies is challenging and may be greatly facilitated through predictive modelling. Here, we review the advances in patient-specific modelling of cardiac mechanics, distinguishing specificity in cardiac geometry, myofibre architecture and mechanical tissue properties. Thereafter, the focus narrows to the mechanics of the infarcted heart and treatment of myocardial infarction with particular attention on intramyocardial biomaterial delivery.

 

Partial LVAD restores ventricular outputs and normalizes LV but not RV stress distributions in the acutely failing heart in silico
KL Sack, B Baillargeon, G Acevedo-Bolton, M Genet, N Rebelo, E Kuhl, L Klein, GM Weiselthaler, D Burkhoff, T Franz and JM Guccione
Int J Artif Organs (2016) 39(8): 421-430
10.5301/ijao.5000520

PURPOSE: Heart failure is a worldwide epidemic that is unlikely to change as the population ages and life expectancy increases. We sought to detail significant recent improvements to the Dassault Systemes Living Heart Model (LHM) and use the LHM to compute left ventricular (LV) and right ventricular (RV) myofiber stress distributions under the following 4 conditions: (1) normal cardiac function; (2) acute left heart failure (ALHF); (3) ALHF treated using an LV assist device (LVAD) flow rate of 2 L/min; and (4) ALHF treated using an LVAD flow rate of 4.5 L/min. METHODS AND RESULTS: Incorporating improved systolic myocardial material properties in the LHM resulted in its ability to simulate the Frank-Starling law of the heart. We decreased myocardial contractility in the LV myocardium so that LV ejection fraction decreased from 56% to 28%. This caused mean LV end diastolic (ED) stress to increase to 508% of normal, mean LV end systolic (ES) stress to increase to 113% of normal, mean RV ED stress to decrease to 94% of normal and RV ES to increase to 570% of normal. When ALHF in the model was treated with an LVAD flow rate of 4.5 L/min, most stress results normalized. Mean LV ED stress became 85% of normal, mean LV ES stress became 109% of normal and mean RV ED stress became 95% of normal. However, mean RV ES stress improved less dramatically (to 342% of normal values). CONCLUSIONS: These simulations strongly suggest that an LVAD is effective in normalizing LV stresses but not RV stresses that become elevated as a result of ALHF.

 

The effect of positioning and diaphragmatic breathing exercises on respiratory muscle activity in people with chronic obstructive pulmonary disease
B Morrow, J Brink, S Grace, L Pritchard and A Lupton-Smith
S Afr J Physiother (2016) 72(1): 315
10.4102/sajp.v72i1.315

BACKGROUND: Body positioning and diaphragmatic breathing may alter respiratory pattern and reduce dyspnoea in people with chronic obstructive pulmonary disease (COPD). OBJECTIVES: To determine the effect of positioning and diaphragmatic breathing on respiratory muscle activity in a convenience sample of people with COPD, using surface electromyography (sEMG). METHODS: This prospective descriptive study recorded sEMG measurements at baseline, after upright positioning, during diaphragmatic breathing and 5 minutes thereafter. Vital signs and levels of perceived dyspnoea were recorded at baseline and at the end of the study. Data were analysed using repeated measures ANOVAs with post hoc t-tests for dependent and independent variables. RESULTS: Eighteen participants (13 male; mean +/- standard deviation age 59.0 +/- 7.9 years) were enrolled. Total diaphragmatic activity did not change with repositioning (p = 0.2), but activity increased from 7.3 +/- 4.2 microV at baseline to 10.0 +/- 3.3 microV during diaphragmatic breathing (p = 0.006) with a subsequent reduction from baseline to 6.1 +/- 3.5 microV (p = 0.007) at the final measurement. There was no change in intercostal muscle activity at different time points (p = 0.8). No adverse events occurred. Nutritional status significantly affected diaphragmatic activity (p = 0.004), with participants with normal body mass index (BMI) showing the greatest response to both positioning and diaphragmatic breathing. There were no significant changes in vital signs, except for a reduction in systolic/diastolic blood pressure from 139.6 +/- 18.7/80.4 +/- 13.0 to 126.0 +/- 15.1/75.2 +/- 14.7 (p < 0.05). CONCLUSION: A single session of diaphragmatic breathing transiently improved diaphragmatic muscle activity, with no associated reduction in dyspnoea.

 

The anisotropic mechanical behaviour of electro-spun biodegradable polymer scaffolds: Experimental characterisation and constitutive formulation
G Limbert, R Omar, H Krynauw, D Bezuidenhout and T Franz
J Mech Behav Biomed Mater (2016) 53(21-39
10.1016/j.jmbbm.2015.07.014

Electro-spun biodegradable polymer fibrous structures exhibit anisotropic mechanical properties dependent on the degree of fibre alignment. Degradation and mechanical anisotropy need to be captured in a constitutive formulation when computational modelling is used in the development and design optimisation of such scaffolds. Biodegradable polyester-urethane scaffolds were electro-spun and underwent uniaxial tensile testing in and transverse to the direction of predominant fibre alignment before and after in vitro degradation of up to 28 days. A microstructurally-based transversely isotropic hyperelastic continuum constitutive formulation was developed and its parameters were identified from the experimental stress-strain data of the scaffolds at various stages of degradation. During scaffold degradation, maximum stress and strain in circumferential direction decreased from 1.02 +/- 0.23 MPa to 0.38 +/- 0.004 MPa and from 46 +/- 11 % to 12 +/- 2 %, respectively. In longitudinal direction, maximum stress and strain decreased from 0.071 +/- 0.016 MPa to 0.010 +/- 0.007 MPa and from 69 +/- 24 % to 8 +/- 2 %, respectively. The constitutive parameters were identified for both directions of the non-degraded and degraded scaffold for strain range varying between 0% and 16% with coefficients of determination r(2)>0.871. The six-parameter constitutive formulation proved versatile enough to capture the varying non-linear transversely isotropic behaviour of the fibrous scaffold throughout various stages of degradation.

 

Chest pain on exertion after the Takeuchi repair of anomalous origin of the left coronary artery: right ventricular ischemia due to severe pulmonary outflow tract obstruction
P van der Bijl, A Doruyter, R de Decker, J Lawrenson, G Comitis and J Hewitson
World J Pediatr Congenit Heart Surg (2015) 6(1): 90-2
10.1177/2150135114544756

Right ventricular (RV) outflow obstruction (in the form of valvar or supravalvular pulmonary stenosis) is a well-known complication of the Takeuchi procedure. We describe a 13-year-old male with exertional chest pain, pulmonary stenosis, RV hypertrophy, and consequent RV ischemia, which was confirmed using stress echocardiography and single-photon emission tomography.

 

Management of valvular disease in pregnancy: a global perspective
K Sliwa, MR Johnson, P Zilla and JW Roos-Hesselink
Eur Heart J (2015) 36(18): 1078-89
10.1093/eurheartj/ehv050

Valvular heart disease (VHD) in pregnant women, whether due to congenital or acquired aetiologies, poses a challenge to clinicians and their patients. Significant valve disease, which can affect a single valve or several valves, increases the risk of pregnancy to the mother and foetus and requires a careful preconception risk assessment and, subsequently during pregnancy, specialized care to minimize maternal and foetal morbidity and mortality. The goal of this paper is to provide a guide to risk assessment and to give an overview of the optimal cardiac and obstetric management, including surgical intervention, taking into consideration the resources available in higher and lower-to-middle income countries. This manuscript provides a practical approach and is not replacing comprehensive guidelines on the management of VHD or cardiovascular disease in pregnancy. It focuses on common valvular diseases and does not cover the large variety of aortic disease with and without valve disease or complex congenital heart disease in detail.

 

Micro-structurally detailed model of a therapeutic hydrogel injectate in a rat biventricular cardiac geometry for computational simulations
MS Sirry, NH Davies, K Kadner, L Dubuis, MG Saleh, EM Meintjes, BS Spottiswoode, P Zilla and T Franz
Comput Methods Biomech Biomed Engin (2015) 18(3): 325-31
10.1080/10255842.2013.793765

Biomaterial injection-based therapies have showed cautious success in restoration of cardiac function and prevention of adverse remodelling into heart failure after myocardial infarction (MI). However, the underlying mechanisms are not well understood. Computational studies utilised simplified representations of the therapeutic myocardial injectates. Wistar rats underwent experimental infarction followed by immediate injection of polyethylene glycol hydrogel in the infarct region. Hearts were explanted, cryo-sectioned and the region with the injectate histologically analysed. Histological micrographs were used to reconstruct the dispersed hydrogel injectate. Cardiac magnetic resonance imaging data from a healthy rat were used to obtain an end-diastolic biventricular geometry which was subsequently adjusted and combined with the injectate model. The computational geometry of the injectate exhibited microscopic structural details found the in situ. The combination of injectate and cardiac geometry provides realistic geometries for multiscale computational studies of intra-myocardial injectate therapies for the rat model that has been widely used for MI research.

 

Pharmacodynamic effects of C-domain-specific ACE inhibitors on the renin-angiotensin system in myocardial infarcted rats
S Sharp, M Poglitsch, P Zilla, NH Davies and ED Sturrock
J Renin Angiotensin Aldosterone Syst (2015) 16(4): 1149-58
10.1177/1470320314568438

INTRODUCTION: The renin-angiotensin system (RAS) is a dynamic network that plays a critical role in blood pressure regulation and fluid and electrolyte homeostasis. Modulators of the RAS, such as angiotensin-converting enzyme (ACE) inhibitors, are widely used to treat hypertension, heart failure and myocardial infarction. METHODS: The effect of ACE inhibitors (lisinopril and C-domain-selective LisW-S) on the constituent peptides of the RAS following myocardial infarction was examined in rats. Ten angiotensin peptides were analysed using a sensitive LC-MS/MS-based assay to examine both the circulating and equilibrium levels of these peptides. RESULTS: Administration of lisinopril or LisW-S caused a significant decrease in Ang 1-8/Ang 1-10 ratios as determined by circulating and equilibrium peptide level analysis. Furthermore, Ang 1-7 levels were elevated by both ACE inhibitors, but only lisinopril decreased the Ang 1-5/Ang 1-7 ratio. This indicates LisW-S C-domain specificity as Ang 1-5 is generated by hydrolysis of Ang 1-7 by the N-domain. Further corroboration of LisW-S C-domain specificity is that only lisinopril increased the circulating levels of the N-domain ACE substrate Ac-SDKP. CONCLUSION: LisW-S is able to effectively block ACE in vivo by C-domain-selective inhibition. The LC-MS/MS-based assay allows the evaluation of the pharmacologic impact of RAS inhibitors in different pathophysiological conditions.

 

A Compartmentalized Profibrotic Immune Response Characterizes Pericardial Tuberculosis, Irrespective of HIV-1 Infection
K Matthews, A Deffur, M Ntsekhe, F Syed, JB Russell, K Tibazarwa, J Wolske, J Brink, BM Mayosi, RJ Wilkinson and KA Wilkinson
Am J Respir Crit Care Med (2015) 192(12): 1518-21
10.1164/rccm.201504-0683LE

 

Coacervate Delivery of Growth Factors Combined with a Degradable Hydrogel Preserves Heart Function after Myocardial Infarction
NR Johnson, M Kruger, KP Goetsch, P Zilla, D Bezuidenhout, Y Wang and NH Davies
ACS Biomater Sci Eng (2015) 1(9): 753-759
10.1021/acsbiomaterials.5b00077

Regenerative therapies to improve prognosis after heart attack and mitigate the onset of heart failure are urgently needed. To this end, we developed a bioactive therapy of sustained release of the morphogen Sonic hedgehog (Shh) and the anti-inflammatory cytokine interleukin-10 (IL-10) from a coacervate delivery vehicle. This is combined with a structural therapy consisting of a biodegradable polyethylene glycol (PEG) hydrogel, harnessing the benefits of both components. Upon injection into the hearts of rats after heart attack, we found that each component synergistically improved the benefit of the other. Furthermore, their combination was critical to preserve heart function. These findings indicate that, when combined, growth factor delivery and an injectable hydrogel represent a promising therapeutic approach for treatment after heart attack.

 

Assessment of the immunogenicity of mechanically induced interferon aggregates in a transgenic mouse model
P Human, H Ilsley, C Roberson, E Grovender, B Van Antwerp, E Fogt and P Zilla
J Pharm Sci (2015) 104(2): 722-30
10.1002/jps.24292

Pump delivery of human interferon alpha-2B (IFNalpha2b) has the potential for inducing immunogenic drug aggregates. We therefore evaluated the immunogenicity of mechanically induced IFNalpha2b aggregates to assess this risk. Transgenic human-IFNalpha2b (TG) and wild-type (WT) FVB/N mice (n = 8 and n = 9/group, respectively) were administered mechanically agitated drug [45 Hz for 6 h (LLA) or 24 h (HLA)], chemically modified drug [low pH (pH 4.0) or metal oxidized (OXD)] or unstressed drug (native). Mice received IFNalpha2b (50 mug; 100 mug/mL; s.c.) formulations on days 0, 7, 14, and 21. Drug-binding and neutralizing antibody titers were determined after 28 d. Aggregate concentrations were highest in OXD and HLA formulations but OXD had more dimers/trimers. Geometric mean titers were 1:131, 1:728, 1:1573, 1:871, and 1:10,240 for WT mice (n = 9) and 1:207, 1:587, 1:1810, 1:571, and 1:2,153 for TG mice (n = 8) for native, LLA, HLA, pH4, and OXD groups, respectively. Mechanical agitation of IFNalpha2b induced equivalent titers of immunoglobulin to that of metal oxidation, both capable of binding to or neutralizing the drug in WT and TG mice. Thus, by limiting metal contamination and by inclusion of a stabilizing agent to mitigate drug aggregation, the risk of anti-drug immunoglobulin may be reduced in a pump delivery scenario.

 

Regulation of tissue ingrowth into proteolytically degradable hydrogels
KP Goetsch, M Bracher, D Bezuidenhout, P Zilla and NH Davies
Acta Biomater (2015) 24(44-52
10.1016/j.actbio.2015.06.009

Regulation of the rate of cell ingrowth into and within a matrix is desirable for efficient tissue regeneration. Polyethylene glycol hydrogels crosslinked with matrix metalloproteinase (MMP) susceptible peptide sequences permit cell-controlled invasion. In this study, hydrogels of the same stiffness polymerised using different ratios of a readily degradable MMP peptide sequence (PAN-MMP) and a MMP peptide with a limited degradation capacity (MMP-9) were assessed both in vitro and in vivo for cellular invasion. The degree of invasion into the various hydrogels was found to be tightly linked to the relative proportion of each peptide both in vitro and in vivo. Furthermore a good correlation between in vitro and in vivo ingrowth was observed. These findings demonstrate a highly tunable model for regulating cellular invasion which is readily translatable to in vivo models. This finding may allow for further optimisation of aspects of regenerative scaffolds such as tissue invasion, growth factor release and cellular encapsulation. STATEMENT OF SIGNIFICANCE: Degradable hydrogels are used in a wide range of tissue regeneration approaches. A particularly advantageous variant of these hydrogels is where due to peptide based crosslinking of the polymeric hydrogels, cell invasion rate is dependent on cellular enzymatic activity. This present study demonstrates a further refinement whereby both cellular and tissue invasion rates are finely regulated through the polymerisation of a hydrogel with varying combinations of enzymatically degradable peptides. Importantly this allows for invasion rates to be controlled without altering the biomechanical properties of the hydrogel such as stiffness. The latter can further influence cellular behaviour thus potentially interfering with the desired outcome.

 

Orbital resonances around black holes
J Brink, M Geyer and T Hinderer
Phys Rev Lett (2015) 114(8): 081102
10.1103/PhysRevLett.114.081102

We compute the length and time scales associated with resonant orbits around Kerr black holes for all orbital and spin parameters. Resonance-induced effects are potentially observable when the Event Horizon Telescope resolves the inner structure of Sgr A*, when space-based gravitational wave detectors record phase shifts in the waveform during the resonant passage of a compact object spiraling into the black hole, or in the frequencies of quasiperiodic oscillations for accreting black holes. The onset of geodesic chaos for non-Kerr spacetimes should occur at the resonance locations quantified here.

 

Polymeric heart valves for surgical implantation, catheter-based technologies and heart assist devices
D Bezuidenhout, DF Williams and P Zilla
Biomaterials (2015) 36(6-25
10.1016/j.biomaterials.2014.09.013

Efficient function and long-term durability without the need for anticoagulation, coupled with the ability to be accommodated in many different types of patient, are the principal requirements of replacement heart valves. Although the clinical use of valves appeared to have remained steady for several decades, the evolving demands for the elderly and frail patients typically encountered in the developed world, and the needs of much younger and poorer rheumatic heart disease patients in the developing world have now necessitated new paradigms for heart valve technologies and associated materials. This includes further consideration of durable elastomeric materials. The use of polymers to produce flexible leaflet valves that have the benefits of current commercial bioprosthetic and mechanical valves without any of their deficiencies has been held desirable since the mid 1950s. Much attention has been focused on thermoplastic polyurethanes in view of their generally good physico-chemical properties and versatility in processing, coupled with the improving biocompatibility and stability of recent formulations. Accelerated in vitro durability of between 600 and 1000 million cycles has been achieved using polycarbonate urethanes, and good resistance to degradation, calcification and thrombosis in vivo has been shown with some polysiloxane-based polyurethanes. Nevertheless, polymeric valves have remained relegated to use in temporary ventricular assist devices for bridging heart failure patients to transplantation. Some recent studies suggest that there is a greater degree of instability in thermoplastic materials than hitherto believed so that significant challenges remain in the search for the combination of durability and biocompatibility that would allow polymeric valves to become a clinical reality for surgical implantation. Perhaps more importantly, they could become candidates for use in situations where minimally invasive transcatheter procedures are used to replace diseased valves. Being amenable to relatively inexpensive mass production techniques, the attainment of this goal could benefit very large numbers of patients in developing and emerging countries who currently have no access to treatment for rheumatic heart disease that is so prevalent in these areas. This review discusses the evolution and current status of polymeric valves in wide-ranging circumstances.

 

A slow-release fibrin matrix increases adeno-associated virus transduction of wound repair cells in vivo
C Schmidt, D Bezuidenhout, P Zilla and NH Davies
J Biomater Appl (2014) 28(9): 1408-18
10.1177/0885328213510331

Virus-mediated gene therapy is a promising strategy for numerous tissue engineering applications. Fibrin-based scaffolds have been previously used as vehicles for localised delivery of adenovirus to wound sites. However, their utility in the delivery of adeno-associated viruses to wound repair cells has not yet been determined. The influence of fibrin concentration on efficacy of delivery of AAV-2 to wound tissue was assessed in this study. Fibrin scaffolds containing recombinant AAV-2 encoding for beta-galactosidase were polymerised in porous polyurethane discs and implanted subcutaneously in rats. A fibrin scaffold with a concentration of 50 mg/ml showed significantly elevated levels of beta-galactosidase activity within explanted discs at 10 days compared to 10 mg/ml and 25 mg/ml fibrin. These findings inform efforts to optimise biodegradable scaffolds for the localised delivery of AAV in tissue engineering.

 

Huge left-ventricular pseudoaneurysm compressing coronary artery 10 weeks after stabbing attack
J Scherman, TD Nguyen, P Zilla and MY Emmert
Eur Heart J (2014) 35(6): 385
10.1093/eurheartj/eht468

 

Massive hemoptysis 18 months after a stabbing attack
J Scherman, TD Linh Nguyen, P Zilla and MY Emmert
Ann Thorac Surg (2014) 98(2): 728
10.1016/j.athoracsur.2014.04.061

 

The performance of cross-linked acellular arterial scaffolds as vascular grafts; pre-clinical testing in direct and isolation loop circulatory models
T Pennel, G Fercana, D Bezuidenhout, A Simionescu, TH Chuang, P Zilla and D Simionescu
Biomaterials (2014) 35(24): 6311-22
10.1016/j.biomaterials.2014.04.062

There is a significant need for small diameter vascular grafts to be used in peripheral vascular surgery; however autologous grafts are not always available, synthetic grafts perform poorly and allografts and xenografts degenerate, dilate and calcify after implantation. We hypothesized that chemical stabilization of acellular xenogenic arteries would generate off-the-shelf grafts resistant to thrombosis, dilatation and calcification. To test this hypothesis, we decellularized porcine renal arteries, stabilized elastin with penta-galloyl glucose and collagen with carbodiimide/activated heparin and implanted them as transposition grafts in the abdominal aorta of rats as direct implants and separately as indirect, isolation-loop implants. All implants resulted in high patency and animal survival rates, ubiquitous encapsulation within a vascularized collagenous capsule, and exhibited lack of lumen thrombogenicity and no graft wall calcification. Peri-anastomotic neo-intimal tissue overgrowth was a normal occurrence in direct implants; however this reaction was circumvented in indirect implants. Notably, implantation of non-treated control scaffolds exhibited marked graft dilatation and elastin degeneration; however PGG significantly reduced elastin degradation and prevented aneurismal dilatation of vascular grafts. Overall these results point to the outstanding potential of crosslinked arterial scaffolds as small diameter vascular grafts.

 

Nitric oxide release from polydimethylsiloxane-based polyurethanes
EB Nguyen, P Zilla and D Bezuidenhout
J Appl Biomater Funct Mater (2014) 12(3): 172-82
10.5301/jabfm.5000192

Localized nitric oxide (NO) release from polymeric materials holds much promise for the prevention of coagulation often associated with implantable and extracorporeal blood-contacting devices. Films of polyurethane (PU) containing incorporated polyethyleneimine were thus exposed to NO gas to form diazeniumdiolates (NONOates) in situ. Donor incorporation and NO gas exposure did not affect the mechanical properties of the films. The NO release capacity increased with increasing polydimethylsiloxane (PDMS) content in the soft segment of the PU: total capacity could be more than doubled (P<0.05) from 0.093 +/- 0.028 to 0.225 +/- 0.004 mmol/g when the PDMS content was increased from 0 to 100%. Release kinetics were best approximated using a modified Korsemeyer-Peppas power law (R2=0.95-0.99). Despite the resultant rapid initial decrease in NO release rates, values above that observed for quiescent endothelial cells (0.83 pmol.cm(-2).s(-1)) were maintained for extended periods of 5-10 days, while rates above that of a stimulated endothelium (2.7-6.8 pmol.cm(-2).s(-1)) were achieved for the first 24 hours. This method of NONOate formation may be advantageous, as potential premature NO release by exposure of diazeniumdiolated donors during incorporation, processing and storage, can be avoided by in situ diazoniumdiolation closer to the time of implantation.

 

Constrictive pericarditis requiring pericardiectomy at Groote Schuur Hospital, Cape Town, South Africa: causes and perioperative outcomes in the HIV era (1990-2012)
AK Mutyaba, S Balkaran, R Cloete, N du Plessis, M Badri, J Brink and BM Mayosi
J Thorac Cardiovasc Surg (2014) 148(6): 3058-65 e1
10.1016/j.jtcvs.2014.07.065

OBJECTIVE: The causes of constrictive pericarditis and predictors of perioperative outcome after pericardiectomy have not been clearly elucidated, especially in Africa, where the disease characteristics differ from those in developed countries. Furthermore, the effect of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) on pericardial constriction and outcomes after surgery is unknown. We investigated the causes of constrictive pericarditis, outcomes after pericardiectomy, and predictors of mortality in Cape Town, South Africa, during a 22-year period of high HIV/AIDS prevalence. METHODS: A retrospective review of the medical records of all patients who had undergone pericardiectomy for constrictive pericarditis at Groote Schuur Hospital from January 1, 1990 to December 31, 2012 was performed. RESULTS: Of 121 patients, 36 (29.8%) had proven tuberculosis, 74 (61.2%) had presumed tuberculosis, 6 (5%) had idiopathic causes, and 5 (4%) had miscellaneous causes of constrictive pericarditis. Seventeen patients (14%) died perioperatively with low cardiac output syndrome the main cause of mortality. On multivariable analysis, serum sodium (hazard ratio, 0.88; 95% confidence interval, 0.80-0.97; P = .009) and preoperative New York Heart Association class IV (hazard ratio, 3.42; 95% confidence interval, 1.29-9.08; P = .014; vs combined class I-III) were independent predictors of early mortality. Of the 121 patients, 14 (11.6%) were HIV positive, with a mean CD4 cell count of 284 +/- 133 cells/muL. No early deaths occurred in the HIV-positive patients. CONCLUSIONS: Tuberculosis is the main cause of constrictive pericarditis in South Africa. Despite its efficacy at relieving the symptoms of heart failure, pericardiectomy is associated with high perioperative mortality that was not influenced by HIV status. New York Heart Association functional class IV and hyponatremia predict for early mortality after pericardiectomy.

 

Computational predictions of improved of wall mechanics and function of the infarcted left ventricle at early and late remodelling stages: comparison of layered and bulk hydrogel injectates
J Kortsmit, NH Davies, R Miller, P Zilla and T Franz
Advances in Biomechanics & Applications (2014) 1(1): 41-55
Acellular intra-myocardial biomaterial injections have been shown to be therapeutically beneficial in inhibiting ventricular remodelling of myocardial infarction (MI). Based on a biventricular canine cardiac geometry, various finite element models were developed that comprised an ischemic (II) or scarred infarct (SDI) in left ventricular (LV) antero-apical region, without and with intra-myocardial biomaterial injectate in layered (L) and bulk (B) distribution. Changes in myocardial properties and LV geometry were implemented corresponding to infarct stage (tissue softening vs. stiffening, infarct thinning, and cavity dilation) and injectate (infarct thickening). The layered and bulk injectate increased ejection fraction of the infarcted LV by 77% (II+L) and 25% (II+B) at the ischemic stage and by 61% (SDI+L) and 63% (SDI+B) at the remodelling stage. The injectates decreased the mean end-systolic myofibre stress in the infarct by 99% (II+L), 97% (II+B), 70% (SDI+L) and 36% (SDI+B). The bulk injectate was slightly more effective in improving LV function at the remodelling stage whereas the layered injectate was superior in functional improvement at ischemic stage and in reduction of wall stress at ischemic and remodelling stage. These findings may stimulate and guide further research towards tailoring acellular biomaterial injectate therapies for MI.

 

Computational mechanics and electro-mechanics in cardiovascular physiology and disease
T Franz
Int J Numer Method Biomed Eng (2014) 30(6): 603-4
10.1002/cnm.2617

 

Does cell mechanics in adipogenesis offer new keys for the prevention and management of obesity?
T Franz
Biophys J (2014) 106(6): 1231-2
10.1016/j.bpj.2014.01.004

 

Pharmacokinetic evaluation of lisinopril-tryptophan, a novel C-domain ACE inhibitor
P Denti, SK Sharp, WL Kroger, SL Schwager, A Mahajan, M Njoroge, L Gibhard, I Smit, K Chibale, L Wiesner, ED Sturrock and NH Davies
Eur J Pharm Sci (2014) 56(113-9
10.1016/j.ejps.2014.01.012

Angiotensin-converting enzyme (ACE, EC 3.4.15.1) is a metallopeptidase comprised of two homologous catalytic domains (N- and C-domains). The C-domain cleaves the vasoactive angiotensin II precursor, angiotensin I, more efficiently than the N-domain. Thus, C-domain-selective ACE inhibitors have been designed to investigate the pharmacological effects of blocking the C-terminal catalytic site of the enzyme and improve the side effect profile of current ACE inhibitors. Lisinopril-tryptophan (LisW-S), an analogue of the ACE inhibitor lisinopril, is highly selective for the C-domain. In this study, we have analysed the ex vivo domain selectivity and pharmacokinetic profile of LisW-S. The IC50 value of LisW-S was 38.5 nM in rat plasma using the fluorogenic substrate Abz-FRKP(Dnp)P-OH. For the pharmacokinetics analysis of LisW-S, a sensitive and selective LC-MS/MS method was developed and validated to determine the concentration of LisW-S in rat plasma. LisW-S was administered to Wistar rats at a dose of 1 mg/kg bodyweight intravenously, 5 mg/kg bodyweight orally. The Cmax obtained following oral administration of the drug was 0.082 muM and LisW-S had an apparent terminal elimination half-life of around 3.1 h. The pharmacokinetic data indicate that the oral bioavailability of LisW-S was approximately 5.4%. These data provide a basis for better understanding the absorption mechanism of LisW-S and evaluating its clinical application.

 

Systemic-pulmonary artery shunts in infants: modified Blalock-Taussig and central shunt procedures
A Brooks
Multimed Man Cardiothorac Surg (2014) 2014(10.1093/mmcts/mmu007

Access is gained through a midline sternotomy, the thymus partially excised and the superior part of the pericardium is opened. The innominate vein is retracted and the innominate artery is mobilized up to the bifurcation. The aorta is retracted to the left, the superior vena cavae to the right and the right atrial appendage inferiorly. The adventitia around the right pulmonary artery (PA) is dissected, taking care to incise the bulky pericardial reflection between the superior vena cavae and the trachea. Heparin is administrated. An occlusive clamp is applied to the right PA to test for haemodynamic tolerance prior to proceeding with the interposition of a suitable size artificial vascular prosthesis, based on the weight of the patient, between the innominate artery, or proximal subclavian artery and the right PA. Alternatively, if a sufficient main PA is present and adequate flow from a patent ductus arteriosus an end-to-side interposition shunt may be constructed between the ascending aorta and the main PA, provided the patient is stable with the test occlusion of the main PA. The management of the patent arterial ductus depends on whether or not there is forward flow through the PA.

 

Off-the-shelf human decellularized tissue-engineered heart valves in a non-human primate model
B Weber, PE Dijkman, J Scherman, B Sanders, MY Emmert, J Grunenfelder, R Verbeek, M Bracher, M Black, T Franz, J Kortsmit, P Modregger, S Peter, M Stampanoni, J Robert, D Kehl, M van Doeselaar, M Schweiger, CE Brokopp, T Walchli, V Falk, P Zilla, A Driessen-Mol, FP Baaijens and SP Hoerstrup
Biomaterials (2013) 34(30): 7269-80
10.1016/j.biomaterials.2013.04.059

Heart valve tissue engineering based on decellularized xenogenic or allogenic starter matrices has shown promising first clinical results. However, the availability of healthy homologous donor valves is limited and xenogenic materials are associated with infectious and immunologic risks. To address such limitations, biodegradable synthetic materials have been successfully used for the creation of living autologous tissue-engineered heart valves (TEHVs) in vitro. Since these classical tissue engineering technologies necessitate substantial infrastructure and logistics, we recently introduced decellularized TEHVs (dTEHVs), based on biodegradable synthetic materials and vascular-derived cells, and successfully created a potential off-the-shelf starter matrix for guided tissue regeneration. Here, we investigate the host repopulation capacity of such dTEHVs in a non-human primate model with up to 8 weeks follow-up. After minimally invasive delivery into the orthotopic pulmonary position, dTEHVs revealed mobile and thin leaflets after 8 weeks of follow-up. Furthermore, mild-moderate valvular insufficiency and relative leaflet shortening were detected. However, in comparison to the decellularized human native heart valve control - representing currently used homografts - dTEHVs showed remarkable rapid cellular repopulation. Given this substantial in situ remodeling capacity, these results suggest that human cell-derived bioengineered decellularized materials represent a promising and clinically relevant starter matrix for heart valve tissue engineering. These biomaterials may ultimately overcome the limitations of currently used valve replacements by providing homologous, non-immunogenic, off-the-shelf replacement constructs.

 

Treatment of thoracic trauma in children: literature review, Red Cross War Memorial Children's Hospital data analysis, and guidelines for management
AB van As, R Manganyi and A Brooks
Eur J Pediatr Surg (2013) 23(6): 434-43
10.1055/s-0033-1363160

INTRODUCTION: Thoracic injuries continue to be a leading cause of childhood trauma, despite the government's efforts to curb the scourge of this problem. Our review focuses on the incidence, etiology, and management of thoracic trauma in the pediatric population with reference to the recent experience at our institution in a developing country. METHODS: For the literature review, the National Library of Medicine's PubMed database was searched for the following terms: "pediatric," "chest trauma," "hemothorax," "hemopneumothorax," "pneumothorax," "diaphragmatic," "esophageal," and "mediastinal injury." For the hospital data analysis, data of all 378 pediatric patients treated with thoracic injuries under the age of 13 years from 2008 to 2012 (a 5-year period), at the Red Cross War Memorial Children's Hospital, were retrospectively analyzed. RESULTS: The male to female ratio was 2.1:1 (255 males and 123 females). The mean age was 6.9 +/- 2.3 years. Blunt chest trauma was responsible for chest injuries in 90.5%, while penetrating trauma caused 9.5% of the injuries. Road traffic crashes were the mean cause (48.9%) with pedestrian injuries in 72.4% and passenger injuries in 27.6%, respectively. Sports injuries were the cause in 4% and falls from a height in 22%. Most injuries occurred at home: inside one's own home (5%), outside one's own home (52%); inside someone else's home (44%); outside someone else's home (2%). Public space injuries occurred at schools or creches in 77%, pavement or roads in 6%, and were not specified in 17%. Overall 74% presented with injuries of the thoracic cage; rib fractures occurred in 13%, chest wall contusions in 40%, and abrasions in 31%. Respiratory system injuries occurred in 22%; hemothoraces in 23%, pneumothoraces in 45%, and hemopneumothoraces in 29%. Cardiovascular injuries occurred in 16% of cases with vascular injuries in five patients (two firearms injuries and three motor vehicle crashes). Management was nonoperative in 79.4%, tube thoracotomy in 17.2%, and open surgery in 3.4%. The mortality rate was 1.3%, all contributed by firearm-related injuries and polytrauma. CONCLUSION: Thoracic trauma has remained a significant cause of morbidity and mortality in the pediatric population. Concerted effort from governments, civil societies, and the medical profession are needed to address this challenge.

 

Differentiating transmural from transanastomotic prosthetic graft endothelialization through an isolation loop-graft model
T Pennel, P Zilla and D Bezuidenhout
J Vasc Surg (2013) 58(4): 1053-61
10.1016/j.jvs.2012.11.093

BACKGROUND: In humans, transanastomotic endothelial outgrowth onto the surface of prosthetic vascular grafts is limited to the immediate perianastomotic region, even after years of implantation. In contrast, continual transanastomotic outgrowth together with short graft lengths has led to early endothelial confluence in most animal models pre-empting endothelialization through transmural capillary sprouting. We describe an isolation loop-graft model that clearly separates these distinctly different events. METHODS: Baseline transanastomotic endothelialization was assessed by implanting low-porosity expanded polytetrafluoroethylene grafts (ePTFE; internal diameter 1.7 mm; internodal distance 15-25 mum; 14.2 +/- 1.6 mm long) for 2, 4, and 6 weeks (n = 6/time point) in the abdominal aorta of Wistar rats. High-porosity polyurethane (internal diameter 1.7 mm-150 mum pore size) grafts were then interposed ("welded") into the midsection of the ePTFE grafts for 2, 4, 6, and 8 weeks (n = 6/time point). Looping the interposition grafts increased their length to 70.3 +/- 8.3 mm. After implantation periods of 6, 8, 12, and 24 weeks (n = 8/time point) isolation loop grafts were analyzed by light, immune-fluorescence (CD31) and scanning electron microscopy, and endothelialization was expressed as maximal transanastomotic endothelial outgrowth (I(max)), mean transanastomotic outgrowth (I(mean)), and segmental graft coverage (GSE). RESULTS: Transanastomotic outgrowth slowed down between 2 and 6 weeks of implantation (proximal: [I(max) from 0.9 +/- 0.5 to 0.3 +/- 0.3 mm/wk; P < .04; I(mean) from 0.3 +/- 0.1 to 0.2 +/- 0.1 mm/wk; nonsignificant (NS)]; distal: [I(max) from 0.7 +/- 0.3 to 0.3 +/- 0.2 mm/wk; P < .02; I(mean) from 0.3 +/- 0.2 to 0.2 +/- 0.0 mm/wk; NS]) but remained constant thereafter (I(max) = 0.5 +/- 0.2 mm/wk; I(mean) = 0.4 +/- 0.2 mm/wk at 24 weeks NS). In straight composite grafts, the ePTFE separation zones were too short to isolate transmural ingrowth beyond week 4. In contrast, a broad endothelial-free separation zone was preserved in all looped composite grafts even after half a year of implantation (25.9 +/- 5.9 vs 8.7 +/- 4.9 mm proximally and 21.9 +/- 13.4 vs 12.3 +/- 6.2 mm distally at 6 and 24 weeks, respectively). Ninety-three percent of patent loop-grafts showed isolated transmural midgraft endothelium after 4 weeks and 97% after 6 weeks. Midgraft preconfluence was reached by 6 weeks (GSE = 55 +/- 45%) and confluence between week 12 and 24 (GSE = 95.0 +/- 10.0% and 84.0 +/- 30.13%). The subintimal thickness stayed constant with a nonsignificant trend toward regression (91.8 +/- 93.9 mm vs 71.4 +/- 59.4 mm at 6 and 24 weeks, respectively; NS). CONCLUSIONS: Transmural endothelialization can be clearly distinguished from transanastomotic outgrowth in a high throughput rat model. A looped interposition graft model provides sufficient isolation length to separate the two events for up to half a year and does not result in an increase in intimal hyperplasia. CLINICAL RELEVANCE: Although the mode of graft deployment has changed over the years, the problem of an absent surface endothelium remains, whether small- to medium-diameter grafts are surgically implanted or placed endovascularly as "covered stents." In contrast to humans, most animal models experience progressive transanastomotic endothelial outgrowth. Together with graft lengths that were too short, the clinically irrelevant transanastomotic endothelialization inadvertently led to early endothelial confluence in the vast majority of experimental vascular graft studies pre-empting or concealing alternative modes of endothelialization. The isolation loop-graft model we propose allows the long-term differentiation of the different modes of endothelialization in a small animal screening model.

 

Protective constriction of coronary vein grafts with knitted nitinol
L Moodley, T Franz, P Human, MF Wolf, D Bezuidenhout, J Scherman and P Zilla
Eur J Cardiothorac Surg (2013) 44(1): 64-71
10.1093/ejcts/ezs670

OBJECTIVES: Different flow patterns and shear forces were shown to cause significantly more luminal narrowing and neointimal tissue proliferation in coronary than in infrainguinal vein grafts. As constrictive external mesh support of vein grafts led to the complete suppression of intimal hyperplasia (IH) in infrainguinal grafts, we investigated whether mesh constriction is equally effective in the coronary position. METHODS: Eighteen senescent Chacma baboons (28.8 +/- 3.6 kg) received aorto-coronary bypass grafts to the left anterior descending artery (LAD). Three groups of saphenous vein grafts were compared: untreated controls (CO); fibrin sealant-sprayed controls (CO + FS) and nitinol mesh-constricted grafts (ME + FS). Meshes consisted of pulse-compliant, knitted nitinol (eight needles; 50 mum wire thickness; 3.4 mm resting inner diameter, ID) spray attached to the vein grafts with FS. After 180 days of implantation, luminal dimensions and IH were analysed using post-explant angiography and macroscopic and histological image analysis. RESULTS: At implantation, the calibre mismatch between control grafts and the LAD expressed as cross-sectional quotient (Qc) was pronounced [Qc = 0.21 +/- 0.07 (CO) and 0.18 +/- 0.05 (CO + FS)]. Mesh constriction resulted in a 29 +/- 7% reduction of the outer diameter of the vein grafts from 5.23 +/- 0.51 to 3.68 +/- 0 mm, significantly reducing the calibre discrepancy to a Qc of 0.41 +/- 0.17 (P < 0.02). After 6 months of implantation, explant angiography showed distinct luminal irregularities in control grafts (ID difference between widest and narrowest segment 74 +/- 45%), while diameter variations were mild in mesh-constricted grafts. In all control grafts, thick neointimal tissue was present [600 +/- 63 mum (CO); 627 +/- 204 mum (CO + FS)] as opposed to thin, eccentric layers of 249 +/- 83 mum in mesh-constricted grafts (ME + FS; P < 0.002). The total wall thickness had increased by 363 +/- 39% (P < 0.00001) in CO and 312 +/- 61% (P < 0.00001) in CO + FS vs 82 +/- 61% in ME + FS (P < 0.007). CONCLUSIONS: In a senescent non-human primate model for coronary artery bypass grafts, constrictive, external mesh support of saphenous veins with knitted nitinol prevented focal, irregular graft narrowing and suppressed neointimal tissue proliferation by a factor of 2.5. The lower degree of suppression of IH compared with previous infrainguinal grafts coincided with a lesser reduction of calibre mismatch in the coronary grafts.

 

Outcomes of myocardial infarction hydrogel injection therapy in the human left ventricle dependent on injectate distribution
R Miller, NH Davies, J Kortsmit, P Zilla and T Franz
Int J Numer Method Biomed Eng (2013) 29(8): 870-84
10.1002/cnm.2551

Myocardial infarction therapies involving biomaterial injections have shown benefits in inhibiting progression towards heart failure. However, the underlying mechanisms remain unclear. A finite element model of the human left ventricle was developed from magnetic resonance images. An anteroapical infarct was represented at acute (AI) and fibrotic (FI) stage. Hydrogel injections in the infarct region were modelled with layered (L) and bulk (B) distribution. In the FI, injectates reduced end-systolic myofibre stresses from 291.6% to 117.6% (FI-L) and 115.3% (FI-B) of the healthy value, whereas all AI models exhibited sub-healthy stress levels (AI: 90.9%, AI-L: 20.9%, AI-B: 30.5%). Reduction in end-diastolic infarct stress were less pronounced for both FI (FI: 294.1%, FI-L: 176.5%, FI-B: 188.2%) and AI (AI: 94.1%, AI-L: 35.3%, AI-B: 41.2%). In the border zone, injectates reduced end-systolic fibre stress by 8-10% and strain from positive (AI) and zero (FI) to negative. Layered and bulk injectates increased ejection fraction by 7.4% and 8.4% in AI and 14.1% and 13.7% in FI. The layered injectate had a greater impact on infarct stress and strain at acute stage, whereas the bulk injectate exhibited greater benefits at FI stage. These findings were confirmed by our previous in vivo results.

 

The effect of hydrogel injection on cardiac function and myocardial mechanics in a computational post-infarction model
J Kortsmit, NH Davies, R Miller, JR Macadangdang, P Zilla and T Franz
Comput Methods Biomech Biomed Engin (2013) 16(11): 1185-95
10.1080/10255842.2012.656611

An emerging therapy to limit adverse heart remodelling following myocardial infarction (MI) is the injection of polymers into the infarcted left ventricle (LV). In the few numerical studies carried out in this field, the definition and distribution of the hydrogel in the infarcted myocardium were simplified. In this computational study, a more realistic biomaterial distribution was simulated after which the effect on cardiac function and mechanics was studied. A validated finite element heart model was used in which an antero-apical infarct was defined. Four infarct models were created representing different temporal phases in the progression of a MI. Hydrogel layers were simulated in the infarcted myocardium in each model. Biomechanical and functional improvement of the LV was found after hydrogel inclusion in the ischaemic models representing the early phases of MI. In contrast, only functional but no mechanical restitution was shown in the scar model due to hydrogel presence.

 

Cell specific ingrowth hydrogels
M Bracher, D Bezuidenhout, MP Lutolf, T Franz, M Sun, P Zilla and NH Davies
Biomaterials (2013) 34(28): 6797-803
10.1016/j.biomaterials.2013.05.057

Extracellular mimetic hydrogels formed from peptide crosslinkers and polyethylene glycol monomers permit cell-controlled invasion. The use of matrix metalloproteinase specific peptides might further allow for selective control of different cell-type invasion. In this study, the invasion of fibroblasts and vascular smooth muscle cells (VSMC) into hydrogels polymerised with either a peptide generally permissive for matrix metalloproteinase (MMP) degradation or peptides preferentially cleaved by MMP-14 or MMP-9 enzymes were compared. The two cell-types invaded the MMP permissive hydrogel equally. However, invasion of VSMC into MMP-14 selective peptide crosslinked hydrogels was diametrically opposite in nature to that of fibroblasts whereby VSMC showed a two-fold increase into these hydrogels relative to that observed in permissive hydrogels whilst fibroblasts had a relative two-fold decrease (p < 0.01). These findings are suggestive that invasion and growth of different cell-types in engineered synthetic extracellular matrix mimics may be controlled selectively by the choice of protease specific peptide crosslinker and this could have general utility in tissue regenerative and engineering approaches.

 

Covalent incorporation and controlled release of active dexamethasone from injectable polyethylene glycol hydrogels
D Bezuidenhout, A Oosthuysen, N Davies, L Ahrenstedt, S Dobner, P Roberts and P Zilla
J Biomed Mater Res A (2013) 101(5): 1311-8
10.1002/jbm.a.34438

Dexamethasone (Dex) is used in a wide range of applications, but may have undesirable systemic side effects. A number of techniques have thus been developed to deliver the substance locally. In this study, dexamethasone was acrylated, pegylated, and tethered to hydrolytically degradable (acrylate based) and nondegradable (vinyl sulfone based) polyethylene glycol hydrogels by nucleophilic addition. Hydrogel swelling, drug elution and drug activity were followed over an extended period in vitro. Nondegradable gels were stable for more than a year, while degradable gels showed increasing swelling ratios due to degradation that resulted in disintegration after 
12 days. Near-linear (zero order) release could be achieved in some cases with the degradable gels, while release from the nondegradable gels approximated first order initial release kinetics. Significantly delayed release was observed in all cases where the Dex was linked to the gels, when compared with controls where the drug was merely physically incorporated. Eluates from the gels containing the tethered drug showed high levels of activity for extended time periods, while the activity of the eluates from gels containing nonbound dexamethasone decreased rapidly within the first few days. Dexamethasone can thus be incorporated using nucleophilic addition chemistry to produce gels that are capable of sustained release of the active drug. The methodology is applicable to a variety of drugs that contain hydroxyl groups.

 

Management of nine cases of Wilms' tumour with intracardiac extension - a single centre experience
Y Abdullah, J Karpelowsky, A Davidson, J Thomas, A Brooks, J Hewitson, A Numanoglu, S Cox and AJ Millar
J Pediatr Surg (2013) 48(2): 394-9
10.1016/j.jpedsurg.2012.11.024

AIM: The aim of this study was to review the management of children with Wilms' tumour who have intracardiac extension. PATIENTS AND METHODS: Data were collected from patient notes regarding presentation, operative details, and outcome. RESULTS: From 1984 through 2011, 264 children with Wilms' tumour were treated at our hospital. Nine (3.4%) had cavo-atrial extension of the tumour thrombus. The thrombus extended into the right ventricle in two children and involved the hepatic veins in both, and also two others. Pre-operative chemotherapy was administered in eight children with complete regression of the intra-cardiac tumour thrombus in two cases. One child died preoperatively of septicaemia and respiratory failure after two doses of chemotherapy. Six children with intra-cardiac tumour were operated on under cardiopulmonary bypass (CPB) with deep hypothermia and circulatory arrest (DHCA). The mean ischemic time was 30 min. There was one peri-operative death in a child with hepatic vein involvement and Budd-Chiari syndrome. All others made a good postoperative recovery. All tumours were favourable histology. To date four children are still alive and disease free. Three children have died as a result of pulmonary metastases. CONCLUSION: Intracardiac extension of Wilms' tumour is rare, and the management is technically challenging. Pre-operative chemotherapy is effective. CPB and DHCA for excision of the cavo-atrial tumour thrombus may be necessary. Distant metastatic disease is common and determines long term prognosis. Hepatic vein extension complicates surgery and remains challenging.

 

Remodeling leads to distinctly more intimal hyperplasia in coronary than in infrainguinal vein grafts
P Zilla, L Moodley, J Scherman, H Krynauw, J Kortsmit, P Human, MF Wolf and T Franz
J Vasc Surg (2012) 55(6): 1734-41
10.1016/j.jvs.2011.11.057

BACKGROUND: Flow patterns and shear forces in native coronary arteries are more protective against neointimal hyperplasia than those in femoral arteries. Yet, the caliber mismatch with their target arteries makes coronary artery bypass grafts more likely to encounter intimal hyperplasia than their infrainguinal counterparts due to the resultant slow flow velocity and decreased wall stress. To allow a site-specific, flow-related comparison of remodeling behavior, saphenous vein bypass grafts were simultaneously implanted in femoral and coronary positions. METHODS: Saphenous vein grafts were concomitantly implanted as coronary and femoral bypass grafts using a senescent nonhuman primate model. Duplex ultrasound-based blood flow velocity profiles and vein graft and target artery dimensions were correlated with dimensional and histomorphologic graft remodeling in large, senescent Chacma baboons (n = 8; 28.1 +/- 4.9 kg) during a 24-week period. RESULTS: At implantation, the cross-sectional quotient (Q(c)) between target arteries and vein grafts was 0.62 +/- 0.10 for femoral grafts vs 0.17 +/- 0.06 for coronary grafts, resulting in a dimensional graft-to-artery mismatch 3.6 times higher (P < .0001) in coronary grafts. Together with different velocity profiles, these site-specific dimensional discrepancies resulted in a 57.9% +/- 19.4% lower maximum flow velocity (P = .0048), 48.1% +/- 23.6% lower maximal cycling wall shear stress (P = .012), and 62.2% +/- 21.2% lower mean velocity (P = .007) in coronary grafts. After 24 weeks, the luminal diameter of all coronary grafts had contracted by 63%, from an inner diameter of 4.49 +/- 0.60 to 1.68 +/- 0.63 mm (P < .0001; subintimal diameter: -41.5%; P = .002), whereas 57% of the femoral interposition grafts had dilated by 31%, from 4.21 +/- 0.25 to 5.53 +/- 1.30 mm (P = .020). Neointimal tissue was 2.3 times thicker in coronary than in femoral grafts (561 +/- 73 vs 240 +/- 149 mum; P = .001). Overall, the luminal area of coronary grafts was an average of 4.1 times smaller than that of femoral grafts. CONCLUSIONS: Although coronary and infrainguinal bypass surgery uses saphenous veins as conduits, they undergo significantly different remodeling processes in these two anatomic positions.

