Transplantation of the heart: An overview of 40 years' clinical and research experience at Groote Schuur Hospital and the University of Cape Town: Part II. Laboratory research experience.

Extensive experimental research on various aspects of heart transplantation was undertaken during the first 2 decades. An overview of this work is presented, and some still unpublished work has been included. Experimental laboratory investigation was an integral activity of the cardiac transplantation programme at the University of Cape Town over these years, and has remained so ever since. These studies provided invaluable fundamental information upon which future clinical work was based. It is therefore necessary to briefly mention and discuss this information, most of which has been published in detail by the various investigators concerned.

Transplantation of the heart: An overview of 40 years' clinical and research experience at Groote Schuur Hospital and the University of Cape Town: Part I. Surgical experience and clinical studies.

The heart transplant programme at Groote Schuur Hospital and the University of Cape Town has continued uninterruptedly since the first human transplant in 1967. Orthotopic heart transplantation was followed by the heterotopic method in 1974, considerably improving the clinical results. In 1983, owing to the advent of cyclosporin A, the orthotopic method was once again predominantly adopted. Early graft failure for various reasons remains a major complication, and heterotopic heart transplantation is perhaps the best way to deal with it.

The first human heart transplant and further advances in cardiac transplantation at Groote Schuur Hospital and the University of Cape Town - with reference to : the operation. A human cardiac transplant : an interim report of a successful operation performed at Groote Schuur Hospital, Cape Town.

Christiaan (Chris) Barnard was born in 1922 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 programme 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. The article describing this remarkable achievement was published in the South African Medical Journal just three weeks after the event and is one of the most cited articles in the cardiovascular field. In the lay media as well, this first transplant remains the most publicised event in world medical history. 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. This first heart transplant and subsequent ongoing research in cardiac transplantation at the University of Cape Town and in a few other dedicated centres over the subsequent 15 years laid the foundation for heart transplantation to become a well-established form of therapy for end-stage cardiac disease. During this period from 1968 to 1983, Chris Barnard and his team continued to make major contributions to organ transplantation, notably the development of the heterotopic ( 'piggy-back') heart transplants; advancing the concept of brain death, organ donation and other related ethical issues; better preservation and protection of the donor heart (including hypothermic perfusion storage of the heart; studies on the haemodynamic and metabolic effects of brain death; and even early attempts at xenotransplantation.

The First Human Heart Transplant and Further Advances in Cardiac Transplantation at Groote Schuur Hospital and the University of Cape Town

Christiaan (Chris) Barnard was born in 1922 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 programme 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. The article describing this remarkable achievement was published in the South African Medical Journal just three weeks after the event and is one of the most cited articles in the cardiovascular field. In the lay media as well; this first transplant remains the most publicised event in world medical history. 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. This first heart transplant and subsequent ongoing research in cardiac transplantation at the University of Cape Town and in a few other dedicated centres over the subsequent 15 years laid the foundation for heart transplantation to become a well-established form of therapy for end-stage cardiac disease. During this period from 1968 to 1983; Chris Barnard and his team continued to make major contributions to organ transplantation; notably the development of the heterotopic ('piggy-back') heart transplants; advancing the concept of brain death; organ donation and other related ethical issues; better preservation and protection of the donor heart (including hypothermic perfusion storage of the heart; studies on the haemodynamic and metabolic effects of brain death; and even early attempts at xenotransplantation

Experimental evaluation of the mitroflow pericardial heart valve prosthesis. Part I. In vivo hemodynamic evaluation.

Evaluation of possible enhanced durability of the Mitroflow pericardial heart valve prosthesis was undertaken in an experimental animal model using the Chacma baboon. For comparison purposes a small series of 4 Ionescu-Shiley pericardial valves were also implanted. The 33 Mitroflow prostheses implanted were all manufacturer's size 21mm and belonged to 4 different groups according to the process used for the preparation of the pericardium (Process I to IV). The Ionescu-Shiley prostheses were all manufacturer's size 19mm and were commercially available valves. The valves were implanted in the mitral position, except one each Mitroflow and Ionescu-Shiley prosthesis that was implanted in the tricuspid position. Four animals died in the early postoperative period, between 2 and 14 days. Two died from a probable viral infection, one from a low cardiac output state and the fourth one from bacterial endocarditis. The clinical evaluation of the animals for an implantation time of up to twelve months was unremarkable. Hemodynamic studies were performed immediately after implantation (n = 29), at an intermediate cardiac catheterization at 9 months after implantation (n = 4) and at the time of terminal elective sacrifice of the animals (n = 33). From the data obtained the resultant prosthetic valve area at the time of elective sacrifice of the animals was also calculated. The data obtained for each of the 5 groups of valves tested are presented in the text. Transvalvular gradients measured at the time of sacrifice of