 

Rheumatic heart disease: the tip of the iceberg
K Sliwa and P Zilla
Circulation (2012) 125(25): 3060-2
10.1161/CIRCULATIONAHA.112.114199

 

Blood pressure target attainment in the background of guidelines: the very elderly in Swiss primary care
HH Schafer, I Sudano, GR Theus, P Zilla, G Noll and M Burnier
Fam Pract (2012) 29(5): 511-20
10.1093/fampra/cms012

BACKGROUND: There are only a few trials for the very elderly population (>79 years). No consensus, which blood pressure (BP) goals and substances should be applied, has been found yet. This survey was undertaken to investigate how octogenarians are treated and attain BP targets in the Swiss primary care. METHODS: Data from 4594 hypertensive patients were collected within 7 days. Eight hundred and seventy-seven patients met the requirement to be >79 years. We assessed substances/combinations and investigated pulse pressure and target blood pressure attainment (TBPA) using three different recommendations [Canadian Hypertension Education Program (CHEP), Swiss Society of Hypertension (SSH), European Society of Hypertension-European Society of Cardiology (ESH-ESC)]. Secondarily, we compared TBPA attained by angiotensin-converting enzyme inhibitor (ACEI)/diuretic (D), angiotensin receptor blocker (ARB)/D and calcium channel blocker (CCB)/D with any other dual therapy and investigated whether Ds/beta-blockers (BBs) or Ds/renin angiotensin-converting enzyme inhibitors (RAAS-Is) lead to higher TBPA. Finally, we assessed the impact of drug administration, practical work experience, location and specialization of GPs on TBPA. RESULTS: Octogenarians attained target blood pressure (TBP) between 44% (ESH-ESC) and 74% (SSH). Optimal/normal BP was reached in 22.8% of patients. Pulse pressure <65 mmHg was shown in 66.4% of patients. Monotherapy was most commonly applied followed by dual single-pill combination with ARB/D (46.5%) or ACEI/D (36.0%). No benefit in TBPA was found comparing a RAASI/D and CCB/D treatment with any other dual combination. There was also no difference between BB/D and RAAS-I/D combination therapy and between single-pill combination and dual free combinations. CONCLUSIONS: GPs adhere to the use of substances proven in outcome trials and attain high TBP. No difference in meeting BP goals could be found using different drug classes. There is an unmet need to harmonize recommendations and to add additional information for the treatment of octogenarians.

 

Recommendations for the treatment of hypertension in the elderly and very elderly--a scotoma within international guidelines
HH Schafer, JN De Villiers, I Sudano, S Dischinger, GR Theus, P Zilla and T Dieterle
Swiss Med Wkly (2012) 142(w13574
10.4414/smw.2012.13574

The recommendations of international scientific societies for the treatment of hypertension in the geriatric population are different. Lack of outcome trials, non-standardised terminology as well as differing levels of evidence contribute to the inconsistencies in the guidelines. This review article compares six international guidelines (ESH-ESC 2007/2009, SHG 2009, DHL 2008, CHEP 2010, NICE 2011 and JNC7 2003) as well as the consensus document of the ACCF/AHA 2011 in terms of their recommendations of drug classes, target blood pressure values and the use of combination therapy. Generally, antihypertensive therapy appears to be clinically beneficial in geriatric patients. Target blood pressure values of <140-150/90 mm Hg and <140/90 mm Hg can be used as a general guideline for octogenarians (80-89 yrs) and septuagenarians (70-79 yrs) respectively. While angiotensin-II converting enzyme inhibitors and diuretics appear to be advantageous in treating combined systolic-diastolic hypertension, calcium-channel blockers and diuretics are to be recommended in the management of isolated systolic hypertension. Combination therapy often increases the efficacy of the treatment as well as patient medication adherence. Furthermore, by making the most of drug combination synergy, lower doses may be used resulting in fewer side-effects.

 

A Computational study of the effect of a layered hydrogel injectate on cardiac function and myocardial mechanics in an infarcted heart
J Kortsmit, NH Davies, R Miller, P Zilla and T Franz
Journal of Biomechanics (2012) 45(DOI:10.1016/S0021-9290(12)70132-X

 

The beneficial effects of deferred delivery on the efficiency of hydrogel therapy post myocardial infarction
K Kadner, S Dobner, T Franz, D Bezuidenhout, MS Sirry, P Zilla and NH Davies
Biomaterials (2012) 33(7): 2060-6
10.1016/j.biomaterials.2011.11.031

Biomaterials are increasingly being investigated as a means of reducing stress within the ventricular wall of infarcted hearts and thus attenuating pathological remodelling and loss of function. In this context, we have examined the influence of timing of delivery on the efficacy of a polyethylene glycol hydrogel polymerised with an enzymatically degradable peptide sequence. Delivery of the hydrogel immediately after infarct induction resulted in no observable improvements, but a delay of one week in delivery resulted in significant increases in scar thickness and fractional shortening, as well as reduction in end-systolic diameter against saline controls and immediately injected hydrogel at both 2 and 4 weeks post-infarction (p < 0.05). Hydrogels injected at one week were degraded significantly slower than those injected immediately and this may have played a role in the differing outcomes. The hydrogel assumed markedly different morphologies at the two time points having either a fibrillar or bulky appearance after injection immediately or one week post-infarction respectively. We argue that the different morphologies result from infarction induced changes in the cardiac structure and influence the degradability of the injectates. The results indicate that timing of delivery is important and that very early time points may not be beneficial.

 

Rheumatic mitral repair versus replacement in a threshold country: the impact of commissural fusion
A Geldenhuys, JJ Koshy, PA Human, JF Mtwale, JG Brink and P Zilla
J Heart Valve Dis (2012) 21(4): 424-32
BACKGROUND AND AIM OF THE STUDY: In developing countries rheumatic heart disease is the predominant indication for cardiac surgery. As the disease tends to progress, reoperation rates for mitral valve repairs are high. Against this background, the predictors of failure were assessed and the overall performance of repairs compared with replacements in a 10-year cohort of rheumatic single mitral valve procedures. METHODS: Between 2000 and 2010, a total of 646 consecutive adult (aged >15 years) patients underwent primary, single mitral valve procedures. All 87 percutaneous balloon valvuloplasties (100%) were rheumatic, compared to 280 of the 345 primary mitral valve replacements (81%) and 69 of the 215 primary mitral valve repairs (32%). As the study aim was to compare the outcome of mitral valve repair versus replacement in rheumatic patients of a threshold country, all 69 repair patients were propensity-matched with 69 of the replacement patients. Based on propensity score analysis, Kaplan-Meier actuarial analysis with log-rank testing was used to evaluate survival and morbidity. RESULTS: The follow up was 100% complete (n = 138), and ranged from 0.6 to 132 months (mean 53.3 +/- 36.5 months). Actuarial freedom from valve-related mortality was 96 +/- 3% and 92 +/- 4% at five years, and 96 +/- 3% and 80 +/- 11% at 10 years for repairs and replacements, respectively (p = NS). Actuarial freedom from all valve-related events (deaths, reoperations and morbidity) was 80 +/- 6% and 86 +/- 5% at five years, and 70 +/- 8% and 69 +/- 11% at 10 years (p = NS). Actuarial freedom from all valve-related events was 57 +/- 11% and 96 +/- 3% at five years (p = 0.0008), and 42 +/- 12% and 96 +/- 3% at 10 years (p < 0.001) for those mitral valve repairs with and without commissural fusion, respectively (p = 0.0002 overall). CONCLUSION: The long-term results for mitral valve replacement in an indigent, rheumatic heart disease population of a developing country were better than generally perceived. Notwithstanding, mitral valve repair has a superior long-term outcome in those patients who do not show commissural fusion at operation.

 

Sustaining neovascularization of a scaffold through staged release of vascular endothelial growth factor-A and platelet-derived growth factor-BB
NH Davies, C Schmidt, D Bezuidenhout and P Zilla
Tissue Eng Part A (2012) 18(1-2): 26-34
10.1089/ten.tea.2011.0192

Tissue regeneration into a three-dimensional scaffold requires the stimulation of blood vessel ingrowth. We have employed a freely interconnecting porous scaffold developed by us to determine the utility of a covalently bound heparin surface coating for the delivery of vascular endothelial growth factor (VEGF) and platelet-derived growth factor BB (PDGF-BB) in vivo. The heparin surface was shown to release VEGF far more rapidly than PDGF-BB in vitro (VEGF: 75 ng/h for 24 h; PDGF-BB: 86 pg/h for >7 days). In rat subcutaneous implants, at 10 days the heparin surface alone increased vessel ingrowth substantially (p<0.05 vs. unmodified scaffold), release of VEGF resulted in a further increase (p<0.05 vs. heparinized scaffold), whereas PDGF-BB had no additional effect. The increase induced by the combination of growth factors was similar to VEGF alone. After 2 months, PDGF-BB, but not VEGF delivery, resulted in a substantial increase in vascularization above that induced by heparin (p<0.05). At the longer time point the combination of growth factors was similar to PDGF-BB. However, only the combination of growth factors significantly elevated the number of ingrowing arterioles (p<0.05 vs. heparinized scaffold). Thus, the covalent modification of a porous scaffold with heparin allows for the differential release of VEGF and PDGF-BB that results in both a rapid and sustained increase in scaffold vascularization.

 

Pulmonary artery banding: still a valuable option in developing countries?
A Brooks, A Geldenhuys, L Zuhlke, P Human and P Zilla
Eur J Cardiothorac Surg (2012) 41(2): 272-6
10.1016/j.ejcts.2011.05.053

OBJECTIVE: We examined whether the socio-economic circumstances of a developing country justify pulmonary artery banding (PAB) for the deferral of perceived high-risk patients requiring biventricular repair. METHODS: A retrospective cohort analysis was done on 143 consecutive patients with ventricular anatomy suitable for a biventricular repair, who had a pulmonary artery band applied between 1 January 2002 and 31 December 2007 as they were considered too high a risk to undergo corrective surgery. The goal in all patients was to lower their risk of definitive surgery by improving their clinical condition. The minimum follow-up period was 2 years with the closing date for data collection being 31 January 2010. The mean weight and age at PAB was 5.34 +/- 2.94 kg and 9.9 +/- 17.3 months. The endpoints of the study were mortality, interval hospital readmission, growth pattern post-banding, whether or not definitive correction was achieved, and the current follow-up status of uncorrected patients. RESULTS: The hospital mortality was 8% (n = 12), the inter-stage mortality 21% (n = 30), and the total mortality 29% (n = 42). Positive growth was not shown in 50% following the banding procedure. The mean number of inter-current hospital admissions was 1.5 +/- 2 times per patient. At the termination of data collection, after a mean interval of 24.5 +/- 14.3 months, debanding and full correction was achieved in 43% (n = 62). In addition to the 29% (n = 42) that were confirmed to be dead, an additional 28% (n = 39) were not corrected and of these almost half were regarded as lost to follow-up. Thus, of the entire cohort of patients, 57% (n = 81) have not achieved definitive correction at the termination of data collection. CONCLUSION: A strategy of deferring biventricular repair by the application of a pulmonary artery band is ineffective under Third World conditions largely due to lack of patient compliance. This study shows that the overall mortality in the inter-stage period following PAB is high prior to definitive correction. Less than half of patients will eventually be repaired in a reasonable time frame and patient follow-up is unreliable. We conclude that consideration should be given to early definitive repair even in perceived high-risk cases.

 

First hominine remains from a 
1.0 million year old bone bed at Cornelia-Uitzoek, Free State Province, South Africa
JS Brink, AI Herries, J Moggi-Cecchi, JA Gowlett, CB Bousman, JP Hancox, R Grun, V Eisenmann, JW Adams and L Rossouw
J Hum Evol (2012) 63(3): 527-35
10.1016/j.jhevol.2012.06.004

We report here on evidence of early Homo around 1.0 Ma (millions of years ago) in the central plains of southern Africa. The human material, a first upper molar, was discovered during the systematic excavation of a densely-packed bone bed in the basal part of the sedimentary sequence at the Cornelia-Uitzoek fossil vertebrate locality. We dated this sequence by palaeomagnetism and correlated the bone bed to the Jaramillo subchron, between 1.07 and 0.99 Ma. This makes the specimen the oldest southern African hominine remains outside the dolomitic karst landscapes of northern South Africa. Cornelia-Uitzoek is the type locality of the Cornelian Land Mammal Age. The fauna contains an archaic component, reflecting previous biogeographic links with East Africa, and a derived component, suggesting incipient southern endemism. The bone bed is considered to be the result of the bone collecting behaviour of a large predator, possibly spotted hyaenas. Acheulian artefacts are found in small numbers within the bone bed among the fossil vertebrates, reflecting the penecontemporaneous presence of people in the immediate vicinity of the occurrence. The hominine tooth was recovered from the central, deeper part of the bone bed. In size, it clusters with southern African early Homo and it is also morphologically similar. We propose that the early Homo specimen forms part of an archaic component in the fauna, in parallel with the other archaic faunal elements at Uitzoek. This supports an emergent pattern of archaic survivors in the southern landscape at this time, but also demonstrates the presence of early Homo in the central plains of southern Africa, beyond the dolomitic karst areas.

 

Knitted nitinol represents a new generation of constrictive external vein graft meshes
P Zilla, L Moodley, MF Wolf, D Bezuidenhout, MS Sirry, N Rafiee, W Lichtenberg, M Black and T Franz
J Vasc Surg (2011) 54(5): 1439-50
10.1016/j.jvs.2011.05.023

OBJECTIVE: Constriction of vein grafts with braided external nitinol meshes had previously led to the successful elimination of neointimal tissue formation. We investigated whether pulse compliance, smaller kink-free bending radius, and milder medial atrophy can be achieved by knitting the meshes rather than braiding, without losing the suppressive effect on intimal hyperplasia. METHODS: Pulse compliance, bending stiffness, and bending radius, as well as longitudinal-radial deformation-coupling and radial compression, were compared in braided and knitted nitinol meshes. Identical to previous studies with braided mesh grafts, a senescent nonhuman primate model (Chacma baboons; bilateral femoral interposition grafts/6 months) mimicking the clinical size mismatch between vein grafts and runoff arteries was used to examine the effect of knitted external meshes on vein grafts: nitinol mesh-constricted (group 1); nitinol mesh-constricted and fibrin sealant (FS) spray-coated for mesh attachment (group 2); untreated control veins (group 3), and FS spray-coated control veins (group 4). RESULTS: Compared with braided meshes, knitted meshes had 3.8-times higher pulse compliance (3.43 +/- 0.53 vs 0.94 +/- 0.12%/100 mm Hg; P = .00002); 30-times lower bending stiffness (0.015 +/- 0.002 vs 0.462 +/- 0.077 Nmm(2); P = .0006); 9.2-times narrower kink-free bending radius (15.3 +/- 0.4 vs 140.8 +/- 22.4 mm; P = .0006), and 4.3-times lower radial narrowing caused by axial distension (18.0% +/- 1.0% vs 77.0% +/- 3.7%; P = .00001). Compared with mesh-supported grafts, neointimal tissue was 8.5-times thicker in group I (195 +/- 45 mum) vs group III (23.0 +/- 21.0 mum; P < .001) corresponding with a 14.3-times larger neointimal area in group I (4330 +/- 957 x 103 mum(2)) vs group III (303 +/- 221x 103 mum(2); P < .00004). FS had no significant influence. Medial muscle mass remained at 43.4% in knitted meshes vs the 28.1% previously observed in braided meshes. CONCLUSION: Combining the suppression of intimal hyperplasia with a more physiologic remodeling process of the media, manifold higher kink-resistance, and lower fraying than in braided meshes makes knitted nitinol an attractive concept in external vein graft protection.

 

Injectable living marrow stromal cell-based autologous tissue engineered heart valves: first experiences with a one-step intervention in primates
B Weber, J Scherman, MY Emmert, J Gruenenfelder, R Verbeek, M Bracher, M Black, J Kortsmit, T Franz, R Schoenauer, L Baumgartner, C Brokopp, I Agarkova, P Wolint, G Zund, V Falk, P Zilla and SP Hoerstrup
Eur Heart J (2011) 32(22): 2830-40
10.1093/eurheartj/ehr059

AIMS: A living heart valve with regeneration capacity based on autologous cells and minimally invasive implantation technology would represent a substantial improvement upon contemporary heart valve prostheses. This study investigates the feasibility of injectable, marrow stromal cell-based, autologous, living tissue engineered heart valves (TEHV) generated and implanted in a one-step intervention in non-human primates. METHODS AND RESULTS: Trileaflet heart valves were fabricated from non-woven biodegradable synthetic composite scaffolds and integrated into self-expanding nitinol stents. During the same intervention autologous bone marrow-derived mononuclear cells were harvested, seeded onto the scaffold matrix, and implanted transapically as pulmonary valve replacements into non-human primates (n = 6). The transapical implantations were successful in all animals and the overall procedure time from cell harvest to TEHV implantation was 118 +/- 17 min. In vivo functionality assessed by echocardiography revealed preserved valvular structures and adequate functionality up to 4 weeks post implantation. Substantial cellular remodelling and in-growth into the scaffold materials resulted in layered, endothelialized tissues as visualized by histology and immunohistochemistry. Biomechanical analysis showed non-linear stress-strain curves of the leaflets, indicating replacement of the initial biodegradable matrix by living tissue. CONCLUSION: Here, we provide a novel concept demonstrating that heart valve tissue engineering based on a minimally invasive technique for both cell harvest and valve delivery as a one-step intervention is feasible in non-human primates. This innovative approach may overcome the limitations of contemporary surgical and interventional bioprosthetic heart valve prostheses.

 

Aneurysm of the left aortic sinus causing acute myocardial infarction
JP Smedema, V Freeman and J Brink
Ann Pediatr Cardiol (2011) 4(2): 189-91
10.4103/0974-2069.84671

This report describes the findings and management of a young male who presented with an acute ST-segment elevation myocardial infarction due to compression of the circumflex coronary artery by a large aneurysm of left sinus of Valsalva.

 

Induced chronic hypoxia negates the pro-angiogenic effect of surface immobilized heparin in a polyurethane porous scaffold
C Schmidt, D Bezuidenhout, L Higham, P Zilla and NH Davies
J Biomed Mater Res A (2011) 98(4): 621-8
10.1002/jbm.a.33150

Porous scaffolds are frequently utilized in tissue regeneration. We have developed a polyurethane (PU) scaffold with a freely interconnecting porosity that can be modified with a covalently linked heparinized surface. The ability of this surface functionality to stimulate vessel and cellular growth into the PU scaffold has been evaluated by subcutaneous implantation of discs in the rat under normoxia and chronic hypoxia (hypobaric chamber) for 10 days. The heparinized surface alone was able to significantly increase vascularization and cellularization under normoxia (p < 0.05), but this response was negated by hypoxia. Addition of vascular endothelial growth factor to heparinized discs resulted in increased vascularity and cellularization under both conditions (p < 0.05). This suggests that endogenous growth factor production was limiting under chronic hypoxia but that an angiogenic response could still occur with exogenous delivery of factors.

 

Complementary and alternative medical therapies for children with attention-deficit/hyperactivity disorder (ADHD)
J Pellow, EM Solomon and CN Barnard
Altern Med Rev (2011) 16(4): 323-37
Attention-deficit/hyperactivity disorder (ADHD) is a commonly diagnosed childhood disorder characterized by impulsivity, inattention, and hyperactivity. ADHD affects up to 1 in 20 children in the United States. The underlying etiologies of ADHD may be heterogeneous and diverse, and many possible risk factors in the development of ADHD have been identified. Conventional treatment usually consists of behavioral accommodations and medication, with stimulant medication most commonly being prescribed. Parents concerned about the side effects and long-term use of conventional medications are increasingly seeking alternatives to pharmacologic treatment. Complementary and alternative medicine (CAM) offers parents various treatment options for this condition, including dietary modifications, nutritional supplementation, herbal medicine, and homeopathy. CAM appears to be most effective when prescribed holistically and according to each individual's characteristic symptoms. Possible etiologies and risk factors for the condition also need to be considered when developing a treatment plan. This article serves to highlight the latest research regarding the most commonly used CAM for children with ADHD.

 

A Numerical Tool for the Coupled Mechanical Assessment of Anastomoses of PTFE Arterio-venous Access Grafts
M Ngoepe, BD Reddy, D Kahn, C Meyer, P Zilla and T Franz
Cardiovasc Eng Technol (2011) 2(3): 160-172
Purpose: The anastomotic angle is assumed to affect the performance of arterio-venous (AV) access grafts by altering wall shear stress (WSS) and wall tension. The objective of this study was to develop a coupled numerical tool to assess fluid and structural anastomotic mechanics of a straight upper arm access graft.

 

Methods: 3D computational fluid dynamics (CFD) and finite element (FE) models were developed for arterial and venous anastomoses with different graft attachment angles. The fluid simulations were executed using flow velocity profiles for anastomotic inlets obtained from a whole-graft CFD model. A mesh adaptation algorithm was developed to couple CFD and FE meshes and capture fluid structure interactions.

 

Results: The coupling algorithm enabled transfer of blood pressure (BP) and WSS predicted with the CFD models to the FE models as loadings. The deformations induced in the FE models were used to update the CFD geometries after which BP and WSS were recalculated and the process repeated until equilibrium between fluid and solid models. Maximum BP in the vein was 181 mmHg. WSS peaked at 2.3 and 0.7 Pa and the structural wall stress reached 3.38 and 3.36 kPa in arterial and venous anastomosis.

 

Conclusions: Since flow-induced wall tension has been identified as a contributor to access graft failure along with WSS, the computational tool will be useful in studying the coupled mechanics in these grafts. Initial investigations of arterial and venous anastomotic end-to-side configuration indicated a slightly better performance of the 90° configuration over 135° arterial and 45° venous configurations.

 

Degradation-induced changes of mechanical properties of an electro-spun polyester-urethane scaffold for soft tissue regeneration
H Krynauw, L Bruchmuller, D Bezuidenhout, P Zilla and T Franz
J Biomed Mater Res B Appl Biomater (2011) 99(2): 359-68
10.1002/jbm.b.31907

The aim of this study was the in vitro investigation of the change in mechanical properties of a fast-degrading electro-spun polymeric scaffold for the use in soft tissue regenerative implants. Tubular scaffolds were electro-spun from a DegraPol(R) D30 polyesther-urethane solution (target outer diameter: 5.0 mm; scaffold wall thickness: 0.99 +/- 0.18 mm). Scaffold samples were subjected to hydrolytic in vitro degradation for up to 34 days. The fiber network structure and fiber surfaces were inspected on scanning electron micrographs. Following vacuum drying and determination of mass, flat samples (9.69 +/- 0.21 x 18.47 +/- 2.62 mm, n = 5) underwent uni-axial tensile testing (5 load cycles, strain epsilon = 0 to 20%; final extension to failure) in circumferential scaffold direction after 5, 10, 14, 18, 22, 26, 30, and 34 days of degradation. Scaffold mass did not change with degradation. Maximum elastic modulus, maximum stress and associated strain were E(max) = 1.14 +/- 0.23 MPa, sigma(max) = 0.52 +/- 0.12 MPa and epsilon(max) = 176.8 +/- 21.9% before degradation and E(max) = 0.43 +/- 0.26 MPa, sigma(max) = 0.033 +/- 0.028 MPa and epsilon(max) = 24.6 +/- 3.0% after 34 days of degradation. The deterioration of mechanical properties was not reflected in the ultrastructural surface morphology of the fibers. The current exploratory study provides a basis for the development of constitutive computational models of biodegradable scaffolds with future extension of the investigation most importantly to capture mechanical effects of regenerating tissue. Future studies will include degradation in biological fluids and assessment of molecular weight for an advanced understanding of the material changes during degradation.

 

Late primary arterial switch for transposition of the great arteries with intact ventricular septum in an african population
F Edwin, RH Kinsley, J Brink, G Martin, H Mamorare and P Colsen
World J Pediatr Congenit Heart Surg (2011) 2(2): 237-42
10.1177/2150135110395335

The arterial switch operation (ASO) is the optimal management of transposition of the great arteries with intact ventricular septum (TGA-IVS) within the first 3 weeks of life; beyond this age optimal treatment is debatable. The authors adopted a strategy of primary ASO for TGA-IVS in the first 10 weeks of life regardless of left ventricular (LV) status. This report reviews the early outcomes with this management approach. Between August 2006 and December 2009, 22 patients with TGA-IVS underwent the primary ASO. Sixteen of them were less than 21 days old (early switch group) and 6 were between 31 and 66 days old (late switch group). A review of their hospital records was performed to determine outcomes in the 2 groups. Operative variables and postoperative outcomes were recorded. There was 1 hospital death in the early switch group (6.3%) but none in the late group (0%). Temporary mechanical circulatory support was required in 1 patient (6.3%) in the early switch group and in 2 of the 6 (33.3%) in the late switch group. One late death of undetermined cause occurred in the late switch group 8 weeks after discharge. No significant difference could be demonstrated between the 2 groups in terms of operative variables and the measured postoperative outcomes. It is concluded that the age limit for the primary ASO can be extended to at least 10 weeks; temporary mechanical circulatory support may be required as a rescue.

 

Patient-specific prediction of intrinsic mechanical loadings on sub-muscular pectoral pacemaker implants based on an inter-species transfer function
MH de Vaal, J Neville, M Litow, J Scherman, P Zilla and T Franz
J Biomech (2011) 44(14): 2525-31
10.1016/j.jbiomech.2011.07.019

With the steady technological development enabling reduced device dimensions and new patient populations, detailed data on mechanical in vivo loads become increasingly important to ensure reliability of implantable medical devices. Based on an intra-species correlation of in-line and transverse force of the Pectoralis major established previously for the Chacma baboon (de Vaal et al., 2010a), a simplified physiological model and a mechanical equivalent model were developed for a sub-muscular pectoral device implant considering Pectoralis major, Pectoralis minor and rib cage. By assessing the morphometric and mechanical parameters of these musculo-skeletal structures and the associated model parameters, the intra-species correlation was shown to exhibit (a) robustness for a larger intra-species subject population and (b) linear scale variance allowing application for humans under consideration of the inter-species difference of the attachment angles of Pectoralis major. The transfer function provides a basis for the prediction of patient-specific maximum mechanical loadings on a sub-muscular pectoral cardiac pacemaker implant through non- or minimal invasive measurements on the patient.

 

A constitutive model for the warp-weft coupled non-linear behavior of knitted biomedical textiles
MS Yeoman, D Reddy, HC Bowles, D Bezuidenhout, P Zilla and T Franz
Biomaterials (2010) 31(32): 8484-93
10.1016/j.biomaterials.2010.07.033

Knitted textiles have been used in medical applications due to their high flexibility and low tendency to fray. Their mechanics have, however, received limited attention. A constitutive model for soft tissue using a strain energy function was extended, by including shear and increasing the number and order of coefficients, to represent the non-linear warp-weft coupled mechanics of coarse textile knits under uniaxial tension. The constitutive relationship was implemented in a commercial finite element package. The model and its implementation were verified and validated for uniaxial tension and simple shear using patch tests and physical test data of uniaxial tensile tests of four very different knitted fabric structures. A genetic algorithm with step-wise increase in resolution and linear reduction in range of the search space was developed for the optimization of the fabric model coefficients. The numerically predicted stress-strain curves exhibited non-linear stiffening characteristic for fabrics. For three fabrics, the predicted mechanics correlated well with physical data, at least in one principal direction (warp or weft), and moderately in the other direction. The model exhibited limitations in approximating the linear elastic behavior of the fourth fabric. With proposals to address this limitation and to incorporate time-dependent changes in the fabric mechanics associated with tissue ingrowth, the constitutive model offers a tool for the design of tissue regenerative knit textile implants.

 

Modification, crosslinking and reactive electrospinning of a thermoplastic medical polyurethane for vascular graft applications
JP Theron, JH Knoetze, RD Sanderson, R Hunter, K Mequanint, T Franz, P Zilla and D Bezuidenhout
Acta Biomater (2010) 6(7): 2434-47
10.1016/j.actbio.2010.01.013

Thermoplastic polyurethanes are used in a variety of medical devices and experimental tissue engineering scaffolds. Despite advances in polymer composition to improve their stability, the correct balance between chemical and mechanical properties is not always achieved. A model compound (MC) simulating the structure of a widely used medical polyurethane (Pellethane) was synthesized and reacted with aliphatic and olefinic acyl chlorides to study the reaction site and conditions. After adopting the conditions to the olefinic modification of Pellethane, processing into flat sheets, and crosslinking by thermal initiation or ultraviolet radiation, mechanical properties were determined. The modified polyurethane was additionally electrospun under ultraviolet light to produce a crosslinked tubular vascular graft prototype. Model compound studies showed reaction at the carbamide nitrogen, and the modification of Pellethane with pentenoyl chloride could be accurately controlled to up to 20% (correlation: rho=0.99). Successful crosslinking was confirmed by insolubility of the materials. Initiator concentrations were optimized and the crosslink densities shown to increase with increasing modification. Crosslinking of Pellethane containing an increasing number of pentenoyl groups resulted in decreases (up to 42%, p<0.01) in the hysteresis and 44% in creep (p<0.05), and in a significant improvement in degradation resistance in vitro. Modified Pellethane was successfully electrospun into tubular grafts and crosslinked using UV irradiation during and after spinning to render them insoluble. Prototype grafts had sufficient burst pressure (>550 mm Hg), and compliances of 12.1+/-0.8 and 6.2+/-0.3%/100 mm Hg for uncrosslinked and crosslinked samples, respectively. It is concluded that the viscoelastic properties of a standard thermoplastic polyurethane can be improved by modification and subsequent crosslinking, and that the modified material may be electrospun and initiated to yield crosslinked scaffolds. Such materials hold promise for the production of vascular and other porous scaffolds, where decreased hysteresis and creep may be required to prevent aneurismal dilation.

 

A Computational Study of Structural Designs for a Small- diameter Composite Vascular Graft Promoting Tissue Regeneration
MS Sirry, P Zilla and T Franz
Cardiovasc Eng Technology (2010) 1(269-281
Purpose: The structural integrity and arterial mechanics are important aspects for tissue regenerative vascular grafts with ingrowth permissible porous scaffolds. This paper presents a computational study of structural designs for a small-diameter vascular graft comprising porous polyurethane scaffold and knitted reinforcement mesh using Nitinol and polyurethane wire, respectively.

 

Methods: Finite element models of the porous scaffold with the knitted mesh as embedded or external reinforcement were generated using validated constitutive models for porous polyurethane and Nitinol. Simulating a luminal pressure of up to 200 mmHg, deformations and stresses were recorded in porous scaffold and knitted mesh.

 

Results: The models predicted compliance between 1.2 and 15.7 %/100mmHg for the reinforced grafts and 65.1 and 106.4 %/100mmHg for the non-reinforced grafts. For the reinforced grafts, maximum stress was 97.0, 28.2 and 0.055 MPa in Nitinol wire, polyurethane wire and porous polyurethane scaffold, respectively, at 120mmHg. The corresponding maximum strain was 0.27, 5.0 and 22.5%. Stress and strain remained safe in the Nitinol mesh and the porous polyurethane but became critical in the polyurethane mesh between 120 and 200 mmHg. Despite compression due to luminal pressure load, the porous scaffold remained ingrowth permissible for cells, capillaries and arterioles up to 200 mmHg. Conclusions: The outcomes of this study provided preliminary concepts for the structural designs for a tissue regenerative composite vascular graft towards improved mechanical performance and structural integrity. The implemented modelling approach can be used in the further development and optimization of small-diameter tissue-regenerating vascular grafts.

 

A simple fluid-structure coupling algorithm for the study of the anastomotic mechanics of vascular grafts
NK Schiller, T Franz, NS Weerasekara, P Zilla and BD Reddy
Comput Methods Biomech Biomed Engin (2010) 13(6): 773-81
10.1080/10255841003606124

Vascular anastomoses constitute a main factor in poor graft performance due to mismatches in distensibility between the host artery and the graft. This work aims at computational fluid-structure investigations of proximal and distal anastomoses of vein grafts and synthetic grafts. Finite element and finite volume models were developed and coupled with a user-defined algorithm. Emphasis was placed on the simplicity of the coupling algorithm. An artery and vein graft showed a larger dilation mismatch than an artery and synthetic graft. The vein graft distended nearly twice as much as the artery while the synthetic graft displayed only approximately half the arterial dilation. For the vein graft, luminal mismatching was aggravated by development of an anastomotic pseudo-stenosis. While this study focused on end-to-end anastomoses as a vehicle for developing the coupling algorithm, it may serve as useful point of departure for further investigations such as other anastomotic configurations, refined modelling of sutures and fully transient behaviour.

 

Aortic valve leaflet mechanical properties facilitate diastolic valve function
TM Koch, BD Reddy, P Zilla and T Franz
Comput Methods Biomech Biomed Engin (2010) 13(2): 225-34
10.1080/10255840903120160

This work was concerned with the numerical simulation of the behaviour of aortic valves whose material can be modelled as non-linear elastic anisotropic. Linear elastic models for the valve leaflets with parameters used in previous studies were compared with hyperelastic models, incorporating leaflet anisotropy with pronounced stiffness in the circumferential direction through a transverse isotropic model. The parameters for the hyperelastic models were obtained from fits to results of orthogonal uniaxial tensile tests on porcine aortic valve leaflets. The computational results indicated the significant impact of transverse isotropy and hyperelastic effects on leaflet mechanics; in particular, increased coaptation with peak values of stress and strain in the elastic limit. The alignment of maximum principal stresses in all models follows approximately the coarse collagen fibre distribution found in aortic valve leaflets. The non-linear elastic leaflets also demonstrated more evenly distributed stress and strain which appears relevant to long-term scaffold stability and mechanotransduction.

 

Children’s heart disease in sub-Saharan Africa: Challenging the burden of disease
J Hewitson and P Zilla
South African Heart Journal (2010) 7(1): 18-21
Children with heart disease in Africa have little or no access to treatment of any kind, and cardiac surgical services are virtually absent outside a handful of centres in a few of the wealthier nations. There is little reliable data concerning the prevalence of congenital or acquired heart disease in African children, but there is sufficient information to indicate that the burden of cardiac disease is vast. This major non-communicable disease is largely hidden, overshadowed by the incidence of communicable diseases. There is as yet little evidence of the hoped-for epidemiological transition toward non-communicable diseases amongst children in Africa. The burden of congenital heart disease is only part of the problem, with rheumatic heart disease (RHD) remaining the commonest cardiac problem, related to poor socioeconomic conditions. RHD is the most preventable form of cardiac disease, yet there is little preventive work being done. The many obstacles to developing paediatric cardiac care are discussed, and some possible ways forward are proposed.

 

A mathematical method for constraint-based cluster analysis towards optimized constrictive diameter smoothing of saphenous vein grafts
T Franz, BD Reddy, P Human and P Zilla
Med Biol Eng Comput (2010) 48(6): 519-29
10.1007/s11517-010-0600-7

This study was concerned with the cluster analysis of saphenous vein graft data to determine a minimum number of diameters, and their values, for the constrictive smoothing of diameter irregularities of a cohort of veins. Mathematical algorithms were developed for data selection, transformation and clustering. Constrictive diameter values were identified with interactive pattern evaluation and subsequently facilitated in decision-tree algorithms for the data clustering. The novel method proved feasible for the analysis of data of 118 veins grafts, identifying the minimum of two diameter classes. The results were compared to outcome of a statistical recursive partitioning analysis of the data set. The method can easily be implemented in computer-based intelligent systems for the analysis of larger data sets using the diameter classes identified as initial cluster structure.

 

Tailored sizes of constrictive external vein meshes for coronary artery bypass surgery
T Franz, P Human, S Dobner, BD Reddy, M Black, H Ilsley, MF Wolf, D Bezuidenhout, L Moodley and P Zilla
Biomaterials (2010) 31(35): 9301-9
10.1016/j.biomaterials.2010.08.054

External mesh constriction of vein grafts was shown to mitigate intimal hyperplasia by lowering circumferential wall stress and increasing fluid shear stress. As under-constriction leaves vein segments unsupported and thus prone to neointimal proliferation while over-constriction may cause wall folding optimal mesh sizing holds a key to clinical success. Diameter fluctuations and the occurrence of wall folding as a consequence of external constriction with knitted Nitinol meshes were assessed in saphenous vein grafts from 100 consecutive coronary artery bypass (CABG) patients. Subsequently, mesh dimensions were identified that resulted in the lowest number of mesh sizes for all patients either guaranteeing tight continual mesh contact along the entire graft length (stipulation A) or preventing wall folding (stipulation B). A mathematical data classification analysis and a statistical single-stage partitioning approach were independently applied alternatively prioritizing stipulation A or B. Although the risk of folding linearly increased when constriction exceeded 24.6% (Chi squared test p = 0.0004) the actual incidence of folding (8.6% of veins) as well as the degree of lumenal encroachment (6.2 +/- 2.1%) were low. Folds were always single, narrow longitudinal formations (height: 23.3 +/- 4.0% of inner diameter/base: 16.6 +/- 18.1% of luminal circumference). Both analytical methods provided an optimum number of 4 mesh sizes beyond which no further advantage was seen. While the size ranges recommended by both methods assured continual tight mesh contact with the vein the narrower range suggested by the mathematical data classification analysis (3.0-3.7 mm) put 20.6 +/- 12.5% of length in 69% of veins at risk of folding as opposed to 21.3 +/- 25.9% being at risk in the wider size range (3.0-4.2 mm) suggested by the statistical partitioning approach. Four mesh sizes would provide uninterrupted mesh contact in 98% of vein grafts in CABG procedures with only 26% of their length being at risk of relatively mild wall folding.

 

Primary arterial switch operation for transposition of the great arteries with intact ventricular septum--is it safe after three weeks of age?
F Edwin, H Mamorare, J Brink and R Kinsley
Interact Cardiovasc Thorac Surg (2010) 11(5): 641-4
10.1510/icvts.2010.243832

In patients with transposition of the great arteries with intact ventricular septum (TGA-IVS), late presentation for surgical treatment is not uncommon. Earlier experience suggested an excess mortality for the primary arterial switch operation (ASO) when performed after the third week of life in such patients. The true age limit for the primary ASO, however, remains speculative. A best evidence topic was written to determine the safety of extending the age limit of the primary ASO for TGA-IVS beyond three weeks of age. Eight of 74 relevant papers constituted the best evidence to address the issue. Sufficient level II evidence was found to suggest that in experienced institutions in the current era, the ASO for TGA-IVS may be performed primarily in infants three to eight weeks of age with comparable early outcomes to younger patients. Kang et al. investigated 275 neonates (younger than 21 days) and 105 infants (age range 21-185 days) undergoing the primary ASO for TGA-IVS. They found no significant difference in terms of in-hospital mortality (5.5% vs. 3.8%) or need for mechanical left ventricular (LV) support (3.6% vs. 5.7%) between the younger and older groups, respectively. Of the younger group, 3.8% developed postoperative LV failure leading to death or mechanical LV support. All nine patients older than two months (age range 61-185 days) survived to discharge although two (aged 69 and 86 days) required mechanical LV support for postoperative LV failure. The postoperative course of the late ASO group, however, was significantly prolonged as reflected in the duration of postoperative ventilation (4.9 vs. 7.1 days, P=0.012) and length of postoperative stay (12.5 vs. 18.9 days, P=0.001). In the report of Sarris et al., 52 patients with TGA-IVS who were older than four weeks of age (36 were older than eight weeks) underwent a primary ASO with early mortality comparable with younger patients (2% vs. 3%, respectively). For infants between the ages of two and six months, the strength of the evidence favoring this management approach is limited by the small sample size of reported series and the increased requirement for mechanical circulatory support for postoperative LV failure.

 

The in vivo assessment of mechanical loadings on pectoral pacemaker implants
MH de Vaal, J Neville, J Scherman, P Zilla, M Litow and T Franz
J Biomech (2010) 43(9): 1717-22
10.1016/j.jbiomech.2010.02.028

Reduced sizes of implantable cardiac pacemakers and clinical advances have led to a higher feasibility of using such devices in younger patients including children. Increased structural demands deriving from reduced device size and more active recipients require detailed knowledge of in vivo mechanical conditions to ensure device reliability. Objective of this study was the proof of feasibility of a system for the measurement of in vivo mechanical loadings on pacemaker implants. The system comprised the following: implantable instrumented pacemaker (IPM) with six force sensors, accelerometer and radio-frequency (RF) transceiver; RF data logging system and video capture system. Three Chacma baboons (20.6+/-1.15 kg) received one pectoral sub-muscular IPM implant. After wound healing, forces were measured during physical activities. Forces during range of motion of the arm were assessed on the anaesthetized animals prior to device explantation. Mass, volume and dimensions of the excised Pectoralis major muscles were determined after device explantation. Remote IPM activation and data acquisition were reliable in the indoor cage environment with transceiver distances of up to 3m. Sampling rates of up to 1,000 Hz proved sufficient to capture dynamic in vivo loadings. Compressive forces on the IPM in conscious animals reached a maximum of 77.2+/-54.6N during physical activity and were 22.2+/-7.3N at rest, compared with 34.6+/-15.7 N maximum during range of motion and 13.4+/-3.3N at rest in anaesthetized animals. The study demonstrated the feasibility of the developed system for the assessment of in vivo mechanical loading conditions of implantable pacemakers with potential for use for other implantable therapeutic devices.

 

Mechanical loadings on pectoral pacemaker implants: correlation of in-line and transverse force of the Pectoralis major
MH de Vaal, J Neville, J Scherman, P Zilla, M Litow and T Franz
Ann Biomed Eng (2010) 38(11): 3338-46
10.1007/s10439-010-0085-4

Recently we presented a method for the assessment of in vivo forces on pectoral device implants motivated from technological and clinical advancements toward smaller implantable cardiac pacemakers and the altered structural demands arising from the reduced device size. Objective of this study was the investigation of the intra-species proportionality of in-line force and transverse reaction force of the Pectoralis major for the characterization of mechanical in vivo loadings on pectoral implants. Two Chacma baboons (23.9 +/- 1.2 kg) received bilaterally one chronic and one acute pectoral sub-muscular instrumented pacemaker (IPM) implant. The Pectoralis major muscle was electrically stimulated and resulting in-line and transverse muscle force were measured. The correlation of in-line force and transverse force of the Pectoralis major was investigated using linear regression analyses. The proportionality of in-line and transverse force of the Pectoralis major was found to be subject-specific (R(2) = 0.17, p < 0.003). Including morphometric parameters, i.e., length along line of action, width over implant and stress, in the regression analysis provided a strong intra-species correlation between in-line and transverse force (R(2) = 0.71, p < 10(-)(7)). The novel intra-species correlation provides a tool toward the characterization of mechanical in vivo loading conditions of pectoral device implants.

 

Covalent surface heparinization potentiates porous polyurethane scaffold vascularization
D Bezuidenhout, N Davies, M Black, C Schmidt, A Oosthuysen and P Zilla
J Biomater Appl (2010) 24(5): 401-18
10.1177/0885328208097565

Porous scaffolds play an integral role in many tissue-engineering approaches, and the ability to improve vascularization, without eliciting an excessive inflammatory response, would constitute an important step towards achieving long-term healing and function of devices made from these materials. After having previously optimized the dimensional requirements of the well-defined pores, the present study aimed at a further shift from inflammation to vascularization via surface immobilization with heparin. Porous polyurethane disks were produced to contain well-defined pores (147 +/- 2 microm) with abundant interconnecting windows (67 +/- 2 microm). After heparinization via copolymer grafting and amination to contain 32 microg of heparin, the modification appeared as a uniform layer on all exposed surfaces, with no signs of pore obliteration or significant changes in pore size. After 28 days implantation in a rat subcutaneous model, the scaffolds were assessed for vascularization/arteriolization and inflammation using CD31/actin and ED-1 staining, respectively. Heparinization resulted in a significant increase in vascularization: capillaries increased by 62% in number (66.2 +/- 0.8 to 107.3 +/- 1.4 vessels/mm( 2); p < 0.03) and 56% in total area (0.9 +/- 0.1 to 1.4 +/- 0.02%; p<0.02). Arteriolization also increased in absolute terms (200% in number; p<0.03), but did not change significantly when normalized to capillary number. Heparinization did not significantly affect the inflammatory response at this time-point, as quantified by ED-1 positive macrophage and foreign body giant cell (FBGC) content. Thus, the in vivo vascularization of porous scaffolds could be increased without concomitant increase in the inflammatory response by employing a simple surface modification technique. This could be a valuable tool for in vivo tissue engineering applications where enhanced vascularization is required.

 

Utilization of shape memory in external vein-graft meshes allows extreme diameter constriction for suppressing intimal hyperplasia: a non-human primate study
P Zilla, M Wolf, N Rafiee, L Moodley, D Bezuidenhout, M Black, P Human and T Franz
J Vasc Surg (2009) 49(6): 1532-42
10.1016/j.jvs.2009.01.068

OBJECTIVE: Constrictive external Nitinol meshes have been shown to suppress neointimal tissue formation and preserve endothelial integrity in vein grafts. As this mitigating effect increased with the degree of constriction, we investigated whether extreme constriction was possible without leading to detrimental luminal encroachment. METHODS: A senescent non-human primate model (Chacma baboons/bilateral femoral interposition grafts) mimicking the clinical size-mismatch between vein grafts and run-off arteries was used. Control grafts were either untreated (group 1) or spray-coated with fibrin glue (group 2). Nitinol meshes constricting the lumen by <or=80% (group 3) were compared with longitudinally pleated meshes of identical circumference that constricted the lumen by >90% (group 4). Anastomotic size mismatch at implantation was expressed as quotient of cross-sectional area of run-off artery to vein graft (Q(C)). RESULTS: At 6 months, all vein grafts without mesh support showed thick eccentric layers of neointimal tissue (group 1: 348 +/- 130 microm [Q(C) median at implant 0.19]; group 2: 318 +/- 142 microm [Q(C) median at implant 0.17]). Fibrin glue-spraying had no effect. In contrast, neointimal tissue was absent in all mesh-supported grafts (P < .007 in all cases) both at 6 weeks/6 months (group 3: 7.5 +/- 8.8 mum and 2.5 +/- 4.4 microm [Q(C) median at implant 1.47]; group 4: 1.3 +/- 0.6 microm and 3.8 +/- 5.6 microm [Q(C) median at implant 3.09]). Except for mild tissue buckling (fold height <356 microm) in one group 3 graft, none of the mesh-constricted grafts showed wall folds. Endothelial coverage was only complete in the mesh-supported groups (100% in group 3 and 4 vs 85 +/- 14%; P < .023 in group 1). Fibrin glue alone (52 +/- 48%) did not preserve endothelialization of control grafts (P < .38). CONCLUSION: Extreme vein graft constriction using external Nitinol meshes is possible without detrimental tissue buckling. Although moderate constriction was found to be sufficient for mitigating diffuse intimal hyperplasia and endothelial detachment, extreme constriction may occasionally be required to eliminate luminal irregularities.

 

The use of finite element methods and genetic algorithms in search of an optimal fabric reinforced porous graft system
MS Yeoman, BD Reddy, HC Bowles, P Zilla, D Bezuidenhout and T Franz
Ann Biomed Eng (2009) 37(11): 2266-87
10.1007/s10439-009-9771-5

The mechanics of arteries result from the properties of the soft tissue constituents and the interaction of the wall layers, predominantly media and adventitia. This concept was adopted in this study for the design of a tissue regenerative vascular graft. To achieve the desired structural properties of the graft, most importantly a diametric compliance of 6%/100 mmHg, finite element methods and genetic algorithms were used in an integrated approach to identify the mechanical properties of an adventitial fabric layer that were required to optimally complement an intimal/medial polyurethane layer with interconnected porosity of three different size classes. The models predicted a compliance of 16.0, 19.2, and 31.5%/100 mmHg for the non-reinforced grafts and 5.3, 5.5, and 6.0%/100 mmHg for the fabric-reinforced grafts. The latter, featuring fabrics manufactured according to the required non-linear mechanical characteristics numerically predicted, exhibited an in vitro compliance of 2.1 +/- 0.8, 3.0 +/- 2.4, and 4.0 +/- 0.7% /100 mmHg. The combination of finite element methods and genetic algorithms was shown to be able to successfully optimize the mechanical design of the composite graft. The method offers potential for the application to alternative concepts of modular vascular grafts and the incorporation of tissue ingrowth and biodegradation.

 

Rapid three-dimensional quantification of VEGF-induced scaffold neovascularisation by microcomputed tomography
C Schmidt, D Bezuidenhout, M Beck, E Van der Merwe, P Zilla and N Davies
Biomaterials (2009) 30(30): 5959-68
10.1016/j.biomaterials.2009.07.044

Microcomputed tomography (micro-CT) is increasingly being used to analyze the three-dimensional structure and architecture of microvascular networks. Therefore we have evaluated a micro-CT analysis of VEGF-induced vessel ingrowth into a porous polyurethane scaffold through comparison with analyses by CD31 immunohistochemistry, vascular perfusion by intravital Lycopersicon esculentum lectin perfusion and vascular corrosion casting. Micro-CT scanning found a similar level of vascularisation within the VEGF treated scaffolds to that determined by the other analytical methods. However, although the relative increase in vascularisation (17 fold above PBS controls p<0.05) induced by VEGF determined by micro-CT was similar to the perfusion based analyses (20.1 and 10.4 fold for lectin perfusion and vascular corrosion respectively p<0.05), it differed substantially from that determined by CD31 immunohistochemistry (3.2 fold p<0.05). This difference was due to a large proportion of unperfused vessels in the PBS control that were not present in the VEGF group. The increase in perfusion probably resulted in part from an increase in average vessel diameter. Though this increase was detected by micro-CT, the actual diameters were overestimated by 60-90% most likely as a consequence of a merging effect for juxtaposed vessels. Thus whilst micro-CT gives an accurate three-dimensional quantification of the VEGF-induced increase in perfused vessels, resolution needs to be maximized for accurate sizing of a microvascular network's components.

 

Dimensional analysis of human saphenous vein grafts: Implications for external mesh support
P Human, T Franz, J Scherman, L Moodley and P Zilla
J Thorac Cardiovasc Surg (2009) 137(5): 1101-8
10.1016/j.jtcvs.2008.10.040

OBJECTIVE: Constrictive external mesh support of vein grafts was shown to mitigate intimal hyperplasia in animal experiments. To determine the degree of constriction required for the elimination of dimensional irregularities in clinically used vein grafts, a detailed anatomic study of human saphenous veins was conducted. METHODS: In 200 consecutive patients having coronary artery bypass grafting, harvested saphenous veins (length 34.4 +/- 10.8 cm) were analyzed regarding diameter irregularities, side branch distribution, and microstructure. RESULTS: The mean outer diameter of surgically distended saphenous veins was 4.2 +/- 0.6 mm (men, 4.3 +/- 0.6 mm vs women, 3.9 +/- 0.5 mm; P < .0001). Although the outer diameter significantly decreased over the initial 18 cm (-7.6%; P < .0001), the overall increase between malleolus and thigh was not significant (+11.2%). Smaller-diameter veins (<3.5 mm) had more pronounced diameter fluctuations than larger veins (31.8% +/- 11.0% vs 21.2% +/- 8.8%; P < .0001), with more than 71% of all veins showing caliber changes of more than 20%. There was 1 side branch every 5.4 +/- 4.3 cm, with a significantly higher incidence between 20 and 32 cm from the malleolus (P < .0001 to distal, P < .0004 to proximal). Generally, women had more side branches than men (0.30 +/- 0.15 cm(-1) vs 0.25 +/- 0.12 cm(-1); P = .0190). Thick-walled veins (565.7 +/- 138.4 mum) had a significantly higher number of large side branches (P < .0001), and thin-walled veins (398.7 +/- 123.2 mum) had significantly more small side branches (P < .0001). Pronounced intimal thickening ("cushions") was found in 28% of vessels (119.8 +/- 28.0 mum vs 40.1 +/- 18.2 mum; P < .0001). CONCLUSION: Although the preferential location of side branches may be addressed by the deliberate discarding of infragenicular vein segments, a diameter constriction of 27% on average would eliminate diameter irregularities in 98% of vein grafts.

 

A synthetic non-degradable polyethylene glycol hydrogel retards adverse post-infarct left ventricular remodeling
S Dobner, D Bezuidenhout, P Govender, P Zilla and N Davies
J Card Fail (2009) 15(7): 629-36
10.1016/j.cardfail.2009.03.003

BACKGROUND: Left ventricular remodeling after myocardial infarction is a key component of heart failure and it has long been postulated that it may result from increased wall stress. It has recently been suggested that an injectable, non-degradable polymer may limit pathological remodeling in a manner analogous to that of cardiac support devices. We have tested a non-degradable polyethylene glycol (PEG) gel in a rat infarction model. METHODS AND RESULTS: After permanent ligation of the left anterior descending artery in male Wistar rats, PEG gel reagents were injected into the infarcted region and polymerized in situ. At 4 weeks, fractional shortening and infarct volume were unchanged relative to a saline injected control, but the infarct-induced left ventricular end-diastolic diameter (LVEDD) increase was substantially reduced (43%, P < .05) and wall thinning was completely prevented. At 13 weeks, the LVEDD were similar for both saline- and PEG-injected hearts. The non-degradable PEG gels did elicit a macrophage-based inflammatory reaction. CONCLUSIONS: The injection of non-degradable synthetic gel was effective in ameliorating pathological remodeling in the immediate postinfarction healing phase, but was unable to prevent the dilation that occurred at later stages in the healed heart.

 

Long-term experience in autologous in vitro endothelialization of infrainguinal ePTFE grafts
M Deutsch, J Meinhart, P Zilla, N Howanietz, M Gorlitzer, A Froschl, A Stumpflen, D Bezuidenhhout and M Grabenwoger
Journal of Vascular Surgery (2009) 49(2): 52-362
doi: 10.1016/j.jvs.2008.08.101. Epub 2008 Dec 25.

Objective: Based on a previous randomized study showing significantly superior patency rates for in vitro endothelialized expanded polytetrafluoroethylene (ePTFE) grafts we investigated whether it was feasible for a nontertiary institution to offer autologous in vitro endothelialization to all elective infrainguinal bypass patients who had no suitable saphenous vein available.

 

 

 

Methods: Over a period of 15 years, 310 out of 318 consecutive nonacute patients (age 64.7 +/- 8.6) received 341 endothelialized ePTFE grafts (308 femoropopliteal: 153 above knee [AK] and 155 below knee [BK] and 33 femorodistal). Autologous endothelial cells were harvested from short segments (3.9 +/- 1.1 cm) of subcutaneous veins (80% cephalic, 11% basilic, 2% external jugular, and 7% saphenous) and grown to mass cultures within 18.9 +/- 4.5 days before being confluently lined onto fibrin glue-coated ePTFE grafts. The graft diameter was 6 mm (64%) or 7 mm (36%). The overall procedure-related delay for graft implantation was 27.6 + 7.8 days. Growth failure prevented 2.5% of patients from receiving an endothelialized graft. The mean observation period was 9.6 years. Primary patencies were obtained from Kaplan-Meier survivorship functions. Explants for morphological analysis were obtained from eight patients.

 

 

 

Results: The overall primary patency rate of femoropopliteal grafts was 69% at 5 years (68% [AK] vs 71% [BK]) and 61% at 10 years (59% [AK] vs 64% [BK]). Primary patency of 7 mm vs 6 mm grafts was 78%/62% at 5 years and 71%/55% at 10 years. The difference between the two groups was statistically significant (log rank test P = .023; Breslow test P = .017). Stage I vs II/III patients showed 5-year patencies of 67% vs 73% (N.S.) and 10-year patencies of 61%% vs 53% (N.S.). The primary patency of femorodistal grafts was 52% at 5 years and 36% at 10 years. The limb salvage rate was 94% (fempop) vs 86% (femdistal) at 5 years and 89% vs 71% at 10 years. All retrieved samples showed the presence of an endothelium after 38.9 +/- 17.8 months.

 

 

 

Conclusion: Autologous in vitro endothelialization was shown to be a feasible routine procedure at a nontertiary hospital. Explants confirmed the presence of an endothelium years after implantation while the primary patency in the particularly challenging subgroup of patients without a suitable saphenous vein resembles that of vein grafts.

 

Association of Ang-2 with integrin beta 2 controls Ang-2/PDGF-BB-dependent upregulation of human peripheral blood monocyte fibrinolysis
L Bezuidenhout, P Zilla and N Davies
Inflammation (2009) 32(6): 393-401
10.1007/s10753-009-9148-9

Angiopoietin-2 (Ang-2), an angiogenic factor that is generally considered an autocrine factor for endothelial cells was shown in a previous study to upregulate peripheral blood monocyte fibrinolysis in concert with platelet-derived growth factor-BB (PDGF-BB). This upregulation of fibrinolysis was demonstrated to be due to upregulation of elements of the matrix metalloproteinase and serine protease fibrinolytic pathways. The manner in which Ang-2 interacts with monocytes was not elucidated though no expression of the angiopoietin receptor tyrosine kinase Tie-2 was found for monocytes. In this study Ang-2 was found to bind to integrin beta(2), and functional inhibition of integrin beta(2) eliminated Ang-2/PDGF-BB-mediated upregulation of monocyte fibrin invasion. Additionally, integrin beta(2) blockade significantly inhibited the Ang-2/PDGF-BB based increase in matrix metalloproteinase-9 (MMP-9) and membrane type-1-MMP (MT1-MMP). Furthermore, Ang-2/PDGF-BB-upregulated urokinase plasminogen-activator receptor (uPAR) was shown to be associated in complexes with integrin beta(2). In addition, Ang-2 was shown to upregulate PDGFR-beta expression in monocytes. Therefore several components of the mechanism via which the novel interaction of Ang-2 and PDGF-BB with monocytes occurs have been identified.

 

The effects of cross-link density and chemistry on the calcification potential of diamine-extended glutaraldehyde-fixed bioprosthetic heart-valve materials
D Bezuidenhout, A Oosthuysen, P Human, C Weissenstein and P Zilla
Biotechnol Appl Biochem (2009) 54(3): 133-40
10.1042/ba20090101

Despite indications that GA (glutaraldehyde)-crosslinked tissues remain prone to long-term degradation and calcification, it is still the reagent of choice in the fixation of bioprosthetic heart valves. We have shown previously that increased GA concentrations and diamine extension of cross-links with lysine incorporation lead to mitigated in vivo calcification, mainly of porcine aortic-wall tissue. The present study was performed to assess the correlation between the cross-link density of all three commonly used tissue types [PW (porcine aortic wall), PL (porcine aortic leaflet) and BP (bovine pericardium)] and tissue calcification in the subcutaneous rat model after GA treatment with or without lysine. The effect of lysine enhancement, and increased GA concentration in the presence of lysine, resulted in significant increases in tissue cross-linking in all three tissue types. Although increased GA concentration on its own resulted in decreased calcification without an increase in cross-link density, overall positive correlations were found between denaturation temperature and RPD (resistance towards protease degradation) [correlation coefficient (rho) values: rhoPW =0.922, rhoPL =0.783 and rhoBP =0.955], whereas negative correlations existed between RPD and calcification (rhoPW=-0.836, rhoPL=-0.929 and rhoBP=-0.579). The combination of lysine enhancement and an increase in GA concentration from 0.2 to 3% resulted in 79, 44 and 56% decreases in calcification in PW, PL and BP. In the case of BP, a decrease in calcification of 81% could be achieved merely by adding lysine extension to low-concentration (0.2 %) GA cross-linking. Thus it is concluded that the increase in cross-link density achieved by lysine incorporation, and by increased GA concentration in the presence of lysine, results in significant and marked decreases in calcification of all three types of tissues commonly used in bioprosthetic heart valves.

 

Constrictive external nitinol meshes inhibit vein graft intimal hyperplasia in nonhuman primates
P Zilla, P Human, M Wolf, W Lichtenberg, N Rafiee, D Bezuidenhout, N Samodien, C Schmidt and T Franz
J Thorac Cardiovasc Surg (2008) 136(3): 717-25
10.1016/j.jtcvs.2008.02.068

OBJECTIVE: External mesh support of vein grafts has been shown to mitigate the formation of intimal hyperplasia. The aim of the present study was to address the issue of optimal mesh size in a nonhuman primate model that mimics the dimensional mismatch typically encountered between clinical vein grafts and their target arteries. METHODS: The effect of mesh size on intimal hyperplasia and endothelial preservation was assessed in bilateral femoral interposition grafts in Chacma baboons (n(Sigma) = 32/n = 8 per mesh size). No mesh support (group I) was compared with external nitinol meshes at three different sizes: loose fitting (group II), 25% diameter constricting (group III), and 50% diameter constricting (group IV). Mesh sizes were seen not only in isolation but also against the background of anastomotic size mismatch at implantation, expressed as quotient of cross-sectional area of host artery to vein graft (Q(C)). RESULTS: Significant amounts of intimal hyperplasia were found in group I (Q(C) median 0.20; intimal hyperplasia 6 weeks = 1.63 +/- 0.34 mm(2); intimal hyperplasia 12 weeks = 1.73 +/- 0.5 mm(2)) and group II (Q(C) median 0.25; intimal hyperplasia 6 weeks = 1.96 +/- 1.64 mm(2); intimal hyperplasia 12 weeks = 2.88 +/- 1.69 mm(2)). In contrast, group III (Q(C) median 0.45; intimal hyperplasia 6 weeks = 0.08 +/- 0.13 mm(2); intimal hyperplasia 12 weeks = 0.18 +/- 0.32 mm(2)) and IV (Q(C) median 1.16; intimal hyperplasia 6 weeks = 0.02 +/- 0.03 mm(2); intimal hyperplasia 12 weeks = 0.11 +/- 0.10 mm(2)) showed dramatically suppressed intimal hyperplasia (P < .01) at both time points. Endothelial integrity was only preserved in group IV (P < .05). There were no significant differences in vascularization and inflammation in either interlayer or intergroup comparisons. CONCLUSION: By using an animal model that addressed the clinical phenomenon of diameter discrepancy between vein graft and bypassed artery, we could demonstrate that suppression of intimal hyperplasia required constrictive mesh sizes.

 

Prosthetic heart valves: catering for the few
P Zilla, J Brink, P Human and D Bezuidenhout
Biomaterials (2008) 29(4): 385-406
10.1016/j.biomaterials.2007.09.033

Prosthetic heart valves epitomize both the triumphant advance of cardiac surgery in its early days and its stagnation into a retrospective, exclusive first world discipline of late. Fifty-two years after the first diseased heart valve was replaced in a patient, prostheses largely represent the concepts of the 1960s with many of their design-inherent complications. While the sophisticated medical systems of the developed world may be able to cope with sub-optimal replacements, these valves are poorly suited to the developing world (where the overwhelming majority of potential valve recipients reside), due to differences in age profiles and socio-economic circumstances. Therefore, it is the latter group which suffered most from the sluggish pace of developments. While it previously took less than 7 years for mechanical heart valves to develop from the first commercially available ball-in-cage valve to the tilting pyrolytic-carbon disc valve, and another 10 years to arrive at the all-carbon bi-leaflet design, only small incremental improvements have been achieved since 1977. Similarly, bioprosthetic valves saw their last major break-through development in the late 1960s when formalin fixation was replaced by glutaraldehyde cross linking. Since then, poorly understood so-called 'anti-calcification' treatments were added and the homograft concept rediscovered under the catch-phrase 'stentless'. Still, tissue valves continue to degenerate fast in younger patients, making them unsuitable for developing countries. Yet, catheter-delivered prostheses almost exclusively use bioprosthetic tissue, thereby reducing one of the most promising developments for patients of the developing world into a fringe product for the few first world recipients. With tissue-engineered valves aiming at the narrow niche of congenital malformations and synthetic flexible leaflet valves being in their fifth decade of low-key development, heart valve prostheses seem to be destined to remain an unsatisfying and exclusive first world solution for a long time to come.

 

A computational study of knitted Nitinol meshes for their prospective use as external vein reinforcement
H van der Merwe, B Daya Reddy, P Zilla, D Bezuidenhout and T Franz
J Biomech (2008) 41(6): 1302-9
10.1016/j.jbiomech.2008.01.016

External reinforcement has been suggested for autologous vein grafts to address the mismatch of mechanical properties and fluid dynamics of graft and host vessel, a main factor for graft failure. A finite-element tool was developed to investigate the mechanical behaviour, in particular radial compliance, of knitted Nitinol meshes (internal diameter: 3.34 mm) with two different knit designs (even versus uneven circumferential loops) and three different wire thicknesses (0.05, 0.0635 and 0.075 mm) under physiological conditions. The Nitinol material parameters were obtained from experimental testing. The compliance predicted for the 80-120 mmHg physiological blood pressure range was 2.5, 0.9 and 0.6%/100 mmHg for the even loop design and 1.2, 0.5 and 0.5%/100 mmHg for the uneven loop design, for wire thicknesses of 0.05, 0.0635 and 0.075 mm. The highest stress, at 120 mmHg, was found in the even loop mesh with the thinnest wire to be 268 MPa, remaining 44.5% below the stress initiating stress-induced phase transformation. The maximum stress decreased to 132 and 91 MPa with increasing wire thickness of the same loop design. The uneven loop design exhibited maximum stress levels of 65.3%, 63.6% and 87.9% of the even loop values at 0.05, 0.0635 and 0.075 mm wire thickness. The maximum strain of 0.7%, at 120 mmHg, remained un-critical considering a typical high-cycle recoverable strain of 2%. It was demonstrated that the numerical approach developed was feasible of effectively evaluating design variations of knitted Nitinol meshes towards vein graft behaviour equivalent to arterial mechanics.

 

Forty years on: the anesthetic for the world's first human-to-human heart transplant remembered
PC Gordon and JG Brink
J Cardiothorac Vasc Anesth (2008) 22(1): 133-8
10.1053/j.jvca.2007.10.019

 

The dosage dependence of VEGF stimulation on scaffold neovascularisation
N Davies, S Dobner, D Bezuidenhout, C Schmidt, M Beck, AH Zisch and P Zilla
Biomaterials (2008) 29(26): 3531-8
10.1016/j.biomaterials.2008.05.007

Growth factors are often used in tissue regeneration to stimulate vascularisation of polymeric scaffolds, with vascular endothelial growth factor (VEGF) having been extensively studied for short-term vessel ingrowth. We have therefore evaluated the effect of different concentrations of VEGF on the vascularisation of a porous scaffold in the short-, intermediate- and long-term, by delivering 15, 150 and 1500ng VEGF/day to polyurethane scaffolds by osmotic pumps for up to 6 weeks. An increased vascularisation months after termination of VEGF delivery was only achieved with 150ng/day (46%, p<0.05). This dosage consistently showed elevated levels of vascularisation (144, 125, 160 and 60% above PBS controls at 10, 20, 30 and 42 days, respectively, p<0.05), whilst the vessels induced by the highest dosage, though initially maximally elevated (265 and 270% at 10 and 20 days, p<0.05) tended to regress after 20 days of VEGF delivery. Pericyte coverage was decreased at 20 days for the highest dosage (30%, p<0.05). Lectin perfusion demonstrated that vessels within the scaffold were connected to the host vasculature at all time points and perfusion was substantially raised by VEGF delivery at day 20. These results suggest concentration of VEGF plays a critical role in the nature and persistence of vasculature formed in a tissue regenerative scaffold.

 

Prosthetic vascular grafts: wrong models, wrong questions and no healing
P Zilla, D Bezuidenhout and P Human
Biomaterials (2007) 28(34): 5009-27
10.1016/j.biomaterials.2007.07.017

In humans, prosthetic vascular grafts remain largely without an endothelium, even after decades of implantation. While this shortcoming does not affect the clinical performance of large bore prostheses in aortic or iliac position, it contributes significantly to the high failure rate of small- to medium-sized grafts (SMGs). For decades intensive but largely futile research efforts have been under way to address this issue. In spite of the abundance of previous studies, a broad analysis of biological events dominating the incorporation of vascular grafts was hitherto lacking. By focusing on the three main contemporary graft types, expanded polytetrafluoroethylene (ePTFE), Dacron and Polyurethane (PU), accumulated clinical and experimental experience of almost half a century was available. The main outcome of this broad analysis-supported by our own experience in a senescent non-human primate model-was twofold: Firstly, inappropriate animal models, which addressed scientific questions that missed the point of clinical relevance, were largely used. This led to a situation where the vast majority of investigators unintentionally studied transanastomotic rather than transmural or blood-borne endothelialization. Given the fact that in patients transanastomotic endothelialization (TAE) covers only the immediate perianastomotic region of sometimes very long prostheses, TAE is rather irrelevant in the clinical context. Secondly, transmural endothelialization seems to have a time window of opportunity before a build-up of an adverse microenvironment. In selecting animal models that prematurely terminate this build-up through the early presence of an endothelium, the most significant 'impairment factor' for physiological tissue regeneration in vascular grafts remained ignored. By providing insight into mechanisms and experimental designs which obscured the purpose and scope of several decades of vascular graft studies, future research may better address clinical relevance.

 

Ang-2 and PDGF-BB cooperatively stimulate human peripheral blood monocyte fibrinolysis
L Bezuidenhout, M Bracher, G Davison, P Zilla and N Davies
J Leukoc Biol (2007) 81(6): 1496-503
10.1189/jlb.1106687

Angiopoietin-2 (Ang-2) is a growth factor, which was identified originally as playing a critical role in vessel remodeling during angiogenesis. More recent evidence has indicated additional involvement in vascular homeostatic responses such as coagulation and inflammation, which are central to wound healing. We therefore determined whether a relationship existed between Ang-2 and monocytes, one of the initial cell types to be recruited to a wound, in the context of fibrin clot invasion. Ang-2 significantly increased monocyte invasion of fibrin in the presence of serum. In the absence of serum, it required a combination of Ang-2 and platelet-derived growth factor BB (PDGF-BB) to increase invasion by threefold. Furthermore, it was shown that the heightened invasion was dependent on serine proteases and matrix metalloproteinases (MMPs) and that the combination of Ang-2 and PDGF-BB increased urokinase plasminogen-activator receptor expression, as well as MMP-9 and membrane type 1 MMP expression. These data give further credence to the concept of Ang-2 as a key regulator of several essential phases of wound healing.

 

Comparison of processing and sectioning methodologies for arteries containing metallic stents
P Rippstein, MK Black, M Boivin, JP Veinot, X Ma, YX Chen, P Human, P Zilla and ER O'Brien
J Histochem Cytochem (2006) 54(6): 673-81
10.1369/jhc.5A6824.2006

The histological study of arteries with implanted metallic scaffolding devices, known as stents, remains a technical challenge. Given that the arterial response to stent implantation can sometimes lead to adverse outcomes, including the re-accumulation of tissue mass within the stent (or in-stent restenosis), overcoming these technical challenges is a priority for the advancement of research and development in this important clinical field. Essentially, the task is to section the stent-tissue interface with the least amount of disruption of tissue and cellular morphology. Although many methacrylate resin methodologies are successfully applied toward the study of endovascular stents by a variety of research laboratories, the exact formulations, as well as subsequent processing and sectioning methodology, remain largely coveted. In this paper, we describe in detail a methyl methacrylate resin-embedding methodology that can successfully be applied to tungsten carbide blade, as well as saw and grinding sectioning methods and transmission electron microscopy. In addition, we present a comparison of the two sectioning methodologies in terms of their effectiveness with regard to morphological, histochemical, and immunohistochemical analyses. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.

 

Bioprosthetic tissue preservation by filling with a poly(acrylamide) hydrogel
A Oosthuysen, PP Zilla, PA Human, CA Schmidt and D Bezuidenhout
Biomaterials (2006) 27(9): 2123-30
10.1016/j.biomaterials.2005.10.008

Glutaraldehyde (GA) fixation has been used for more than 40 years as the preferred treatment to suppress immunogenicity and increase durability of bioprosthetic tissues (BPT) used in heart valve prostheses. This fixative and its reaction products have, however, been implicated in the calcific degeneration and long-term failure of these devices. The current study investigates stabilization of BPT and the mitigation/prevention of calcification by filling aortic wall samples with a synthetic poly(acrylamide) (pAAm) hydrogel, with and without pre-treatment with GA. Histological and gravimetric analysis showed full penetration of the acrylamide (AAm) into the fresh tissue, while only partial filling could be achieved with GA pre-fixed tissue. The observed decrease in amino-group content (0.157+/-0.012-0.123+/-0.021 micromol/mg, p<0.03) and corresponding increase in shrinkage temperature (67.2+/-0.8-78.1+/-1.8 degrees C, p<0.0001) when fresh tissue was filled, indicate the participation of tissue-amines in a process that leads to BPT crosslinking. These effects were much less pronounced when the tissue was pre-fixed with GA. Filling increased the tensile stiffness of fresh tissue (to levels half that of 0.2% GA fixed tissue), but decreased the stiffness of GA pre-fixed tissue. When compared to standard 0.2% GA fixed samples, fresh tissue filled with AAm showed 88% (p<0.0001) less calcification while exhibiting similar resistance toward degradation by protease. Filling did not result in significant decreases in calcification when the tissue was pre-fixed with GA.

 

Reduction of calcification of carbodiimide-processed heart valve tissue by prior blocking of amine groups with monoaldehydes
F Everaerts, M Gillissen, M Torrianni, P Zilla, P Human, M Hendriks and J Feijen
J Heart Valve Dis (2006) 15(2): 269-77
BACKGROUND AND AIM OF THE STUDY: Failure of implanted bioprostheses due to calcification is a commonly occurring phenomenon. In order to prevent calcification, many alternative cross-linking methods to glutaraldehyde (GA) have been developed and evaluated. METHODS: In a novel approach an improved carbodiimide (EDC) cross-linking method that comprises a two-step process was developed. First, the available amine groups in (tissue) collagen were blocked with a monoaldehyde, followed by an EDC-activated cross-linking reaction of the carboxyl groups in the tissue with a poly (propylene glycol) bis 2-(amino-propyl) ether (Jeffamine). RESULTS: Samples processed via this method have shown a significantly reduced calcification in a subdermal juvenile rat model compared to samples with standard GA treatment. In the present study, heart valve tissue was blocked with various monoaldehydes, followed by reaction with Jeffamine using carbodiimide cross-linking chemistry. Leaflet calcification was almost eliminated using different aldehydes, whereas wall calcification was maximally 95% reduced when propionaldehyde was used as blocking agent, as compared to a carbodiimide cross-linked control without Jeffamine and blocked amine groups. CONCLUSION: Amine blocking and cross-linking technology appears promising in the design of the next generation of tissue valves. Calcification was significantly reduced compared to GA cross-linking. The mechanistic insight of decreased wall calcification is still unknown, and research investigations are ongoing.

 

Cardiac transplantation following storage of the donor heart by a portable hypothermic perfusion system: the initial clinical experience
DK Cooper, WN Wicomb and D Novitzky
Clin Transpl (2006) 552-4

 

Diamine-extended glutaraldehyde- and carbodiimide crosslinks act synergistically in mitigating bioprosthetic aortic wall calcification
P Zilla, D Bezuidenhout, M Torrianni, M Hendriks and P Human
J Heart Valve Dis (2005) 14(4): 538-45
BACKGROUND AND AIM OF THE STUDY: The extension of glutaraldehyde (GA) crosslinks with diamine bridges was shown previously to reduce bioprosthetic heart valve calcification to a significant degree. The aim of the present study was to investigate whether the additional crosslinking of functional carboxyl groups could augment this anticalcific effect at the low glutaraldehyde concentrations typically used in commercial heart valve production. METHODS: Entire aortic roots of medium-sized pigs were fixed after 48 h of cold storage. Crosslinking of amino-functional groups was achieved either by GA fixation alone (0.2% or 0.7%) or with an interim treatment with the diamine L-lysine (25, 50 or 100 mM; 37 degrees C; 2 days). Carboxyl groups were activated with carbodiimide (N'-3-dimethylaminopropyl-N-ethyl carbodiimide hydrochloride (EDC), 240 mM) and crosslinked with an oligomeric diamine (polypropylene glycol-bis-aminopropyl ether (Jeffamine), 60 mM, 230D). By permutation of treatments and combinations thereof, a total of 17 groups was compared. Aortic wall discs (12 mm diameter) were implanted subcutaneously into seven-week-old Long-Evans rats for 60 days. Tissue calcification was determined by histology and atomic absorption spectrophotometry. RESULTS: There was no significant difference in tissue calcification if either GA or carbodiimide fixation was used alone. Equally, the combined crosslinking with GA and EDC/Jeffamine did not achieve a mitigation of tissue calcification below levels seen in at least one of the two treatments alone. When commercial GA fixation was mildly diamine-enhanced with L-lysine (25 mM), additional EDC/Jeffamine crosslinking of carboxyl groups resulted in a distinct additive effect in both 0.2% (-31%; p < 0.0002) and 0.7% (-36%; p = 0.0073) GA-fixed tissue. Relative to conventional GA fixation, this combination mitigated aortic wall calcification by 43% (p < 0.0001) and 34% (p = 0.0014) in 0.2% and 0.7% GA-fixed tissue, respectively. An increase in L-lysine concentration to 100 mM further reduced calcification of 0.7% GA-fixed tissue (18.5%; p = 0.016), but had no additional effect on 0.2% GA-fixed tissue (0.6%; p = 0.463). CONCLUSION: A distinct reduction in bioprosthetic aortic wall calcification can be achieved by combining diamine-extended conventional GA fixation with a diamine-extended carbodiimide based crosslinking step.

 

Carbodiimide treatment dramatically potentiates the anticalcific effect of alpha-amino oleic acid on glutaraldehyde-fixed aortic wall tissue
P Zilla, D Bezuidenhout and P Human
Ann Thorac Surg (2005) 79(3): 905-10
10.1016/j.athoracsur.2003.12.026

BACKGROUND: Bifunctional amines were previously found to act as bridging molecules between the terminal ends of incomplete glutaraldehyde (GA) cross-links. The additional cross-links thus formed between -NH2 groups of tissue were seen to significantly inhibit bioprosthetic calcification. In the current study, the potential ability of alpha-amino oleic acid (AOA) to act as a bridging molecule between -NH2- and COOH-dependent cross-links was hypothesized to similarly augment the anticalcification effect of the AOA molecule. METHODS: Porcine aortic wall tissue from Medtronic Freestyle valve bioprostheses incorporating the AOA anticalcification process additionally underwent carboxyl-group cross-linking with Jeffamine (poly[propylene glyco]-bis-[aminopropyl ether]) using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC). Tissue was subdermally implanted into 5-week-old Long-Evans rats for 60 days. Standard 0.2% GA-fixed tissue served as a control. To further assess the impact of storage solution on AOA tissue, samples were either stored in GA (0.2%GA) or EDC (25 mmol/L carbodiimide) before implantation. Tissue calcification was assessed by atomic absorption spectroscopy and histochemical staining. RESULTS: Aldehyde end-capping with AOA achieved only a modest reduction of calcification in GA-treated aortic wall tissue (-20.0%; p < 0.05). Replacing GA with EDC as a storage solution led to a further 32.4% (p < 0.01) mitigation of calcification in Freestyle tissue. Incorporating an intermediate EDC/Jeffamine cross-linking step achieved a distinct additional reduction of calcification by 40.4% (p < 0.05). Overall, aortic wall calcification was 59.7% (p < 0.0001) lower if commercial Freestyle tissue underwent an additional EDC/Jeffamine cross-linking step and subsequent storage in EDC. Relative to control GA-fixed tissue, this represented a 67.8% (p < 0.0001) reduction. Incorporation of AOA was essential for the beneficial effect of the additional EDC/Jeffamine cross-linking step. CONCLUSIONS: Potentially utilizing both the amino- and the carboxyl moieties of AOA for tissue binding dramatically reduces aortic wall calcification of GA-fixed tissue.

 

Enhanced endothelial cell retention on shear-stressed synthetic vascular grafts precoated with RGD-cross-linked fibrin
JG Meinhart, JC Schense, H Schima, M Gorlitzer, JA Hubbell, M Deutsch and P Zilla
Tissue Eng (2005) 11(5-6): 887-95
10.1089/ten.2005.11.887

Clinical in vitro endothelialization has been shown to increase the patency of synthetic vascular grafts. The shear stress resistance of the cultured autologous endothelium represents a crucial cornerstone of the concept. We investigated whether an enrichment of the precoating matrix with adhesion sites can augment endothelial cell attachment. Adult human saphenous vein endothelial cells (AHSVECs) were seeded confluently ([58 +/- 11] x 10(3) AHSVECs/cm2) onto 10-cm-long ePTFE (expanded polytetrafluorethylene) vascular grafts (n = 24) precoated with commercial clinically approved fibrin gel (Tisseal) containing various concentrations of cross-linked RGD peptide (0.0, 4.0, 8.0, or 16.0 mg of RGD per milliliter of Tisseal fibrinogen component). Endothelialized grafts were postcultivated for 9 days before they were exposed to a pulsatile circulation model mimicking peak physiological shear stress conditions of the femoral artery (12 dyn/cm2; min/max, -60/+28 dyn/cm2). Cell loss after 24 h was quantitatively determined by image analysis of vital stains. Initial 24-h cell loss was 27.2 +/- 1.7% in grafts precoated with the non-RGD-enriched fibrin matrix. In contrast, cell loss was significantly less on fibrin containing 4.0 mg of RGD peptide per milliliter of Tisseal fibrinogen component (13.3 +/- 7.9%; p < 0.05). Cell loss on fibrin containing 8 and 16 mg of RGD per milliliter of Tisseal fibrinogen component was 41.0 +/- 27.4 and 43.0 +/- 23.2% (p > 0.05), respectively. We conclude that low concentrations of RGD peptide cross-linked into commercial fibrin matrices used for clinical in vitro lining of vascular grafts led to significantly increased endothelial cell retention. The failure of higher RGD concentrations to enhance endothelial cell attachment may be explained by competitive binding of endothelial cells to non-cross-linked RGD.

 

The selective modulation of endothelial cell mobility on RGD peptide containing surfaces by YIGSR peptides
MH Fittkau, P Zilla, D Bezuidenhout, MP Lutolf, P Human, JA Hubbell and N Davies
Biomaterials (2005) 26(2): 167-74
10.1016/j.biomaterials.2004.02.012

The ability of the biomimetic peptides YIGSR, PHSRN and RGD to selectively affect adhesion and migration of human microvascular endothelial cells (MVEC) and vascular smooth muscle cells (HVSMC) was evaluated. Cell mobility was quantified by time-lapse video microscopy of single cells migrating on peptide modified surfaces. Polyethylene glycol (PEG) hydrogels modified with YIGSR or PHSRN allowed only limited adhesion and no spreading of MVEC and HVSMC. However, when these peptides were individually combined with the strong cell binding peptide RGD in PEG hydrogels, the YIGSR peptide was found to selectively enhance the migration of MVEC by 25% over that of MVEC on RGD alone (p<0.05). No corresponding effect was observed for HVSMC. This suggests that the desired response of specific cell types to tissue engineering scaffolds could be optimized through a combinatory approach to the use of biomimetic peptides.

 

Heart transplantation: the contributions of Christiaan Barnard and the University of Cape Town/Groote Schuur Hospital
JG Brink and DK Cooper
World J Surg (2005) 29(8): 953-61
10.1007/s00268-005-0154-2

Christiaan (Chris) Neethling Barnard was born in South Africa and qualified in medicine at the University of Cape Town in 1946. Following surgical training in South Africa and the USA, Barnard established a successful open-heart surgery program at Groote Schuur Hospital and the University of Cape Town in 1958. In 1967, he led the team that performed the world's first human-to-human heart transplant. Although the first heart transplant patient survived only 18 days, four of Groote Schuur hospital's first 10 patients survived for more than one year, two living for 13 and 23 years, respectively. This relative success amid many failures worldwide did much to generate guarded optimism that heart transplantation would eventually become a viable therapeutic option, Barnard then developed the operation of heterotopic heart transplantation (the socalled "piggy-back" transplant), which had some advantages in the pre-cyclosporine era when immunosuppressive therapy was limited. His group was the first to successfully transport donor hearts using a hypothermic perfusion storage device in 1981. Several studies on the haemodynamic and metabolic sequelae of brain death were carried out in his Department's cardiovascular research laboratories at the University of Cape Town, and the concept of hormonal replacement therapy in organ donors was developed. An active heart transplant program still continues in the Chris Barnard Division of Cardiothoracic Surgery at Groote Schuur Hospital and the University of Cape Town, but the thrust of clinical activity within the Division and the research within its state-of-the-art cardiovascular research laboratories is now directed towards valvular and ischaemic heart diseases, which are common in the African population.

 

Bioprosthetic heart valves: the need for a quantum leap
P Zilla, P Human and D Bezuidenhout
Biotechnol Appl Biochem (2004) 40(Pt 1): 57-66
10.1042/BA20030211

More than 250,000 bioprosthetic heart valves are being implanted annually. Although the majority of recipients are elderly developed-world patients, the most urgent need for tissue valves is in younger patients, where rapid degeneration of contemporary prostheses remains a serious obstacle. After decades of empirical and mostly futile attempts to extend the longevity of tissue valve prostheses, new insights and solutions are on the horizon. Aetiologically, a shift of focus from mineralization to immune responses and inflammation emerges. On the development side, new engineering approaches to both selective extraction of tissue components and cross-links are increasingly defining the new direction. In order to dramatically improve the performance of bioprosthetic heart valves, these new developments need to lead to a broad consensus for a paradigm shift in a hitherto rather stagnant field of medical research.

 

Cell-demanded release of VEGF from synthetic, biointeractive cell ingrowth matrices for vascularized tissue growth
AH Zisch, MP Lutolf, M Ehrbar, GP Raeber, SC Rizzi, N Davies, H Schmokel, D Bezuidenhout, V Djonov, P Zilla and JA Hubbell
FASEB J (2003) 17(15): 2260-2
10.1096/fj.02-1041fje

Local, controlled induction of angiogenesis remains a challenge that limits tissue engineering approaches to replace or restore diseased tissues. We present a new class of bioactive synthetic hydrogel matrices based on poly(ethylene glycol) (PEG) and synthetic peptides that exploits the activity of vascular endothelial growth factor (VEGF) alongside the base matrix functionality for cellular ingrowth, that is, induction of cell adhesion by pendant RGD-containing peptides and provision of cell-mediated remodeling by cross-linking matrix metalloproteinase substrate peptides. By using a Michael-type addition reaction, we incorporated variants of VEGF121 and VEGF165 covalently within the matrix, available for cells as they invade and locally remodel the material. The functionality of the matrix-conjugated VEGF was preserved and was critical for in vitro endothelial cell survival and migration within the matrix environment. Consistent with a scheme of locally restricted availability of VEGF, grafting of these VEGF-modified hydrogel matrices atop the chick chorioallontoic membrane evoked strong new blood vessel formation precisely at the area of graft-membrane contact. When implanted subcutaneously in rats, these VEGF-containing matrices were completely remodeled into native, vascularized tissue. This type of synthetic, biointeractive matrix with integrated angiogenic growth factor activity, presented and released only upon local cellular demand, could become highly useful in a number of clinical healing applications of local therapeutic angiogenesis.

 

Detoxification on top of enhanced, diamine-extended glutaraldehyde fixation significantly reduces bioprosthetic root calcification in the sheep model
AE Trantina-Yates, P Human and P Zilla
J Heart Valve Dis (2003) 12(1): 93-100; discussion 100-1
BACKGROUND AND AIM OF THE STUDY: Increased concentrations of glutaraldehyde (GA), diamine-extension (DA) of crosslinks and subsequent extraction of excess GA all reduce bioprosthetic calcification in the subdermal rat model. The study aim was to demonstrate the combined effect of all three treatments in a circulatory sheep model. METHODS: Two fixation treatments were used for GA detoxification (urazole in acetate buffer, 0.1 M; pH 4.5; 37 degrees C; 7 days): (i) conventional 0.2% GA fixation (4 degrees C; 7 days); and (ii) enhanced 3.0% GA fixation (4 degrees C; 2 days, followed by a DA interim step; 100 mM L-lysine; 37 degrees C; 2 days, followed by GA; 3.0%; 37 degrees C; 5 days). Entire porcine root prostheses were implanted in the distal aortic arch of young sheep for 12 weeks (n = 5 per group). Non-detoxified 0.2% GA-treated roots served as controls (n = 5). Calcium analysis was based on atomic absorption spectrophotometry; morphology was assessed using light and transmission electron microscopy. RESULTS: Detoxification alone resulted in an 83% reduction of leaflet calcification (p = 0.086), but achieved only 23% (p = 0.145) and 12% (p = 0.362) mitigation of calcification in aortic wall and sinus tissue, respectively. When combined with DA-enhanced 3% GA fixation, detoxification led to a 95% reduction in leaflet calcification (p = 0.057), followed by 79% in sinus (p = 0.003) and 79% in aortic wall tissue (p = 0.0003). Morphologically, detoxification primarily affected leaflets and the subadventitial layer of aortic wall tissue, whereas enhanced fixation seemed to affect all structures. CONCLUSION: It was shown in a circulatory sheep model that a combination of DA-enhanced fixation with an extraction process of excess GA leads to a distinct mitigation of leaflet and aortic wall calcification.

 

Left ventricular sub-valvar mitral aneurysms
HJ Du Toit, UO Von Oppell, J Hewitson, J Lawrenson and J Davies
Interact Cardiovasc Thorac Surg (2003) 2(4): 547-51
10.1016/S1569-9293(03)00141-5

We retrospectively reviewed the surgical treatment of 12 patients (nine female, mean age 16.1+/-8.7 years) with sub-mitral aneurysms managed in our institution between 1991 and 2002. We identified three groups of patients in accordance with the degree of posterior mitral annular involvement by the aneurysm. A single aneurysm neck was found in seven patients, multiple necks in two and involvement of the entire posterior mitral annulus in three patients. Involvement of the entire posterior annulus by the aneurysmal process has not been previously described. The mean age of this latter group 29+/-5.1 years was significantly older than the former (P=0.001), suggesting a possible progressive nature of sub-mitral aneurysms. An intracardiac surgical approach was used in six patients and a combined intra and extracardiac approach in the remainder. There was no operative mortality. The mitral valve was initially repaired in eight patients. Failure of closure of the aneurysm necessitating reoperation occurred in four patients (33.3%). An understanding of the inter-relationship between the aneurysm and mitral valve is essential for successful surgical repair. Histology of the aneurysm tissue showed rheumatic heart disease in two patients and tuberculosis in two patients. Hence, although sub-valvar aneurysms are thought to be congenital, a third of our patients had evidence of co-existent rheumatic heart disease or tuberculosis.

 

Tissue engineering of vascular prostheses: Beyond the hype
P Zilla
International Journal of Arftificial Organs (2002) 25(7): 629-632
https://doi.org/10.1177/039139880202500717

 

Dissected aortic sinuses repaired with gelatin-resorcin-formaldehyde (GRF) glue are not stable on follow up
UO von Oppell, Z Karani, A Brooks and J Brink
J Heart Valve Dis (2002) 11(2): 249-57
BACKGROUND AND AIM OF THE STUDY: The chemical glue, gelatin, resorcin and formaldehyde (GRF) is widely used to obliterate the false lumen of acute dissected aortic wall tissue. METHODS: A retrospective review of 41 consecutive patients operated upon for ascending aortic dissection between 1993 and 2000 was conducted. This study focused on 19 patients with acute aortic dissection in whom the aortic valve was resuspended and GRF glue used in the proximal aortic sinuses. These patients were compared with ascending aortic dissection patients in whom the aortic valve was not resuspended. In total, nine acute and 13 chronic dissections were performed in which aortic valve replacement, valve-sparing root reconstruction (without GRF glue), or no aortic valve surgery was carried out. RESULTS: The operative mortality for ascending aortic dissections was 24.4%; identified risk factors included the specific surgeon involved. Third-degree heart block occurred only in patients in whom GRF glue was used in the proximal aortic sinus (15% incidence). Operative survivors in whom the aortic valve was resuspended and GRF glue used in the proximal aortic sinus, had a 64% incidence of late recurrent aortic regurgitation requiring reoperation due to recurrent aortic sinus aneurysm formation with or without recurrent proximal aortic dissection. No recurrence of aortic regurgitation or proximal disease occurred in the other two groups (p <0.01). Actuarial survival of patients in whom the aortic valve was resuspended with GRF glue was 52.1+/-11.6% at five years and 27.8+/-14.3% at eight years, compared with 55.6+/-16.6% at five years if the aortic valve was not resuspended using GRF glue. CONCLUSION: The use of GRF glue to repair acute dissected aortic sinuses combined with the resuspension of the aortic valve is associated with an unacceptable incidence of failure of aortic valve repair and recurrence of aortic regurgitation. It may be more appropriate to resect all acute dissected aortic sinus tissue.

 

Antihypertensive effects of angiotensin converting enzyme inhibition by lisinopril in post-transplant patients
LH Opie, M Haus, PJ Commerford, B Levetan, K Moore and J Brink
Am J Hypertens (2002) 15(10 Pt 1): 911-6
10.1016/s0895-7061(02)02992-8

BACKGROUND: It is not known whether strict control of blood pressure (BP) in mild post-transplant hypertension gives any benefit. Our primary objective was to test the antihypertensive effects of lisinopril added to standard therapy on ambulatory BP (ABP) of post-transplant patients. The secondary objective was to monitor echocardiographic and hemodynamic end points. METHODS: Post-transplant patients with an abnormality of the 24-h ABP recording were recruited to this double-blind randomized prospective study that started 2 to 3 months after transplantation. Patients were then evaluated at 6, 12, 18, and 24 months after transplantation. RESULTS: Lisinopril decreased the clinic BP and ABP, the latter from 134/85 to 126/82 mm Hg at 6 months (P =.01 v placebo) and 121/79 mm Hg after 2 years (P =.03 v placebo). Fewer patients in the lisinopril group required added amlodipine to control the BP (P =.01). Data on left ventricular (LV) mass are difficult to interpret because by coincidence in this small study, the lisinopril group had lower initial values than placebo. However, in the lisinopril group mean LV mass decreased by 10% (P =.02) and mass index by 13% (P =.01), whereas placebo LV mass and index did not change. The LV end-diastolic diameter increased only in the placebo group (P =.008). There were no significant changes in any of the other secondary outcomes, including the cardiac index and systemic vascular resistance. CONCLUSIONS: Thus, in these post-transplant patients, stricter BP control to normal levels by the addition of lisinopril to existing therapy, reduced BP and modestly decreased LV mass without altering cardiac hemodynamic function.

 

Hyperlipidemia coincides with reversible growth impairment of cultured human autologous endothelial cells
J Meinhart, W Halbmayer, M Deutsch and P Zilla
Endothelium (2002) 9(4): 239-246
Patient-related risk factors for the growth of autologous endothelial cells were assessed in a clinical series of 100 consecutive recipients of in vitro endothelialized prosthetic vascular grafts. For all patients, the indication for bypass operation was arteriosclerotic occlusive disease of the distal arteries. Endothelial cells were harvested from a small piece of subdermal vein and cultured in medium containing 20% of autologous serum. Growth was continually monitored. In cultures that failed to grow, the autologous serum supplement to the culture medium was replaced by pooled homologous serum from young healthy donors. The comparison of a multitude of serum parameters between patients whose endothelial cells failed to grow and those showing normal growth revealed a significant difference in serum lipid content: triglycerides: 4.76 +/- 3.36 versus 2.83 +/- 2.28 mmol/L (p = .001); cholesterol: 6.78 +/- 1.69 versus 5.69 +/- 1.32 mmol/L (p = .003); and lipoprotein (a): 35.9 +/- 28.3 versus 22.2 +/- 26.6 mg/dl (p = .04). Following serum exchange with low-lipid pool serum that contained 1.74 mmol/L triglycerides, 4.86 mmol/L cholesterol, 5 mg/dl lipoprotein (a), and 5.79 mmol/L glucose, a remarkable recovery occurred in 85% of these cultures, resulting in fully restored proliferative capacity. As a consequence, population doubling time did not differ between the two groups at any point in time and mass cultures sufficient for confluent graft endothelialization were obtained with hardly any delay. The authors conclude that hyperlipidemia may lead to growth impairment of cultured human endothelial cells. This growth inhibition is reversible if the supplemented autologous serum is replaced by pooled serum with low lipid content.

 

Optimization of diamine bridges in glutaraldehyde treated bioprosthetic aortic wall tissue
P Huma, D Bezuidenhout, M Torrianni, M Hendriks and P Zilla
Biomaterials (2002) 23(10): 2099-103
10.1016/s0142-9612(01)00302-7

OBJECTIVE: Bioprosthetic calcification can be significantly mitigated by both increased concentrations of glutaraldehyde (GA) and the introduction of diamine (DA) bridges. The purpose of the present study was to evaluate whether an optimal effect of DA-enhanced fixation can be achieved by titration of dialdehyde and diamine concentrations. METHODS: Porcine aortic roots were fixed at 0.05% GA (under-fixation) or 0.2% GA and 0.7% GA (commercial fixation). An interim step of DA treatment (L-Lysine; 0, 25, 50 or 100 mM; 37 degrees C; 2 days) was followed by completion of the GA fixation (37 degrees C; 5 days). Aortic wall coupons (12 mm) were punched out and implanted subcutaneously into seven-week old Long-Evans rats for 60 days. Calcium content was assessed by atomic absorption spectroscopy and histology. RESULTS: Increasing the L-Lysine concentrations beyond 25 mM was essential to achieve the anti-calcific effect of DA-enhanced fixation. This effect was proportional to the GA concentrations applied. Compared to non-enhanced GA fixation (0 mM DA), calcification increased by 17.4% (p = 0.2114) in 0.05% fixed tissue but decreased by 32.0% (p < 0.0001) and 45.1% (p < 0.0002) in 0.2% and 0.7% GA, respectively, when the DA concentration was 100 mM. Histologically the extent, but not the pattern of calcification, was affected. CONCLUSION: The calcium mitigating effect of diamine-treatment as an interim step of glutaraldehyde fixation is proportional to the GA concentration applied. Within commercial 0.7% GA fixation 100 mM DA has the potential to practically halve aortic wall calcification.

 

The challenge of pediatric cardiac services in the developing world
J Hewitson, J Brink and P Zilla
Semin Thorac Cardiovasc Surg (2002) 14(4): 340-5
10.1053/stcs.2002.35298

Pediatric cardiac services are too expensive for most developing nations. Problems other than cardiac disease take priority when it comes to budget allocations. Poor health infrastructure and referral systems, malnutrition, and the HIV/AIDS pandemic aggravate the situation, and the increasing economic divide is threatening what services do exist. We highlight how the practice of pediatric cardiac surgery in South Africa compares with first-world standards and outline some of the problems faced by pediatric cardiac services in developing nations.

 

Evaluation of peripheral blood CD4 and CD8 lymphocyte subsets, CD69 expression and histologic rejection grade as diagnostic markers for the presence of cardiac allograft rejection
P Creemers, J Brink, H Wainwright, K Moore, E Shephard and D Kahn
Transpl Immunol (2002) 10(4): 285-92
10.1016/s0966-3274(02)00072-2

We investigated the dynamics of the CD4+ and CD8+ lymphocyte subsets, and the expression of activation markers in cardiac transplant recipients. We tested 132 peripheral blood samples from 62 cardiac transplant recipients using fluorescent staining and flow cytometry analysis. The results were correlated with histological rejection grade of concurrently taken biopsies, and 5-year survival of the recipients. A decrease in the total T lymphocyte subset, and in CD4+ lymphocytes was associated with higher rejection grade and lesser survival. An increase (5-11%) of double positive CD4+ CD8+ lymphocytes was observed; these were mostly CD4brightCD8dim. The CD4/CD8 ratio was significantly (P < 0.00) lower in the transplant recipients than in normal individuals. CD69 expression was higher than CD54 and CD154 expression on CD4 and CD8 lymphocytes of cardiac transplant recipients; correlation between these activation markers was excellent (P < 0.001). Fluorescent staining for CD69 was often of low intensity. Multiple regression for % CD8+ CD69+ cells and survival, and for % CD69+ T cells and rejection grade yielded a significant correlation (P < 0.050). Both % CD8+ CD69+ and % CD69+ T cells were significantly higher in samples with severe and moderate rejection grade (grades 3A, 3B and 4) than in samples which showed no, minimal or mild rejection (grades < or = 2); P-values were 0.052 and 0.003, respectively. Preliminary results indicated that false negative results could be contributed to increased immunosuppression. We conclude that CD69 expression on circulating CD4 and CD8 lymphocytes is a useful parameter for the diagnosis of moderate and severe rejection.

 

Effect of well defined dodecahedral porosity on inflammation and angiogenesis
D Bezuidenhout, N Davies and P Zilla
ASAIO J (2002) 48(5): 465-71
10.1097/00002480-200209000-00004

Porosity is an important factor in the healing of prosthetic devices. To better understand this phenomenon, porous polyurethane scaffolds were produced by a variation of the phase inversion/porogen extraction technique in which a prepacked column of spherical porogen particles was infiltrated with a polymer solution before polymer precipitation and porogen extraction. Scaffolds contained pores of well defined shape (approaching open faced pentagonal dodecahedra), narrow size distributions (66.1 +/- 1.3 microm, 84.2 +/- 1.7 microm, and 156.9 +/- 1.2 microm) and high interconnectivity (interconnecting windows of 30.1 +/- 0.8 microm, 41.9 +/- 1.5 microm, and 76.4 +/- 2.0 microm, respectively). A high degree of accessible macroporosity (>80%) could be achieved while limiting the mostly inaccessible microporosity to below 2%. The neovascularization and inflammatory responses to the scaffolds were evaluated in the subcutaneous rat model for 4 weeks. The inflammatory response index and foreign body giant cell index could be reduced by 56% (p < 0.05) and 21% (p < 0.02), respectively, when the pore size was increased from 66 microm to 157 microm, whereas the vascularization index and arteriolar index remained unchanged. Thus, a significant decrease in inflammatory response could be achieved without adversely affecting the degree of neovascularization by increasing the size of the pores.

 

The anticalcific effect of glutaraldehyde detoxification on bioprosthetic aortic wall tissue in the sheep model
P Zilla, C Weissenstein, M Bracher and P Human
J Card Surg (2001) 16(6): 467-72
10.1111/j.1540-8191.2001.tb00551.x

BACKGROUND: Increasing concentrations of glutaraldehyde (GA) lead to a decreased rather than increased calcification of bioprosthetic aortic wall tissue. This study determined to what extent the benefit of better cross-linking is masked by the intrinsic propensity of GA towards calcification. MATERIALS AND METHODS: Porcine aortic roots were immediately fixed at the abattoir at three different concentrations of GA (0.2%, 1.0%, and 3.0% for 1 week at 4 degrees C). Subsequently, roots underwent a GA extraction process using high volumes of Urazole solution (acetic acid buffer, pH 4.5, 37 degrees C, 1 week) followed by NaBH4 reduction (2 days, 37 degrees C). Roots were implanted in the distal aortic arch of young sheep for 6 weeks and 6 months. Calcium analysis was quantitatively done by atomic absorption spectrophotometry and qualitatively assessed by light microscopy on Von Kossa stains. RESULTS: There was a distinct anticalcification effect of GA detoxification after 6 weeks (56.8% to 97.9%; 95% confidence interval [CI]), which stabilized on a more moderate level after 6 months of implantation (19.1% to 31.6%; 95% CI). The most pronounced effect of GA extraction was seen in 0.2% fixed tissue, where aortic wall calcification was mitigated by 97% and 32% after 6 weeks and 6 months, respectively. Mitigation of aortic wall calcification was 71% (6 weeks) and 21% (6 months) in the 3.0% GA group. The combined effect of higher cross-link density and detoxification achieved an 82% (6 weeks) and 48% (6 months) reduction of calcium levels in the 3.0% GA group. In long-term implants (6 months), detoxification alone on top of standard 0.2% GA fixation was as effective (from 174.1 +/- 11.9 microg/mg without detoxification to 119.3 +/- 19.3 microg/mg with detoxification) as 3.0% fixation (114.8 +/- 10.0 microg/mg without detoxification to 91.3 +/- 11.5 microg/mg with detoxification). CONCLUSION: We were able to determine in the circulatory sheep model to what degree the intrinsic procalcific effect of GA counteracts the protective effect of higher cross-link density. Our study also established that the effect of detoxification is particularly pronounced in commercial low-grade fixation.

 

Diamine extension of glutaraldehyde crosslinks mitigates bioprosthetic aortic wall calcification in the sheep model
P Zilla, D Bezuidenhout, C Weissenstein, A van der Walt and P Human
J Biomed Mater Res (2001) 56(1): 56-64
10.1002/1097-4636(200107)56:1<56::aid-jbm1068>3.0.co;2-3

We previously have been able to show that fixation at increasing concentrations of glutaraldehyde (GA) leads to mitigated rather than facilitated tissue calcification. The purpose of the present study was to introduce additional crosslinks and provide evidence that crosslink density may be an underlying inhibitory principle. Entire aortic roots were chosen to verify the concept on the challenging aortic wall tissue. Porcine aortic roots were crosslinked with 0.2% GA, 3%GA, and 3% GA containing an interim step that introduced diamine bridges. Crosslink efficiency was determined on the basis of shrinkage temperature (SrT degrees ), resistance to protease digestion (RPD), residual amine analysis (RA), and tensile modulus (E(10)). Calcium levels, calcification patterns, and inflammation were assessed after 6 and 24 weeks of implantation in a sheep circulatory model. Crosslink efficiency in aortic wall tissue was moderately affected by increasing the fixative concentration from 0.2% GA to 3% GA (SrT degrees from 85.7 degrees +/- 0.3 degrees to 87.5 degrees +/- 0.3 degrees C, p < 0.002; RPD from 24.2 +/- 1.2 to 29.1 +/- 0.7%, p < 0.003; RA from 0.069 +/- 0.004 to 0.058 +/- 0.003 micromol/mg, p < 0.03, and E(10) from 1.9 +/- 0.11 to 2.94 +/- 0.34 MPa, p < 0.01), but it was distinctly enhanced when diamine bridges were introduced (SrT degrees from 87.5 degrees +/- 0.3 degrees to 93.4 degrees +/- 0.3 degrees C, p << 0.0001; RPD from 29.1 +/- 0.7 to 68.4 +/- 1.8%, p << 0.0001; and E(10) from 2.94 +/- 0.34 to 6.80 +/- 0.61 MPa, p < 0.0003). Aortic wall calcification was reduced significantly by increasing the GA concentration from 0.2 to 3% [37.8%, p = 0.076 (6 weeks) and 34.0%, p = 0.008 (24 weeks)] and further reduced by the introduction of additional diamine [84.0%, p = 0.006 (6 weeks) and 29.8%, p = 0.037 (24 weeks)]. The combined effect of increased GA concentration plus an interim diamine step on aortic wall tissue resulted in a 90% and 53.7% reduction of calcification after 6 weeks and 24 weeks, respectively. The correlation coefficients between calcification and SrT degrees, RDP, and E(10) was -0.9767, -0.9460, and -0.9740, respectively (6 weeks). The inflammatory host reaction regularly found in 0.2% fixed tissue was practically abolished through the introduction of diamine bridges. Our study demonstrated a distinct correlation between the mitigation of aortic wall calcification and three parameters used to assess crosslink density.

 

Prosthetic heart valves: why biological?
UO von Oppell and P Zilla
J Long Term Eff Med Implants (2001) 11(3-4): 105-13
The replacement of heart valves only became feasible after the development of the heart-lung machine in 1953. Two groups of prosthetic heart valves were subsequently developed: biological valves that do not require anticoagulation and mechanical valves that require life-long anticoagulation with Coumadin. The incidence of heart surgery and the demographics of patients who require heart valve surgery vary worldwide; these factors influence the choice of prosthetic valve for the individual patient and are briefly reviewed. Improved biological tissue-fixation methods are also increasing the durability of biological prosthetic valves and will further favor the implantation of biological valves in the future.

 

Biocor No- React stentless aortic valve--short-term results
UO Von Oppell, F Stemmet, B Levetan, SA Heijke and J Brink
Cardiovasc J S Afr (2001) 12(3): 152-8
OBJECTIVES: Short-term results of the bioprosthetic Biocor No-React composite porcine stentless aortic valve (Biocor Industria e Pesquisas LTDA, Belo Horizonte, Brazil) implanted in patients in whom anticoagulation was thought to be contraindicated or expected to be non-compliant. METHODS: Retrospective review of 52 consecutive prospective patients in whom this valve was implanted, between September 1994 and May 1998. RESULTS: Average age was 44 +/- 17 years; 75% of patients were operated on for rheumatic heart disease and combined procedures were done in 40% of cases. Early mortality was 5.8%, and related to pre-operative ejection fraction ( P < 0.03), New York Heart Association (NYHA) class (P < 0.01), and bacterial endocarditis (P < 0.04). On discharge, 84% of survivors were in NYHA class I and 16% in class II. The average postoperative prosthetic valve peak gradient on echocardiography was 19.9 +/- 11 mmHg and was related to pre-operative ejection fraction and smaller valve sizes. Postoperative residual trivial or mild aortic regurgitation was seen in 19 patients (36.6%), resolved on follow-up in 10 cases, and did not correlate with structural deterioration, re-operation, mortality, or widening of the non-coronary sinus. The non-coronary aortic sinus was widened on closure, because of perceived crowding of the adjacent stentless valve commisures, in 52% of cases. This was thought to be related to the use of an oblique as opposed to transverse aortotomy. Patient survival, inclusive of operative deaths, was 88.5%, and event-free survival was 80.0% at 4 years. CONCLUSION: The short-term results of this stentless aortic valve in a young predominantly third-world population group are acceptable, and appear to be superior to the results for mechanical valves in a similar patient group. We would recommend a transverse aortotomy above the sinotubular ridge to be the more appropriate aortotomy incision when using stentless aortic valves.

 

Effectiveness of two radiofrequency ablation systems in atrial tissue
UO von Oppell, T Rauch, G Hindricks, H Kottkamp and F Mohr
Eur J Cardiothorac Surg (2001) 20(5): 956-60
10.1016/s1010-7940(01)00961-7

OBJECTIVE: The efficacy of the left atrial radiofrequency ablation procedure, for the curative treatment of atrial fibrillation, is dependent upon obtaining a confluent transmural line of hyperthermic cellular death. We compare the in vitro effectiveness of obtaining transmural hyperthermic cellular death (>55 degrees C) of both the Osypka single electrode and Boston Scientific Thermaline multi-electrode radiofrequency systems. METHODS: Isolated cadaver porcine hearts were used to measure epicardial temperatures either 'central' or at the 'edge' in relation to an endocardial applied radiofrequency electrode. Reference set point was 70 degrees C, and 4-6-mm thick atrial tissue was used for all applications. 'Edge' temperatures with the Boston Scientific unit were measured whilst activating both adjacent electrodes. RESULTS: Boston Scientific: Probe temperature closely approximated the set point. 'Central' epicardial temperature was lower than probe temperature until after 40 s application (P<0.05), 55 degrees C was reached at 50 s, maximal mean temperature 63.0+/-8.9 degrees C was reached at 100 s. Epicardial 'edge' temperature remained lower than probe temperature for the entire 120 s (P<0.05). Osypka: Probe temperature tended to overshoot the set point. 'Central' epicardial temperature paralleled and occasionally exceeded probe temperature reaching 55 degrees C within 10 s, maximal mean temperature 76.3+/-12.7 degrees C was reached at 10 s and exceeded the set point thereafter. 'Edge' temperature was no different to probe temperature or 'central' epicardial temperature. The mean epicardial temperatures produced with a 65 degrees C set point was no different to that with the 70 degrees C set point, except for a lower final temperature at 60 s. CONCLUSIONS: The Boston Scientific system (70 degrees C set point) requires a minimum in vitro application of 40 s to transmurally increase 4-6 mm atrial tissue temperature above 55 degrees C, and 120-s duration per application would appear to be a reasonable clinical recommendation. The Osypka system transfers thermal energy more effectively, requiring less than 10 s in vitro to achieve a similar transmural temperature, and a 30-s application can be recommended. However, a tendency to overshoot both probe and set point temperature, suggests that a lower set point of 65 degrees C might be safer and as effective.

 

Mitigation of bioprosthetic heart valve degeneration through biocompatibility: in vitro versus spontaneous endothelialization
AE Trantina-Yates, P Human, M Bracher and P Zilla
Biomaterials (2001) 22(13): 1837-46
10.1016/s0142-9612(00)00365-3

BACKGROUND: Glutaraldehyde-related cytotoxicity and transanastomotic ingrowth inhibition prevent the spontaneous endothelialization of bioprosthetic heart valves. In order to evaluate the ability of improved biocompatibility to reduce tissue degeneration, conventionally fixed aortic root prostheses were both glutaraldehyde-detoxified and in vitro endothelialized. METHODS: Entire aortic roots were fixed in 0.2% glutaraldehyde (GA) (control group) and either detoxified in acetic acid-buffered urazole (0.1 M) or detoxified and in vitro lined with cultured, autologousjugular vein endothelial cells. The valved roots were inserted in the distal aortic arch of 15 juvenile Merino sheep for a period of 12 weeks. Upon explant, leaflets, sinuses and aortic wall of the prostheses were analysed by SEM to assess the surface endothelium, histologically regarding tissue inflammation, and by atomic absorption spectrophotometry to determine the content of tissue calcium. RESULTS: There was no endothelium on control grafts, except for a short anastomotic pannus. The detoxified group showed an incomplete patchy endothelium on the aortic wall but hardly any on the leaflets, whereas, the in vitro lined group had aortic wall, sinuses and most of the leaflets confluently endothelialized. Tissue inflammation was prominent in the control group and least expressed in the endothelialized group (p < 0.05). Detoxification significantly reduced leaflet calcification. In the aortic wall, both detoxification and endothelial lining were required to significantly mitigate calcification. CONCLUSION: In the 12 week circulatory sheep model, the calcium mitigating effect of detoxification was more pronounced than that of in vitro endothelialization. Nevertheless, there was a distinct overall benefit if detoxification was combined with endothelialization.

 

Stentless bioprosthetic heart valve research: sheep versus primate model
A Trantina-Yates, C Weissenstein, P Human and P Zilla
Ann Thorac Surg (2001) 71(5 Suppl): S422-7
10.1016/s0003-4975(01)02502-4

BACKGROUND: The mild inflammatory response against stented bioprosthetic heart valves in the sheep model is often opposed by a more distinct response in failing human implants. With the emergence of stentless root prostheses with their significantly larger proportion of tissue interacting with the immune system of the host, a more relevant animal model than the sheep may be needed. METHODS: Valved, porcine aortic roots of 5 cm length were fixed in 0.2% glutaraldehyde and implanted in the upper descending aorta of Merino sheep (n = 5; 43+/-3 kg) and Chacma baboons (n = 5; 17+/-3 kg). After 6 weeks of tissue calcification, pannus outgrowth and inflammation were assessed by atomic absorption spectrophotometry, histologic damage scoring (0 to 3), image analysis, and transmission electron microscopy. RESULTS: The main difference between the two animal models was in aortic wall calcification (64.8+/-39.8 microg/mg in the sheep model versus 4.1+/-5.9 microg/mg in the primate model; p > 0.005). In both models, leaflet calcification was negligible (2.6+/-2.4 microg/mg in the sheep versus 2.5+/-1.9 microg/mg in the primate), and the overall extent of inflammation was comparable (1.2+/-0.8 versus 0.98+/-0.7; p = 0.18 in the sheep and the primate, respectively). Qualitatively, the sheep demonstrated a macrophage-dominated reaction whereas the inflammatory demarcation often resembled a granulocyte-dominated xenograft response in the primate. Pannus outgrowth was comparable in length (8.4+/-2.3 mm versus 9.1+/-4.3 mm proximally and 7.1+/-3.4 mm versus 7.4+/-5.1 mm distally, in the sheep and baboon, respectively; p > 0.05). CONCLUSIONS: Our results confirm the sheep as a significantly stronger calcification model for stentless aortic heart valves than the primate. Remaining antigenicity of porcine tissue as a result of incomplete cross-linking, however, elicits a distinctly stronger xenograft-type reaction in the primate model.

 

Postpneumonectomy aortic arch mycotic aneurysm
F Stemmet, JQ Davies and UO von Oppell
Ann Thorac Surg (2001) 71(3): 1030-2
10.1016/s0003-4975(00)02434-6

A 31-year-old woman who had undergone left pneumonectomy for a tuberculosis-destroyed left lung 3 years previously presented in respiratory distress after a pregnancy complicated by preeclampsia and aspiration pneumonia. Investigation revealed a large aortic arch aneurysm as well as a filling defect in the descending thoracic aortic lumen. Emergency aortic arch reconstruction was performed for a massive pseudoaneurysm or contained rupture filling the entire postpneumonectomy space. Pathologic and microbiological examination demonstrated Aspergillus fumigatus and active inflammation.

 

Cyclic stretch induces the expression of vascular endothelial growth factor in vascular smooth muscle cells
JD Smith, N Davies, AI Willis, BE Sumpio and P Zilla
Endothelium (2001) 8(1): 41-8
10.3109/10623320109063156

OBJECTIVE: Accumulating evidence links the release of vascular endothelial growth factor (VEGF) by vascular smooth muscle cells (VSMC) to normal endothelial cell (EC) function, repair and maintenance. Using an in vitro model we investigate the role of cyclic stretch on both the release of VEGF by VSMC and the phosphorylation of a VEGF receptor on EC. METHODS: Bovine VSMC and EC were exposed to 10% cyclic strain for 4 hours. VEGF mRNA steady-state levels of VSMC were analysed by northern blot hybridisation. The presence of secreted VEGF from VSMC was determined by assaying the migration of EC. VEGF receptor phosphorylation on stretched EC was assayed by immunoblotting. RESULTS: The steady-state level of VEGF mRNA in stretched VSMC increased 3.3 (+/- 0.6) fold above that of unstretched VSMC (p < 0.005). Migration of EC was stimulated 8.3 (+/- 1.1) and 14.6 (+/- 1.3) fold by media from unstretched and stretched VSMC respectively, demonstrating a 1.8 fold increase due to stretch alone (p < 0.05). Cyclic stretch resulted in phosphorylation of the VEGF receptor KDR. CONCLUSION: Exposure of VSMC to physiological levels of stretch induces a biologically significant increase in VEGF secretion and may provide an arterial stimulus for maintenance of steady state levels of VEGF essential for EC survival.

 

Engineering of vascular ingrowth matrices: are protein domains an alternative to peptides?
C Merzkirch, N Davies and P Zilla
Anat Rec (2001) 263(4): 379-87
10.1002/ar.1118

Anastomotic intimal hyperplasia and surface thrombogenicity are the main reasons for the high failure rate of prosthetic small-diameter vascular grafts. While anastomotic intimal hyperplasia is a multifactorial event, ongoing surface thrombogenicity is primarily caused by the lack of an endothelium, even after years of clinical implantation. After decades of poorly performing synthetic artery-grafts, tissue engineering has emerged as a promising approach to generate biologically functional bio-synthetic hybrid grafts mimicking native arteries regarding the presence of an endothelial lining on the blood surface. "In vitro endothelialization" represented the first generation of such tissue-engineered vascular grafts, utilising cell culture techniques for the creation of a confluent autologous endothelium on ePTFE grafts. The clinical long-term results with this method in almost 200 patients are highly encouraging, showing patencies equal to vein grafts. Since "in vitro endothelialization" requires cell culture facilities, it will always be confined to large centres. Therefore, research of the 1990s turned to the development of spontaneously endothelializing implants, to make tissue-engineered grafts amenable to the entire vascular-surgical community. Apart from scaffold designs allowing transmural ingrowth, biological signalling through a facilitating ingrowth matrix holds a key to spontaneous endothelialization. In biological signalling, the increasingly deeper understanding of bio-active molecules and the discovery of domains and peptide sequences during the 1980s created the expectation in the 1990s that peptide signalling may be all that is needed. This present review highlights the possible problems associated with such a reductionist approach. Using the fibronectin molecule, we demonstrated that domains may be more suitable modules in tissue engineering than peptide sequences.

 

Clinical autologous in vitro endothelialization of 153 infrainguinal ePTFE grafts
JG Meinhart, M Deutsch, T Fischlein, N Howanietz, A Froschl and P Zilla
Ann Thorac Surg (2001) 71(5 Suppl): S327-31
10.1016/s0003-4975(01)02555-3

BACKGROUND: Over the past 17 years, our group has developed and clinically applied an in vitro endothelialization procedure whereby infrainguinal expanded polytetrafluoroethylene (ePTFE) prostheses are confluently lined with cultured autologous endothelial cells before implantation. After a successful randomized pilot study from 1989 to 1993, the procedure was adopted for routine operations. METHODS: Since June 1993, 153 endothelialized ePTFE grafts were implanted in the infrainguinal position in 136 patients (102 above knee (AK) and 51 below knee (BK), 89 men and 47 women, mean age 64.7+/-9.4 years). Seventeen patients received an endothelialized prosthesis bilaterally. Autologous endothelial cells were harvested from 4- to 5-cm segments of a subcutaneous vein (in 86% the cephalic vein), grown to first-passage mass cultures and confluently lined onto 6- (n = 113) or 7-mm (n = 40) inner diameter (ID) ePTFE grafts, precoated with fibrin glue. The observation period for 6-mm grafts was 7 years, and for 7-mm grafts was 4 years. Patency assessment for Kaplan-Meier survivorship analyses was based on duplex sonography and angiography. RESULTS: Kaplan-Meier survivorship function revealed a primary patency rate of 62.8% after 7 years (SE = 0.05) for all infrainguinal reconstructions (60% AK/70.8% BK). The primary patency for stage II and III patients was 64.4% after 7 years. The more recent group of 7-mm ID grafts showed a primary patency of 83.7% after 4 years. CONCLUSIONS: Our data provide strong evidence that autologous endothelial cell lining distinctly improves the patency of small diameter vascular grafts.

 

Characterization of the immune response to valve bioprostheses and its role in primary tissue failure
P Human and P Zilla
Ann Thorac Surg (2001) 71(5 Suppl): S385-8
10.1016/s0003-4975(01)02492-4

BACKGROUND: The role of an immune response in the failure of bioprosthetic heart valves is poorly understood and disregarded by many. To elucidate the nature of the immune response to glutaraldehyde-treated tissue and the possible role of graft-specific antibody in graft mineralization, we performed immune-calcification studies in the rabbit and correlated those results with the analysis of specific antibodies. METHODS: Aortic wall buttons (6 mm) were punched from porcine aortic wall tissue fixed with 0.2% glutaraldehyde and detoxified with urazole and then subsequently perforated under sterile conditions. The perforated buttons were then incubated with either immune serum prepared by immunization of New Zealand White rabbits (n = 5) with Freund's incomplete adjuvant emulsions of tissue homogenates of similarly treated aortic wall tissue, or incubated with the corresponding control preimmune sera obtained before immunization of the same animals. The tissue was then implanted subdermally on the back of unrelated New Zealand White rabbits (n = 8) for a period of 3 weeks. After the buttons were explanted, tissue calcium levels were determined by atomic absorption spectroscopy. RESULTS: Tissue calcium was increased in all five immune serum-treated replicates (range, 61.8% to 431.2%; mean, 225.9%+/-73.2%) when compared with control samples treated with preimmune sera. Overall, the mean calcium level was significantly increased (p < 0.0001) when tissue was treated with immune sera (66.0+/-10.0 microg/mg versus 22.6+/-4.8 microg/mg in control tissue). Graft specificity of immune sera was confirmed by Western blot analysis. CONCLUSIONS: These results strongly suggest a role of circulating graft-specific antibody in the disease of bioprosthetic graft calcification.

 

The possible role of immune responses in bioprosthetic heart valve failure
P Human and P Zilla
J Heart Valve Dis (2001) 10(4): 460-6

 

Inflammatory and immune processes: the neglected villain of bioprosthetic degeneration?
P Human and P Zilla
J Long Term Eff Med Implants (2001) 11(3-4): 199-220
In an attempt to avoid the destructive process of bioprosthetic heart-valve calcification associated with the use of glutaraldehyde, valves are today prepared using low concentrations of the crosslinking reagent. In this review, we summarize our findings and those of others that confirm that the immunogenicity of such tissue is not sufficiently masked and that a defined humoral response is indeed mounted against a repertoire of antigens unrelated to those associated with vascularized and non-cross-linked xenograft organs. We demonstrate the need for increased cross-linking of tissue to satisfactorily mitigate that response; furthermore, we examine the impact of increased cross-link density on the macrophage as antigen presenting cell with respect to its involvement in both tissue erosion and pannus overgrowth. Finally we present evidence for a role of circulating antibodies in bioprosthesis calcification.

 

Fixation-related autolysis and bioprosthetic aortic wall calcification
P Human, C Weissenstein, A Trantina and P Zilla
J Heart Valve Dis (2001) 10(5): 656-65
BACKGROUND AND AIM OF THE STUDY: It has been established previously that immediate fixation and increased glutaraldehyde (GA) concentrations are required to prevent severe autolytic tissue damage during bioprosthetic aortic root production. The study aim was to verify that structure-preserving fixation also reduces aortic wall calcification. METHODS: Porcine aortic roots were fixed either instantly or after being kept on ice for 48 h (phosphate-buffered saline, PBS). Two concentrations of GA (0.2% and 3.0%) were chosen (4 degrees C, seven days, PBS). Discs of aortic wall tissue (1.2 cm diameter) were implanted subcutaneously in rats for 60 days (n = 10 per group), while aortic roots were implanted in the distal aortic arch of sheep for six weeks (n = 3 per group) and six months (n = 4 per group). Calcification was assessed by atomic absorption spectrophotometry and light microscopy. Fixation-related tissue damage was determined by transmission electron microscopy, and correlated with calcification. RESULTS: No significant difference in calcification was found between immediate and delayed fixation if tissue was fixed with 0.2% GA. In the 3.0% GA group, both animal models showed a significantly lower level of calcification if tissue was immediately fixed. In the subcutaneous rat model, immediate fixation reduced calcification by 26% (p <0.0001). In the circulatory sheep model immediate fixation did not affect calcification in the short-term six-week implants, but markedly lowered it by 37% (p = 0.035) after six months. Ultrastructurally, there was a significant correlation between membrane damage, vacuolization and vesicle shedding on the one hand, and calcification on the other. CONCLUSION: Coincidental fixation-related ultrastructural damage and increased calcification was demonstrated in bioprosthetic aortic wall tissue.

 

The bridge graft: a new concept for infrapopliteal surgery
M Deutsch, J Meinhart, N Howanietz, A Froschl, B Heine, R Moidl, H Mendel, A Sisel, A Stumpflen and P Zilla
Eur J Vasc Endovasc Surg (2001) 21(6): 508-12
10.1053/ejvs.2001.1361

BACKGROUND: The long-term results of ePTFE grafts are particularly poor in crural reconstructions. We report on a novel surgical technique, whereby both run-off and anastomotic mismatches are concomitantly addressed. PATIENTS AND METHODS: Short segments of vein grafts (5-15 cm in length) were used to bridge two crural artery segments. Subsequently, a femoro-distal ePTFE graft was anastomosed to the bridge graft. Venous valves were made incompetent to allow bi-directional flow. In a retrospective series of 45 patients with crural bridge grafts, 12 patients were in stage III and 33 in stage IV. In 18 patients the reconstruction was the first procedure and in the remaining 28 patients it was the first or second re-operation. RESULTS: The primary patency rate at 1, 2, 3 and 4 years was 53, 44, 35 and 26% respectively. The secondary patency rate was 67, 53, 49 and 39% respectively. The corresponding limb salvage rate was 70, 61, 56 and 45%. In a small subgroup of patients, in which the crural bridge was the first reconstructive procedure, the primary patency was 76 at 1 year and 64 at 4 years. CONCLUSION: convincing long-term crural bridge grafts should be considered in those patients who have more than one crural or pedal artery available for grafting and an insufficient length of saphenous vein.

 

Rupture of the auricle of the right atrium of the heart and pericardium after blunt trauma
E Degiannis, J Brink, M Haagensen, P Williams and K Boffard
Eur J Surg (2001) 167(6): 472-4
10.1080/110241501750243879

 

Matrix metalloproteinases and tissue valve degeneration
M Bracher, D Simionescu, A Simionescu, N Davies, P Human and P Zilla
J Long Term Eff Med Implants (2001) 11(3-4): 221-30
Bioprosthetic heart valves have been used as replacements for diseased heart valves for over 30 years. More than 50% of bioprosthetic valves fail within 15 years because of structural deterioration. The role of proteolytic degradation, with particular reference to the matrix metalloproteinases (MMPs) in the degeneration of aortic bioprostheses, is appraised in this minireview. It is clear that both the intrinsic and host-derived proteolytic activities present in heart-valve bioprostheses may combine with mechanical stress to bring about valve failure.

 

Comments on the first human-to-human heart transplant. 1993
CN Barnard
Cardiovasc J S Afr (2001) 12(4): 192-4

 

High glutaraldehyde concentrations mitigate bioprosthetic root calcification in the sheep model
P Zilla, C Weissenstein, P Human, T Dower and UO von Oppell
Ann Thorac Surg (2000) 70(6): 2091-5
10.1016/s0003-4975(00)02011-7

BACKGROUND: Fixation at high glutaraldehyde (GA) concentrations mitigated bioprosthetic calcification in the rat model. The present study intended to verify this observation in the circulatory sheep model. METHODS: Porcine aortic roots were either fixed in 0.2%, 1.0%, or 3.0% GA. Eight roots per group were implanted in the distal aortic arch of sheep. After six weeks and six months calcification and inflammation were quantitatively and qualitatively assessed. RESULTS: By increasing the GA concentration from 0.2% to 3.0%, aortic wall calcification could be reduced by 38% after 6 weeks and 34% after 6 months of implantation (p < 0.01). Mineralization coincided with the presence of elastin although calcium was predominantly found in cell nuclei and membranes. Leaflet calcification was absent in all groups after 6 weeks but in a few leaflets presented as heterogeneous, nodular spongiosa deposits after 6 months. Overall, differences between 0.2%-, 1.0%-, and 3.0%-fixed tissue were quantitative but not qualitative regarding distribution patterns. There was no significant difference in inflammatory host reaction between all groups. CONCLUSIONS: We have shown in the circulatory sheep model that the anticalcific effect of better cross-linking seems to outweigh the intrinsic pro-calcific effect of GA accumulation in bioprosthetic aortic wall tissue.

 

Glutaraldehyde detoxification in addition to enhanced amine cross-linking dramatically reduces bioprosthetic tissue calcification in the rat model
C Weissenstein, P Human, D Bezuidenhout and P Zilla
J Heart Valve Dis (2000) 9(2): 230-40
BACKGROUND AND AIM OF THE STUDY: Enhanced fixation of bioprosthetic tissue by both increased concentrations of glutaraldehyde (GA) and the introduction of additional cross-links with L-lysine significantly reduces calcification. We have previously reported that prolonged exposure to high-volume amino-compounds under warm, acidic conditions leads to thorough, non-rebounding GA detoxification. The aim of the present study was to prove that removal of excess GA can amplify the benefits of enhanced GA cross-linking with regard to bioprosthetic tissue calcification. METHODS: Porcine ascending aortas and leaflet tissue, and bovine pericardium were immediately fixed using three GA concentrations (0.2%, 1.0%, 3.0% (v/v)) for seven days at 4 degrees C. Samples were allocated to nine groups. Groups I to III received no further treatment (one at each GA concentration); groups IV to IX underwent an additional L-lysine interim step (48 h/37 degrees C/0.1 M) two days before completion of standard seven-day GA fixation; and groups VII to IX were additionally treated with a GA extraction process using high-volume urazole solution (acetic acid buffer, pH 4.5, 37 degrees C, one week) followed by NaBH4 reduction (2 days, 37 degrees C). Samples were implanted subcutaneously in rats (six per group) for six weeks. Tissue calcium was measured by atomic absorption spectrophotometry and examined histologically after von Kossa staining. RESULTS: Calcification was reduced in all three tissue types by enhanced cross-linking and by extraction of excess GA. Increasing the GA concentration from 0.2% to 3.0% led to a reduction in calcification of 11.5% (p = 0.074; Student's t-test) in leaflets; 63.6% (p <0.0001) in pericardium; and 17.5% (p = 0.034) in aortic wall tissue. The introduction of additional cross-links with L-lysine resulted in a significant reduction of calcium in all tissues (maximally 42.5%, p = 0.0003 in leaflets; 79.3%, p = 0.005 in pericardium; and 49.6%, p <0.0001 in aortic wall; Student's t-test). Optimal reduction in calcification could be achieved with the combined effect of 3.0% GA fixation, L-lysine enhancement and urazole detoxification. When compared with 0.2% GA-fixed tissue, calcification could be reduced by 99.1% in leaflets, 95.9% in pericardium, and 90.8% in aortic wall tissue (p <0.0001 for all tissue types; Student's t-test). CONCLUSION: Removal of excess GA from fixed bioprosthetic tissue was capable of markedly improving the anti-calcific effect of enhanced GA cross-linking.

 

Ischemic mitral valve repair surgery
UO von Oppell, F Stemmet, J Brink, PJ Commerford and SA Heijke
J Heart Valve Dis (2000) 9(1): 64-73; discussion 73-4
BACKGROUND AND AIM OF THE STUDY: The management of concomitant moderate or severe ischemic mitral regurgitation in the presence of ischemic heart disease is important for long-term prognosis. Mitral repair by either a suture or ring annuloplasty method has been advocated, although clear superiority of either method has not been established. METHODS: Combined coronary artery bypass and mitral valve surgery for ischemic mitral incompetence was performed on 68 consecutive patients between January 1996 and December 1998. The outcome in 63 of these patients (35 females, 28 males) who underwent mitral valve repair was reviewed. RESULTS: Average patient age was 61+/-9.4 years (range: 39-81 years). Average left ventricular ejection fraction (LVEF) was 42.1%; a suture annuloplasty was used in 84% and a ring in 16%. The average number of distal anastomoses was 3.9+/-1.1 (range: 1-6) and aortic cross-clamp time was 131+/-35 min (range: 58-238 min). Operative mortality rate (<30 days or in-hospital) was 12.7% and only requirement for intra-aortic balloon pumping either before or during surgery (21%) was predictive (p<0.05). On discharge, 98.2% of patients were in NYHA class I or II. Follow up (range: 1-35 months) was complete in 95% of cases. Moderate mitral regurgitation on discharge occurred in nine patients and was not related to the type of annuloplasty. Predictive risk factors were preoperative severe mitral regurgitation (p<0.04), poor LVEF (p = 0.05), and was predictive of deterioration of NYHA class (p<0.02), progression of regurgitation (p<0.05), and poor outcome (p<0.01). Poor outcome was also related to surgeon's experience. Structural valvular deterioration occurred in 21.8% of operative survivors, and there was one reoperation and four late deaths. The survival rate (including operative deaths) at 35 months was 68.3 +/- 13.1%, and event-free survival rate (no mortality, reoperation or angina) 65.2+/-6.2%. CONCLUSIONS: The type of annuloplasty used did not influence outcome. The risk of structural mitral valve dysfunction on follow up was related to severe preoperative mitral regurgitation, poor LVEF, surgeon's experience, and was predictive of poor outcome.

 

Penetrating thoracic injuries: what we have learnt
UO von Oppell, P Bautz and M De Groot
Thorac Cardiovasc Surg (2000) 48(1): 55-61
10.1055/s-2000-8891

BACKGROUND: Thoracic injuries, especially cardiac, vascular, and transmediastinal injuries, are amongst the most lethal of penetrating injuries. METHOD: Our experience at Groote Schuur Hospital is reviewed, where up to 1,000 patients were admitted annually with penetrating chest wounds between 1982 and 1997. RESULTS: The approximate pre-hospital mortality was 86% with penetrating cardiac injuries, 92 % with extrapericardial vascular injuries, and 11 % with pulmonary injuries. Less than 2% of pneumothorax cases and less than 10% of haemothorax cases required surgical intervention. Thoracoscopic evacuation of retained clots was successful in the majority of the latter. Most penetrating injuries of the thoracic duct required surgical exploration. The mortality of penetrating cardiac injuries varied according to clinical presentation (moribund 52%, hypovolaemia 20% and tamponade 2-5%) and the chamber involved. Higher mortalities were associated with atrial injuries. CONCLUSIONS: The appropriate use of intercostal drains and therapeutic thoracoscopy are important considerations in penetrating non-cardiac thoracic trauma. Rapid transportation, immediate triage, open-minded use of emergency room thoracotomy, and aggressive surgical management with liberal use of sub-xiphisternal pericardial windows are important factors in improving the survival of penetrating cardiac trauma.

 

Endothelial Cell Seeding – Revisiting the issue
M Deutsch, J Meinhart, J Schense, JA Hubbell and P Zilla
Journal of Vascular Surgery (2000) 31(1265-1268
The primary patency rates of synthetic vascular grafts are significantly lower than those of saphenous vein grafts, necessitating alternatives like endothelial cell seeding to improve outcomes. This study investigates the efficacy of in vitro endothelialization techniques over almost a decade of clinical trials involving 140 patients, revealing improved patency rates for endothelialized ePTFE grafts compared to conventional strategies. Notably, endothelialized grafts showed distinct advantages in both above-knee and below-knee positioning, particularly when using an RGD-enriched fibrin matrix to enhance cell retention.

 

Endothelial cell transplantation
P Zilla, M Deutsch and J Meinhart
Semin Vasc Surg (1999) 12(1): 52-63
After more than 20 years of autologous endothelial cell transplantation, controversy is slowly giving way to consensus. The ongoing discussion regarding the optimal methods of creating an endothelial layer on synthetic vascular prostheses has been replaced by the realization that both in vitro endothelialization with cultured venous endothelial cells and mixed microvascular sodding result in equilibrated luminal tissue layers covered by a persistant endothelium. Clinical trials with almost 200 in vitro endothelialized prostheses are in their 10th year, and patency results are distinctly better than in nonendothelialized prostheses, particularly in below-the-knee grafts.

 

Dysphagia lusoria
DI Kettles, SE Latouf and U Von Oppell
Clin Cardiol (1999) 22(11): 751
10.1002/clc.4960221117

 

Endothelial cell Transplantation in Vascular Surgery: A Breakthrough at Last
M Deutsch, J Meinhart and P Zilla
Italian Journal of Vascular Surgery (1999) 6(1-21

 

Clinical autologous in vitro endothelialization of infrainguinal ePTFE grafts in 100 patients: a 9-year experience
M Deutsch, J Meinhart, T Fischlein, P Preiss and P Zilla
Surgery (1999) 126(5): 847-55
BACKGROUND: Clinical in vitro endothelialization was assessed for its ability to improve the long-term patency of prosthetic femoropopliteal bypass grafts. METHODS: Between June 1989 and May 1998, 100 patients received 113 in vitro endothelialized expanded polytetrafluoroethylene grafts (ePTFE). Bilateral implantations were performed in 13 patients. In phase 1 of the study, 24 patients received 27 endothelialized grafts and 16 patients received 17 untreated grafts. In phase 2, endothelialization was offered to all patients who did not have a suitable saphenous vein available. Phase 2 began in June 1993 and included 76 patients who received 86 endotheliazed ePTFE grafts. In all, 100 patients had autologous endothelial cells harvested from 4- to 5-cm segments of a subcutaneous vein. In phase 1, the external jugular vein was used. In phase 2, the cephalic vein was used. These cells were grown to first-passage mass cultures and were lined confluently onto 6-mm ePTFE grafts, pre-coated with fibrin glue. Patency assessment for Kaplan-Meier survivorship analysis was determined by using duplex sonography and angiography. RESULTS: In phase 1, the Kaplan-Meier method revealed a primary 9-year patency rate for 65% for the endothelialized group, versus 16% for the control group (log-rank test, P = .002; Wilcoxon test, P = .003). In phase 2, the 5-year primary patency rate for all in vitro endothelialized infrainguinal reconstructions was 68% (66% for above-the-knee grafts and 76% for below-the-knee grafts). CONCLUSIONS: Nine years of clinical in vitro endothelialization provided strong evidence that autologous endothelial cell lining improves the patency of small-diameter vascular grafts and that a cell culture-dependent procedure can be used in a clinical routine.

 

Developing biotechnology around the world
JA Brink, B Prior and EJ DaSilva
Nat Biotechnol (1999) 17(5): 434-6
10.1038/8602

 

Mistaken angiographic diagnosis of traumatic aorto-atrial fistula
S Williams-Jones, S Beningfield and J Brink
Australas Radiol (1998) 42(3): 264-6
10.1111/j.1440-1673.1998.tb00515.x

A case of angiographically occult traumatic aorto-caval fistula masquerading as aorto-right atrial fistula is presented. The importance of angiographic vigilance in the imaging of arterio-venous fistula is emphasized.

 

Tissue adhesives in cardiovascular surgery
UO von Oppell and P Zilla
J Long Term Eff Med Implants (1998) 8(2): 87-101
Tissue adhesives are increasingly being used in cardiovascular surgery as adjuncts to obtain more rapid hemostasis, as tissue reinforcing agents, as carriers for prolonged local release of antibiotics, to spatially fix long saphenous vein grafts that could otherwise possibly kink, and to promote endothelialization of prosthetic graft surfaces. The available tissue adhesives, their current indications for use, and possible future trends are discussed.

 

New solution for prolonged myocardial preservation for transplantation
H Schwalb, L Grinberg, E Yaroslavsky-Houminer, G Lazarovici, U Von Oppell, M Worthington, G Merin and JB Borman
J Heart Lung Transplant (1998) 17(2): 222-9
BACKGROUND: A solution for prolonged cold storage of the heart has been developed. The Jerusalem-Cape Town Solution (JCT) is an "intracellular" type cardioplegic solution and is formulated to (1) minimize hypothermic-induced cell swelling, (2) diminish intracellular acidosis, (3) prevent the expansion of the interstitial space during the reperfusion, (4) protect against oxygen free radical injury during early reperfusion, and (5) provide substrates for regenerating high-energy phosphates. METHODS: With a Langendorff model, rat hearts were subjected to 15 minutes of perfusion with Krebs-Henseleit, 10 minutes of cardioplegic infusion and 20 hours of cold storage (5 degrees to 6 degrees C). Hearts were reperfused for 60 minutes and hemodynamic recovery was assessed. The hearts were assigned to three groups (eight hearts in each), according to the cardioplegic solution used: group 1, JCT; group 2, Bretschneider's HTK cardioplegic solution; and group 3 University of Wisconsin cold storage solution. RESULTS: After 60 minutes of reperfusion, the recovery of the coronary artery flow in group 1 (JCT) was significantly better than in group 2, and slightly better than in group 3 (64% +/- 8.9%, 47.2% +/- 11.6%, 52.5% +/- 19.9%, mean +/- SD, respectively; group 1 versus group 2, p < 0.01). The recovery of the left ventricular developed pressure (LVDP) was significantly better in group 1 compared with group 2 and group 3 (60.2% +/- 14.5%, 41.1% +/- 12.6% and 36.5% +/- 10.1%, respectively; p < 0.01). The recovery of the heart contractility expressed by the product of LVDP and the heart rate (LVDP x heart rate) was significantly higher in group 1 than in group 2 and group 3 (47.5% +/- 3.4%, 23.6% +/- 9.6%, and 28.7% +/- 8.3%, respectively, p < 0.001). In hearts stored for 12 hours in JCT or HTK, the recovery of the heart contractility did not differ significantly (73.4% +/- 12.7% or 70.8% +/- 30.8%, respectively). Modified reperfusion aimed to improve postischemic heart recovery did not bring significant changes in cardiac mechanical function but resulted in an increase in postischemic coronary artery flow recovery in hearts reperfused with amino acid-enriched buffer. CONCLUSIONS: The JCT solution is effective (as well as HTK) in preserving the ischemic hearts for up to 12 hours. It is superior to HTK or University of Wisconsin solution at 20 hours of isolated ischemic storage.

 

Blunt cardiac rupture
JO Fulton, L Nel, KM de Groot and UO von Oppell
S Afr J Surg (1998) 36(4): 132-5
Cardiac rupture as a result of blunt trauma is not commonly encountered. Seven patients with this injury have been treated at Groote Schuur Hospital over the past 14 years. All presented with cardiovascular collapse and 4 developed signs of cardiac tamponade. A clinical diagnosis was made in 4 patients and echocardiography was done in 3. Pericardiocentesis was used in 1 patient to confirm the diagnosis. Significant diagnostic delay occurred in 1 patient with associated liver rupture. Two patients required emergency room thoracotomy. All other patients were approached using a median sternotomy. Five patients survived, giving an overall survival rate of 71%. Five patients had right atrial ruptures and 2 right ventricular ruptures. One patient with right ventricular rupture died in the operating room, while another patient with multiple right atrial ruptures died from multiple organ failure after 11 days. We also briefly review the history, mechanisms and pathology.

 

Blunt cardiac rupture caused by zip gun backfire
JO Fulton, M De Groot, UO Von Oppell and T Ruttman
Ann Thorac Surg (1998) 65(3): 837-9
10.1016/s0003-4975(98)00005-8

A 16-year-old boy who sustained right ventricular rupture after backfiring of a homemade zip gun is reported. The unusual nature of this case together with the mechanisms and management of blunt cardiac rupture are briefly discussed.

 

Improved ultrastructural preservation of bioprosthetic tissue
P Zilla, Y Zhang, P Human, W Koen and U von Oppell
J Heart Valve Dis (1997) 6(5): 492-501
BACKGROUND AND AIMS OF THE STUDY: Poor ultrastructural tissue preservation of bioprosthetic heart valves is associated with a higher propensity for calcification. In spite of this realization, commercial valve fixation remains suboptimal. METHODS: In an attempt to maintain tissue integrity through improved cross-linking procedures, transmission electron microscopy and a 21-point damage score were applied to assess the ultrastructural preservation of aortic wall tissue-the main component of contemporary aortic valve bioprostheses. An ideal glutaraldehyde (GA) concentration was assessed by immediate tissue fixation at 4 degrees C comparing 0.2%, 0.5%, 0.65%, 1.0%, 2.0%, 3.0% and 4.0% GA in phosphate-buffered saline (PBS). Subsequently, an optimal concentration of 3.0% GA was used to determine the effect of fixation temperature (4 degrees, 22 degrees and 37 degrees C). Finally, the superior glutaraldehyde concentration (3.0%) and cross-linking temperature (4 degrees C) were used to assess tolerance towards delayed fixation. RESULTS: When different GA concentrations were used almost identical damage scores of 6.3 and 5.8 were found for 0.2% and 0.65% fixation. The first significant improvement was found at a concentration of 1.0% (score 3.3; p < 0.01) followed by a further improvement at 3.0% (score 2.6; p = 0.05). The optimal fixation temperature was 4 degrees C (3.7) with the worst results obtained at room temperature (score 9.2; p < 0.03). When fixation was delayed, the most significant damage occurred during the initial 30 min after slaughter (from 2.3 to 7.4; p < 0.02) followed by another significant deterioration between 4 and 16 h (from 5.6 to 9.7; p < 0.02). CONCLUSIONS: In summary, the prerequisites for an ideal ultrastructural preservation of bioprosthetic aortic wall tissue are immediate fixation (within 30 min), high GA concentrations (> 1.0%) and cold-temperature fixation (4 degrees C).

 

High glutaraldehyde concentrations reduce rather than increase the calcification of aortic wall tissue
P Zilla, C Weissenstein, M Bracher, Y Zhang, W Koen, P Human and U von Oppell
J Heart Valve Dis (1997) 6(5): 502-9
BACKGROUND AND AIMS OF THE STUDY: This study was performed in order to: (i) determine whether a similar reduction of tissue calcification as seen after prolonged storage can be achieved through higher concentrations of glutaraldehyde (GA); and (ii) verify that well-preserved tissue integrity can suppress calcification. METHODS: Before fixation in 0.2% GA (PBS, 4 degrees C, seven days) porcine aortas were kept on ice for 48 h. Alternatively, tissue was immediately fixed at the abattoir in 0.2%, 1.0% or 3% glutaraldehyde (PBS, 4 degrees C, seven days). A second group of immediately fixed tissue (0.2%, 1.0%, 3.0% GA) (PBS, 4 degrees C, two days) had an interim step of L-lysine treatment (0.1M, 37 degrees C, acetic acid buffer, two days) in order to enhance cross-linking followed by warm-temperature fixation (PBS, 37 degrees C, five days). Two animal models were compared: subcutaneous implantation in rats (12 weeks) and vascular implantation in non-human primates, Chacma baboons (six weeks). RESULTS: In both animal models the highest level of calcification was found in the group with delayed fixation in 0.2% GA. In the rat model there was an inverse correlation between tissue calcification and the GA concentration used, with 3% GA-fixed tissue showing the lowest level of tissue calcium. Overall, increasing GA concentration had a significant benefit on calcification (p < 0.0001; two-factor analysis of variance). Enhancement of cross-linking with L-lysine further abrogated tissue calcium levels at all GA concentrations (p < 0.0001; two- factor analysis of variance). Although the short-term baboon model showed lower tissue calcium levels, the trend seen in the rat model was confirmed. CONCLUSIONS: Our results demonstrate the detrimental effect of delayed fixation and further suggest that, against previous beliefs, fixation at higher glutaraldehyde concentrations reduces the calcification tendency of cross-linked aortic tissue.

 

Glutaraldehyde detoxification of aortic wall tissue: a promising perspective for emerging bioprosthetic valve concepts
P Zilla, L Fullard, P Trescony, J Meinhart, D Bezuidenhout, M Gorlitzer, P Human and U von Oppell
J Heart Valve Dis (1997) 6(5): 510-20
BACKGROUND AND AIMS OF THE STUDY: Due to its superb crosslinking activity, glutaraldehyde (GA) is still the most widely used fixative for bioprosthetic heart valves. At the same time, however, GA is also believed to be partly responsible for tissue calcification and the lack of surface re-endothelialization, both of which may contribute to valve degeneration. Although excess GA has previously been extracted from thin leaflet tissue, this treatment proved insufficient for the detoxification of thick aortic wall tissue of stentless valves or root prostheses. METHODS: In order to establish a detoxification procedure which thoroughly extracts biologically active GA from aortic wall tissue, we used a highly sensitive bioassay where endothelial cells were seeded onto glutaraldehyde-fixed aortic wall discs following various detoxification procedures. Absolute cell numbers and morphologic shape were correlated with shrinkage temperature and shrinkage extent of the tissue to determine the potential of the treatments to reverse crosslinks. To optimize treatment conditions, pH (3.2 versus 4.5), temperature (22 degrees C versus 37 degrees C) and incubation time (48 h versus one week) were varied. In order to identify an optimal detoxification agent, 12 different amino-reagents from four chemical groups were compared: low pKa aromatic amines, amino acids, low pKa N-heterocyclic compounds and amino sugars. RESULTS: Amino-reagent treatment required warm temperature (37 degrees C), prolonged reaction time (one week) and a pH of 4.5 to achieve long-term cell growth on glutaraldehyde-fixed aortic wall. All 12 amino-reagents were able to detoxify aortic tissue satisfactorily; and all mildly reversed crosslinks, although there were differences between candidates. When summarized data were ranked correlating cell growth and quality with shrinkage temperature and shrinkage extent, seven reagents had a rank sum above the overall mean value, and five below with statistically significant differences between candidates. The additional stabilization of the detoxification reaction through borohydride-reduction had no further effect on tissue biocompatibility and crosslinks. CONCLUSIONS: Efficient detoxification of thick aortic wall tissue is possible if a one-week incubation in an acetic acid buffer-based amino-reagent is carried out at 37 degrees C.

 

Pulmonary resection as an adjunct in the treatment of multiple drug-resistant tuberculosis
M van Leuven, M De Groot, KP Shean, UO von Oppell and PA Willcox
Ann Thorac Surg (1997) 63(5): 1368-72; discussion 1372-3
BACKGROUND: Over the past decade the incidence of pulmonary disease due to drug-resistant strains of Mycobacterium tuberculosis has increased worldwide. We reviewed our local experience to clarify the benefits and risks of pulmonary resection in the management of drug-resistant strains of Mycobacterium tuberculosis. METHODS: A retrospective review was performed of 62 patients undergoing pulmonary resection for drug-resistant strains of Mycobacterium tuberculosis between January 1990 and November 1995. RESULTS: Fifty-three percent were men and 47% women with an average age of 34 years (range, 16 to 72 years). There was one postoperative death, for a perioperative (30-day) mortality of 1.6%. Sixteen complications occurred in 14 patients for an overall morbidity of 23%. Eighteen of 24 patients (75%) who were persistently sputum positive at the time of operation immediately converted to a negative sputum smear and culture. For all patients who were sputum negative after operation 80% remain relapse-free by actuarial analysis. CONCLUSIONS: We believe that operation plays an important ancillary role in the treatment of drug-resistant strains of Mycobacterium tuberculosis. The operation can be performed with acceptable morbidity and mortality and must be combined with appropriate and well-monitored pre- and postoperative antituberculous drug therapy.

 

Pulmonary artery banding: adequacy and long-term outcome
P Pinho, UO Von Oppell, J Brink and J Hewitson
Eur J Cardiothorac Surg (1997) 11(1): 105-11
10.1016/s1010-7940(96)01049-4

OBJECTIVE: Pulmonary artery banding remains a palliative option for patients with congenital heart disease and excessive pulmonary blood flow, if there is unfavourable anatomy or frail condition. In contrast to more developed countries, our patients at Red Cross Children's Hospital, Cape Town, often present to medical services late and in poor nutritional condition. We retrospectively reviewed patients undergoing pulmonary artery banding to determine major variables that influenced long-term outcome. METHODS: In a 10-year period ending June 1992, 135 consecutive patients underwent pulmonary artery banding; 89 with ventricular septal defect type non-mixing disorders, and 46 with mixing or complex disorders. The median age was 3.0 months and weight 3.5 kg with 74.8% of patients weighing less than the third percentile (NCHS adapted), and 39.3% had an additional serious medical illness. RESULTS: Pulmonary banding mortality was 8.1%, and was higher in neonates (22.2%), P = 0.04) but was not related to congenital disorder, associated medical illness, or associated coarctation or interrupted aortic arch. The pulmonary band was inadequate at follow-up in 28.9%, which occurred more commonly if banding was necessary before 3 months of age (41.5%, P = 0.003) but was not related to weight, congenital disorder or associated respiratory infection. Sixty patients (44.4%) have now proceeded to definitive repair with a mortality of 23.3%, which was increased if the pulmonary band was inadequate at the time of definitive repair (44.4%: P = 0.02), but was not related to the congenital disorder. CONCLUSIONS: An inadequate pulmonary artery band adversely affects outcome and demands further aggressive management prior to definitive repair.

 

Role of thoracic surgery for childhood tuberculosis
JP Hewitson and UO Von Oppell
World J Surg (1997) 21(5): 468-74
10.1007/pl00012271

Lymphadenopathy is the hallmark of intrathoracic tuberculosis in children. The role of the thoracic surgeon in treating childhood tuberculosis is to relieve the more severe symptoms of lymphadenopathy, prevent the more long-term secondary damage that lymphadenopathy may cause to the lung, and treat the sequelae of thoracic tuberculosis. We reviewed the role of surgery in childhood tuberculosis at Red Cross Children Hospital from January 1981 to January 1996 in 161 children under 13 who were admitted for 168 therapeutic surgical interventions for proved intrathoracic tuberculosis and its related complications. We classified patients according to the pathophysiology of their disease to clarify the role of surgery in their management. Successful decompression of lymph nodes that were acutely compromising major airways was done in 25 children, and decompression for chronic airway compression was successful in 8 of 11 children. Therapeutic bronchoscopy successfully opened an airway obstructed by intraluminal tissue in 68% of 28 patients, with long-term pulmonary reexpansion in 50%. Pulmonary resections for postprimary tuberculous damage were done in 72 patients with a mortality of 2.7% and morbidity of 16.7%. Another 17 patients were operated on for pleural disease and 15 for other tuberculosis-related problems. The mortality for all patients undergoing surgery for complications of tuberculosis during childhood was 1.9% (3/161), suggesting that when indicated, an aggressive surgical approach is relatively safe.

 

Penetrating injuries involving the intrathoracic great vessels
JO Fulton, KM de Groot, NJ Buckels and UO von Oppell
S Afr J Surg (1997) 35(2): 82-6
Forty-four consecutive patients with injuries to the intrathoracic great vessels admitted to our department from January 1982 to June 1994 were reviewed retrospectively. Forty-two patients (95%) sustained stabwounds and 2 (5%) patients had gunshot wounds. The most frequent radiological abnormality was mediastinal widening in 26 patients (59%). Eighteen patients (41%) were haemodynamically stable on admission with the remainder being unstable (46%), agonal (11%) or lifeless (2%). Twenty-two patients (50%) underwent angiography with 1 false-negative study. A total of 48 arterial and 16 venous injuries were identified with the innominate artery (N = 17, 39% of patients) and left innominate vein (N = 8, 18% of patients) the most frequently injured structures. Associated injuries to thoracic viscera occurred in 13 patients (30%). Two patients required cardiopulmonary bypass to repair their injuries. Arterial shunts were not used in any case. Overall mortality was 5% (2/44) and complications occurred in 7 patients (16%).

 

Complex thoracic vascular injury repair using deep hypothermia and circulatory arrest
JO Fulton and JG Brink
Ann Thorac Surg (1997) 63(2): 557-9
10.1016/s0003-4975(96)01110-1

A 61-year-old man with a penetrating injury to the innominate artery, left common carotid artery, and left subclavian artery at their origins from the aortic arch with associated injuries to both innominate veins and an innominate artery to vein fistula after a single stab wound is described. The patient was managed successfully using cardiopulmonary bypass together with deep hypothermia and circulatory arrest. Presentation and management are discussed.

 

In vitro endothelialization of expanded polytetrafluoroethylene grafts: a clinical case report after 41 months of implantation
M Deutsch, J Meinhart, M Vesely, T Fischlein, P Groscurth, U von Oppell and P Zilla
J Vasc Surg (1997) 25(4): 757-63
10.1016/s0741-5214(97)70307-0

PURPOSE: Forty-one months after we performed bilateral implantation of in vitro endothelialized femoropopliteal bypass grafts in a 69-year-old patient, we obtained a central graft segment for histologic and ultrastructural investigation. METHODS: Before implantation the grafts were confluently lined with autologous first passage mass cultures of pure cephalic vein endothelial cells. The precoating of the expanded polytetrafluoroethylene prosthesis was done with fibrinolytically inhibited fibrin glue. Reoperation became necessary because of symptomatic unilateral atherosclerotic lesions located in the center of one of the two in vitro lined grafts. A 21 cm long graft segment was removed and replaced by a new in vitro endothelialized expanded polytetrafluoroethylene graft. RESULTS: On scanning electron microscopy a confluently covering mature endothelium was found throughout the whole length of the removed prosthesis. The endothelial identity was confirmed by a positive immunohistochemical CD 34, von Willebrand factor-staining, and the ultrastructural demonstration of Weibel Pallade bodies. The endothelium rested on a collagen IV positive basement membrane. Histologic cross sections revealed uniformly developed subintimal tissue of 1.21 +/- 0.19 mm thickness, which was separated from the intima by a distinct internal elastic membrane. The cells of this cell-rich matrix stained strongly positive for actin. Ultrastructurally, this matrix was dominated by highly contractile myofibroblasts loaded with peripherally located well-developed actin fillaments. A number of these cells also showed signs of secretory cells with a distinct endoplasmic reticulum and a Golgi complex. In areas of atherosclerotic lesions the subendothelial matrix was partially exposed, and the internal elastic membrane had to a certain extent disintegrated. Only in these areas KP-1 and MG-M1 positive foamy macrophages and CD 34 positive capillaries were found. The myofibroblasts of this diseased part of the subintimal tissue contained large lipid vacuoles. CONCLUSIONS: We conclude that the confluent in vitro lining of synthetic vascular grafts with pure autologous endothelial cells facilitates graft healing, which may result in a hybrid structure with features of a native vessel.

 

Interaction between panel reactive antibodies, auto- and cold reactive antibodies, and a positive B cell cross-match in renal and cardiac allograft survival
P Creemers, J Brink and D Kahn
Clin Transplant (1997) 11(2): 134-8
We analyzed the influence on allograft survival of pretransplant panel reactive antibodies (PRA) < 10%, PRA > 10%, autoantibodies, cold antibodies and a positive B cell crossmatch in 807 renal and 237 cardiac transplant recipients. Donors and recipients were predominantly of mixed ancestry (Khoi, San, Xhosa and Caucasoid). Log rank analysis showed that PRA < 10%, cold antibodies, and a positive B cell cross-match did not influence allograft survival. Autoantibodies were present only in renal recipients; they appeared to have a beneficial effect on allograft survival (P = 0.06). PRA > 10% appeared to have a detrimental effect on allograft survival in both renal (P = 0.07) and cardiac (P = 0.06) recipients. Since autoantibodies and PRA > 10% had opposing effects, the results of renal recipients were reanalyzed after omission of the recipients with autoantibodies and coexisting PRA > 10%. This resulted in augmentation of the protective effect for autoantibodies (P = 0.027) and of the detrimental effect for PRA > 10% (P = 0.020). Two-year survival curves showed that when autoantibodies coexisted with PRA > 10%, the long term, but not the short-term, detrimental effect of PRA > 10% was attenuated. Patients with a positive B cell cross-match clustered in the PRA > 10% group in both renal (PRA negative vs. PRA < 10%; P = 0.0251; PRA < 10% vs. PRA > 10%: P = 0.0011) and cardiac (PRA negative vs. PRA > 10%: P = 0.0085) recipients. We conclude that PRA > 10% is the best indicator to identify recipients at high risk for rejection, and that the influence of antibodies on graft survival can not reliably be established without taking coexisting antibodies into account.

 

The surgical cure of atrial flutter or fibrillation
UO von Oppell and RN Scott Millar
S Afr Med J (1996) 86(3): 276-7

 

Acute traumatic rupture of the thoracic aorta. A comparison of techniques
UO Von Oppell, J Brink, J Hewitson, P Pinho and P Zilla
S Afr J Surg (1996) 34(1): 19-24
Twenty-eight patients were treated for acute blunt thoracic aortic rupture at Groote Schuur Hospital between January 1984 and March 1994. Aortic arch ruptures occurred in 2 patients and were successfully repaired by means of hypothermic circulatory arrest. Descending aortic ruptures were repaired more safely by insertion of an interposition graft as opposed to direct suture reapproximation, and with the aid of partial heparinless bypass as opposed to simple aortic cross-clamping.

 

Surgical cure of atrial flutter
U von Oppell, RN Scott Millar, JO Fulton and P Zilla
South African Medical Journal (1996) 86(C22 - C24
Atrial flutter and atrial fibrillation are associated with palpitations, impaired haemodynamics and a risk of thrombo-embolism, all of which c,an be corrected by a new surgical procedure. Cox's maze procedure was used to correct surgically a symptomatic paroxysmal atrial flutter in a 31-year-old woman who required closure of a secundum atrial septal defect. Six months post- operatively, she remains asymp- tomatic in normal sinus rhythm on no medication.

 

Syphilitic aortic aneurysm eroding through the sternum
JO Fulton, P Zilla, KM De Groot and UO Von Oppell
Eur J Cardiothorac Surg (1996) 10(10): 922-4
10.1016/s1010-7940(96)80324-1

Syphilitic aortic aneurysms are uncommon today. A syphilitic aneurysm eroding through the anterior chest wall with successful surgical treatment is reported. The large size these aneurysms reach, in conjunction with the overlying pressure-induced skin necrosis necrosis can represent a technical challenge to the surgeon, both in the method of repairing the aneurysm as well as reconstructing the chest wall. Syphilitic aortic disease is also briefly reviewed.

 

Stab wounds of the innominate artery
JO Fulton, MK De Groot and UO von Oppell
Ann Thorac Surg (1996) 61(3): 851-3
10.1016/0003-4975(95)01154-4

BACKGROUND: Innominate artery stab wounds are rarely encountered, and the optimal management of this injury is different from that of blunt innominate injury in that permanent bypass shunting should not be necessary. METHODS: The records of 19 patients with stab wounds of the innominate artery who were treated by our department from January 1982 to June 1995 were reviewed. RESULTS: Eighteen patients (95%) sustained zone 1 neck stabs, with a similar proportion having only a single stab wound. Seventeen (89%) of the 18 patients having chest roentgenograms had mediastinal widening. Thirteen patients (68%) were hemodynamically stable at admission; the remainder were unstable (26%) or moribund (5%). Fourteen patients (74%) underwent angiography, with no false-negative studies for arterial injury. Associated injuries to thoracic viscera occurred in 4 patients (21%). All injuries were repaired with either direct suture (18 of 19) or prosthetic interposition grafting (1 of 19). One patient required cardiopulmonary bypass to repair complex injuries. The overall mortality rate was 5% (1 of 19), and complications occurred in 2 patients (11%). CONCLUSIONS: Innominate artery stab wounds can be managed successfully without permanent bypass shunting and with a low mortality rate.

 

The government and organ transplantation
CN Barnard
S Afr Med J (1996) 86 Suppl 3(C128

 

Isolated thoracic duct injury after penetrating chest trauma
MG Worthington, M de Groot, AJ Gunning and UO von Oppell
Ann Thorac Surg (1995) 60(2): 272-4
10.1016/0003-4975(95)00415-h

BACKGROUND: Isolated thoracic duct injuries as a result of penetrating chest trauma without any major vascular or tracheoesophageal injury seldom are seen. METHODS: A retrospective 13-year review identified 8 patients with this injury. RESULTS: Seven had supraclavicular or suprascapular knife stabs, and the eighth had a low-velocity gunshot injury entering the mid-lateral right chest wall. All 7 stab victims presented with left-sided chylothoraces, and the site of injury of the thoracic duct was within Poirier's triangle, the borders of which are the arch of aorta, the left subclavian artery, and the vertebral column as seen from a lateral approach. Five patients initially were treated conservatively for 13.4 +/- 4.4 days without success. Surgical intervention thus was necessary and was successful in all 8 patients. The thoracic duct injury was controlled successfully through a left posterolateral thoracotomy in 6 patients. A supraclavicular repair was attempted in 1 patient but failed to control the leak and required reexploration via the supraclavicular approach. The right chylothorax from the gunshot injury was explored via a right posterolateral thoracotomy; the leak into the pleura was identified and obliterated. CONCLUSIONS: As conservative management was uniformly unsuccessful, we advocate early operative management through a thoracotomy on the side of the chylothorax for this relatively rare injury.

 

Aortic dissection repair with GRF glue complicated by heart block
UO Von Oppell, D Chimuka, JG Brink and P Zilla
Ann Thorac Surg (1995) 59(3): 761-3
10.1016/0003-4975(94)00775-6

Gelatin-resorcin-formaldehyde-glutaraldehyde (GRF) biologic glue is an available adjunct to repair acute ascending aortic dissections. Permanent complete heart block complicated the operative repair of 2 of 6 patients. The pathophysiology of heart block resulting from either the acute dissecting process or the technique of applying GRF glue is discussed.

 

Limited private practice- the other issue
U von Oppell, J Brink, M de Groot, J Hewitson, M Worthington and P Zilla
South African Medical Journal (1995) 85(929

 

The first heart transplant--background and circumstances
CN Barnard
S Afr Med J (1995) 85(9): 924, 926

 

In vitro-lined endothelium: initial integrity and ultrastructural events
P Zilla, P Preiss, P Groscurth, F Rosemeier, M Deutsch, J Odell, C Heidinger, R Fasol and U von Oppell
Surgery (1994) 116(3): 524-34
BACKGROUND: The early fate of in vitro-endothelialized prosthetic vascular grafts was assessed in the nonhuman primate. METHODS: Each of 17 male chacma baboons received a control and a confluently endothelialized 4 mm polytetrafluoroethylene graft in femoro-femoral positions (8.2 +/- 0.8 cm). All experimental grafts were precoated with fibrinolytically inhibited fibrin glue and lined with cultured autologous endothelial cells (EC) from the external jugular vein. The average time period needed to obtain first-passage mass-cultures sufficient for preconfluent graft endothelialization was 19.8 +/- 5.2 days. Before implantation in vitro-lined grafts were kept in culture for another 16.1 +/- 4.3 days to achieve complete confluence and maturation of the EC cytoskeleton. RESULTS: After 9 days of implantation, endothelial-lined grafts still showed a confluent endothelium that was free of any fibrin deposits. However, the EC density was significantly lower than at implantation (39.7 +/- 7.6 x 10(3) versus 59.9 +/- 8.5 x 10(3) EC/cm2; p < 0.05), and occasional 10-microns-wide intercellular gaps with adherent platelets and leukocytes were visible. Transmission electron microscopy showed leukocytes and cell debris in the underlying fibrin glue. After 4 weeks of implantation, the endothelium of experimental prostheses had regained a high cell density (72.7 +/- 10.5 x 10(3) EC/cm2) with a mature and well-differentiated morphologic appearance. At both observation periods, the surface of control grafts showed a wide range from fibrin deposits to an amorphous protein coverage containing spread platelets. CONCLUSIONS: The endothelium of in vitro-endothelialized vascular prostheses remains confluent after implantation and is nonthrombogenic in spite of a moderate initial cell loss.

 

Traumatic aortic rupture: twenty-year metaanalysis of mortality and risk of paraplegia
UO von Oppell, TT Dunne, MK De Groot and P Zilla
Ann Thorac Surg (1994) 58(2): 585-93
10.1016/0003-4975(94)92270-5

A metaanalysis of articles concerning the surgical management of acute traumatic rupture of the descending thoracic aorta published in the English-language literature between 1972 and July 1992 was performed. The overall mortality of 1,742 patients who arrived at the hospital alive was 32.0%, one-third died before surgical repair was started. Paraplegia was noted preoperatively in 2.6% of these hospitalized patients, and paraplegia complicated the surgical repair in 9.9% of 1,492 patients who reached the operating room in a relatively stable condition. Patients then were analyzed according to the surgical intervention used. Simple aortic cross-clamping (n = 443) was associated with a hospital mortality of 16.0% and incidence of paraplegia of 19.2%, despite lower average mean cross-clamp times (32 minutes; p < 0.01 versus passive or active methods of providing distal perfusion). In a subset of 290 patients in whom individual data were available, the cumulative risk of paraplegia was shown to increase substantially if the duration of aortic cross-clamping exceeded 30 minutes, but only when distal perfusion was not augmented (p < 0.00001). "Passive" perfusion shunts (n = 424) were associated with a mortality of 12.3%, and the incidence of paraplegia decreased to 11.1% (p < 0.001). However, shunts inserted from the apex of the left ventricle had a contradictory high 26.1% incidence of paraplegia compared with shunts from the ascending aorta (8.2%; p < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

 

Spinal cord protection in the absence of collateral circulation: meta-analysis of mortality and paraplegia
UO von Oppell, TT Dunne, KM De Groot and P Zilla
J Card Surg (1994) 9(6): 685-91
10.1111/j.1540-8191.1994.tb00903.x

A meta-analysis of paraplegia complicating aortic surgery on patients having neither intercostal nor spinal collaterals, epitomized by patients with acute traumatic aortic rupture, was done. Index Medicus and Medline were searched for all suitable English publications between 1972 and 1992. New paraplegia occurred in 9.9% of 1492 patients who underwent surgery. However, 19.2% of patients undergoing surgery with only simple aortic cross-clamping developed paraplegia, in contrast to 6.1% if distal aortic perfusion was augmented by either "passive" or "active" methods (p < 0.00001). The risk of paraplegia increased progressively as cross-clamp times lengthened if simple aortic cross-clamping was used (p < 0.00001), but only once did the cross-clamp time exceed 30 minutes (p < 0.05). Paraplegia occurred in 8.2% of patients with "passive" shunts from the ascending aorta (p < 0.001 vs simple cross-clamping). Shunts from the left ventricular apex, however, had an incidence of paraplegia of 26.1% and, therefore, did not decrease the risk of paraplegia. "Active" augmentation of distal perfusion had the lowest risk of paraplegia: 2.3% (p < 0.00001 vs simple cross-clamping or "passive" shunts). Mortality, however, was higher in these potentially polytraumatized patients when they were perfused distally using methods requiring full systemic heparinization (18.2%), compared to mortality with methods not requiring heparin (11.9%; p < 0.01). In conclusion, simple aortic cross-clamping has a high risk of paraplegia if the cross-clamp time extends beyond 30 minutes. "Active" modalities of augmenting distal perfusion provide optimal spinal protection.

 

High-dose aprotinin in cardiac surgery--a prospective, randomized study
MJ Swart, PC Gordon, PB Hayse-Gregson, RA Dyer, AL Swanepoel, NJ Buckels, R Schall and JA Odell
Anaesth Intensive Care (1994) 22(5): 529-33
10.1177/0310057X9402200505

Fifty patients undergoing primary coronary artery bypass surgery and 50 patients undergoing valve surgery received either high-dose aprotinin (2 million units loading dose, 2 million units added to the CPB prime, and 500,000 units/hr maintenance infusion) or placebo. Mean postoperative blood loss in the first six hours was reduced from 321 ml in the placebo group to 172 ml in the aprotinin group (95% confidence interval (CI) for difference = 95 to 189 ml). Seven patients in the placebo group and 16 patients in the aprotinin group did not require transfusion with homologous blood. This study adds to the growing body of evidence that the administration of high-dose aprotinin reduces blood loss and blood transfusion requirements associated with primary cardiac surgery.

 

The endothelium: a key to the future
P Zilla, U von Oppell and M Deutsch
J Card Surg (1993) 8(1): 32-60
10.1111/j.1540-8191.1993.tb00574.x

The vascular endothelium is a complex modulator of a variety of biological systems and may well be the key to definitive success in the treatment of cardiovascular disorders. Surgically-induced endothelial injury may occur preoperatively during cardiac catheterization and intraoperatively from mechanical manipulation, ischemia, hypothermia, and exposure to cardioplegic solutions. The normal endothelium is antithrombogenic and yet promotes platelet aggregation and coagulation if injured. Vasospasm, occlusive intimal hyperplasia, and accelerated arteriosclerosis can also all occur as a result of endothelial injury. Furthermore, endothelial injury is harmful even in the absence of disruption of its monolayer integrity. Thus, preservation of the endothelium should be an additional objective for all cardiovascular surgeons. Synthetic vascular grafts, cardiac valves, and artificial ventricles do not spontaneously endothelialize and thus usually require some form of anticoagulation to maintain patency. Hence, endothelialization of prosthetic implants became an attractive concept. A number of different methods of obtaining an endothelial lining of prosthetic material has since been developed; these include facilitated endothelial cell migration, and endothelial cell seeding by using either venous or microvascular endothelial cells. Manipulating the endothelium might well provide the next major advancement for therapeutic and preventive measures for cardiovascular disease.

 

Surgical relief of acute airway obstruction due to primary tuberculosis
MG Worthington, JG Brink, JA Odell, J Buckels, MK de Groot, M Klein and AJ Gunning
Ann Thorac Surg (1993) 56(5): 1054-62
10.1016/0003-4975(95)90013-6

Primary pulmonary tuberculosis in children remains a leading cause of mortality and morbidity in developing countries. Thirteen children requiring urgent thoracotomy for relief of acute respiratory distress resulting from critical major airway narrowing caused by enlarged tuberculous mediastinal lymph nodes were admitted to two hospitals over a 4-year period. Ages ranged from 2 months to 10 years. The condition of each patient had deteriorated despite appropriate antituberculosis therapy and an oral corticosteroid. At operation, the enlarged tuberculous subcarinal or paratracheal lymph nodes or both were decompressed. Surgical complications included a bronchial tear and a pulmonary artery laceration. Additional procedures included a right upper lobectomy, two pneumonectomies, plication of a hemidiaphragm, and mobilization of two muscle flaps. Postoperatively all children showed dramatic improvement. The trachea to main bronchi diameter ratio improved by 49.1% on the left and 44.9% on the right in the immediate postoperative period. In children with respiratory distress produced by compression of the main bronchi between enlarged subcarinal and paratracheal lymph nodes, surgical decompression of the lymph nodes is indicated if there is no marked initial response to appropriate medical therapy. At operation, lymph nodes should be decompressed only by incision and curettage. Attempts at lymph node excision are associated with increased complications.

 

Sequestration of the left coronary artery from the aorta
MJ Swart, JA Odell and RC Fraser
Ann Thorac Surg (1993) 55(2): 523-4
10.1016/0003-4975(93)91035-l

A patient with the left coronary artery isolated from the ascending aorta is discussed. This is the seventh case described and the third diagnosed preoperatively. In contrast to other patients she had predominant aortic incompetence and was much older (52 years compared with the other patients, all younger than 25 years). She also had two angiograms demonstrating progressive isolation of the coronary artery with time. The patient was managed by aortic valve replacement. It is our belief that the condition is acquired and resulted from fusion of the free edge of the aortic valve leaflet to the supravalvar ridge secondary to an inflammatory process.

 

Pathology of chronic cardiac rejection: An analysis of the epicardial and intramyocardial coronary arteries and myocardial alterations in 43 human allografts
AG Rose, L Viviers and JA Odell
Cardiovasc Pathol (1993) 2(1): 7-19
10.1016/1054-8807(93)90009-Q

Forty-three cardiac allografts (39 autopsies and 4 surgically resected hearts) showing chronic rejection-defined as greater than 75% narrowing of one or more major coronary arteries (MCA) with or without severe narrowing of intramyocardial coronary arteries (ICA)-were studied histologically. MCA showed purely concentric narrowing in 24 patients (56%), and 19 patients (44%) showed eccentric narrowing in some arteries. Fibrofatty (collipid) plaques were seen in 54%, abundant foam cells sans free lipid in 33%, purely fibrous plaques in 14%, and calcification in 9%. Four pathologic alterations separated graft atherosclerosis from usual atherosclerosis: (i) the presence in the MCA and/or ICA of either active or healed vasculitis, (ii) outer medial defects attributable to mediolysis and/or foam cell transformation in the MCA, (iii) the diffuse nature of the atherosclerotic-like changes, and (iv) obliterative narrowing of the ICA. No difference was found between early and late survivors with regard to features of graft atherosclerosis. The majority of the patients studied had received steroid-based immunosuppression. MCA and/or ICA active vasculitis was observed in the absence of acute myocardial rejection in some patients. ICA showed intimal thickening in 37% of patients, active vasculitis in 21%, healed vasculitis in 7%, and combination of the latter two changes in 12%. Acute myocardial ischemia, present in 33 hearts (77%), had the following distribution: subendocardial in 42%, focal in 36%, and regional transmural in 21%. Myocytolysis (83%), coagulative necrosis (26%), and contraction band necrosis (16%) were noted. Replacement fibrosis of the myocardium was frequently observed (44%), followed by interstitial (33%) and perivascular fibrosis (1%). Patients with chronic rejection showed no difference with regard to the incidence and severity of rejection episodes during life compared with patients without chronic rejection.

 

Massive thymic hyperplasia
AG Linegar, JA Odell, WM Fennell, PM Close, MK De Groot, DR Casserly and JI Perold
Ann Thorac Surg (1993) 55(5): 1197-201
10.1016/0003-4975(93)90033-e

Massive thymic hyperplasia is an extremely rare form of true thymic hyperplasia most often described in infants and children. Hyperplasia of this order is not known to occur in any other organ, and its etiology and prognostic significance remain unknown. As there is no accurate way of preoperatively differentiating massive thymic hyperplasia from other tumors of the thymus and anterior mediastinum, we advise excision in all cases for histological analysis and relief of mediastinal compression. This description of 4 cases updates the 30 previously reported cases, and includes a literature review.

 

Extended cardiopulmonary preservation: University of Wisconsin solution versus Bretschneider's cardioplegic solution
PA Human, J Holl, S Vosloo, J Hewitson, JG Brink, H Reichenspurner, D Boehm, AG Rose, JA Odell and B Reichart
Ann Thorac Surg (1993) 55(5): 1123-30
10.1016/0003-4975(93)90018-d

Application of the University of Wisconsin cold storage solution has rapidly expanded to include medium-term to long-term preservation of virtually all intraabdominal organs. Its use in intrathoracic organ transplantation has also been suggested. We therefore examined the efficacy of the University of Wisconsin solution in a primate allotransplantation model for preservation of hearts, and as a simple single-solution system for static preservation of heart-lung blocks, for periods of ischemia ranging from 6 to 24 hours. For comparison, we employed the histidine-tryptophane-ketoglutarate cardioplegic solution of Bretschneider. University of Wisconsin solution provided superior results with regard to clinical outcome and hemodynamic recovery of hearts after ischemic periods of up to 16 hours. This was in contrast to Bretschneider's solution, which allowed storage of hearts for periods of only up to 10 hours. Heart-lung blocks were equally well preserved with either University of Wisconsin or Bretschneider's solution after 6 to 12 hours, although the University of Wisconsin solution group exhibited a more notable increase in pulmonary water content. This was in accordance with histological data, which suggested that, although hemodynamic recovery of hearts stored for periods longer than 10 hours was poor, preservation of pulmonary ultrastructure was far superior using Bretschneider's solution as compared with University of Wisconsin solution after an ischemic period of up to 16 hours.

 

Severe pneumococcal pneumonia complicated by massive pulmonary gangrene
JM Hammond, C Lyddell, PD Potgieter and J Odell
Chest (1993) 104(5): 1610-2
10.1378/chest.104.5.1610

Massive pulmonary gangrene is a rare complication of pneumonia, particularly in the postantibiotic era. We report two cases of community-acquired Streptococcus pneumoniae pneumonia in young patients with a background of heavy alcohol abuse, but no other preexisting disease, which failed to respond to appropriate antibiotic therapy and intensive care. In both, there was extensive unilateral involvement, with initial dense consolidation followed by cavitation, but the previously reported classic later radiologic feature of coalescence into a large cavity with free-floating slough was not seen. Owing to ongoing sepsis with the development of multiple organ failure and the obvious failure of appropriate medical therapy, both patients underwent pneumonectomy with a successful outcome. These cases serve to emphasize the role of surgery in the management of massive pulmonary gangrene.

 

Autopsy-determined causes of death following cardiac transplantation. A study of 81 patients and literature review
AG Rose, L Viviers and JA Odell
Arch Pathol Lab Med (1992) 116(11): 1137-41
The principal and contributory causes of death in 81 autopsied heart transplant patients who died at Groote Schuur Hospital, Cape Town, South Africa, were investigated and subdivided according to the immunosuppressive regimen used as well as the postoperative survival period. Mean graft survival was 488 days. Chronic rejection (30%), infection (23%), and acute rejection (20%) were the most common principal causes of death. Both fatal and nonfatal infections involved the lung predominantly. A review of the literature revealed 198 other autopsied heart transplant patients whose principal cause of death could be analyzed; infection accounted for almost half of these latter deaths, followed by acute and chronic rejection. Contributory causes of death in the 81 patients were as follows: infection (17%), acute rejection (16%), chronic rejection (14%), miscellaneous conditions (14%), embolism (14%), pancreatitis (11%), peptic ulcer (9%), inadequate donor heart (3%), and malignancy (1%). We conclude that infection, together with acute and/or chronic rejection, are still the major causes of death in heart transplant patients.

 

Long-term results of the Ivalon baffle mitral valve repair
JA Odell, JO Schurek, CN Barnard and PJ Commerford
Ann Thorac Surg (1992) 54(2): 283-5
10.1016/0003-4975(92)91385-m

In the evolution of mitral valve surgery, Ivalon sponge was sutured to the posterior leaflet of the mitral valve to obtain competency. Between August 1959 and October 1962, 18 patients had this procedure. All patients were discharged home. Three patients were lost to follow-up 5 to 10 years after operation. Valve replacement was necessary in 7 patients 10.4 +/- 8.5 years after repair. Bacterial endocarditis causing late death occurred in 5 patients within 4 years. Five embolic episodes occurred. The estimated probability of survival and need for valve replacement at 28 years were 29.2% +/- 12.3% and 12.4% +/- 6.7%, respectively.

 

Heart transplantation in South Africa--a critical appraisal
JA Odell and JG Brink
S Afr Med J (1992) 82(6): 394-6

 

Tracheobronchial foreign bodies. Experience at Red Cross Children's Hospital, 1985-1990
AG Linegar, UO von Oppell, S Hegemann, M de Groot and JA Odell
S Afr Med J (1992) 82(3): 164-7
Ninety-six children with suspected tracheobronchial foreign bodies were referred to the Department of Cardiothoracic Surgery at Red Cross War Memorial Children's Hospital, Cape Town, between February 1985 and February 1990. Foreign bodies were removed by rigid bronchoscopy from 63 patients, 79% of whom were under 5 years of age. The majority of patients (59%) presented more than 24 hours after aspiration of the foreign body, and this delay in definitive management was associated with an increased incidence of complications (P = 0.01). Complications occurred in 28 patients, and there was one fatality at bronchoscopy due to overwhelming aspiration of an unanticipated release of pus, following the removal of a chronically impacted foreign body. The complete classic diagnostic triad (sudden onset of coughing, wheezing and decreased air entry) was seldom present, and we recommend diagnostic bronchoscopy in children presenting with either a history of sudden choking or a witnessed aspiration of a foreign body, an unexplained acute wheeze or cough or a chronic pulmonary infection. This report also highlights the continued need for increased awareness on the part of both parents and medical practitioners of the need for early referral if a foreign body is suspected. Furthermore, public education is needed as regards the dangers of allowing young children to eat peanuts. Peanuts were the commonest foreign bodies removed.

 

Donor heart coronary sinus ostium atresia in a successful cardiac transplant
NJ Buckels, S Vosloo, AG Rose and JA Odell
Ann Thorac Surg (1992) 53(6): 1096-7
10.1016/0003-4975(92)90396-l

 

Growth properties of cultured human endothelial cells on differently coated artificial heart materials
P Zilla, R Fasol, M Grimm, T Fischlein, T Eberl, P Preiss, O Krupicka, U von Oppell and M Deutsch
J Thorac Cardiovasc Surg (1991) 101(671-680
The cultivation of autologous endothelial cells on the blood surface of artificial hearts might prevent their detrimental thromboembolic complications. To investigate the growth characteristics of endothelial cells on theoretically suitable biomaterials, we compared three polyurethanes (Pellethane, Biomer, Enka) and three silicone rubbers (Elastosil, 3145 RTV, Medical Adhesive). All synthetic surfaces were precoated with an extracellular matrix (group 1), fibronectin (group 2), or a glutaraldehyde-preserved cellular matrix (group 3). After the seeding of 2.5 × 104/cm2 human endothelial cells onto the various surfaces, primary adherence, growth kinetics, and maintenance of monolayer integrity were studied for 13 days. On the three polyurethanes all precoating procedures resulted in endothelial cell proliferation and the formation of persistent monolayers. In contrast, on silicone rubbers a persistent coverage with a confluent endothelium could be achieved only on the glutaraldehyde-preserved cellular matrix. When endothelial cell growth was quantitatively assessed on all precoating substrates, the glutaraldehyde-preserved cellular matrix proved to be far superior on each of the synthetics (p < 0.001). These results demonstrate the theoretical feasibility of endothelialization of artificial hearts in vitro. Provided such an endothelium can withstand the mechanical forces within an artificial heart, in vitro endothelialization might contribute to a regained attractiveness of the elective long-term implantation of artificial hearts.

 

Endothelialization of vascular grafts
P Zilla
Curr Opin Cardiol (1991) 6(6): 877-86
10.1097/00001573-199112000-00004

Although work on endothelial cell seeding of vascular prostheses was first published in 1978, no clinical breakthrough had yet been achieved. Clinical data on single-staged procedures using freshly harvested autologous venous or microvascular endothelial cells are scarce and controversial. The alternative approach--the application of culture techniques--has the disadvantage of being restricted to major centers. Moreover, this in vitro endothelialization is confined to elective cases because of the delay caused by cell cultivation. Nevertheless, initial clinical trials with this two-staged technique are encouraging and indicate that the creation of an endothelium on the inner surface of prosthetic grafts is feasible in humans.

 

Traumatic rupture of the descending thoracic aorta
UO von Oppell, CF Thierfelder, SJ Beningfield, JG Brink and JA Odell
S Afr Med J (1991) 79(10): 595-8
The management of acute traumatic rupture of the descending thoracic aorta at Groote Schuur Hospital between January 1984 and December 1989 is reviewed. Aortic rupture was diagnosed angiographically in 18 of 150 patients (12%), who underwent aortography because this injury was suspected. However, 3 of these patients had false-positive angiograms. The diagnosis was initially missed in 31% of patients, and this contributed to morbidity and mortality. Simple aortic cross-clamping (N = 8) was used before September 1988 and 3 patients died--1 intra-operatively from cardiac arrhythmia and 2 postoperatively, where major peri-operative haemorrhage had occurred. In contrast, partial heparin-less bypass (N = 5) using a centrifugal vortex pump was used after September 1988, and there were no haemorrhagic or paraplegic complications or mortality in this group. This technique is safe and appears to be superior to simple aortic cross-clamping in managing this condition.

 

Effect of oxygenation and consequent pH changes on the efficacy of St. Thomas' Hospital cardioplegic solution
UO von Oppell, LM King, EF Du Toit, P Owen, B Reichart and LH Opie
J Thorac Cardiovasc Surg (1991) 102(3): 396-404
The hypothesis tested is that shifts in pH, induced when a cardioplegic solution is oxygenated, can be detrimental. We added either 100% nitrogen, 95% nitrogen and 5% carbon dioxide, 100% oxygen, or 95% oxygen and 5% carbon dioxide to the cardioplegic solution (St. Thomas' Hospital No. 2 plus glucose 11 mmol/L), and determined postischemic recovery of isolated rat hearts after 3 hours of 10 degrees C cardioplegic protected ischemia. Hearts were arrested and reinfused every 30 minutes throughout the ischemic period with cardioplegic solution. When 5% carbon dioxide was added to nitrogen, the pH of the cardioplegic solution decreased from 9.1 (100% nitrogen) to 7.0 (95% nitrogen: 5% carbon dioxide), a change associated with improved postischemic functional recovery. Aortic output improved from 52.3% +/- 2.7% to 63.9% +/- 2.8%, p less than 0.05, and cardiac output from 60.8% +/- 3.6% to 75.4% +/- 3.3%, p less than 0.01. This improvement was associated with diminished efflux of lactate during ischemia but increased postischemic release of lactate dehydrogenase. When nitrogen was replaced with oxygen, the addition of 5% carbon dioxide resulted in a similar decrease of pH, which again was associated with improved postischemic functional recovery. Aortic output improved from 66.3% +/- 2.8% (100% oxygen) to 88.9% +/- 3.7% (95% oxygen: 5% carbon dioxide), p less than 0.005, and cardiac output from 75.3% +/- 4.1% to 88.9% +/- 2.4%, p less than 0.01. The efflux of lactate during ischemia and the postischemic release of lactate dehydrogenase were similar in both groups. Furthermore, provision of additional oxygen with perfluorocarbons in an electrolyte solution identical to the St. Thomas' Hospital plus glucose solution and oxygenated with 95% oxygen: 5% carbon dioxide conferred no extra protection. In conclusion, the St. Thomas' Hospital No. 2 plus glucose cardioplegic solution should be oxygenated but with 95% oxygen: 5% carbon dioxide and not 100% oxygen because of the additive effect of a relatively "acidotic" pH.

 

Effect of pH shifts induced by oxygenating crystalloid cardioplegic solutions
UO von Oppell, LM King, EF Du Toit, P Owen, B Reichart and LH Opie
Ann Thorac Surg (1991) 52(4): 903-7
10.1016/0003-4975(91)91253-r

Oxygenation of a bicarbonate-containing crystalloid cardioplegic solution alters the partial pressure of both oxygen (O2) and carbon dioxide (CO2). Therefore, oxygenating St. Thomas' Hospital II plus glucose (11 mmol/L) cardioplegic solution with 95% O2 + 5% CO2 induces a pH shift to 7.0 (10 degrees C) as opposed to pH 9.3 with 100% O2. In an isolated working rat heart model, we show that pH 7.0 (10 degrees C) improves mechanical postischemic recovery in the absence or presence of O2. However, in the absence of O2, pH 7.0 appears to inhibit glycolysis and diminish the stability of cellular membranes. The provision of O2 independently improved mechanical recovery and at pH 7.0, improved the preservation of the sarcolemma. Increasing the O2 content by including a perfluorocarbon (FC-43) in the oxygenated St. Thomas' plus glucose cardioplegia is not additionally beneficial. St. Thomas' Hospital plus glucose cardioplegic solution should be oxygenated, but with 95% O2 + 5% CO2 and not 100% O2.

 

St. Thomas' Hospital cardioplegic solution. Beneficial effect of glucose and multidose reinfusions of cardioplegic solution
UO von Oppell, EF Du Toit, LM King, P Owen, T Dunne, B Reichart and LH Opie
J Thorac Cardiovasc Surg (1991) 102(3): 405-12
The intention of this study was to determine whether glucose is beneficial in a cardioplegic solution when the end products of metabolism produced during the ischemic period are intermittently removed. The experimental model used was the isolated working rat heart, with a 3-hour hypothermic 10 degrees C cardioplegic arrest period. Cardioplegic solutions tested were the St. Thomas' Hospital No. 2 and a modified Krebs-Henseleit cardioplegic solution. Glucose (11 mmol/L) was beneficial when multidose cardioplegia was administered every 30 minutes. Including glucose in Krebs-Henseleit cardioplegic solution improved postischemic recovery of aortic output from 57.0% +/- 1.8% to 65.8% +/- 2.2%; p less than 0.025. The addition of glucose to St. Thomas' Hospital No. 2 cardioplegic solution improved aortic output from 74.6% +/- 1.9% to 87.4% +/- 1.9%; p less than 0.005. Furthermore, a dose-response curve showed that a glucose concentration of 20 mmol/L gave no better recovery than 0 mmol/L, and glucose in St. Thomas Hospital No. 2 cardioplegic solution was beneficial only in the range of 7 to 11 mmol/L. In addition, we showed that multidose cardioplegia was beneficial independent of glucose. Multidose St. Thomas' Hospital No. 2 cardioplegia, as opposed to single-dose cardioplegia, improved aortic output recovery from 57.4% +/- 5.2% to 74.6% +/- 1.9%; p less than 0.025, and with St. Thomas' Hospital No. 2 cardioplegic solution plus glucose (11 mmol/L) aortic output recovery improved from 65.9% +/- 2.9% to 87.4% +/- 1.9%; p less than 0.005. Hence, at least in this screening model, the St. Thomas' Hospital cardioplegic solution should contain glucose in the range of 7 mmol/L to 11 mmol/L, provided multidose cardioplegia is given. We cautiously suggest extrapolation to the human heart, on the basis of supporting clinical arguments that appear general enough to apply to both rat and human metabolisms.

 

Successful management of aortoesophageal fistula due to thoracic aortic aneurysm
UO von Oppell, M de Groot, C Thierfelder, P Zilla and JA Odell
Ann Thorac Surg (1991) 52(5): 1168-70
10.1016/0003-4975(91)91305-f

Aortoesophageal fistulas due to atherosclerotic thoracic aneurysms are usually fatal, with few reported survivors. We report an aortoesophageal fistula managed successfully in one stage by resection and replacement of the aortic aneurysm with a prosthetic graft and total esophageal resection. Immediate esophageal reconstruction was attained using orthotopic gastric interposition with omentopexy around the prosthetic aortic graft.

 

Histopathology of hyperacute rejection of the heart: experimental and clinical observations in allografts and xenografts
AG Rose, DK Cooper, PA Human, H Reichenspurner and B Reichart
J Heart Lung Transplant (1991) 10(2): 223-34
The histologic findings in a total of 112 experimental heart transplants comprising allografts (baboon to baboon: n = 37), concordant xenografts (vervet monkey to baboon: n = 52), and discordant xenografts (pig to baboon: n = 23), in which the roles of ABO blood group incompatibility, corcordance, and immunosuppression were evaluated, are described. Hyperacute (vascular, humoral) rejection was characterized by disruption of the microcirculation, with interstitial hemorrhage and edema, rather than by intravascular thrombosis; the features were basically similar whether hyperacute rejection occurred in an ABO-incompatible allograft, concordant xenograft, or discordant xenograft. Hyperacute rejection was noted in all 23 discordant xenografts, in 12 to 52 concordant xenografts, and in four of 17 ABO-incompatible allografts. A unique mixture of acute and hyperacute rejection was observed in three ABO-incompatible allografts and in 10 concordant xenografts. Intensive antirejection therapy was associated with a reduced incidence of hyperacute rejection in corcordant xenografts but also with a significant number of fatal treatment-related complications.

 

Surgical drainage of lung abscess complicating acute community-acquired pneumonia
PD Potgieter, JM Hammond, G Musson and J Odell
Chest (1991) 99(5): 1280-2
10.1378/chest.99.5.1280

Two cases of severe community-acquired pneumonia requiring IPPV and complicated by the development of lung abscess were successfully treated with early surgical drainage. This procedure may be a life-saving measure in certain instances.

 

Surgery for the Wolff-Parkinson-White syndrome. The Groote Schuur Hospital experience
RN Millar, DA Milne, UO von Oppell and B Reichart
S Afr Med J (1991) 79(10): 583-7
Surgical division of accessory atrioventricular (AV) connections has been performed on 9 patients with the Wolff-Parkinson-White (WPW) syndrome at Groote Schuur Hospital. All patients had symptomatic paroxysmal tachycardia. The indication for surgery in 5 patients was poor control on antiarrhythmic drugs. Surgery was performed on a 15-year-old boy to prevent lifelong dependence on drugs, although his atrial fibrillation (ventricular rate greater than 300/min) was controllable with sotalol 1,280 mg daily. The remaining 3 patients required cardiac surgery for other indications and therefore their accessory pathways (APs) were divided concurrently. The AP was localised by pre-operative endocardial mapping and intra-operative epicardial mapping. There were 4 posteroseptal, 3 left free-wall and 2 right free-wall pathways. An endocardial approach was used to divide the pathways. All 5 free-wall APs were successfully divided without complications or recurrence. However, 1 patient with paroxysmal atrial fibrillation and severe unstable angina due to coronary artery disease died unexpectedly 10 days after 4-vessel coronary bypass grafting and division of a posteroseptal AP. Postoperative complications occurred in a further 2 patients with posteroseptal APs. One patient developed complete heart block and is now asymptomatic with a DDD pacemaker, while the other had recurrence of retrograde bypass conduction postoperatively, but is now successfully controlled on sotalol. Therefore 7 of the 8 survivors are free of recurrence of tachycardia on no anti-arrhythmic drugs after a mean follow-up of 14.3 months. New insights into the surgical technique, particularly for division of posteroseptal pathways, can be expected to improve the outlook.

 

A milestone in cardiac transplantation
BD Mahon, JG Brink, CN Barnard and J Odell
S Afr Med J (1991) 80(3): 159

 

Allogenic, multidonor in vitro endothelialization of small diameter PTFE grafts in baboons
R Fasol, P Zilla, P Preiss, J Odell and B Reichart
J Cardiovasc Surg (1991) 25(64-71
The early effect of allogenic in vitro endothelialization was assessed in small- diameter vascular prostheses. Cryopreserved and pooled venous endothelial cells (ECs) from 13 baboons of similar blood group were used for confluent in vitro endothelialization of fibrin glue-coated polytetrafluoroethylene vascular grafts. Bilateral femoral interpositions (12 cm) of experimental and control grafts were subsequently implanted into a separate group of 18 male baboons with the same blood group as that of the pooled cells. After sixteen days of implantation the patency rate of grafts of the endothelialized group was similar to that of the control group (55.6% vs 61.1%, p>0.1). Scanning electron microscopy revealed that 44.4% of experimental grafts were completly free of endothelium, while the remaining grafts showed a moderate mean EC coverage of 34.4 17.1%. These remaining ECs were found mainly as small islands densely covered by leukocytes. The majority of these white cells resembled granulocytes, although adherent lymphocytes were also regularly observed. Since surface morphology does not explain the mechanism of EC loss, further experiments must elucidate this question. If rejection is found to be the primary cause for this cell loss, the use of major histocompatibility complex (MHC) matched EC subpools might be considered.

 

Adenosine cardioplegia: reducing reperfusion injury of the ischaemic myocardium?
DH Boehm, PA Human, U von Oppell, P Owen, H Reichenspurner, LH Opie, AG Rose and B Reichart
Eur J Cardiothorac Surg (1991) 5(10): 542-5
10.1016/1010-7940(91)90108-v

Hyperkalaemia-induced hypopolarization of the sarcolemnal membrane during standard crystalloid cardioplegic arrest potentiates calcium influx during reperfusion and is associated with depletion of high-energy phosphate reserves. Adenosine has been shown to induce fast cardiac arrest whilst preserving membrane hyperpolarization in an isolated rat heart model. In this study we compared the efficacy of adenosine, both as an arresting agent and as an ultrastructural, haemodynamic and high-energy phosphate preserving agent, in an in situ global ischemia model in the baboon with St. Thomas' Hospital solution No. 2 (ST2; n = 8) and with Krebs-Henseleit buffer (KHB; n = 7). The addition of 10 mM adenosine to the non-cardioplegic KHB (ADO; n = 8) improved haemodynamic recovery significantly in terms of cardiac index (91.6% +/- 7.2 vs 59.9% +/- 9.9) and stroke volume index (101.6% +/- 8.9 vs 55.6 +/- 10.0) and was not statistically distinguishable from the ST2 with regard to cardiac index (91.6% +/- 7.2 vs 94.8% +/- 5.8), stroke volume index (101.6% +/- 8.9 vs 114.0% +/- 8.3) or left ventricular dP/dt (73.1% +/- 9.9 vs 87.0% +/- 12.4). Adenosine triphosphate was best preserved with ADO (103.5% +/- 21.1 vs 67.9% +/- 9.3 and 48.5% +/- 8.7) although this was not statistically significant. This suggests therefore that the mechanism of cardioprotection by adenosine occurs by means other than its role as high-energy phosphate precursor.

 

In situ cannulation, microgrid follow-up and low-density plating provide first passage endothelial cell masscultures for in vitro lining
P Zilla, R Fasol, U Dudeck, S Siedler, P Preiss, T Fischlein, W Muller-Glauser, G Baitella, D Sanan, J Odell and et al.
J Vasc Surg (1990) 12(2): 180-9
A rapid and reliable harvest and culture technique was developed to provide a sufficient number of autologous endothelial cells for the confluent in vitro lining of cardiovascular prostheses. Enzymatic endothelial cell detachment was achieved by the in situ application of collagenase to short vessel segments. This harvest technique resulted in a complete lack of contaminating smooth muscle cells in all of 124 cultures from nonhuman primates and 13 cultures from human adults. The use of a microgrid technique enabled the daily in situ quantification of available endothelial cells. To assess ideal plating densities after passage the population doubling time was continuously related to the cell density. Surprisingly, a low plating density of 1.5 X 10(3) endothelial cells/cm2 achieved 43% shorter cell cycles than the usual plating density of 1.0 X 10(4) endothelial cells/cm2. Moreover, low density plating enabled mass cultures after one single cell passage, thereby reducing the cell damaging effect of trypsin. When the growth characteristics of endothelial cells from five anatomically different vessel sites were compared, the external jugular vein--which would be easily accessible and dispensable in each patient--proved to be an excellent source for endothelial cell cultures. By applying in situ administration of collagenase, low density plating and microgrid follow-up to adult human saphenous vein endothelial cells, 14,000,000 first passage endothelial cells--sufficient for the in vitro lining of long vascular prostheses--were obtained 26.2 days after harvest. (95% confidence interval:22.3 to 32.2 days).

 

Mitral valve replacement in infancy. A case report
SM Vosloo, BA Reichart and MM de Moor
S Afr Med J (1990) 77(10): 533-5
A 5-month-old infant with congenital mitral valve disease successfully managed by replacement with a mechanical prosthetic valve is reported. The incidence and management of congenital mitral valve defects is discussed.

 

Inflow occlusion in the surgical management of a penetrating aortic arch injury: case report
SM Vosloo and BA Reichart
J Trauma (1990) 30(4): 514-5
The acute surgical management of a 22-year-old male patient with a stab wound below the left sternoclavicular junction causing partial transsection of the origin of the innominate artery, laceration of the posterior wall of the ascending aorta, as well as an innominate artery-vein fistula, is described and the value of inflow occlusion in the surgical repair discussed.

 

Endothelial cell toxicity of solid-organ preservation solutions
UO von Oppell, S Pfeiffer, P Preiss, T Dunne, P Zilla and B Reichart
Ann Thorac Surg (1990) 50(6): 902-10
10.1016/0003-4975(90)91117-t

Endothelial cell damage caused by myocardial cardioplegic solutions (Bretschneider HTK and St. Thomas' Hospital No. 2) or renal and hepatic cold storage solutions (modified Collins and University of Wisconsin solution) was assessed in monolayer cultures of adult human venous endothelial cells at 4 degrees to 10 degrees C with phase-contrast microscopy. St. Thomas' Hospital solution caused the cells to contract, resulting in disruption of monolayer integrity and opening of intercellular gaps, and resulted in a 24-hour postexposure survival of 51.0% +/- 2.4%. Bretschneider HTK solution altered cellular morphology less and produced the best postexposure survival (80.2% +/- 2.6%; p less than 0.001). Although morphology was altered the least with University of Wisconsin solution, postexposure survival with this solution, which was similar to that with modified Collins solution, was superior to that with St. Thomas' (p less than 0.01) but inferior to that with Bretschneider HTK (p less than 0.05). The superior protection provided by Bretschneider HTK was due to its additives histidine, tryptophan, and KH-2-oxygluterate (p less than 0.005), and to its low chloride content (p less than 0.005). Furthermore, modifying St. Thomas' solution by decreasing its chloride content improved cell survival to 71.2% +/- 2.3% (p less than 0.001). Normothermic (37 degrees C) exposure to Bretschneider HTK, modified Collins, and University of Wisconsin solution was cytotoxic, whereas normothermic exposure to St. Thomas' cardioplegia was not. In conclusion, the preservation solution that is the least harmful to endothelial cells at hypothermia is Bretschneider HTK cardioplegic solution.

 

Endothelial cell cytotoxicity of cardioplegic solutions used in South Africa
UO Von Oppell, S Pfeffer, P Preiss, D Boehm, T Dunne and P Zilla
Cardiovascular Journal of Southern Africa (1990) 1(182-188
The hypothesis tesled Is that cardioplegic solutions, used to protect the myocardium during open-heart surgery, could be cytoto,oc to endothelial cells. Vascular endotheUal damage would be detrimental to postopera- tive myocardial function. Cultured monolayen of human endothelial ceDs were exposed for 12 hours at room temperature (220 C) to crystalloid cardiopleg.ic solutIons currently in use in South Africa, and to two internationally used solutions.

 

The International St Thomas' Hospital No.2 (ST) and Bre
cbnelder (B-HTK) cardioplegic solutions pro- duced 24-bour post-exposure endotbelial cell survivals of 81,0 ± 1,9% and 76,5 ± 4,1%respectively. The ST + gJucose (10 mM) cardioplegic solution used al Groote Schuur Hospital produced a sim.llar survival - 78,8 ± 2.9%. The best endothelial survival of 87,1 ± 2,2% was obtained with a modified ST plus &Jucose solution containlng histidine (SO mM), tbe more powerful buffer included in B-HTK, which was significantly better than ST and B-HTK (P < 0,05).

 

In contrast, crystalloid cardioplegic solutions used elsewhere in South Africa were aU cytotoxic to endothe- Ual ceDs. S A B A X cardioplegia was associated with a 24-hour survival of 0,6 ± 0,3%. which was significantly worse than that obtained with ST (P <0,001). Plasma- Iyte B-based formulations produced no survival, and were also significantly worse Ihan ST (P < 0,001). The cytoto"lcity of these solutions was due to acalcaemia, exceS.!ilvely high pOlaS.!ilum concentrations and too Uttle magnesium.

 

Effect of pharmacologic immunosuppression on donor heart survival in a closely related nonhuman primate xenograft model
H Reichenspurner, PA Human, AG Rose, B Reichart and DK Cooper
Transplant Proc (1990) 22(3): 1086-7

 

15-Deoxyspergualin after cardiac and renal allotransplantation in primates
H Reichenspurner, A Hildebrandt, PA Human, DH Boehm, AG Rose, HU Schorlemmer and B Reichart
Transplant Proc (1990) 22(4): 1618-9

 

15-Deoxyspergualin for induction of graft nonreactivity after cardiac and renal allotransplantation in primates
H Reichenspurner, A Hildebrandt, PA Human, DH Boehm, AG Rose, JA Odell, B Reichart and HU Schorlemmer
Transplantation (1990) 50(2): 181-5
10.1097/00007890-199008000-00001

In order to assess the immunosuppressive potentials of 15-deoxyspergualin (15-DS) in a preclinical experiment, heterotopic cardiac (n = 27, group I) and classic renal (n = 25, group II) allotransplantations were performed in Chacma baboons. The following immunosuppressive regimens were applied: Groups IB and IIB were treated with 15-DS alone (4 mg/kg/day) for p.o. days 0-9. Groups IC and IIC were treated with cyclosporine A (10-40 mg/kg/day) for p.o. days 0-30. Groups ID and IID received a combination of 15-DS (for p.o. days 0-9) and CsA (for p.o. days 0-30). Groups IA and IIA served as control and received no medication. The mean graft survival was 11.0 days for group IA, 28.2 days for group IB (P less than 0.05; IB vs. IA), 32.4 days for group IC, and 43.1 days for group ID (P less than 0.025; ID vs. IA). After renal transplantation, the corresponding figures were 12.3 days for group IIA, 8.5 days for group IIB, 30.4 days for group IIC and 148.9 days for group IID (P less than 0.025; IID vs. IIA). After cardiac and renal transplantation, acute rejection was the main cause of graft failure. Treatment-related side effects, mainly gastrointestinal complications, were observed only in primates, who were treated with 15-DS alone. After cardiac transplantation, permanent graft non-reactivity was not achieved, but a delayed rejection occurred within a mean of 21.8 days after immunosuppression had been stopped. Following renal transplantation, graft nonreactivity was also not achieved in groups IIB and IIC. In group IID, however, 4 of 8 animals (50%) were graft-tolerant 340, 256, 244, and 164 days after treatment discontinuation. Thus, the combination of 15-DS and CsA led to a significant prolongation of graft survival in both groups. Long-term nonreactivity was achieved only after renal transplantation, when initially treated with 15-DS and CsA.

 

Surgical management of heart-lung transplantation
B Reichart, S Vosloo and J Holl
Ann Thorac Surg (1990) 49(2): 333-40
10.1016/0003-4975(90)90169-7

Using cyclosporin A, long-term survival after heart-lung transplantation became possible. The drug blocks the immune system more selectively and leaves the tracheal wound healing unimpaired. Since 1981, 501 clinical cases have been collected by the registry of the International Society for Heart Transplantation. Candidates for heart-lung transplantation reveal signs of irreversible heart and lung diseases that may have been caused by cardiac lesions (valvular diseases, Eisenmenger reaction due to congenital malformations) or by pulmonic disorders (primary pulmonary hypertension, emphysema, fibrosis). The standard surgical procedure, which combines donor and recipient tracheas, right atria, and aortas, makes three anastomoses necessary. Immunosuppressive regimen includes cyclosporin A (blood trough levels of 300 to 500 ng/mL), azathioprine (1 to 2 mg/kg), and rabbit antithymocyte globulin (1 to 4 mg immunoglobulin G/kg). After the first two postoperative weeks, rabbit antithymocyte globulin is replaced by methylprednisolone (0.3 to 0.1 mg/kg; 500 mg are given intravenously after opening the aortic cross-clamp; 3 x 125 mg on postoperative day 1). After heart-lung transplantation an extreme variety of problems may evolve. Early postoperative complications (within the first postoperative month) comprise acute isolated lung rejection, multiorgan failure, and bacterial pneumonia. Diagnosis of acute lung rejection proves difficult; it includes clinical signs, chest radiographic appearances, and cytoimmunological monitoring. Transbronchial lung biopsies are of similar value for precise diagnosis as are endomyocardial specimens after heart transplantation. Late postoperative complications (after 1 postoperative month) comprise viral pneumonia, fungal infection, tuberculosis, and chronic obliterative bronchiolitis.(ABSTRACT TRUNCATED AT 250 WORDS)

 

Histocompatibility matching between humans and baboons
FA Neethling, PJ Nortman and DK Cooper
Transplant Proc (1990) 22(3): 1067-9

 

Cytoimmunologic monitoring after heart and heart-lung transplantation
RM May, DK Cooper, ED Du Toit and B Reichart
J Heart Transplant (1990) 9(2): 133-5
The ability of cytoimmunologic monitoring to detect acute rejection in heart and heart-lung transplant recipients was assessed. Seventeen heart and nine heart-lung transplant patients treated with cyclosporine as the primary immunosuppressive agent were monitored after operation. Seventeen acute rejection episodes occurred in the heart-only recipients and 12 in the combined heart-lung recipients. These acute rejection reactions were accompanied by increased numbers of "activated" lymphocytes in all but one case, providing cytoimmunologic monitoring a sensitivity of 100% in the heart-lung recipients and 94% in the heart recipients. The specificity was, however, low (68% in the heart recipients and 55% in the heart-lung recipients). Seventy-two percent of the false-positive results were associated with viral infections, particularly cytomegalovirus infections.

 

Heterotopic heart transplantation: mid-term hemodynamic and echocardiographic analysis--the concern of arteriovenous-valve incompetence
A Hildebrandt, H Reichenspurner, GD Gordon, AR Horak, JA Odell and B Reichart
J Heart Transplant (1990) 9(6): 675-81; discussion 682
To assess the hemodynamic contribution of both hearts after heterotopic heart transplantation, we examined recipients by cardiac catheterization and Doppler echocardiography. Since September 1984, immunosuppression consisted of cyclosporine, azathioprine, methylprednisolone, and antithymocyte globulin. In this time interval, 55 orthotopic and 14 heterotopic transplants have been performed. The indications for heterotopic transplant were elevated pulmonary vascular resistance (greater than 4 Wood units), in 10 patients, or gross (greater than 20%) donor-recipient weight mismatch, in six patients. Two patients belonged to both groups. The 1-year survival rate was 63%; currently seven of the 14 patients are alive. Cardiac output (as measured by dye dilution curves and by the Fick method) increased from 4.2 L/min preoperatively to 6.1 L/min in both groups postoperatively (mean follow up, 5.3 months; p less than 0.0005); the transpulmonary gradient fell from 18.5 to 12.3 mm Hg, the pulmonary vascular resistance from 4.4 to 2.4 Wood units (p less than 0.01). The echocardiographic findings were as follows: left ventricular end-diastolic diameter (mm) in the recipient heart was 67.4 +/- 12 and in the donor heart, 42.6 +/- 8.7. Fractional shortening (%) in the recipient heart was 7.1 +/- 2.9 and in the donor heart, 30.4 +/- 10.4. The Doppler technique revealed a cardiac output contribution-ratio (CO donor/CO recipient) of 3.0 +/- 0.61 on average. In all recipient hearts mild and moderate mitral and tricuspid regurgitation was discovered. In the donor heart all mitral and tricuspid valves were found to be incompetent; this was severe in 66% and 11% of the mitral and tricuspid valves, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

 

Intrinsic obstruction of the Procter-Livingstone tube
KM De Groot, AJ Gunning and JA Odell
S Afr J Surg (1990) 28(1): 14-5
Four instances of intrinsic obstruction of a Procter-Livingstone tube inserted for oesophageal carcinoma are described. The exact cause of the blistering is unknown, but it is thought to occur by absorption through the latex. It is suggested that if this complication is found, relief of obstruction may be obtained by perforation of the blister.

 

Accelerated cardiac allograft rejection associated with administration of liver cell extract in the baboon
DK Cooper, N Harris, AG Rose and D Novitzky
Transplant Proc (1990) 22(4): 1966-9

 

Adenosine and its role in cardioplegia: effects on postischemic recovery in the baboon
DH Boehm, PA Human, H Reichenspurner, U von Oppell, P Owen, LH Opie and B Reichart
Transplant Proc (1990) 22(2): 545-6

 

Reply to: Blood Platelets and Bypass
P Zilla
J Thorac Cardiovasc Surg (1989) 98(5 Pt 1): 797-800

 

Adenosine cardioplegia. Adenosine versus potassium cardioplegia: effects on cardiac arrest and postischemic recovery in the isolated rat heart
T Schubert, H Vetter, P Owen, B Reichart and LH Opie
J Thorac Cardiovasc Surg (1989) 98(6): 1057-65
Adenosine is a potential cardioplegic agent by virtue of its specific inhibitory properties on nodal tissue. We tested the hypothesis that adenosine could be more effective than potassium in inducing rapid cardiac arrest and enhancing postischemic hemodynamic recovery. Isolated rat hearts were perfused with Krebs-Henseleit buffer or cardioplegic solutions to determine the time to cardiac arrest and the high-energy phosphate levels at the end of cardioplegia. Cardioplegic solutions contained adenosine 10 mmol/L, potassium 20 mmol/L, or adenosine 10 mmol/L + potassium 20 mmol/L and were infused at a rate of 2 ml/min for 3 minutes at 10 degrees C. Both time taken and total number of beats to cardiac arrest during 3 minutes of cardioplegia were reduced by adenosine 10 mmol/L and adenosine 10 mmol/L + potassium 20 mmol/L when compared with potassium 20 mmol/L alone (p less than 0.001). Tissue phosphocreatine was conserved by adenosine 10 mmol/L when compared with potassium 20 mmol/L, being 7.1 +/- 0.2 (mumol/gm wet weight (n = 7) and 6.0 +/- 0.3 mumol/gm wet weight (n = 5), respectively (p less than 0.05). Postischemic hemodynamic recovery was tested in isolated working rat hearts. After initial cardiac arrest, the cardioplegic solution was removed with Krebs-Henseleit buffer at a rate of 2 ml/min for 3 minutes at 10 degrees C, and thereafter total ischemia was maintained for 30 or 90 minutes at 10 degrees C before reperfusion. Adenosine 10 mmol/L enhanced recovery of aortic output when compared with potassium 20 mmol/L or adenosine 10 mmol/L + potassium 20 mmol/L, the percentage recovery after 30 minutes of ischemia being 103.0% +/- 4.4% (n = 6), 89.0% +/- 5.8% (n = 6), and 86.6% +/- 4.3% (n = 6), respectively (p less than 0.05 for comparison between adenosine 10 mmol/L and potassium 20 mmol/L). Thus adenosine cardioplegia caused rapid cardiac arrest and improved postischemic recovery when compared with potassium cardioplegia and with a combination of these two agents.

 

Optimalization of immunosuppression after xenogeneic heart transplantation in primates
H Reichenspurner, PA Human, DH Boehm, AG Rose, R May, DK Cooper, P Zilla and B Reichart
J Heart Transplant (1989) 8(3): 200-7; discussion 207-8
Xenogeneic heart transplantation is becoming increasingly attractive because of the shortage of suitable donor organs. In small infants and neonates, for whom suitable human grafts are difficult to obtain, this may play a particularly important role. To evaluate the optimal immunosuppressive regimen after xenogeneic transplantation, cervical heterotopic heart transplantation was performed with vervet monkeys as donors and chacma baboons as recipients. The following groups were investigated: group 1 (n = 9): control, no immunosuppressive medication; group 2 (n = 5): cyclosporine in combination with azathioprine and methylprednisolone; group 3 (n = 6): cyclosporine, azathioprine, and methylprednisolone in combination with antithymocyte globulin for postoperative days 0 to 9; group 4 (n = 7): cyclosporine, azathioprine, and methylprednisolone in combination with 15-deoxyspergualin for postoperative days 0 to 9. Because of severe treatment-related side effects that were observed in group 4, further immunosuppression was modified as follows: group 5 (n = 5): 15-deoxyspergualin was combined with cyclosporine and methylprednisolone only. Acute rejection episodes were diagnosed by cytoimmunologic monitoring on alternate days and weekly myocardial biopsies and were treated with 500 mg methylprednisolone intravenously for 3 to 5 consecutive days. The graft survival after xenogeneic heart transplantation was best in group 3 with 43.3 days compared with 10.3 days in the control group. Still 2.3 acute rejections occurred, which in most cases led to graft failure in these animals. In group 4 the graft survival was prolonged to 20.1 days on average. Only 0.5 acute rejections per animal occurred, but severe gastrointestinal complications and infections were observed that made further experiments necessary to minimize these treatment-related complications.(ABSTRACT TRUNCATED AT 250 WORDS)

 

Heterotopic heart transplantation in 1988--recent selective indications and outcome
H Reichenspurner, A Hildebrandt, D Boehm, HG Kaulbach, S Willems, JA Odell, A Horak and B Reichart
J Heart Transplant (1989) 8(5): 381-6
Considering a worldwide average 1-year survival rate of nearly 90% after orthotopic heart transplantation, the question arises as to whether there is still an indication for heterotopic heart transplantation. Since 1967, 132 heart transplantations have been performed at our institution. From 1974 to 1983 only heterotopic transplantations were performed. Since 1985, quadruple-drug therapy has been used for immunosuppression. This consists of low dose cyclosporine in combination with azathioprine, methylprednisolone (in lower dosages), and rabbit antithymocyte globulin (for the first 4 to 6 days after operation and as rescue therapy for severe rejections). Fifty-five transplantations have been performed with this therapy (44 orthotopic and 11 heterotopic). The indications for heterotopic transplantations were either elevated pulmonary vascular resistance (4 to 6 Wood units, n = 6), or a gross donor and recipient weight mismatch (more than 20%) in candidates who showed signs of severe cardiac decompensation (n = 6). One patient had both indications. The 1-year survival rate for those patients was 83%. Currently seven of the 11 patients are alive with life spans ranging from 6 months to 2.5 years after operation. Causes of deaths were infections (n = 3) and chronic graft rejection (n = 1). The recipients were restudied with right-sided heart catheterizations performed from 2 months to 2 years after transplantation. In all patients the cardiac output increased significantly from a mean of 4.0 to 5.8 L/min (p less than 0.0005). In patients with elevated pulmonary vascular resistance, this value decreased after heterotopic transplantation from a mean of 4.9 to 2.4 Wood units.(ABSTRACT TRUNCATED AT 250 WORDS)

 

Surgery of the thoracic aorta. Recent experience at Groote Schuur and Red Cross War Memorial Children's Hospitals, Cape Town
JA Odell, EA Becerra, U von Oppell, HC Reichenspurner and B Reichart
S Afr Med J (1989) 76(8): 409-13
Between September 1984 and June 1988, 46 patients (8 traumatic rupture, 10 acute and 11 chronic dissection, 17 true aneurysms) with lesions of the thoracic aorta were managed surgically. Four patients died after surgery for acute dissection, 2 after management of chronic aneurysm and 1 after replacement of the descending aorta for a chronic degenerative aneurysm. In 2 patients the operation was complicated by paraplegia.

 

Inotropic effect of triiodothyronine (T3) in low cardiac output following cardioplegic arrest and cardiopulmonary bypass: an initial experience in patients undergoing open heart surgery
D Novitzky, DK Cooper and A Swanepoel
Eur J Cardiothorac Surg (1989) 3(2): 140-5
10.1016/1010-7940(89)90092-4

A significant reduction in plasma free triiodothyronine (T3) (P less than 0.0001) has been observed in patients undergoing open heart surgery. The beneficial effect of T3 would appear to be associated with increased synthesis and utilization of myocardial high energy stores. We have therefore administered T3 (4-10 micrograms iv) to 10 patients either when difficulty was being experienced in weaning from cardiopulmonary bypass (CPB) support (n = 5), or when myocardial function remained extremely poor (n = 5), despite inotropic and intraaortic balloon pump support. Mean preoperative NYHA functional class of the 10 patients was 3.2, left ventricular enddiastolic pressure (LVEDP) 20 mm Hg and ejection fraction (EF) 40%. The mean myocardial ischaemia time was 72 min (range 40-120 min). Within 1 h of T3 administration the mean plasma free T3 level had risen from 1.03 to 3.56 micrograms/ml and CPB was discontinued in all 5 cases. Balloon pump support (n = 2) was no longer essential within 3 h. At 1 h, the mean arterial pressure (MAP) had risen from 42 to 78 mm Hg, and heart rate (HR) from 90 to 104 beats/min; the left atrial pressure (LAP) had fallen from 30 to 14 mm Hg, and the central venous pressure (CVP) from 20 to 11 cm H2O. (All changes significant at P less than 0.0001.) Inotropic support had been significantly reduced or discontinued. To our knowledge, T3 has not been administered previously as an inotropic agent to patients who have undergone cardiac surgery. We believe that T3 may have an important role in the rescue of failing hearts following a period of myocardial ischaemia in patients who have undergone open heart surgery.

 

Diagnosis of acute cardiac rejection by changes in left ventricular volumes
D Novitzky, DK Cooper, J Boniaszczuk and AG Rose
Transplant Proc (1989) 21(1 Pt 3): 2533

 

Heart transplantation--the treatment of choice for patients with end-stage ischaemic heart disease
A Hildebrandt, H Reichenspurner and B Reichart
Thorac Cardiovasc Surg (1989) 37(1): 37-41
10.1055/s-2007-1013902

Between December, 1967 and August, 1988, 147 heart transplants (64 orthotopic, 68 heterotopic procedures; 15 heart-and-lung replacements) were performed on 128 patients. In the majority of the recipients, dilated cardiomyopathy or end-stage ischaemic heart disease was diagnosed. From 1985 to the present, 70 transplants (45 orthotopic, 11 heterotopic and 14 heart-lung) took place. Seventeen of these patients (mean age 46.6 years) suffered from end-stage disabling (NYHA IV) coronary artery disease; in each case the angiogram verified severe stenosis or occlusion of the three main coronary artery systems. Their histories revealed a total of 22 previous myocardial infarctions; 8 patients needed a total of 9 surgical revascularization procedures. The left ventricular ejection fraction (LVEF) ranged from 9% to 24% (mean 15.3%). Before transplantation three patients required intraaortic balloon pump (IABP) support. Fourteen of the 17 patients are at present still alive with post operative periods ranging from 8 weeks to 3.5 years (the actuarial 90-days and 1-year-survival rates being respectively 91.7% and 81.5%). Twelve of the patients are in NYHA class I; 2 are in class II. Three late deaths occurred: one from pneumocystic carinii/cytomegalovirus pneumonia, a second from atypical pneumonia and a third from chronic graft rejection. Radionuclide ventricular studies demonstrated postoperative left ventricular ejection fractions ranging from 54%-81% (mean 71%).(ABSTRACT TRUNCATED AT 250 WORDS)

 

The pathophysiological effects of brain death on potential donor organs, with particular reference to the heart
DK Cooper, D Novitzky and WN Wicomb
Ann R Coll Surg Engl (1989) 71(4): 261-6
Major electrocardiographic, haemodynamic, and histopathological changes take place during the development of brain death; myocardial and pulmonary injury may result. Significant depletion of certain circulating hormones occurs, resulting in an inhibition of mitochondrial function, leading to reduced aerobic metabolic oxidative processes, affecting the body as a whole. Major organ energy stores are therefore diminished, leading to deterioration of function. Replacement of the depleted hormones, in particular triiodothyronine (T3), cortisol, and insulin, leads to rapid replacement of organ energy stores, associated with a return to normal function. T3 alone leads to reactivation of the mitochondria, stimulating aerobic metabolism. Hormonal therapy to brain-dead potential organ donors has been shown to lead to metabolic and haemodynamic stability, resulting in no wastage of organs, and in improved function after transplantation.

 

The role of ABO blood group compatibility in heart transplantation between closely related animal species. An experimental study using the vervet monkey to baboon cardiac xenograft model
DK Cooper, PA Human, AG Rose, J Rees, M Keraan, B Reichart, E Du Toit and R Oriol
J Thorac Cardiovasc Surg (1989) 97(3): 447-55
The role of ABO blood group compatibility on graft survival when transplantation is performed between closely related animal species is uncertain. Heart transplants (in the neck) were performed between donor vervet monkeys and recipient baboons; no immunosuppressive therapy was given. Survival in ABO-compatible pairs (group 1, n = 9) was for a mean of 10.3 (+/- 5.2) days, which was not significantly different from that in ABO-incompatible pairs (group 2, n = 9: mean survival 7.3 +/- 5.6 days). In group 2, however, three hearts were rejected hyperacutely within 60 minutes, whereas in group 1 only one heart was rejected within 24 hours (not significant). Preformed anti-vervet monkey antibody was present in only one of 18 baboons, but developed in eight others. ABO-specific antibodies were present in all nine group 2 baboons and increased in titer in six cases. Histopathologic features of vascular (humoral) rejection, sometimes associated with cellular infiltration, were seen in a majority of hearts in both groups. Though the number of animals in this study was small, ABO-incompatibility would not appear to be a major factor in cardiac xenograft survival when transplantation is performed between closely related primate species, though early hyperacute rejection would seem more likely to occur when blood group incompatibility is present.

 

Can cardiac allografts and xenografts be transplanted across the ABO blood group barrier?
DK Cooper, PA Human, AG Rose, J Rees, M Keraan, E DuToit and R Oriol
Transplant Proc (1989) 21(1 Pt 1): 549-50

 

Coronary artery plaque rapidly induced by local electromagnetic stimulation in the baboon
H Breuer, J Fincham, P Hinrichsen, CJ Uys, H Weich and B Reichart
Eur Surg Res (1989) 21(2): 123-8
10.1159/000129012

A reliable method has been developed to produce stenosis of the right coronary artery of baboons as a consequence of electrostimulation of the vessel at a chosen position. At that site a pair of electrodes were implanted and activated with a train of 9-volt pulses (length: 10 ms, separation: 100 ms) for 30 min, 5 days/week, up to 6 weeks. 13 animals were included in the experiment, 2 of those served as controls. Pathohistologically the structure of the artificially produced constrictions is similar to atherosclerotic lesions. On average the stenoses occupied 55% of the available lumen; total occlusion and no stenosis were observed in 1 case each.

 

Effects of hormonal therapy on subsequent organ (kidney) storage in the experimental animal
WN Wicomb, D Novitzky and DK Cooper
Transplant Proc (1988) 20(5 Suppl 7): 55-8

 

Added effects of organ (heart) storage after brain death in the experimental animal
WN Wicomb, DK Cooper and D Novitzky
Transplant Proc (1988) 20(5 Suppl 7): 39-43

 

Anomalous left superior vena cava in combined heart-lung transplantation
UO von Oppell, JA Odell, H Reichenspurner, B Reichart, P Zilla and R Fasol
J Heart Transplant (1988) 7(6): 445-7
An anomalous left superior vena cava (SVC) was identified in two recipients during combined heart-lung transplantation. In the first patient an interposition Gore-Tex graft was used to reconstitute the venous drainage from the aberrant left SVC to the right atrium. In the second patient a new method of reconstituting the drainage from the left SVC with the donor innominate vein is described. It is recommended that excision of the donor heart and lung should include the innominate vein, as it may be used to create a venous channel for an aberrant left SVC if present in the recipient.

 

Cardiac rupture caused by blunt trauma as well as false angiographic aortic rupture. A case report
UO von Oppell, SJ Beningfield, JA Odell and B Reichart
S Afr Med J (1988) 74(10): 519-20
A patient with a ruptured heart as a result of severe blunt trauma is described. There was also a false angiographic appearance of a ruptured aorta due to a ductal diverticulum. The association of aortic and cardiac rupture is discussed.

 

Heterotopic thyroid tissue in the heart
AG Rose, D Novitzky and SK Price
Am J Cardiovasc Pathol (1988) 1(3): 401-4
Heterotopic thyroid tissue, presumably due to an embryological developmental abnormality, was discovered incidentally within the right atrial wall of an elderly woman who underwent coronary arterial aortic saphenous vein bypass grafting. As far as we are aware, this is only the third patient with thyroid heterotopia of the heart to be documented.

 

Myocardial and pulmonary histopathologic changes
AG Rose, D Novitzky and DK Cooper
Transplant Proc (1988) 20(5 Suppl 7): 29-32

 

Malignant fibrous histiocytoma of the heart. A case report
AG Rose, PJ Commerford, DK Cooper and BA Reichart
S Afr Med J (1988) 74(8): 418-20
Malignant fibrous histiocytoma is a recently recognised common sarcoma of late adult life which, rarely, may arise in the heart. Unlike the atrial myxoma, which it may mimic clinically, malignant fibrous histiocytoma is a far more aggressive tumour with a greater tendency for local recurrence and infiltration. A case of a primary intracardiac malignant fibrous histiocytoma is reported and relevant published reports reviewed.

 

Initial experience with heart and lung transplantation
H Reichenspurner, JA Odell, DK Cooper, D Novitzky, AG Rose, W Klinner and B Reichart
Tex Heart Inst J (1988) 15(1): 3-6
Between February 1983 and July 1987, twelve patients underwent heart-lung transplantation at the University of Cape Town and the University of Munich. The patients included eight men and four women, whose ages ranged from 15 to 49 years (mean, 27 years). The underlying pathologic condition was idiopathic primary pulmonary hypertension in five cases, Eisenmenger's syndrome in four cases, idiopathic pulmonary fibrosis in one case, diffuse fibrosing alveolitis in one case, and chronic emphysema in one case. The immunosuppressive regimen consisted of cyclosporine A, azathioprine, and rabbit antithymocyte globulin (RATG) during the first 2 postoperative weeks; RATG was subsequently replaced by methylprednisolone. Pulmonary rejection frequently occurred in the absence of cardiac rejection; in one case, however, this situation was reversed. Two patients required retransplantation, which was undertaken for caseating pulmonary tuberculosis with obliterative bronchiolitis after 1 year in one case and for early pulmonary insufficiency after 2 days in the other case. There were no operative deaths, but three early deaths occurred, owing to respiratory insufficiency of unknown origin (10 days postoperatively), multiorgan failure (10 days postoperatively), and acute liver dystrophy (11 days postoperatively). Five weeks after operation, a fourth patient died of multi-organ failure. There were five late deaths, all of which resulted from infectious complications. Three patients, including one who underwent retransplantation, remain alive and well, 10 to 36 months postoperatively.

 

[The technic of combined heart-lung-transplantation]
B Reichart
Chirurg (1988) 59(8): 519-25

 

Injury of myocardial conduction tissue and coronary artery smooth muscle following brain death in the baboon
D Novitzky, AG Rose and DK Cooper
Transplantation (1988) 45(5): 964-6
10.1097/00007890-198805000-00025

Experimental brain death was induced in 36 chacma baboons. In group A (n = 17), brain death was induced with no pharmacologic or surgical manipulation. Group B (n = 7) underwent bilateral vagotomy, unilateral left cardiac sympathectomy, or bilateral adrenalectomy before induction of brain death. Group C (n = 7) underwent total cardiac sympathectomy. Group D (n = 5) was pretreated with verapamil hydrochloride. Following induction of brain death, group A animals were maintained on a ventilator for a mean of 12 hr and 6 hr for the remaining groups. At the end of the experiment, the heart was excised, and tissue blocks were examined with light microscopy at (A) the atriaventricular node-bundle of His; (B) the major coronary arteries; and (C) myocardial tissue from the ventricular septum or left ventricular wall. In group A, 41% of the hearts showed histologic features of injury to the conduction tissue, 70% presented contraction band necrosis of the smooth muscle of the coronary arteries, and an incidence of 100% of the groups showed myocyte injury, more evident in the subendocardial area. In group B animals, conduction tissue injury was seen in 6 animals; the coronary arteries were not examined in this group; the incidence of myocyte injury was seen in 80% of the animals. Animals in groups C and D show no histopathologic injury in the conduction tissue (group A vs. C P less than 0.04), nor in the coronary arteries (group A vs. C P less than 0.002; group A vs. D P less than 0.01), preserving the myocytes (P less than 0.001). The catecholamine storm associated to acute increment of the endocranial pressure at the time of induction of brain death induces major histopathologic changes in the myocardium, as a result of endogenous catecholamines released inducing calcium overflow injury, affecting the conduction tissue, the smooth muscle of the coronary arteries, and the contractile myocardium. This can be prevented by calcium blockers or cardiac denervation.

 

Inotropic effect of triiodothyronine following myocardial ischemia and cardiopulmonary bypass: an experimental study in pigs
D Novitzky, PA Human and DK Cooper
Ann Thorac Surg (1988) 45(1): 50-5
10.1016/s0003-4975(10)62396-x

A significant reduction (p less than 0.0001) in plasma-free triiodothyronine (T3), which is known to have an inotropic effect, has been documented in patients undergoing open-heart procedures. To investigate the effect of this observation, 22 pigs underwent 2 hours (Group 1, r = 10) or 3 hours (Group 2, r = 12) of myocardial ischemia during cardiopulmonary bypass (CPB) at 26 degrees C; the myocardium was protected by cardioplegic solution and cold saline solution at 30-minute intervals. After the pig was rewarmed to 37 degrees C, CPB was discontinued, and measurements of hemodynamic function were made 10 and 70 minutes later. Half of the pigs (Subgroup B) received 6 micrograms of T3 intravenously immediately after removal of the aortic cross-clamp; the remainder (Subgroup A) received no T3. After 2 hours of ischemia, untreated pigs showed significantly reduced myocardial function 10 minutes after discontinuation of CPB. By 70 minutes after the end of CPB, 2 of 5 untreated pigs (Subgroup A) had died of low cardiac output, but all 5 treated pigs (Subgroup B) survived. After 3 hours of ischemia, both groups showed some reduced function at 10 minutes, though the reduction was more marked in untreated animals. By 70 minutes, 4 of 6 untreated pigs had died of myocardial failure and all treated pigs remained alive (p less than 0.03). Surviving pigs in both groups still demonstrated some reduced function compared with values obtained before CPB. When all pigs are considered together, overall survival of those that did not receive T3 was significantly less than those that did (p less than 0.006).(ABSTRACT TRUNCATED AT 250 WORDS)

 

Effect of triiodothyronine (T3) on myocardial high energy phosphates and lactate after ischemia and cardiopulmonary bypass. An experimental study in baboons
D Novitzky, PA Human and DK Cooper
J Thorac Cardiovasc Surg (1988) 96(4): 600-7
Cardiopulmonary bypass is associated with a reduction in plasma free triiodothyronine in patients undergoing cardiac operations. A previous experimental study in pigs demonstrated a marked inotropic effect when triiodothyronine was administered after a period of myocardial ischemia and cardiopulmonary bypass; this was associated with a significant reduction in mortality compared with the mortality in control pigs. To clarify the effect of triiodothyronine on myocardial high energy phosphate stores and lactate, a series of experiments was done in baboons undergoing 3 hours of myocardial ischemia while supported by cardiopulmonary bypass. Seven baboons received no triiodothyronine and six received 6 micrograms of triiodothyronine at the end of the ischemic period. Seventy minutes after cardiopulmonary bypass, the myocardial adenosine triphosphate level was significantly higher (p less than 0.01) in the treated animals. In untreated animals, a steady increase in myocardial lactate occurred after cardiopulmonary bypass; by 120 minutes after ischemia (70 minutes after cardiopulmonary bypass) there was a significant difference in lactate levels between the two groups (p less than 0.01). We postulate that a combination of global ischemia and depletion of triiodothyronine results in reduced mitochondrial function, inhibition of the tricarboxylic acid cycle, and increased anaerobic metabolism and depletion of myocardial phosphates. Triiodothyronine replacement therapy leads to improved mitochondrial function and increased aerobic metabolism, which results in increased synthesis of myocardial phosphates. We suggest that there may be a place for the administration of triiodothyronine in patients undergoing cardiac operations with a prolonged myocardial ischemic period or in whom there is any evidence of low cardiac output after discontinuation of cardiopulmonary bypass.

 

Endocrine changes and metabolic responses
D Novitzky, DK Cooper and WN Wicomb
Transplant Proc (1988) 20(5 Suppl 7): 33-8

 

The effects of denervation and acute rejection on left ventricular volumes measured by radionuclide ventriculography following cardiac transplantation in the chacma baboon
D Novitzky, DK Cooper, AG Rose, S Isaacs, J Boniaszczuk, JA Smith, B Reichart and MP Iturralde
Semin Nucl Med (1988) 18(3): 213-20
10.1016/s0001-2998(88)80029-1

Seven baboons underwent autotransplantation of the heart or heart and both lungs (group A). Eleven allografts were performed (group B) (nine orthotopic heart transplants and two en bloc transplants of the heart and both lungs). Radionuclide ventriculography was performed both pretransplant and at intervals posttransplant in all animals, and provided measurements of ejection fraction (EF) and left ventricular volumes (LVv) (end-diastolic volume [EDV], end-systolic volume [ESV], and stroke volume [SV]). In seven animals, a total of 20 endomyocardial biopsies were taken. Correlation was made between histopathological features of acute rejection seen on endomyocardial biopsy and changes in EF and LVv measured by radionuclide imaging. A significant increase of 12% in the EF (P less than 0.01) and significant falls in the LVv were observed in all animals (groups A and B) on the first posttransplant day, presumably a result of total cardiac denervation. EDV was reduced by 50% (P less than 0.005), ESV by 62% (P less than 0.0001), and SV by 43% (P less than 0.0001). In autografted baboons (group A) EF and LVv showed no further changes until reinnervation of the heart had occurred, when they reverted to pretransplant levels. In the allografted baboons (group B) further significant reductions in the LVv occurred as acute cardiac rejection progressed. From the first post-transplant day to the time of the final study before the animals' death, the EF decreased by 10% (P less than 0.01), the EDV by 38% (P less than 0.005), and SV by 73% (P less than 0.003): the decrease in ESV did not reach statistical significance.(ABSTRACT TRUNCATED AT 250 WORDS)

 

Change from aerobic to anaerobic metabolism after brain death, and reversal following triiodothyronine therapy
D Novitzky, DK Cooper, D Morrell and S Isaacs
Transplantation (1988) 45(1): 32-6
10.1097/00007890-198801000-00008

Brain-dead organ donors are depleted of circulating triiodothyronine (T3) and show features suggestive generally of anaerobic metabolism at the tissue level, accompanied by deteriorating hemodynamic function. The principle of single-bolus kinetics with labeled carbon compounds (14C-R), with subsequent measurement of both plasma activity and of exhaled 14C O2 has therefore been used to study glucose, pyruvate, and palmitate utilization under conditions of (1) sedation, (2) brain death, and (3) brain death with T3 therapy in the baboon. Serum lactate and plasma-free fatty acid concentrations were also measured. There was a major change in metabolic oxidative processes following brain death. The rate of glucose, pyruvate, and palmitate utilization was markedly reduced, and there was an accumulation of lactate and free fatty acids in the plasma, indicating a general change from aerobic to anaerobic metabolism. The administration of T3 to the brain-dead baboon resulted in a dramatic increase in the rate of metabolite utilization, and a reduction in the plasma concentrations of plasma lactate and free fatty acids, indicating an apparent reversal from tissue anaerobic to aerobic metabolism. We suggest that T3 should be administered to all brain-dead potential organ donors to correct and maintain a more physiologic metabolic status and thus to improve organ function.

 

Prediction of acute cardiac rejection by changes in left ventricular volumes
D Novitzky, DK Cooper and J Boniaszczuk
J Heart Transplant (1988) 7(6): 453-5
Sixteen patients underwent heart transplantation (11 orthotopic, five heterotopic). Monitoring for acute rejection was by both endomyocardial biopsy (EMB) and multigated equilibrium blood pool scanning with technetium 99m-labelled red blood cells. From the scans information was obtained on left ventricular volumes (stroke, end-diastolic, and end-systolic), ejection fraction, and heart rate. Studies (208) were made in the 16 patients. There was a highly significant correlation between the reduction in stroke volume and end-diastolic volume (and a less significant correlation in end-systolic volume) and increasing acute rejection seen on EMB. Heart rate and ejection fraction did not correlate with the development of acute rejection. Correlation of a combination of changes in stroke volume and end-diastolic volume with EMB showed a sensitivity of 85% and a specificity of 96%. Radionuclide scanning is therefore a useful noninvasive tool for monitoring acute rejection.

 

Results of hormonal therapy in human brain-dead potential organ donors
D Novitzky and DK Cooper
Transplant Proc (1988) 20(5 Suppl 7): 59-62

 

The role of nuclear cardiology procedures in the evaluation of cardiac function following heart transplantation
M Iturralde, D Novitzky, DK Cooper, AG Rose, J Boniaszczuk, JA Smith, B Reichart and S Isaacs
Semin Nucl Med (1988) 18(3): 221-40
10.1016/s0001-2998(88)80030-8

Heart transplantation is, today, an accepted and recommended modality in the management of selected patients suffering from terminal heart disease. However, acute rejection and infection remain the major complications of this operation. Serial endomyocardial biopsy (EB), considered as the standard for diagnosis of cardiac rejection, is an invasive and delicate operation, not free of complications, even when done by skilled personnel in specialized centers. The object of this study was to compare and correlate between radionuclide ventriculography (RNV) and the histologic findings of EB. Furthermore, to validate the use of nuclear cardiology techniques that allow noninvasive, reliable, and rapid quantitation of ventricular function and myocardial perfusion for the diagnosis and management of rejection in patients with heart transplants. Radionuclide studies of left ventricular function were performed in 3 heterotopic heart transplant patients (HHT) with long term survival and early after the operation in 5 patients with HHT, 12 orthotopic heart transplants (OHT) and in 2 heart and lung transplants (HLT). Simultaneous EBs were performed in the early posttransplant patients and a histologic score for acute rejection was obtained. First pass (FP) and multigated equilibrium blood pool ventriculography, using the in vivo 99mTc-labelling of RBCs was used to measure left ventricular volumes (LVV) such as stroke volume (SV), end-diastolic volume (EDV), end-systolic volume (ESV), and both global and regional ejection fraction (EF, REF). The histological grading of acute rejection was classified into four groups: (1) no rejection, (2) mild rejection, (3) moderate rejection, and (4) severe rejection. The median of each LVV parameter was calculated and correlated with the EB using a nonparametric one way analysis of variance. A percentage change of LVVs was used rather than the difference of the calculated LVVs. During moderate acute rejection, SV had the highest correlation in P less than 0.004, followed by the EDV (P less than 0.05), and finally ESV (P less than 0.02). During severe acute rejection the correlation was SV (P less than 0.0008), EDV (P less than 0.001), and ESV (P less than 0.006). Myocardial perfusion scintigraphy using 201T1 was performed in the HHT patients, although, at this stage we have not attempted a correlation with the histologic findings. In one patient with long term survival OHT, increased 131I-metaiodobenzylguanidine (MIBG) myocardial uptake was evident during a rejection episode.

 

Management of pulmonary atresia or critical pulmonary stenosis and intact ventricular septum with a small or hypoplastic right ventricle
MM de Moor, DG Human and B Reichart
Int J Cardiol (1988) 19(2): 245-53
10.1016/0167-5273(88)90085-x

Twenty-one neonates and infants less than 3 months old undergoing cardiac surgery for an obstructed right ventricular outflow tract, intact ventricular septum and a small or hypoplastic right ventricle were retrospectively analyzed, in order to assess the effects of a change in management protocol. Seven of the 8 patients with critical pulmonary stenosis survived surgery using a transannular outflow patch, whereas only 1 of the 8 patients with pulmonary atresia survived the same operation. Two patients in the latter group died 2 and 3 months after surgery but with complications arising from surgery. Of 5 patients with pulmonary atresia who had a modified Blalock Taussig shunt, 3 patients survived the surgery and were discharged home. These results significantly indicate that there is an unacceptably high mortality for the relief of pulmonary atresia (with intact septum) using a transannular outflow patch, and a Blalock Taussig shunt is the preferred operation. The transannular outflow patch is a safe operation for neonates with critical pulmonary stenosis, irrespective of the size of the right ventricle.

 

Initial experimental experience with a "replaceable" cardiac valve prosthesis
DK Cooper, WN Wicomb, GM Gould and D Boonzaier
Ann Thorac Surg (1988) 45(5): 554-8
10.1016/s0003-4975(10)64532-8

An easily "replaceable" cardiac valve prosthesis has been designed. It consists of two parts: (1) a sewing ring incorporating a circlip and (2) a functioning valve (either mechanical or tissue). The circlip is encased in a sewing ring, which is sutured into the natural valve annulus, and grips the functional part of the prosthesis, thereby preventing dislodgment. A simple instrument has been designed to open the circlip a few millimeters to allow easy removal or insertion of the functional element. This sewing ring/circlip with the functional element of a Bjork-Shiley prosthesis was used in 10 baboons undergoing mitral valve replacement. Removal and replacement of the functional element was carried out at a second operation between 1 and 12 weeks later. There were no operative deaths. Baboons were electively killed one day to twelve months after the second operation. There were no complications related to the prosthesis; cardiac catheterization showed normal hemodynamics before and after the second operative procedure.

 

Assessment and selection of patients for heart transplantation
DK Cooper, P Sumpter, D Novitzky, J Chaffin, AE Greer, CN Barnard and N Zuhdi
J Okla State Med Assoc (1988) 81(3): 137-40

 

Indications for heterotopic heart transplantation and report on two patients
DK Cooper, CA Romero, Jr., RM Clark, J Chaffin, A Greer, D Novitzky, CN Barnard and N Zuhdi
J Okla State Med Assoc (1988) 81(8): 513-7

 

Hormonal therapy in the brain-dead experimental animal
DK Cooper, D Novitzky and WN Wicomb
Transplant Proc (1988) 20(5 Suppl 7): 51-4

 

Hemodynamic and electrocardiographic responses
DK Cooper, D Novitzky and WN Wicomb
Transplant Proc (1988) 20(5 Suppl 7): 25-8

 

Cardiac allotransplantation across major blood group barriers in the baboon
DK Cooper, G Lexer, AG Rose, M Keraan, J Rees, E Du Toit and R Oriol
J Med Primatol (1988) 17(6): 333-46
In heterotopic heart transplantation experiments in Chacma baboons, some of the animals were significantly immunosuppressed with cyclosporine, resulting in prolonged cardiac allograft survival. ABO blood group incompatibility between recipient and donor did not significantly influence mean allograft survival, but early hyperacute (vascular) or acute (cellular) rejection occurred only when ABO incompatibility was present.

 

Effects of cyclosporine and antibody adsorption on pig cardiac xenograft survival in the baboon
DK Cooper, PA Human, G Lexer, AG Rose, J Rees, M Keraan and E Du Toit
J Heart Transplant (1988) 7(3): 238-46
The problem of donor heart supply would be solved if hearts could be transplanted from readily available animals such as the pig or sheep. We have investigated heterotopic heart transplantation (in the neck) with the pig as donor and baboon as recipient. Five experimental groups were studied. Control hearts (group 1, n = 4) were rejected within 4 minutes to 8 hours. Splenectomy done before transplantation (group 2, n = 3) did not extend survival significantly (30 minutes to 8 hours). Donor heart survival in baboons receiving immunosuppressive therapy of cyclosporine and methylprednisolone (group 3, n = 5) was from 15 to 75 minutes only in four animals and for 5 days in one animal. Anti-pig antibody adsorption from baboon blood by pretransplant donor-specific kidney hemoperfusion (group 4, n = 7) resulted in cardiac function for 6 to 12 hours in three cases and from 4 to 5 days in four cases (p less than 0.02). A combination of pretransplant antibody adsorption and immunosuppression (group 5, n = 4) resulted in graft survival of 8 to 20 hours in three cases and of 4 days in one case (p less than 0.03). Histopathologic features of vascular (hyperacute) rejection were seen in all hearts except one (the 5-day survivor in group 3). Pretransplant adsorption of antibody clearly prolonged survival of discordant cardiac xenografts in some cases. Further exploration of this technique appears justified.

 

Virological implications of the use of primates in xenotransplantation
FS Van der Riet, PA Human, DK Cooper, B Reichart, JE Fincham, SS Kalter, PJ Kanki, M Essex, DL Madden, MT Lai-Tung and et al.
Transplant Proc (1987) 19(5): 4068-9

 

Twenty years of heart transplantation at Groote Schuur Hospital
H Reichenspurner, JA Odell, DK Cooper, D Novitzky, PA Human, U Von Oppell, E Becerra, DH Boehm, A Rose, R Fasol and et al.
J Heart Transplant (1987) 6(6): 317-23
Between December 1967 and July 1987, 110 heart transplantations (61 heterotopic and 49 orthotopic) and 12 heart-lung transplantations were done at Groote Schuur Hospital in Cape Town, South Africa. Twelve procedures were retransplantations, including two third interventions. The patients were divided into three groups: Group A (n = 55) from 1967 to 1982 received so-called conventional treatment of azathioprine, methylprednisolone, and antithymocyte globulin. Group B (n = 15) from 1983 to 1984 had cyclosporine in high dosages together with methylprednisolone. Group C (n = 30) received quadruple drug therapy of low-dosage cyclosporine, together with azathioprine, methylprednisolone in lower dosages, and antithymocyte globulin (for the first 4 to 6 days and rescue antithymocyte globulin for severe rejection). From Group A, nine of 55 patients are alive up to 17 years after transplantation. The main causes of death were acute rejections and infections (in 60% altogether). From group B, six of 15 patients are alive. Acute rejections and infections were the causes of death in 12% of the patients, but multiple organ failure was a major cause in 24% most probably because of the high dosages of cyclosporine. From group C, 23 of 30 patients have survived. In this group the results after heterotopic heart transplantation do not differ significantly from orthotopic transplantation, which justifies this procedure in particular situations. If all heterotopic and orthotopic transplantations are compared, orthotopic procedures have a substantially better outcome. With the modified immunosuppressive regimen (group C) combined with precise donor and recipient selection and more sophisticated rejection monitoring, the actuarial survival rate within the last 12 months is 94%.

 

Heart transplantation at Groote Schuur Hospital, Cape Town. Twenty years' experience
BA Reichart, HC Reichenspurner, JA Odell, DK Cooper, D Novitzky, PA Human, UO Von Oppell, EA Becerra, DH Boehm and AG Rose
S Afr Med J (1987) 72(11): 737-9
Human allogeneic heart transplantation was started at Groote Schuur Hospital in Cape Town in 1967. Since then 110 hearts (61 heterotopic and 49 orthotopic) and 12 heart-lung transplantations have been performed in the unit. Ten procedures were retransplantations including 2 third interventions. The patients fall into three groups according to their immunosuppressive therapy: group A (N = 55) from 1967 to 1982 received the so-called 'conventional treatment' (azathioprine, methylprednisolone and antithymocyte globulin (ATG)); group B (N = 15) from 1983 to 1984 received cyclosporin A in high dosage, together with methylprednisolone; and group C (N = 30) received quadruple drug therapy of low-dose cyclosporin A, together with azathioprine, methylprednisolone in lower dosages and antithymocyte globulin (for the first 4-6 days and rescue-ATG for severe rejection). The results have improved significantly over the years. The actuarial survival rate after heart transplantation within the last 12 months is 94%. Several important steps have been inaugurated: in 1973 heterotopic heart transplantation was initiated and in 1984 hormonal therapy of brain-dead organ donors was started. Radionuclide scanning, in combination with endomyocardial biopsies, has proved to be a very sensitive means of monitoring rejection.

 

Is pulmonary ischemia a factor in the reperfusion response? An experimental study in the chacma baboon
BA Reichart, PA Human, AG Rose, D Novitzky and DK Cooper
J Heart Transplant (1987) 6(4): 238-43
A reimplantation or reperfusion response has been described in both the experimental animal and the human patient after various procedures involving pulmonary ischemia. We have investigated this phenomenon in a primate model. Ten chacma baboons were placed on cardiopulmonary bypass and cooled to 20 degrees C. Circumferential segments of the right main bronchus and pulmonary artery were denuded of all surrounding tissue. Each structure was then cross-clamped, which rendered the lung ischemic, during which time the organ was immersed in cold saline solution. Ischemia was maintained for 1.5 to 5 hours; after reperfusion and discontinuation of bypass, the right lung was biopsied and the chest closed. Chest radiographs, lung biopsies, and arterial blood gases were taken at intervals for up to 16 to 28 days. Right lung shadowing on chest radiography with concomitant histopathologic changes, indicative of a reperfusion reaction, were seen in only one animal, which had undergone lung ischemia for 1.5 hours. In one other animal that was ischemic for 5 hours, patchy opacification of the lung was seen on two occasions (days 8 and 15) with concomitant mild histopathologic changes. In conclusion, therefore, a major reperfusion response after pulmonary ischemia in the chacma baboon is possible but unusual. This would suggest that the appearance of pulmonary opacification on chest radiography within the first 4 weeks after heart-lung transplantation in humans is most likely attributable to some other condition, such as isolated lung rejection or infection.

 

The value of hormonal therapy in improving organ viability in the transplant donor
D Novitzky, DK Cooper and B Reichart
Transplant Proc (1987) 19(1 Pt 3): 2037-8

 

Brain death, triiodothyronine depletion, and inhibition of oxidative phosphorylation: relevance to management of organ donors
D Novitzky, DK Cooper, D Morrell and S Isaacs
Transplant Proc (1987) 19(5): 4110-1

 

Cardiac transplantation using discordant xenografts in a nonhuman primate model
G Lexer, DK Cooper, WN Wicomb, AG Rose, J Rees, M Keraan, B Reichart and E Du Toit
Transplant Proc (1987) 19(1 Pt 2): 1153-4

 

Cardiac allograft survival in ABO blood group incompatible baboons
DK Cooper, G Lexer, AG Rose, J Rees, M Keraan, E Du Toit and R Oriol
Transplant Proc (1987) 19(1 Pt 2): 1036-8

 

Is ABO compatibility essential in xenografting between closely related species?
DK Cooper, PA Human and AG Rose
Transplant Proc (1987) 19(6): 4437-40

 

Prolongation of cardiac xenograft (vervet monkey to baboon) function by a combination of total lymphoid irradiation and immunosuppressive drug therapy
DK Cooper, PA Human and B Reichart
Transplant Proc (1987) 19(6): 4441-2

 

Are there indications for heterotopic heart transplantation today?
E Becerra, DK Cooper, D Novitzky and B Reichart
Transplant Proc (1987) 19(1 Pt 3): 2512-3

 

Further cardiac transplant procedures in patients with heterotopic heart transplants
D Novitzky, DK Cooper, RP Lanza and CN Barnard
Ann Thorac Surg (1985) 39(2): 149-54
10.1016/s0003-4975(10)62555-6

Seven patients with heterotopic heart transplants have undergone further heart transplant procedures. In 5, the first heterotopically placed donor heart was excised and replaced with the second donor heart. In 2, the first heterotopic donor heart was left in situ and the patient's own heart (then nonfunctioning) was excised and replaced by the second donor heart; thus, these patients underwent orthotopic transplantation and were left with two donor hearts. The decision to perform retransplantation in a patient undergoing irreversible acute rejection is usually straightforward, but the timing of a further transplant procedure in a patient with advanced graft arteriosclerosis may present a difficult problem. Two of the 7 patients in this series died of infectious complications within the first 3 months after retransplantation. A third patient acutely rejected the second donor heart within 5 days, but survived an additional 17 months with the support of his own cardiomyopathic heart. Four patients remain alive and well between 5 and 36 months following the second transplant and between 17 and 54 months following the first transplant procedure.

 

The significance of left ventricular volume measurement after heart transplantation using radionuclide techniques
D Novitzky, D Cooper, J Boniaszczuk, S Isaacs, RC Fraser, PJ Commerford, CJ Uys, AG Rose, JA Smith and CN Barnard
J Heart Transplant (1985) 4(2): 206-9
Multigated equilibrium blood pool scanning using Technetium 99m labeled red blood cells was used to measure left ventricular volumes in three heterotopic and one orthotopic heart transplant recipient(s). Simultaneously, an endomyocardial biopsy was performed and the degree of acute rejection was assessed by a histological scoring system. The scores were correlated to changes in ejection fraction and heart rate. Technetium 99m scanning data were pooled according to the endomyocardial biopsy score: no rejection; mild rejection; moderate rejection, and severe rejection. In each group, the median of the left ventricular volume parameters was calculated and correlated with the endomyocardial biopsy score, using a non-parametric one-way analysis of variance. A decrease in stroke volume correlated best with the endomyocardial biopsy score during acute rejection. A decrease in end-diastolic left ventricular volumes did not correlate as well. Changes in the end-systolic left ventricular volumes were not statistically significant, but using a simple correlation between end-systolic left ventricular volumes and endomyocardial biopsy the correlation reached significance. Changes in left ventricular volumes measured by Technetium 99m scanning may be useful to confirm the presence or absence of acute rejection in patients with heart grafts.

 

Does the electrocardiogram detect early acute heart rejection
DK Cooper, RG Charles, AG Rose, RC Fraser, S Isaacs, D Novitzky and CN Barnard
J Heart Transplant (1985) 4(5): 546-9
Changes in electrocardiographic parameters, particularly a reduction of the voltage of the QRS complex, have been held to indicate acute rejection of a transplanted heart. In a series of heterotopic heart recipients, changes in electrocardiographic parameters were correlated with histopathological evidence of acute rejection seen on endomyocardial biopsies obtained by the percutaneous transvenous technique. No statistically significant correlation was found between the electrocardiographic changes and the histopathological features. The electrocardiogram appears to be an unreliable predictor of early acute rejection in patients with heterotopic heart transplants.

 

Cardiac transplantation following storage of the donor heart by a portable hypothermic perfusion system
WN Wicomb, DK Cooper, D Novitzky and CN Barnard
Ann Thorac Surg (1984) 37(3): 243-8
10.1016/s0003-4975(10)60333-5

Four patients have undergone heterotopic heart transplantation with donor hearts stored by a portable hypothermic perfusion system. Total ischemic periods ranged from 6 hours 55 minutes to 16 hours 50 minutes. One heart, transplanted into a patient who had acutely rejected a previous graft, suffered accelerated, irreversible, acute rejection within five days, associated with strong antibody formation; donor heart function was never good. In the 3 remaining patients, donor heart function was good after initially being poor for a few hours in 2 patients. One patient died of long-term rejection after 6 months and 1 of tuberculous meningitis after 10 months; 1 remains alive at 15 months. Neither preservation of the donor heart for periods in excess of approximately 4 hours nor the use of continuous hypothermic perfusion as a method of preservation appears to have been reported previously in the context of the clinical situation.

 

Valve replacement in patients over 70 years of age
AZ Sukkar, DK Cooper, J De Nobrega, J Hassoulas, D Novitzky, HE Sanchez and CN Barnard
S Afr Med J (1984) 65(10): 370-3
Between 1 August 1975 and 31 October 1982, 76 patients aged between 70 and 82 years (mean 73,4 years) underwent elective (71) or emergency (5) valve replacements. Fifty patients underwent aortic valve replacement (including 5 with additional coronary artery bypass grafts), 19 mitral valve replacement including 3 with coronary artery bypass grafts, and 7 double valve replacements. There were 3 early deaths (3,9%) and 9 late deaths (11,8%) during the follow-up periods of 1 month - 86 months (mean 29 months). Actuarial analysis showed a survival rate of 95% at 1 year, 89% at 2 years, and 77% at 5 years. The clinical result of operation was judged to be good or excellent in all patients except one. It is concluded that valve replacement in patients over 70 years carries a low operative risk, statistically similar to that for younger patients at our institution, and is accompanied by a satisfactory result.

 

The surgical treatment of tetralogy of Fallot
HE Sanchez, EM Cornish, FC Shih, J de Nobrega, J Hassoulas, J Netto, RE Thornington and CN Barnard
Ann Thorac Surg (1984) 37(5): 431-6
10.1016/s0003-4975(10)60774-6

This is a review of the last 307 patients with tetralogy of Fallot who were operated on in our unit at Groote Schuur Hospital and Red Cross War Memorial Children's Hospital. Complete repair was undertaken in 301 patients, and shunts were performed in 6 children. There were 17 hospital deaths and 1 late death. The mortality was 5.5% for children less than 12 years old and 6.6% in patients between 12 and 20 years old. During this study period, there was a change in our policy as to when complete repair should be attempted. At present, we perform systemic-pulmonary shunts in patients less than 6 months old and delay complete repair until the child is 2 years old. In deciding whether a shunt should precede complete repair, our experience has shown that age is not as important a consideration as the anatomy of the outflow tract of the right ventricle and pulmonary arteries.

 

Surgical management of congenital heart disease. A review of 7 years' experience
HE Sanchez, RD Cooke, D Human, J De Nobrega, J Hassoulas and CN Barnard
S Afr Med J (1984) 66(10): 359-66
This is a review of the results of surgical treatment of congenital heart disease in children aged less than 12 years over the period 1975 - 1981 (1254 cases). The patients are divided into two groups, those treated between 1975 and 1979 (903 cases) and those treated in 1980 and 1981 (351 cases). Only 19,7% of the patients in the first group were under the age of 1 year, but 26,5% in the second group were in this age group. This reflects a change in policy and an attempt at surgical correction at a much younger age than was previously the case. Our present policy in cardiac emergencies in infants will be discussed. Despite the higher percentage of infants aged under 1 year who were treated in 1980 - 1981, the mortality rate was lower than that for the period 1975 - 1979. This probably reflects greater experience in the post-operative management of patients under the age of 1 year.

 

The significance of femoral pulses in coarctation of the aorta
D Novitzky, HE Sanchez, D Human and CN Barnard
S Afr Med J (1984) 65(19): 755-7
Between January 1974 and December 1981, 80 patients aged between 1 and 13 years underwent surgical correction of coarctation of the aorta. At pre-operative examination 45 patients had absent femoral pulses (group A) and 35 had palpable femoral pulses (group B). Nineteen patients were lost to late follow-up; the remaining 61 (76%) were followed up for between 3 months and 7 years. Of the patients in group A 89% had systolic and 87% diastolic hypertension, while in group B the respective figures were 80% and 77%. At follow-up after surgery, systolic hypertension was present in 36% of patients in group A and in 16% of those in group B. Diastolic hypertension was present in 73% of patients in group A but only in 19% of those in group B (P less than 0,0001). It would appear that children with coarctation of the aorta and absent femoral pulses are more likely to continue to have diastolic hypertension after surgical correction of the anomaly than are children in whom the femoral pulses are palpable. Early operation might reduce the incidence of hypertension in this group.

 

Primary cardiac haemangiomas. A report of 2 cases
D Novitzky, AG Rose, JA Morgan and CN Barnard
S Afr Med J (1984) 66(7): 267-70
Primary heart tumours are extremely rare. Over a period of 25 years 22 primary cardiac tumours were diagnosed clinically or at autopsy at Groote Schuur Hospital. Fourteen patients with myxomas, 1 with lymphocytic lymphoma and 2 with haemangiomas underwent surgery. A further 4 myxomas and 1 histiocytoma were found at autopsy. In both the cases of haemangioma the diagnosis of a vascular tumour was made before surgery. One tumour had infiltrated the lateral wall of the left ventricle and was unresectable; only a biopsy specimen was taken. The patient, however, remains well some 6 years later. In the second patient the haemangioma was situated in the outflow tract of the right ventricle and was successfully excised. The clinical history, pathological features and management of both cases are presented.

 

The value of recipient heart assistance during severe acute rejection following heterotopic cardiac transplantation
D Novitzky, DK Cooper, AG Rose and CN Barnard
J Cardiovasc Surg (Torino) (1984) 25(4): 287-95
Acute rejection remains a major complication of cardiac transplantation. One of the advantages of heterotopic as opposed to orthotopic heart transplantation is that the recipient heart remains in situ, and may provide valuable support for the circulation if donor heart function is severely reduced during an acute rejection episode. Details are presented of 11 patients who underwent acute rejection severe enough to cause loss of significant function of the donor heart, during which time life was maintained by the patient's own diseased heart. In 5 cases the acute rejection proved reversible, with patient survival extending from 10 weeks to 61/2 years, though only 2 remain alive today. In 6 cases rejection was irreversible; 4 of these patients underwent a second heart transplant, but only 1 remains alive today.

 

Circulatory assistance with allograft
D Novitzky, DK Cooper and CN Barnard
Ann Thorac Surg (1984) 37(2): 179
10.1016/s0003-4975(10)60312-8

 

Prediction of acute cardiac rejection using radionuclide techniques
D Novitzky, J Boniaszczuk, DK Cooper, S Isaacs, AG Rose, JA Smith, CJ Uys, CN Barnard and R Fraser
S Afr Med J (1984) 65(1): 5-7
Radionuclide scanning of the donor left ventricle using technetium-99m-labelled red cells was used to monitor acute rejection after heterotopic heart transplantation and compared with histopathological evidence of rejection obtained at examination of an endomyocardial biopsy specimen. The ejection fraction and end-diastolic, end-systolic and stroke volumes were calculated at each examination; an equation was derived from these data to predict the degree of acute rejection, using histopathological examination of endomyocardial biopsy specimens as criteria of the presence and severity of rejection. A highly significant multiple correlation between radionuclide scanning parameters and endomyocardial biopsy was found. The advantages of non-invasive radionuclide scanning over the invasive procedure of endomyocardial biopsy are discussed.

 

Comparison of patients with ischemic, myopathic, and rheumatic heart diseases as cardiac transplant recipients
RP Lanza, DK Cooper, ST Boyd and CN Barnard
Am Heart J (1984) 107(1): 8-12
10.1016/0002-8703(84)90125-x

Fifty-four human-to-human cardiac transplants (10 orthotopic and 44 heterotopic) in 50 patients were performed between December, 1967, and December, 1981. The underlying cardiac pathology was ischemic (IHD) in 29, cardiomyopathic (CM) in 17, rheumatic (RHD) in four, and mixed or other pathology in four. Patients with RHD survived for a mean period over three times as long as those with either CM (p less than 0.02) or IHD (p less than 0.05). Although CM patients were on average over a decade younger than those in other groups, they had a lower survival rate. There was a higher incidence of death from chronic rejection in patients with IHD, in whom there was also a higher incidence of thromboembolic episodes. Major infections were over twice as frequent in IHD patients as in CM patients (p less than 0.01). Noncompliance with regard to adherence to instructions and therapy was a significant factor in morbidity and mortality, especially in CM patients. Our data suggest that survival and morbidity of recipients of heart transplants might be influenced to some extent by the nature of the underlying primary cardiac condition, RHD being considered a favorable survival factor when compared with IHD, and CM being particularly unfavorable.

 

Lack of efficacy of high-dose verapamil in preventing brain damage in baboons and pigs after prolonged partial cerebral ischemia
RP Lanza, DK Cooper and CN Barnard
Am J Emerg Med (1984) 2(6): 481-5
10.1016/0735-6757(84)90068-8

There has been mounting speculation that calcium antagonists may be useful in reducing or preventing brain damage after cardiopulmonary resuscitation. To test the clinical usefulness of these agents in averting such damage, high-dose verapamil was administered to baboons and pigs after partial cerebral ischemia for varying periods of time. In Group A baboons and pigs, the major aortic branches supplying the carotid and vertebral circulations were clamped for periods ranging from 15 to 150 minutes, and neurological recovery was observed. In Group B, verapamil hydrochloride 0.7 mg/kg was given by intravenous infusion after similar periods of arterial occlusion. The administration of verapamil did not lead to any clinically improved neurological outcome. The use of verapamil after prolonged periods of partial cerebral ischemia did not improve neurological recovery in baboons and pigs.

 

Heterotopic cardiac transplantation. A 7-year experience at Groote Schuur Hospital, Cape Town
J Hassoulas and CN Barnard
S Afr Med J (1984) 65(17): 675-82
Between November 1974 and February 1982 40 patients underwent heterotopic heart transplantation at Groote Schuur Hospital, Cape Town. In 4 of these patients retransplantation was carried out, bringing the total number of heterotopic heart transplant operations to 44. Fourteen patients are alive to date, from 4 months to more than 7 years after transplantation. The 1-year survival rate has been 60%. Three of the first 6 patients in this series have survived for 6 years or more, while 6 of the 7 patients who received transplants during 1981 (including 2 who underwent retransplantation) are alive. Retransplantation of the donor heart, donor heart procurement from distant sources using prolonged myocardial preservation techniques and the reasons why heterotopic cardiac transplantation is more advantageous than other methods are discussed. The surgical technique and some modifications introduced since this method was first described in 1975 are presented in detail.

 

Immunosuppression in the baboon cardiac allograft model: effects of splenectomy, bolus methylprednisolone, propranolol, high-dose azathioprine, cyclophosphamide, and a niridazole metabolite
DK Cooper, D Novitzky, RP Lanza, AG Rose, WN Wicomb and CN Barnard
Transplantation (1984) 38(3): 299-301

 

Heterotopic versus orthotopic heart transplantation
CN Barnard and DK Cooper
Transplant Proc (1984) 16(3): 886-92

 

Toxoplasmosis of donor and recipient hearts after heterotopic cardiac transplantation
AG Rose, CJ Uys, D Novitsky, DK Cooper and CN Barnard
Arch Pathol Lab Med (1983) 107(7): 368-73
Toxoplasmosis of both donor and recipient hearts was diagnosed by means of endomyocardial biopsy specimens after heterotopic cardiac transplantation for dilated cardiomyopathy. Before transplantation, the donor had raised antibody titers to Toxoplasma, and the recipient was negative. When toxoplasmosis was diagnosed on the basis of endomyocardial biopsy specimen, the recipient had a greatly elevated antibody titer of 1:1,027. This suggests that the infection could have been transferred with the donor heart. The mononuclear cell response elicited by disrupted toxoplasmic cysts interferes with the diagnosis of rejection in graft biopsy specimens. Electron microscopy is valuable in confirming a light microscopic diagnosis of toxoplasmosis. Drug therapy eradicated the toxoplasmosis, but the patient died later of tuberculous meningitis.

 

Trends in cardiac surgery at the University of Cape Town, 1971-1981
MM Parry, DK Cooper and CN Barnard
S Afr Med J (1983) 63(6): 189-93
A review has been undertaken of the number and types of surgical procedures performed in the Department of Cardiac Surgery of the University of Cape Town during the 11-year period 1971-1981, together with data on associated mortality. A yearly average of 560 operations was carried out, of which 75% were for acquired and 25% for congenital heart disease. The number of patients treated continues to rise, from 434 in 1971 to 690 in 1981. There has been a slight reduction in the overall average yearly mortality, from 6.1% between 1971 and 1975 to 5.0% between 1976 and 1981. There was a significant increase in the number of valve replacements in 1975 and 1976 and a more recent, continuing increase in operations for ischaemic heart disease, which now form 19% of the total operations. In both these groups the average yearly mortality has fallen during the period of study. The number of operations each year for congenital heart disease has remained fairly constant, but, disappointingly, there has been no significant reduction in mortality.

 

Coarctation of the aorta in infants under 1 year of age
D Novitzky, HE Sanchez and CN Barnard
S Afr Med J (1983) 64(24): 934-6
Untreated coarctation of the aorta in infants is associated with a high mortality, reaching up to 90%. During a period of 7 years 26 infants underwent surgical repair of this condition, the youngest being 6 days old and the oldest 11 months. Two underwent emergency surgery after catheterization, while the rest had an elective or semi-elective operation. Associated anomalies were present in 85% of the whole group; of the 22 patients with anomalies, a ventricular septal defect (VSD) and patent ductus arteriosus (PDA) were present in 11 patients, a PDA in 7, a VSD in 6, transposition of the great arteries in 3, an atrial septal defect in 3, a single ventricle in 1, a hypoplastic aortic arch in 1, a hypoplastic left ventricle in 1 and a partial anomalous pulmonary venous defect in 1. Four patients (15%) had no other associated anomaly. The surgical techniques used were coarctectomy and end-to-end anastomosis in 61,5%, subclavian flap aortoplasty in 27%, and Dacron patch aortoplasty in 11,5%. Additional pulmonary artery banding was performed in 6 patients; in 2 patients lung biopsies were also carried out in order to establish the severity of pulmonary hypertension. The overall hospital mortality was 30,7%. No patients with uncomplicated coarctation died.

 

The surgical technique of heterotopic heart transplantation
D Novitzky, DK Cooper and CN Barnard
Ann Thorac Surg (1983) 36(4): 476-82
10.1016/s0003-4975(10)60492-4

The surgical technique of heterotopic heart transplantation is detailed and illustrated. The donor heart is excised after cardioplegic arrest and topical cooling; its preparation and implantation in the recipient are described. Emphasis is placed on ensuring nonrestrictive anastomoses between the left and right atria of the recipient and the donor, on estimating the optimal length of the donor aorta, and on the insertion of a prosthetic graft between the donor and the recipient pulmonary arteries. Forty-six such transplants have been performed to date without operative or early postoperative mortality related to technical problems.

 

Survival after cardiac transplantation
RP Lanza, DK Cooper, D Novitzky and CN Barnard
S Afr Med J (1983) 64(26): 1007

 

Malignant neoplasms occurring after cardiac transplantation
RP Lanza, DK Cooper, MJ Cassidy and CN Barnard
JAMA (1983) 249(13): 1746-8
Fifty-seven cardiac transplants in 53 patients have been performed; 30 survived for at least three months. Malignant neoplasms developed in three (10%) of these patients. This incidence is more than double that in recipients of donor kidneys at our institution. Kaposi's sarcoma developed in three patients in the combined groups and accounted for 30% of all malignant neoplasms. The possible reasons for these high incidences are discussed.

 

Analysis of surgical versus medical therapy in active complicated native valve infective endocarditis
CH Croft, W Woodward, A Elliott, PJ Commerford, CN Barnard and W Beck
Am J Cardiol (1983) 51(10): 1650-5
10.1016/0002-9149(83)90203-5

From 1972 to 1980, 23 patients (Group A) with native valve infective endocarditis underwent surgical intervention, often for multiple indications, during the active stage of the infective process because of progressive class III and IV (New York Heart Association) heart failure (12 patients), persistent severe hypotension (3 patients), uncontrolled infection for over 21 days (11 patients), aortic root abscess (2 patients), and pericarditis (1 patient). Eighty-five patients (Group B) with active native valve endocarditis, matched for severity of illness, were treated medically. Two patients (9%) in Group A and 43 patients (51%) in Group B died during the hospital admission (p less than 0.001). Any difference in long-term cumulative survival rate between the 2 groups was largely due to the beneficial impact of surgical management on the hospital mortality. Of 23 patients in Group A, 11 (48%) had an entirely uncomplicated postoperative course. Long-term mortality rates in those with aortic valve endocarditis treated medically (79%) were significantly higher than in those with mitral valve involvement (47%) (p less than 0.05). Patients with aortic valve involvement treated surgically had a better hospital (p less than 0.005) and long-term (p less than 0.0005) survival rate than those treated medically. Two groups at risk for postoperative complications were identified; 3 of 11 patients (27%) with uncontrolled infection had an early postoperative recurrence, and 4 of 7 patients (57%) with an aortic root abscess had postoperative prosthetic paravalvular regurgitation. Surgery therefore effects a substantial reduction in hospital mortality in patients with complicated active infective endocarditis (9% versus 51%), but patients with preoperative prolonged periods of uncontrolled infection or with aortic root abscess are liable to postoperative complications.

 

Orthotopic allotransplantation and autotransplantation of the baboon heart following 24-hr storage by a portable hypothermic perfusion system
DK Cooper, WN Wicomb, AG Rose and CN Barnard
Cryobiology (1983) 20(4): 385-94
10.1016/0011-2240(83)90028-7

A nonpulsatile perfusion apparatus, based on the air-lift pump principle, has been developed. Circulation of the perfusate, as well as oxygenation and maintenance of acid-base balance, is provided by the flow of a mixture of 97% oxygen and 3% carbon dioxide. The system is easily and entirely portable. Eleven baboons underwent orthotopic allotransplantation with donor hearts stored by continuous hypothermic (4-10 degrees C) perfusion for periods of up to 24 hr. Three were electively killed after 2 to 3 days; the remaining eight, immunosuppressed with methylprednisolone and either azathioprine or cyclosporin A, survived to rejection at between 10 and 49 days. Cardiac catheterization performed in six animals 7-14 days after allotransplantation showed virtually normal hemodynamic data. Three more baboons underwent heart excision and storage by hypothermic perfusion for 24 hr, and subsequent othotopic autotransplantation, the circulation of the baboon being maintained in the interim by an allograft. One animal survives 8 months later with hemodynamic data at cardiac catheterization differing little from that obtained before autotransplantation. This perfusion system has subsequently been used to store four human donor hearts prior to heterotopic transplantation.

 

Infectious complications after heart transplantation
DK Cooper, RP Lanza, S Oliver, AA Forder, AG Rose, CJ Uys, D Novitzky and CN Barnard
Thorax (1983) 38(11): 822-8
10.1136/thx.38.11.822

Infection has been the major cause of death and morbidity in patients undergoing cardiac transplantation at Groote Schuur Hospital. Twenty-two (55%) patients suffered at least one major episode of infection, which accounted for 10 (59%) of the deaths in the first year. The major site of origin of infection was the lung, though dissemination was not infrequent. Bacteria accounted for 22 (59%) infections; but viral, fungal and protozoal infections were not uncommon and in fact accounted for seven (64%) of the fatal infections. Several unusual causative microorganisms have been isolated in this group of immunocompromised subjects. There is a higher incidence of infection in patients over the age of 35 years and in patients who did not comply with instructions and advice.

 

Twenty-four-hour preservation of the pig heart by a portable hypothermic perfusion system
WN Wicomb, DK Cooper and CN Barnard
Transplantation (1982) 34(5): 246-50
10.1097/00007890-198211000-00002

A portable hypothermic perfusion system for storage of hearts has been developed. The system uses the airlift pump principle, whereby the flow of gas maintains circulation of the perfusate through the heart; no other energy source is required. Performance on ex vivo functional testing of 10 pig hearts stored for 20 to 24 hr using this system (group 3) was compared with that of freshly excised hearts (group 1) and hearts stored simply in the perfusate under hypothermic conditions, but not perfused (group 2). Group 2 hearts performed less well on functional testing than those of groups 1 and 3 which showed little statistical difference, suggesting good preservation by hypothermic perfusion. This has been confirmed by orthotopic transplantation of similarly preserved baboon hearts with survival until rejection at a mean of 27 days. The importance of the various constituents of the perfusate and the significance of weight gain during the storage and reperfusion periods are discussed.

 

Orthotopic transplantation of the baboon heart after 20 to 24 hours' preservation by continuous hypothermic perfusion with an oxygenated hyperosmolar solution
W Wicomb, DK Cooper, J Hassoulas, AG Rose and CN Barnard
J Thorac Cardiovasc Surg (1982) 83(1): 133-40
Baboon hearts were rapidly excised after being flushed with 500 ml of cardioplegic solution at 4 degrees C and then immersed in cold 4 degrees C saline or cardioplegic solution for 2 minutes. The hearts were then perfused at 8 to 10 cm H2O pressure for 20 to 24 hours under refrigeration with a hyperosmolar clear fluid maintain perfusate at 6 to 8 degrees C, through which 95% oxygen and 5% carbon dioxide were continually bubbled to maintain the perfusate pH between 7.2 and 7.4. Myocardial temperature remained at approximately 6 to 8 degrees C. The hearts were then orthotopically transplanted into recipient baboons matched for size and AB blood group. Two groups (A and B) were studied, differing significantly only with respect to the constitution of the cardioplegic solution and perfusate used. The cardioplegic agent used in Group B contained a higher concentration of magnesium than that used in Group A and included the calcium antagonist verapamil. Perfusate B had higher osmolality than perfusate A, largely due to the inclusion of sucrose. A preliminary group of 10 baboons in Group A received no immunosuppression. Five of the remaining six immunosuppressed baboons in this group survived more than 48 hours to rejection or until killed at 2 to 29 days. All six of the baboons in Group B survived to rejection between 6 and 33 days, with mean survival 19.5 days. Cardiac catheterization was performed in six surviving baboons (Group A, four; Group B, two) between postoperative days 6 and 10 and showed good hemodynamic function. Histologic examination of hearts after death has shown only minor ischemic changes in those hearts which functioned well.

 

Changes in indications for heart transplantation. An additional argument for the preservation of the recipient's own heart
JG Losman, H Levine, CD Campbell, RL Replogle, J Hassoulas, D Novitsky, DK Cooper and CN Barnard
J Thorac Cardiovasc Surg (1982) 84(5): 716-26
The 1 year survival rate after heart transplantation since 1967 from +/-30% to +/-70%, and the 5 year survival rate is now +/-50%. This improvement has brought renewed interest in this procedure, now done in about twenty centers in eight countries, and increased confidence has widened the indication to patients who are less than terminally ill, to restore quality of life. This trend is illustrated by the Cape Town series, which can be divided into two parts: 10 patients treated by orthotopic heart transplantation (OHT), from 1967 to 1973, and 40 patients treated by heterotopic heart transplantation (HHT), from 1974 to 1981. The HHT group was younger (mean 37 +/- 10 years versus 51 +/- 9 years, p less than 0.001), had been ill for a shorter length of time (mean 3.6 +/- 0.7 years versus 6.6 +/- 1.4 years, p less than 0.091), and were in a lower New York Heart Association (NYHA) class (mean 3.45 +/- 0.11 versus 3.9 +/- 1.0, p less than 0.006). The improved survival is linked to patient selection, progress in management, and switch to HHT, but not to progress in matching between donor and recipient. Since there is no means to predict tolerance of the donor heart, HHT limits the risks from unforseeable mismatch. The recipient's heart is a built-in assist device, maintaining life when the donor heart fails acutely at operation or during acute [three cases] or chronic [two cases] rejection. Had these patients undergone OHT they would have died. Comparing the 10 oldest HHT patients with the OHT series, no difference in pretransplant parameters was found. However, survival of HHT recipients was longer during the critical post-HHT period: at 3 months, p less than 0.011; at 6 months, p less than 0.05. Larger series will separate the effects of progress in management from the intrinsic advantages of HHT. Retaining the recipient's heart is logical and has brought few complications. Survival rate of 40 HHT patients was 73% at 6, 65% at 12, and 51% at 36 months; 85% of survivors are in NYHA Class I. In patients in less than desperate condition, but who refuse to remain cripples, HHT eliminates the growing ethical problem of removing a recipient's heart that may still support the patient.

 

Joint transplantation of the heart and lungs. Past experience and present potentials
JG Losman, CD Campbell, RL Replogle and CN Barnard
J Cardiovasc Surg (Torino) (1982) 23(6): 440-52
The history of experimental and clinical attempts at allogenic transplantation of the heart and lungs is reviewed and the physiological, technical and pathological implications of this procedure are illustrated by the unreported case of a 49 year-old male who underwent cardiopulmonary transplantation for terminal respiratory failure due to chronic obstructive airways disease and cor pulmonale. While there have been dramatic complications, the patient survived 23 days without major signs of cardiopulmonary dysfunction. The surgical technique, the post-operative management and the vicissitudes of this third human cardiopulmonary graft are described and the promises of this method discussed.

 

Heterotopic heart transplantation: a valid alternative to orthotopic transplantation: results, advantages, and disadvantages
JG Losman and CN Barnard
J Surg Res (1982) 32(4): 297-312
10.1016/0022-4804(82)90106-8

 

Effect of ABO blood-group antigens on long-term survival after cardiac transplantation
RP Lanza, DK Cooper and CN Barnard
N Engl J Med (1982) 307(20): 1275-6
10.1056/NEJM198211113072018

 

Mitral valve replacement in children
DG Human, HS Joffe, CB Fraser and CN Barnard
J Thorac Cardiovasc Surg (1982) 83(6): 873-7
Mitral valve replacement (MVR) is associated with higher mortality and morbidity rates in children than in adults, and the use of heterograft valves has been encouraged. The results of MVR in 56 consecutive patients, aged 2 to 12 years, presenting between January, 1972, and January 1979, were reviewed to test these beliefs. The etiology of mitral valve disease was rheumatic in 46, congenital in eight, and acute bacterial endocarditis in two. All children were seriously disabled (NYHA Classes III and IV). Cardiac catheterization in 36 patients revealed mixed valve disease in 26, pure mitral regurgitation in seven, and pure mitral stenosis in three. Seventeen Starr-Edwards (SE), five Lillehei (L), Bjork-Shiley (BS), eight Hancock (H), and 25 Carpentier-Edwards (CE) mitral prosthesis were inserted. Operative mortality was 2% (1 BS) and late mortality was 10% (three SE, one L, two CE). Serious late complications occurred in 30% of survivors, including 11 instances of calcific valve stenosis (five H, six CE), one case of valve thrombosis (1 L), and two embolic episodes (1 SER, 1 H). Survival curves were similar for patients with heterograft and mechanical valves (92% and 77% at 5 years). Event-free curves showed heterograft valves to have a far higher complication rate than mechanical valves (10% complication free at 4 years compared to 84% free at 5 years). Early operative results in children are excellent, and the overall mortality (10%) compares favorably with figures for MVR in adults. However the long-term durability and choice of prostheses remain problematical, since less than 10% of heterograft valves survive beyond 5 years.

 

Tricuspid atresia corrected by the Fontan method
J Hassoulas, MS Barnard, H Sanchez and CN Barnard
S Afr Med J (1982) 62(11): 356-8
The Fontan procedure was applied to correct 13 cases of tricuspid atresia, all with concordant arterial connections. Seven of the patients had had a total of ten previous operations to create palliative shunts. There were 3 early deaths, all due to low cardiac output states, but no late deaths. The postoperative management of the survivors was not unduly complicated, except in the 1st patient. Complete heart block developed transiently in 2 patients. The results are classified as good to very good in all 10 survivors. Our experience supports the opinion that the Fontan procedure gives good symptomatic relief in patients with tricuspid atresia. We discuss the possibility of improving long-term left ventricular function by early complete correction.

 

Low-dose versus high-dose steroid therapy in the prevention of acute rejection in baboon heterotopic cardiac allografts
DK Cooper, AG Rose and CN Barnard
Transplantation (1982) 34(2): 107-8
10.1097/00007890-198208000-00011

 

Transplantation of the heart
DK Cooper, D Novitzky, J Hassoulas and CN Barnard
Br J Clin Pract (1982) 36(10): 337-45

 

Technique, complications, and clinical value of endomyocardial biopsy in patients with heterotopic heart transplants
DK Cooper, RC Fraser, AG Rose, O Ayzenberg, GS Oldfield, J Hassoulas, D Novitzky, CJ Uys and CN Barnard
Thorax (1982) 37(10): 727-31
10.1136/thx.37.10.727

A review of 157 consecutive biopsies of donor endomyocardium in patients with heterotopic heart transplants is reported. The technique of percutaneous transvenous endomyocardial biopsy after this operation is described; manipulation of the catheter and bioptome into the junction of the donor superior vena cava and right atrium can be difficult when this anastomotic junction is small, as a result either of operative surgical technique or of subsequent contraction. The complication rate was 4%, but one patient may have died from infection resulting from biopsy when the bioptome had to be introduced at the groin. The histopathological changes seen in the biopsy specimens have been graded according to a scoring system to give the clinician a guide to the severity of rejection. Histopathological assessment was of clinical value in 96% of cases, but was inaccurate on two occasions, once because an opinion was given on what was in retrospect an inadequate sample. In patients undergoing persistent low-grade acute or chronic rejection there was difficulty in detecting or appreciating the true extent of myocardial fibrosis; this led to inadequate immunosuppressive treatment in two patients. Attention is drawn to the fact that ischaemic fibrosis resulting from the vascular changes of chronic rejection may spare the endomyocardium, which is kept viable by intracavitary blood, and that this may lead to a misleading histopathological report.

 

Medical, legal and administrative aspects of cadaveric organ donation in the RSA
DK Cooper, JC De Villiers, LS Smith, Y Crombie, ST Boyd, JE Jacobson and CN Barnard
S Afr Med J (1982) 62(25): 933-8
A shortage of donors remains the major limiting factor as regards the number of kidney and heart transplants performed in South Africa each year. The medical, legal and administrative aspects of cadaveric organ donation in this country are reviewed. The pathophysiology of brain death and the criteria necessary for a definite diagnosis are described, together with the criteria for the selection of cadaveric organ donors. The statutory requirements pertaining to the removal of human hearts and kidneys for the purposes of transplantation are detailed. The subsequent management of the brain-dead donor up to the time of excision of the required organ is described, and a note regarding the preservation and transportation of the donor organs is added.

 

The assessment and selection of patients for heterotopic heart transplantation
DK Cooper, RG Charles, W Beck and CN Barnard
S Afr Med J (1982) 61(16): 575-8
In the 2-year period 1979-1980, 34 patients were assessed at Groote Schuur Hospital as candidates for heterotopic heart transplantation. Ischaemic heart disease was the most common underlying cause (19 patients), with cardiomyopathy (9), rheumatic heart disease (2), failed transplants (3), and endomyocardial fibrosis (1) as the other causes of myocardial disease. Five patients were not accepted into the transplant programme, 2 declined after being accepted, and in 3 the initial decision of acceptance was later reversed. Nine patients died while awaiting suitable donors, the mean survival time from the date of acceptance being only 26 days. Fifteen patients underwent heterotopic heart transplantation, 11 remaining alive at the end of the period of study; 8 had normally functioning donor hearts but 3 had suffered irreversible rejection and awaited a second transplant.

 

Ex vivo functional evaluation of pig hearts subjected to 24 hours' preservation by hypothermic perfusion
W Wicomb, ST Boyd, DK Cooper, AG Rose and CN Barnard
S Afr Med J (1981) 60(6): 245-8
A system has been developed for the ex vivo functional testing of isolated hearts. Three groups, each of 10 pig hearts, have been studied: group 1--freshly excised hearts; group 2--heart hypothermically perfused for 20 - 24 hours with Krebs-Henseleit solution; group 3--hearts similarly perfused with a clear fluid hyperosmolar solution. Group 2 hearts performed poorly on functional testing and would clearly have been unsuitable for transplantation. Haemodynamic observations on group 3 hearts showed little statistical difference from those of group 1, suggesting good preservation. The value of the ex vivo testing system as a reliable means of assessing myocardial function is discussed, and has been confirmed by subsequent successful orthotopic transplantation of baboon hearts stored under identical conditions.

 

[The aorto-coronary by-pass. Personal clinical experience (author's transl)]
CA Curcio, MS Barnard, P Berloco and CN Barnard
G Ital Cardiol (1981) 11(3): 297-302
The surgical treatment of coronary artery disease still remains controversial, despite the fact that the surgical indications are widely recognized and so the efficacy of the aortocoronary bypass in relieving angina and in improving the prognosis of the patients with left mainstem lesions. However, one gets the impression that the criteria for surgery not always are correctly applied, with the consequence that the bypass is often performed on patients that could still benefit from proper medical treatment. At Groote Schuur Hospital, during the period 1976-78, we have bypassed a total of 395 coronary arteries in 204 patients. All the patients were in NYHA class III and IV. The peculiarity of this rather small series is based on the conservatism of the selection criteria, the operation being offered only to candidates with a very long history of angina uncontrolled by adequate medical treatment. The early mortality rate has been 1.47%, the late mortality rate 3.5% and the perioperative infarction rate 10.8%. All the patients have been followed up for 12-48 months (mean follow up 30.3 months). 80% of the patients returned in class I and 13.5% in class II. 80 out of 112 patients operated during 1976-77 have had routine coronary angiography one year post-surgery: the graft patency rate in this group has been 71%. The majority of the obstructed grafts were related to small vessels of 1 mm in diameter. On the basis of these clinical results we conclude that no controversy is justified once and adequate trial with proper medical treatment has already failed.

 

Tricuspid valve replacement for Ebstein's anomaly. A 19 year review of the first case
RG Charles, CN Barnard and W Beck
Br Heart J (1981) 46(5): 578-80
10.1136/hrt.46.5.578

 

An investigation of the immunosuppressive effects of niridazole and metronidazole in rat and baboon heterotopic cardiac allograft models
ST Boyd, DK Cooper, R Baigrie, AG Rose and CN Barnard
Transplantation (1981) 31(5): 326-9
10.1097/00007890-198105010-00004

Niridazole alone (at 50 mg/kg/day) and particularly in combination with azathioprine and prednisolone showed potent immunosuppressive activity, far surpassing that produced by conventional agents, in the rat heterotopic cardiac allograft model. Benzoylmetronidazole or metronidazole (at 50 mg/kg/day) either alone or in combination with azathioprine and prednisolone demonstrated little immunosuppressive activity. The potent immunosuppression obtained with niridazole in the rat could not be reproduced in the baboon heterotopic cardiac allograft model in the doses used; niridazole at 50 mg/kg/day seems to be toxic in this animal.

 

Clinical transplantation of the heart: a review of 13 years' personal experience
CN Barnard and DK Cooper
J R Soc Med (1981) 74(9): 670-4
The results of the heart transplantation operations performed personally by one surgeon (CNB) at Groote Schuur Hospital between 1967 and 1980 are reviewed. Of 9 orthotopic transplants performed between 1967 and 1973, 4 survived for more than one year and 2 remain alive today twelve and ten years later. Of 11 heterotopic transplants performed since 1974, one-year patient survival has been 82%, though one patient survived on his own heart after irreversible graft rejection. Three of the original 4 patients remain alive over five years later. These results are rather better than the overall results of our unit, where a total of 37 heterotopic transplants has been performed; the possible reasons for this are discussed. One patient, previously unreported, who underwent transplantation of the heart and both lungs in 1971, died after 23 days from pulmonary complications. Heterotopic transplantation using a xenograft (baboon or chimpanzee heart) has been performed on two occasions as a means of temporary circulatory support in patients with acutely failing hearts when no human donor was available. The chimpanzee heart supported the circulation satisfactorily for four days.

 

The present status of heterotopic cardiac transplantation
CN Barnard, MS Barnard, DK Cooper, CA Curchio, J Hassoulas, D Novitsky and A Wolpowitz
J Thorac Cardiovasc Surg (1981) 81(3): 433-9
In the period November, 1974 to May, 1980, 30 patients underwent heterotopic heart transplantation at Groote Schuur Hospital. One patient subsequently underwent retransplantation for rejection. There were no operative deaths. Fifteen patients are alive 4 months to almost 5 1/2 years after transplantation. The 1 year survival rate has been 61%. Three of six patients have survived for more than 4 years. Eight of nine patients whose initial transplant operation was performed during the past 18 months remain alive. Seven patients died from infection, five from rejection, and three from other causes. The advantages of heterotopic over orthotopic heart transplantation, in particular in allowing patients survival even after graft destruction by irreversible rejection, are discussed.

 

Long-term survival after orthotopic and heterotopic cardiac transplantation
DK Cooper, RG Charles, RC Fraser, W Beck and CN Barnard
Br Med J (1980) 281(6248): 1093-6
10.1136/bmj.281.6248.1093

Five long-term survivors of heart transplantation were reinvestigated. Two patients had undergone orthotopic heart transplantation over 11 and 9 years earlier and constitute two of the world's longest-surviving patients after this procedure. Three patients had undergone heterotopic heart transplantation (one left heart bypass alone and two biventricular bypass) four to six years earlier. Four of the five patients had had only one or no documented acute rejection episodes. Three had been given blood transfusions. None had had particularly good tissue matching in relation to the donor on HLA typing. All five patients were leading full and active lives. At review two patients had significant coronary artery disease, one severe, presumably due to chronic immune-complex deposition. Heart transplantation remains a major undertaking, but it can offer the patient many years of good-quality life.

 

[Heterotopic cardiac transplantation]
A Wolpowitz, CN Barnard and MS Barnard
Rev Med Interna Neurol Psihiatr Neurochir Dermatovenerol Med Interna (1979) 31(2): 101-9

 

A review of experience with cardiac transplantation
A Wolpowitz, CN Barnard and MS Barnard
Isr J Med Sci (1979) 15(3): 212-7
Despite the hazards of rejection and the complications of immunosuppression, cardiac transplantation is the only available treatment for myocardial disease that is refractory to medical therapy and in which no other form of surgery can be offered. There are disadvantages to orthotopic cardiac transplantation, which have led to the development by this department of the heterotopic cardiac transplant, which functions as a natural left-heart and right-heart assist device. The results of 19 cases are presented.

 

Annular subvalvular idiopathic left ventricular aneurysms in the black African
A Wolpowitz, B Arman, MS Barnard and CN Barnard
Ann Thorac Surg (1979) 27(4): 350-5
10.1016/s0003-4975(10)63314-0

The case of a Black African patient with an annular subvalvular left ventricular aneurysm of unknown origin is described, and the pathological findings in this condition together with a review of the literature is presented. We have operated on 12 patients with this condition between 1958 and 1978. Ventricular aneurysm in the Black African is extremely rare; aneurysms resulting from ischemic heart disease have not been encountered in this racial group, and contrary to earlier reports in the literature, syphilis is not the most common cause of left ventricular aneurysms in this group. The aneurysms arise in the fibrous rings below either the aortic or the mitral valve, extend around the valves in this situation, and may occur either singly or in both positions in the same heart. After various etiological factors are excluded, it is probable that in this group of patients the aneurysms develop initially as pulsion diverticula through a congenital weakness in the ventricular wall in the region of the atrioventricular groove.

 

The pathology of human cardiac transplantation: an assessment after 11 years' experience at Groote Schuur Hospital
CJ Uys, AG Rose and CN Barnard
S Afr Med J (1979) 56(22): 887-96
Over a period of 11 years, commencing in December 1967, 31 cardiac transplants, 10 orthotopic and 21 heterotopic, were performed at Groote Schuur Hospital. Two patients with orthotopic transplants have a long survival, 1 for 7 1/2 and 1 for 9 1/2 years, and 1 with a heterotopic transplant for 4 years. Eighteen patients have died, and autopsy was performed from 13 to 623 days postoperatively. Rejection of the donor heart was found in 61,1% and was the cause of death in 44,4% of cases. Infection, attributable to immunosuppression, was a common finding and consisted of extensive pneumonia, usually due to Klebsiella aerogenes and Pseudomonas aeruginosa (38,8%), herpesvirus infection (38,8%), cytomegalic virus infection (37,5%), aspergillosis and other opportunistic infections. A combination of cardiac rejection and infection accounted for most of the deaths. The cardinal microscopic features of acute rejection were interstitial lymphocytic infiltration and myocytolysis, while chronic rejection was typified by obliterative myo-intimal proliferation of coronary arteries, with concurrent lipid deposition in the major coronary arteries. These lesions resembled atherosclerosis and caused graft failure due to myocardial ischaemia. Ultrastructurally, severe myofibre damage was reflected in extensive loss of cytoplasmic myofilaments. The advantages of heterotopic over orthotopic transplantation are discussed.

 

Morphological changes in 49 chacma baboons after cardiac allografts
AG Rose, CJ Uys, JG Losman and CN Barnard
S Afr Med J (1979) 56(22): 880-6
The morhpological changes in 49 chacma baboons after cardiac transplantation were studied by light and electron microscopy. Non-immunosuppressed grafts were tolerated for an average of 10 days and immunosuppressed grafts for 18 days. Serial biopsy specimens of non-immunosuppressed grafts showed a progression in severity of rejection changes. Electron microscopy mirrored the light microscopic changes. Rejection changes in the baboon appear similar to those encountered in human and canine allografts. Heterotopic transplants showed more severe grades of rejection than would be compatible with life in orthotopic transplants.

 

Controlled sequential pacing in isolated perfused auxiliary rat hearts
OC Penn, ST Boyd, JB Korrubel, LH Opie and CN Barnard
Eur J Cardiol (1979) 10(3): 229-42
An important question after clinical auxiliary heart transplantation is whether controlled pacing of both hearts is desirable in order to protect the diseased recipient heart. A comparison of the effects of spontaneous beating with three types of pacing (random, simultaneous and sequential) was undertaken in an isolated perfused working double rat heart. The two hearts were attached to each other by the atria, in a way comparable to the clinical situation. During controlled sequential pacing of both normal hearts, the peak systolic pressure fell and diastolic pressure rose, but the combined cardiac output did not changes. In contrast, during simultaneous pacing, systolic pressure rose, diastolic pressure fell and coronary flow was less than with sequential pacing, but the oxygen uptake was higher. Hence the effects of sequential pacing could be expected to be beneficial when function of one of the hearts was depressed by left main coronary artery ligation. During sequential pacing the cardiac output was significantly improved from 10 to 30 ml/min (P less than 0.001) and coronary flow rose. Myocardial oxygen consumption increased from 80 to 110 microliters/g/min (P less than 0.05). Thus sequential pacing could improve the severely depressed hemodynamics of the coronary-ligated heart in the presence of an auxiliary heart. The increased myocardial oxygen consumption is viewed as a beneficial effect of increased diastolic perfusion pressure and was not associated with increased enzyme release. It is concluded that the effects of sequential pacing warrant assessment in clinical auxiliary heart transplantation.

 

Heterotopic versus orthotopic heart transplantation
CN Barnard and A Wolpowitz
Transplant Proc (1979) 11(1): 309-12
Since November 1974, heterotopic cardiac transplants have been performed at this unit in preference to orthotopic transplants. A number of reasons have led us to prefer this technique, namely donor malfunction in the immediate postoperative period and during rejection; right ventricular failure of the donor heart in the orthotopic position in patients with pulmonary hypertension; the ease of patient management; and the use of the donor heart as a temporary method of cardiac support. Disadvantages are the later recognition of rejection and the difficulty in performing transvenous endomyocardial biopsies. The results are satisfactory giving a 1, 2, and 3-year survival rate of 62%, 58%, and 50%, respectively.

 

Human heterotopic cardiac transplantation: current status
A Wolpowitz, JG Losman, CA Curcio, MS Barnard, HE Sanchez and CN Barnard
S Afr J Surg (1978) 16(2): 99-102

 

Intraoperative posterior left ventricular wall rupture associated with mitral valve replacement
A Wolpowitz, MS Barnard, HE Sanchez and CN Barnard
Ann Thorac Surg (1978) 25(6): 551-4
10.1016/s0003-4975(10)63607-7

An unusual but often lethal complication of mitral valve replacement is rupture of the left ventricle. The two recognized types of rupture are discussed, and the literature and pathology are reviewed. It is stressed that this complication can be prevented, and the factors involved in prevention are outlined.

 

Intensive care nursing after cardiac surgery
A Wolpowitz and CN Barnard
Rhod Nurse (1978) (1978) 25-32

 

Impotence after heart transplantation
A Wolpowitz and CN Barnard
S Afr Med J (1978) 53(18): 693

 

Double outlet right ventricle: clinical and anatomical spectrum
EK Weir, HS Joffe, CN Barnard and W Beck
Thorax (1978) 33(3): 283-9
10.1136/thx.33.3.283

Thirty-two patients with double outlet right ventricle (DORV) were studied between 1960 and 1976. Associated congenital defects frequently compounded the difficulty of clinical diagnosis. Cardiac catheterisation was performed in 27 patients, and the ventriculograms were studied with particular regard to the relative positions of the great vessels to each other and to the ventricular septal defect. These relationships determine which corrective operation is possible. Correction has been performed in 12 patients with a perioperative mortality of 25%. Although mitral-aortic discontinuity was demonstrated in all cases, consideration of the anatomical spectrum included in the term DORV suggests that discontinuity is not an essential feature. In common with other clinical data and in contrast with necropsy studies, none of our patients was found to show the normal relationship of the great vessels to each other, in which the aorta lies posterior and to the right of the pulmonary artery. The reason for this difference between the clinical and necropsy findings is not apparent. A similar disparity was shown with regard to pulmonary stenosis, which was demonstrated at catheterisation in 68% of the 27 patients (mean gradient 68 +/- 3 mmHg), in contrast with incidences of 18% and 25% in recent necropsy series. Patients in the necropsy studies were frequently neonates or infants, in whom death may have been the result of intractable cardiac failure secondary to excessive pulmonary blood flow. In older patients without pulmonary stenosis and with pulmonary hypertension, frequent observation is imperative so that surgical treatment can be instituted before the development of irreversible pulmonary vascular disease.

 

Evaluation of endomyocardial biopsy in the diagnosis of cardiac rejection. A study using bioptome samples of formalin-fixed tissue
AG Rose, CJ Uys, JG Losman and CN Barnard
Transplantation (1978) 26(1): 10-3
10.1097/00007890-197807010-00004

The reliability of endomyocardial bioptome samples in detecting cardiac rejection was assessed in 26 formalin-fixed previously transplanted hearts. Thirteen human donor hearts (mean postoperative survival 128 days) and 13 baboon donor hearts (mean survival 16.5 days) were studied. Twenty samples were taken under direct vision from the endomyocardium of each heart with an Olympus bioptome catheter. A total of 397 tissue samples was examined "blindly" histologically (177 human and 220 baboon). The bioptome samples were assigned a histological rejection score and then compared with the score accorded multiple tissue sections from the same heart. Sample scores agreed with tissue section scores as follows: humans 86% (samples showed more severe alterations in 5% and less severe in 9%) and baboons 57% (samples more severe in 40% and less severe in 3%). Only 2 false-negative samples were encountered among 285 tissue samples from hearts showing rejection. Changes of rejection were equally distributed between the left and right ventricles. Endomyocardial sampling proved an accurate means of detecting the presence of rejection. In the baboon hearts the endomyocardium tended to show more severe changes than the rest of the myocardium.

 

Risk factors in surgical correction of congenital heart defects in early childhood
JG Losman, HS Joffe and CN Barnard
S Afr Med J (1978) 53(10): 351-7
The technique of surface-induced hypothermia, circulatory arrest and limited extracorporeal circulation was used in the surgical correction of congenital heart defects in 125 young children. Hospital mortality was 18% and no death could be attributed to the surgical technique. An analysis of risk factors demonstrated that successful corrective surgery was not significantly related to age, body weight or pulmonary vascular obstructive disease. In transposition of the great arteries, the presence of a ventricular septal defect was associated with an increased mortality. Emergency operations performed because of severe hypoxaemia carried a high mortality, especially in patients with tetralogy of Fallot.

 

Use of a double atrial-triggered standby pacemaker system for a patient with a biventricular bypass heterotopic cardiac homograft
BM Kennelly, LW Piller, PP Tarjan, JG Losman, CN Barnard and W Beck
Am J Cardiol (1978) 41(2): 341-4
10.1016/0002-9149(78)90177-7

In a patient who had a biventricular bypass heterotopic cardiac homograft a double atrial-triggered standby pacemaker system was implanted to allow sequential atrial pacing of both hearts. The system design permitted either the recipient or the donor heart to dictate the rate of its fellow, depending on which heart had the faster spontaneous sinus rate at any time. Alternative methods for achieving sequential pacing are discussed.

 

Results after mitral valve replacement with cloth-covered Starr-Edwards prostheses (models 6300, 6310/6320, and 6400)
R Forman, W Beck and CN Barnard
Br Heart J (1978) 40(6): 612-6
10.1136/hrt.40.6.612

The actuarial survival and thromboembolic rates for the three types of cloth-covered Starr-Edwards mitral prostheses, models 6300, 6310/6320, and 6400 followed 6, 5, and 2 years, respectively, were not significantly different throughout the years they were followed. The combined cumulative survival and thromboembolic proportion at 5 years for these prostheses were 71 and 66 per cent, respectively. The thromboembolic rates were not different in the following two groups: (a) 238 patients receiving anticoagulants, and (b) 52 patients who had discontinued or who were not receiving anticoagulants. Four patients thrombosed their mitral prostheses. Another 8 per cent had class 3 symptoms after operation, which were attributed to myopathic or restrictive left ventricular dysfunction or other valvular disease.

 

Fistula of the sinus of Valsalva
HE Sanchez, CN Barnard and MS Barnard
J Thorac Cardiovasc Surg (1977) 73(6): 877-9
Operative repair of sinus of Valsalva aneurysms and fistulas was performed in 10 patients between 1960 and 1976. Associated cardiac defects were corrected in 6 patients. There were no postoperative deaths, and the 8 patients observed to date are still alive and well. Only 2 patients required a second operation. The employment of a transchanber or a transaortic approach or both continues to be a matter of individual preference.

 

Myocardial fibrinolytic activity in allogenic cardiac rejection
JG Losman, AG Rose and CN Barnard
Transplantation (1977) 23(5): 414-22
10.1097/00007890-197705000-00006

The relationship between alterations in myocardial fibrinolytic activity and the degree of graft tolerance or rejection was studied in 22 nonimmunosuppressed heterotopic cardiac transplants in chacma baboons. Fibrinolysis was evaluated on tissue sections and tissue extracts. Fibrinolytic activity was compared with electrocardiographic voltage alterations and multiple myocardial biopsies and terminal heart specimens were examined by light and electron microscopy. Histopathology and reduction in fibrinolytic activity proved superior to electrocardiographic voltage reductions in assessing early cardiac rejection. The two former modalities correlated well with one another. Myocardial histology showed rejection change earlier than fibrinolytic activity reduction.

 

Results of valve replacement with the Lillehei-Kaster disc prosthesis
R Forman, W Beck and CN Barnard
Am Heart J (1977) 94(3): 282-6
10.1016/s0002-8703(77)80469-9

The results of valve replacement in 150 patients with Lillehei-Kaster aortic and mitral prostheses followed for 20 to 40 months are reviewed. Actuarial analysis showed 78 per cent cummulative thromboembolic-free rate three years following mitral valve replacement and 89 per cent following aortic valve replacement. Five patients had a total of six episodes of mitral valve thrombosis despite anticoagulant therapy. Early detection of mitral valve obstruction was difficult because a mid-diastolic murmur and absence of an opening sound was frequently encountered in normally functioning prostheses. Hemodynamic results assessed clinically in patients with nonthrombosed prostheses were satisfactory.

 

[The heterotopic heart transplantation: first clinical experiences (author's transl)]
AC Curcio, A Wolpowitz, MS Barnard, J Hassoulas and CN Barnard
G Ital Cardiol (1977) 7(11): 1098-104
Ten patients, all men, have been operated of heterotopic heart transplantation since the end of 1974. Ages ranged from 59 to 24 years with an average of 38 years. Six of them suffered from ischaemic heart disease, two from cardiomiopathy and two from rheumatic heart disease. All of them presented end stage cardiac disease. The first two patients underwent to left ventricular bypass only, in the remaining eight a right and left bypass was performed. At the present time, June 1977, 6 of the original 10 patients are alive all of them in functional class I. Five of them have resumed a full time job, the sixth will be soon able to do so. Four patients died. There were no deaths from acute rejection, but three died from infection, and the fourth one from a pulmonary embolus, 4 months after transplantation. There has been only one episode of acute rejection which has responded well to the treatment. The advantages of the heterotopic versus the orthotopic cardiac transplantation are discussed.

 

Heterotopic cardiac transplantation with a xenograft for assistance of the left heart in cardiogenic shock after cardiopulmonary bypass
CN Barnard, A Wolpowitz and JG Losman
S Afr Med J (1977) 52(26): 1035-8
One of the indications for the use of the heterotopic cardiac transplant is temporarily to support a failing heart in the anticipation of its recovery when all other measures of support have been unsuccessful. Human donors are not always available when required and we decided to use a xenograft for this purpose when the need arose. This report details our experience with a baboon and a chimpanzee cardiac xenograft transplant in the heterotopic position. We have found (a) that the operation is technically feasible; (b) that the xenograft will support the failing circulation, but that the more support required, the bigger the xenograft should be and the species chosen accordingly; (c) that severe acute rejection will occur within 4 days and the procedure should therefore only be employed where there is evidence that the patient's own heart function will recover rapidly.

 

The advantage of heterotopic cardiac transplantation over orthotopic cardiac transplantation in the management of severe acute rejection
CN Barnard, JG Losman, CA Curcio, HE Sanchez, A Wolpowitz and MS Barnard
J Thorac Cardiovasc Surg (1977) 74(6): 918-24
The major problems with organ transplantation are rejection of the allograft and the side effects of antirejection therapy. This report describes the successful treatment of a patient in whom rejection of the donor heart developed 10 months after implantation. The recipient's own heart had been left intact and was able to support the circulation during the period of rejection. Indications are that the "rest" period of 10 months was beneficial to the myopathic left ventricle of the recipient's heart.

 

Circadian rhythmic aspects of human cardiovascular function: a review by chronobiologic statistical methods
MH Smolensky, SE Tatar, SA Bergman, JG Losman, CN Barnard, CC Dacso and IA Kraft
Chronobiologia (1976) 3(4): 337-71

 

Circadian Rhythmic Characteristics of Innervated and Non-Innervated Cardiac Tissue of Single and Double-Heart Transplanted Patients
MH Smolensky, SA Bergman, Jr., CN Barnard, W Beck and IA Kraft
Cardiovasc Dis (1976) 3(2): 150-168

 

Arrhythmias in two patients with left ventricular bypass transplants
BM Kennelly, P Corte, J Losman and CN Barnard
Br Heart J (1976) 38(7): 725-31
10.1136/hrt.38.7.725

Two patients who underwent left ventricular bypass transplants are described. Both patients sustained postoperative rhythm disturbances of their own hearts during sinus rhythm of the donor hearts. Illustrative examples of atrial flutter, ventricular flutter, ventricular fibrillation, blocked atrial extrasystoles, and double ventricular parasystole in the recipient hearts are presented. The patients tolerated all these arrhythmias well during uninterrupted sinus rhythm in the donor heart. The problems in interpretation of arrhythmias in the presence of two hearts are discussed.

 

Heterotopic versus orthotopic heart transplantation
CN Barnard
Transplant Proc (1976) 8(1): 15-9

 

The autopsy findings in a case of heterotopic cardiac transplantation with left ventricular bypass for ischaemic heart failure
CJ Uys, AG Rose and CN Barnard
S Afr Med J (1975) 49(49): 2029-35
The autopsy findings in a White man aged 59 years are presented; he underwent heterotopic cardiac transplantation with left ventricular bypass for irreversible left ventricular failure caused by severe ischaemic heart disease. Microscopically, the donor heart showed mild signs of chronic rejection with negligible loss of functional myocardium, and no complications attributable to the surgical technique. Severe, generalised atherosclerosis had resulted in fibrous replacement of the recipient left ventricular myocardium and intra-operative atheromatous embolisation to the brain, the latter being the main contributory factor in the patient's death. Other significant findings were bilateral femoral vein thrombosis with recurrent pulmonary infarction, Aspergillus granulomata of the right lung, cytomegalovirus infection of lungs and oesophagus, Herpes simplex infection of the tongue and oesophagus, and duodenal ulceration with haemorrhage.

 

Corrective surgery for transposition of the great arteries
HS Joffe, MS Barnard, H Sanchez, TJ Voss, W Beck and CN Barnard
S Afr Med J (1975) 49(28): 1121-5
The results of corrective surgery in 32 patients with transposition of the great arteries (TGA) are reviewed. Patients with TGA and associated defects comprised 47% of the series. The over-all long-term mortality rate was 31%. An acceptable mortality rate of 17,5% was achieved in simple TGA by using a Mustard repair. Good results were obtained with the Rastelli operation for patients with TGA, ventricular septal defect and severe pulmonary stenosis. Results were poor in patients with TGA and unrestricted ventricular septal defects, in whom palliative pulmonary artery banding or corrective surgery under 6 months of age is advocated. The major late complication was patch contraction resulting in pulmonary or systemic venous obstruction.

 

Recent results in the surgical treatment of Fallot's tetralogy
MS Barnard and CN Barnard
S Afr Med J (1975) 49(6): 173-5
Tetralogy of Fallot consists essentially of two abnormalities: a large, unrestrictive ventricular septal defect and severe obstruction to the outflow of the right ventricle. A clear understanding of the principles described in this article should result in a mortality of under 5% after complete correction of tetralogy of Fallot.

 

Left ventricular bypass
CN Barnard and JG Losman
S Afr Med J (1975) 49(9): 303-12
The removal of the patient's own diseased heart in order to perform a total cardiac transplantation has several disadvantages. A new technique for bypassing the patient's diseased left ventricle by using a cardiac allograft has been developed in our laboratory and applied clinically in 2 patients. This technique carried no direct surgical mortality, and no complications resulting from the patient's own heart being left in situ have been observed thus far. The presence of a second heart lying partly in the anterior mediastinum and partly in the right pleural space appeared to have no deleterious effects. Several advantages over the conventional transplant have been noted and are discussed.

 

The surgical correction of Fallot's tetralogy
CN Barnard and MS Barnard
Isr J Med Sci (1975) 11(2-3): 116-21
The success of total repair of tetralogy of Fallot depends on a clear understanding of the morbid anatomy and deranged hemodynamics of this anomaly, which consists essentially of two abnormalities, namely, a large unrestrictive ventricular septal defect and a severe obstruction to the outflow of the right ventricle. The ventricular septal defect acts as a safety valve and, therefore, cannot be closed unless the obstruction to the outflow of the right ventricle is adequately relieved. In severe cases, this often necessitates reconstruction of the outflow. With an adequate bypass technique and a clear understanding of the principles described in this article, complete correction of tetralogy of Fallot can be accomplished with a low mortality. In a series of 100 consecutive patients presented, the mortality was only 3%.

 

The present status of heart transplantation
CN Barnard
S Afr Med J (1975) 49(7): 213-7
Heart transplantation still remains the only form of treatment for patients suffering from terminal heart failure as the result of diffuse myocardial disease. The lack of enthusiasm for this operation has no scientific or moral basis. Our own limited experience and the much wider experience of other workers in this field show that with proper patient and donor selection and careful postoperative management, the results of this operation compare very favourably with those of any transplantation of other organs and in the surgical treatment of other types of terminal diseases.

 

The management of intractable angina pectoris using saphenous vein bypass grafts. Experience in Cape Town
EK Weir, JE Stevens, W Beck, TG O'Donovan, M Barnard and CN Barnard
S Afr Med J (1974) 48(1): 13-7

 

The role of surgical revascularisation in the treatment of ischaemic heart disease. A review article
CN Barnard
S Afr Med J (1974) 48(46): 1933-6

 

The postoperative intensive care after cardiac surgery in the neonate
A Wolpowitz, TJ Voss, CN Barnard and MS Barnard
S Afr Med J (1973) 47(11): 472-9

 

Supravalvular stenosing ring of the left atrium associated with corrected transposition of the great vessels
E Chesler, W Beck, CN Barnard and V Schrire
Am J Cardiol (1973) 31(1): 84-8
10.1016/0002-9149(73)90815-1

 

The treatment of congenital heart disease in infants. Surface cooling, deep hypothermia, limited cardiopulmonary bypass and circulatory arrest
MS Barnard, TJ Voss and CN Barnard
S Afr Med J (1973) 47(11): 469-71

 

Heart transplantation in the treatment of cardiomyopathy
CN Barnard
Recent Adv Stud Cardiac Struct Metab (1973) 2(827-8

 

A good death
CN Barnard
Fam Health (1973) 5(4): 40-42+

 

Advice on heart transplants
CN Barnard
Br Med J (1973) 2(5862): 363
10.1136/bmj.2.5862.363

 

[Surgical treatment of congenital heart disease in infants, with superficial hypothermia, short extracorporeal circulation and circulatory arrest]
LA Bandera, CN Barnard and MS Barnard
G Ital Cardiol (1973) 3(2): 165-70

 

Surgical closure of ventricular septal defect in infancy
TG O'Donovan, V Schrire and CN Barnard
S Afr Med J (1972) 46(26): 883-5

 

Medicine and the mass media
CN Barnard
Am J Cardiol (1972) 30(5): 579-80
10.1016/0002-9149(72)90055-0

 

Changes of serum enzyme activities in dogs receiving heterotopic cardiac allografts
BK Semb, GM Potgieter and CN Barnard
Scand J Thorac Cardiovasc Surg (1971) 5(2): 116-9
10.3109/14017437109135542

 

Electrocardiographic changes during the unmodified rejection of heterotopic canine heart allografts
BK Semb, AM Abrahamsen and CN Barnard
Scand J Thorac Cardiovasc Surg (1971) 5(2): 120-4
10.3109/14017437109135543

 

Hemodynamic studies in two long-term survivors of heart transplantation
W Beck, CN Barnard and V Schrire
J Thorac Cardiovasc Surg (1971) 62(2): 315-20

 

Serological investigations in patients with cadaver allografts
JR Ackermann, MC Botha, E du Toit and CN Barnard
Rev Eur Etud Clin Biol (1971) 16(3): 243-5

 

Renal transplantation at Groote Schuur Hospital: a report of 13 cases
CJ Uys, JR Ackermann, GN Thatcher, B Myers, A Forder, L Eales, SC Bosman, J Terblanche, M Du Preez, MC Botha, E Du Toit and CN Barnard
S Afr Med J (1970) 44(20): 582-6

 

Immediate and long-term results of aortic valve replacent with University of Cape Town aortic valve prosthesis
V Schrire, W Beck, RP Hewitson and CN Barnard
Br Heart J (1970) 32(2): 255-63
10.1136/hrt.32.2.255

Aortic valve replacement with the University of Cape Town lenticular prosthesis was performed in 149 patients during a six-year period, almost all patients being severely disabled with advanced heart disease. There was a hospital mortality of 12 per cent. Bacterial endocarditis was a serious complication and accounted for three hospital and five long-term deaths. The survivors were followed for periods of up to 72 months (average 24), the minimum period of observation being six months. There were 23 late deaths due to heart disease, of which 5 where due to myocardial failure. Myocardial failure unrelieved or only temporarily alleviated by the operation occurred in three surviving patients. The main problems have been sudden death and systemic embolism. Some of the cases of sudden death were due to coronary artery embolism, but in a number the cause could not be determined even at necropsy, and they were presumed to be due to arrhythmia. Both complications appeared to be related to valve design. A bare steel seat was associated with a high incidence of both complications, whereas a woven Dacron-velour cloth-covered seat almost eliminated embolism and reduced the incidence of sudden death. Long-term anticoagulant therapy appears to be of no real value with the cloth-covered valve. Gratifying results were obtained in the surviving patients with loss of all symptoms in 80 per cent and improvement in almost all patients. This improvement or relief of symptoms was maintained in most patients throughout the period of study.

 

Immediate and long-term results of mitral valve replacement with University of Cape Town mitral valve prosthesis
V Schrire and CN Barnard
Br Heart J (1970) 32(2): 245-54
10.1136/hrt.32.2.245

We describe seven years' experience with the University of Cape Town lenticular mitral valve prosthesis in 122 patients. All the patients had severe mitral valve disease. In 98 severe mitral stenosis was present with or without incompetence and in 24 the dominant or sole lesion was mitral incompetence. Other valves, particularly the tricuspid, were also frequently affected. The disability was severe or total in almost every patient. One hundred and five patients were discharged from hospital, and in 90 per cent of these the clinical improvement was most gratifying, with the disappearance of pulmonary oedema, paroxysmal dyspnoea, angina pectoris, and congestive cardiac failure. Return to full normal activity including physical work was the rule. The hospital mortality was 14 per cent and a further 38 per cent died during the follow-up period. The major post-operative complication was systemic embolism which could occur at any time after operation. The most important factor influencing the frequency of this complication was the nature of the valve seat. A bare steel seat was associated with a 100 per cent embolism, and a significant reduction occurred when a cloth-covered seat of Dacron-velour was introduced. Anticoagulant therapy appeared to prevent large or fresh clots but had no effect on the deposition of fibrin or platelet thrombi. The only other factor of importance was the age of the patient: after the age of 50 life expectancy and trouble-free long-term survival was reduced.

 

The clinical course of patients who have survived heart transplantation
V Schrire and CN Barnard
Laval Med (1970) 41(4): 564-70

 

[Exchange transfusion and cross circulation with baboons in the treatment of acute liver failure]
SJ Saunders, SC Bosman, CN Barnard and J Terblanche
Internist (Berl) (1970) 11(3): 77-84

 

We interview: Christian N. Barnard, M. D
CN Barnard and OK Harlem
Tidsskr Nor Laegeforen (1970) 90(10): 1106-9

 

Experience at Cape Town with human to human heart transplantation
CN Barnard
Laval Med (1970) 41(2): 119-24

 

Some electrocardiographic changes in human heart transplants
V Schrire, CN Barnard and W Beck
Isr J Med Sci (1969) 5(4): 931-7

 

The diagnosis of rejection in human heart transplantation
V Schrire and CN Barnard
Prog Cardiovasc Dis (1969) 12(2): 190-200
10.1016/0033-0620(69)90017-6

 

Cardiac surgery for the cyanotic infant
TG O'Donovan, RP Hewitson, MS Barnard, V Schrire, W Beck and CN Barnard
S Afr Med J (1969) 43(51): 1539-44

 

Haemodynamic studies after repair of ventricular septal defect
MS Gotsman, W Beck, CN Barnard and V Schrire
Br Heart J (1969) 31(1): 63-71
10.1136/hrt.31.1.63

 

Results of repair of tetralogy of Fallot
MS Gotsman, W Beck, CN Barnard, TG O'Donovan and V Schrire
Circulation (1969) 40(6): 803-21

 

Heart rate after cardiac transplantation
W Beck, CN Barnard and V Schrire
Circulation (1969) 40(4): 437-45
10.1161/01.cir.40.4.437

 

Total body perfusion for cardiac transplantation
MS Barnard, J van Heerden, A Hope, TG O'Donovan and CN Barnard
S Afr Med J (1969) 43(3): 64-7

 

Human heart transplantation
CN Barnard
Can Med Assoc J (1969) 100(3): 91-104

 

[Heart transplantation in man]
CN Barnard
Eksp Khir Anesteziol (1969) 14(2): 46-51

 

A new approach to the treatment of rejection: experience with the third human-to-human heart transplantation performed in Cape Town
CN Barnard
Prog Cardiovasc Dis (1969) 12(2): 201-11
10.1016/0033-0620(69)90018-8

 

[Immunosuppresive treatment after cardiac transplantation]
BK Semb and CN Barnard
Nord Med (1968) 79(24): 783-4

 

Acute hepatic coma treated by cross-circulation with a baboon and by repeated exchange transfusions
SJ Saunders, J Terblanche, SC Bosman, GG Harrison, R Walls, R Hickman, J Biebuyck, D Dent, S Pearce and CN Barnard
Lancet (1968) 2(7568): 585-8
10.1016/s0140-6736(68)90692-2

 

The surgical relief of transposition of the great vessels in infancy
TG O'Donovan, CN Barnard and MS Gotsman
Thorax (1968) 23(3): 256-60
10.1136/thx.23.3.256

The necessity for palliative surgery in transposition of the great vessels is indicated and the basic haemodynamics of the condition are outlined. The clinical picture of infants with transposition is divided into three types, and a method of surgical treatment is suggested for the two most common types. Our technique of investigation and treatment is described and the reasons for our choice of therapy are discussed. The results of cases operated upon are presented.

 

Successful thrombo-embolectomy in long-standing thrombo-embolic pulmonary hypertension
ES Nash, S Shapiro, A Landau and CN Barnard
Thorax (1968) 23(2): 121-30
10.1136/thx.23.2.121

The operative removal of thrombo-emboli from the pulmonary arteries in acute pulmonary embolism is an accepted method of treatment. The removal of thrombi that have been present for many months has been attempted less often. This case report covers the operative treatment and the pre- and post-operative physiological studies in a patient with long-standing thrombo-embolic pulmonary hypertension, in whom a large thrombus was removed under cardiopulmonary bypass from the left pulmonary artery. Dramatic clinical improvement resulted. A plea is made for a more radical approach to thrombo-embolic pulmonary hypertension when a local obstruction can be demonstrated.

 

Some problems of permanent artificial pacing
MS Gotsman, LW Piller, W Beck, CN Barnard and V Schrire
Br Med J (1968) 1(5588): 343-6
10.1136/bmj.1.5588.343

 

Investigation of the ill infant with heart disease
MS Gotsman, W Beck, M Klein, TG O'Donovan, CN Barnard and V Schrire
S Afr Med J (1968) 42(26): 663-70

 

Changes in chest radiograph after aortic valve replacement
MS Gotsman, W Beck, CN Barnard and V Schrire
Br Heart J (1968) 30(2): 219-25
10.1136/hrt.30.2.219

 

Cross-circulation between man and baboon
SC Bosman, J Terblanche, SJ Saunders, GG Harrison and CN Barnard
Lancet (1968) 2(7568): 583-5
10.1016/s0140-6736(68)90691-0

 

Ivalon baffle for posterior leaflet replacement in the treatment of mitral insufficiency: a follow-up study
CN Barnard and V Schrire
Surgery (1968) 63(5): 727-30

 

[Ethical problem in transplants]
CN Barnard
Rev Circ Odontol Cordoba (1968) 34(2): 3-6

 

What we have learned about heart transplants
CN Barnard
J Thorac Cardiovasc Surg (1968) 56(4): 457-68

 

Human cardiac transplantation. An evaluation of the first two operations performed at the Groote Schuur Hospital, Cape Town
CN Barnard
Am J Cardiol (1968) 22(4): 584-96
10.1016/0002-9149(68)90166-5

 

Human heart transplantation. The diagnosis of rejection
CN Barnard
Am J Cardiol (1968) 22(6): 811-9
10.1016/0002-9149(68)90176-8

 

Aortic valve replacement with the University of Cape Town lenticular prosthesis. A follow-up evaluation
V Schrire, W Beck, RP Hewitson and CN Barnard
Am J Cardiol (1967) 20(6): 796-802
10.1016/0002-9149(67)90392-x

 

Cardiac surgery in the infant group
TG O'Donovan, MS Gotsman, V Schrire and CN Barnard
S Afr Med J (1967) 41(41): 1073-6

 

Changes in the appearances of the chest radiograph after a repair or replacement operation on the mitral valve
MS Gotsman, W Beck, CN Barnard and V Schrire
Br J Radiol (1967) 40(478): 724-39
10.1259/0007-1285-40-478-724

 

The operation. A human cardiac transplant: an interim report of a successful operation performed at Groote Schuur Hospital, Cape Town
CN Barnard
S Afr Med J (1967) 41(48): 1271-4

 

Syphilitic coronary ostial occlusion
V Schrive, CN Barnard and W Beck
S Afr Med J (1966) 40(24): 553-5

 

An analysis of cardiac surgery at Groote Schuur and Red Cross War Memorial Children's Hospitals, Cape Town, for the 14 years April 1951-April 1965
V Schrire, S Beck and CN Barnard
S Afr Med J (1966) 40(20): 461-7

 

Modified technique for long-term endocardial pacemaking
MS Gotsman, W Beck, LW Piller, SC Bosman, CN Barnard and V Schrire
Br Med J (1966) 2(5526): 1357-60
10.1136/bmj.2.5526.1357

 

The use of implantable cardiac pacemaker in the treatment of complete heart block
MS Gotsman, W Beck, CN Barnard and V Schrire
S Afr Med J (1966) 40(26): 607-13

 

The hemodynamics of the University of Cape Town aortic prosthetic valve
W Beck, CN Barnard and V Schrire
Circulation (1966) 33(4): 517-27
10.1161/01.cir.33.4.517

 

Hypokalaemia during extracorporeal circulation
MS Barnard, SJ Saunders, L Eales and CN Barnard
Lancet (1966) 1(7431): 240
10.1016/s0140-6736(66)90057-2

 

Hypokalaemia during extracorporeal circulation. An experimental study
MS Barnard, SJ Saunders, L Eales and CN Barnard
S Afr Med J (1966) 40(47): 1132-8

 

Thrombo-embolic complications following total mitral valve replacement with the UCT lenticular mitral prosthesis. An experimental study
MS Barnard and CN Barnard
S Afr Med J (1966) 40(12): 263-4

 

The surgical approach to tetralogy of Fallot
CN Barnard and V Schrire
S Afr Med J (1966) 40(15): 330-9

 

Live storage of kidneys: a preliminary communication
JR Ackermann, AJ Fisher and CN Barnard
Surgery (1966) 60(3): 720-4

 

The effect of direct infusions of cortisone into the renal artery of a transplanted kidney
JR Ackermann and CN Barnard
S Afr Med J (1966) 40(5): 83-7

 

Successful storage of kidneys
JR Ackermann and CN Barnard
Br J Surg (1966) 53(6): 525-32
10.1002/bjs.1800530608

 

In vitro kidney storage. I. Hypothermia and hyperbaric oxygen
JR Ackermann and CN Barnard
S Afr Med J (1966) 40(24): 560-6

 

Fracture of a Guide Wire during Cardiac Catheterization. Underdeveloped Right Ventricle and Tricuspid and Pulmonary Stenosis
DJ Fergusson, W Beck, V Schrire and CN Barnard
Am J Cardiol (1965) 15(407-12
10.1016/0002-9149(65)90338-3

 

Hemodynamic findings following replacement of the mitral valve with the University of Cape Town prosthesis
W Beck, DJ Fergusson, CN Barnard and V Schrire
Circulation (1965) 32(5): 721-31
10.1161/01.cir.32.5.721

 

Syphilitic obstruction of coronary ostia successfully treated by endarterectomy
W Beck, CN Barnard and V Schrire
Br Heart J (1965) 27(6): 911-5
10.1136/hrt.27.6.911

 

Further Experiences with the U.C.T. Mitral, Tricuspid, and Aortic Prostheses
CN Barnard, V Schrire, RW Frater and CC Goosen
Surgery (1965) 57(211-9

 

The surgical treatment of tetralogy of Fallot
CN Barnard
N Z Med J (1965) 64(400): Suppl:24-5

 

Surgical treatment of Ebstein's malformation with U.C.T. tricuspid prosthesis
CN Barnard
N Z Med J (1965) 64(400): Suppl:30-1

 

Mitral replacement with the U.C.T. prosthesis
CN Barnard
N Z Med J (1965) 64(400): Suppl:50-2

 

Surgical treatment of acquired aneurysms of the thoracic aorta
CN Barnard
N Z Med J (1965) 64(400): Suppl:61-3

 

In vivo kidney storage. A preliminary communication
JR Ackermann, AJ Fisher and CN Barnard
S Afr Med J (1965) 39(35): 794-6

 

The Diagnostic Importance of Abnormal Urinary Sediment Stains in Canine Renal Homografts
JR Ackermann and CN Barnard
S Afr Med J (1965) 39(571-4

 

Observations on the Early Diagnosis and Chemotherapeutic Treatment of Threatened Renal Rejection in Dogs
N Ackerman, Jr., J Terblanche, DR Devilliers and CN Barnard
S Afr Med J (1965) 39(295-301

 

The Pre-Operative Assessment of Mitral-Valve Disease
V Schrire and CN Barnard
S Afr Med J (1964) 38(721-8

 

Renal Function during and Immediately after Profound Hypothermia. Ii
LC Isaacson, J Terblanche, L Eales and CN Barnard
Surgery (1964) 56(957-69

 

Open-Heart Surgery for Rheumatic Disease of the Mitral Valve: Experience at the University of Cape Town Medical School
RW Frater, CN Barnard and V Schrire
S Afr Med J (1964) 38(776-81

 

Aortic-Left Atrial Fistula. Surgical Cure of a Syphilitic Ascending Aortic Aneurysm with Rupture into the Left Atrium
W Beck, V Schrire and CN Barnard
Am J Cardiol (1964) 14(717-9
10.1016/0002-9149(64)90065-7

 

Complete Replacement of Both Mitral and Aortic Valves
CN Barnard and V Schrire
S Afr Med J (1964) 38(765-8

 

Endocarditis Following Cardiac Surgery Due to the Fungus Paecilomyces
CJ Uys, PA Don, V Schrire and CN Barnard
S Afr Med J (1963) 37(1276-80

 

Atrial septal defect. I. Secundum and sinus venosus defects
V Schrire, W Beck, L Vogelpoel, M Nellen and CN Barnard
S Afr Med J (1963) 37(727-38

 

Atrial Septal Defect. Ii. Endocardial-Cushion Defects
V Schrire, W Beck, L Vogelpoel, M Nellen and CN Barnard
S Afr Med J (1963) 37(839-47

 

Aneurysm of the ascending aorta obstructing right ventricular outflow and producing severe "pulmonary stenosis"
V Schrire, W Beck and CN Barnard
Am Heart J (1963) 65(396-403
10.1016/0002-8703(63)90015-2

 

The surgical cure of a cardiac aneurysm of unknown cause
V Schrire and CN Barnard
J Cardiovasc Surg (Torino) (1963) 4(5-10

 

The protective effect of human gastric juice on experimentally induced ulceration in the rat
AM Nell and CN Barnard
S Afr Med J (1963) 37(112-4

 

Complete replacement of the mitral valve
CN Barnard, V Schrire, CC Goosen and LV Holmgren
S Afr Med J (1963) 37(97-100

 

Total Aortic Valve Replacement
CN Barnard, V Schrire and CC Goosen
Lancet (1963) 2(7313): 856-9
10.1016/s0140-6736(63)92745-4

 

The surgical treatment of acquired aneurysm of the throracic aorta
CN Barnard and V Schrire
Thorax (1963) 18(2): 101-15
10.1136/thx.18.2.101

 

Surgical Correction of Ebstein's Malformation Withprosthetic Tricuspid Valve
CN Barnard and V Schrire
Surgery (1963) 54(302-8

 

Temperature gradients during profound hypothermia with extracorporeal circulation. An experimental study
J Terblanche and CN Barnard
S Afr Med J (1962) 36(337-40

 

The use of heparinized blood in open-heart surgery: a review of 250 cases
MC Botha and CN Barnard
S Afr Med J (1962) 36(911-8

 

Prosthetic replacement of the mitral valve
CN Barnard, CC Goosen, LV Holmgren and V Schrire
Lancet (1962) 2(7265): 1087-9
10.1016/s0140-6736(62)90789-4

 

Renal function during and immediately after profound hypothermia
J Terblanche, LC Isaacson, L Eales and CN Barnard
Surgery (1961) 50(869-76

 

Organic and functional pulmonary atresia with intact ventricular septum
V Schrire, GJ Sutin and CN Barnard
Am J Cardiol (1961) 8(100-8
10.1016/0002-9149(61)90183-7

 

Profound hypothermia and the helix reservoir bubble oxygenator
CN Barnard, J Terblanche and J Ozinsky
S Afr Med J (1961) 35(107-10

 

Surgical correction of a right coronary artery aneurysm communicating with the right ventricle: a case report
CN Barnard, V Schrire and W Beck
Ann Surg (1961) 154(6): 925-30

 

The surgical correction of endocardial cushion defects
CN Barnard and V Schrire
Surgery (1961) 49(500-9

 

Surgery of mitral incompetence
CN Barnard and V Schrire
Postgrad Med J (1961) 37(433): 666-78
10.1136/pgmj.37.433.666

 

The surgical treatment of the tetralogy of Fallot
CN Barnard and V Schrire
Thorax (1961) 16(4): 346-55
10.1136/thx.16.4.346

 

A surgical approach to mitral insufficiency
CN Barnard, KM Mc and V Schrire
Br J Surg (1961) 48(655-62
10.1002/bjs.18004821217

 

[The surgical treatment of mitral insufficiency]
CN Barnard and KM Mc
Arch Mal Coeur Vaiss (1961) 54(377-86

 

The surgical correction of chronic aortic regurgitation
CN Barnard and DR De Villiers
Med Monde (1961) 37(58-67

 

Abnormal restraints of cleft anteromedial leaflet of mitral valve in endocardial cushion defects
CN Barnard
Br Med J (1961) 1(5227): 719
10.1136/bmj.1.5227.719

 

Profound hypothermia using extracorporeal circulation without an artificial oxygenator. An experimental study
J Terblanche and CN Barnard
S Afr Med J (1960) 34(1003-8

 

Induced ventricular fibrillation. An experimental study with special reference to the use of this technique for the prevention of systemic air embolism
MB McKenzie and CN Barnard
S Afr J Lab Clin Med (1960) 6(171-9

 

Left atrial myxoma. Report of a case successfully treated using extracorporeal oxygenation
CN Barnard, A Swanepoel, KM Mc and WL Phillips
Br J Surg (1960) 48(73-8
10.1002/bjs.18004820713

 

Preparation and assembly of the stainless steel sponge debubbler for use in the helix reservoir bubble oxygenator
CN Barnard, KM Mc and DR De Villiers
Thorax (1960) 15(3): 268-72
10.1136/thx.15.3.268

 

The experimental use of halothane anaesthesia in open-heart surgery with cardio-pulmonary bypass
AB Bull, GJ Rossouw, JE Kench and CN Barnard
S Afr Med J (1959) 33(1097-9

 

Some experiences with intracardiac surgery using the helixreservoir bubble oxygenator with total cardio-pulmonary bypass. A review of the first 30 cases treated at the Groote Schuur and Red Cross War Memorial Children's Hospitals, Cape Town
CN Barnard, WL Phillips, DR De Villiers, RD Casserley, RP Hewitson, RL Van Der Riet and KM Mc
S Afr Med J (1959) 33(789-96

 

The electrical pulse duplicator--its use in testing valve prostheses with special reference to the aortic and mitral valves
CN Barnard, KM Mc and DR De Villiers
S Afr J Med Sci (1959) 33(859-62

 

Pre- and post-operative care of patients undergoing open cardiac surgery
CN Barnard, RA Dewall, RL Varco and CW Lillehei
Dis Chest (1959) 35(2): 194-211
10.1378/chest.35.2.194

 

Serum transaminase patterns following intracardiac surgery
DD Snyder, CN Barnard, RL Varco and CW Lillehei
Surgery (1958) 44(6): 1083-91

 

The genesis of intestinal atresia
CN Barnard
Surg Forum (1957) 7(393-6

 

Duplication of the alimentary tract; report of case of double uterus, vagina, large bowel and anus
CN Barnard
Minn Med (1957) 40(4): 257-60

 

A method of operating on fetal dogs in utero
CN Barnard
Surgery (1957) 41(5): 805-7

 

The genesis of intestinal atresia
CN Barnard and JH Louw
Minn Med (1956) 39(11): 745; passim

 

Hypothermia; a method of intragastric cooling
CN Barnard
Br J Surg (1956) 44(185): 296-8
10.1002/bjs.18004418512

 

Congenital intestinal atresia; observations on its origin
JH Louw and CN Barnard
Lancet (1955) 269(6899): 1065-7
10.1016/s0140-6736(55)92852-x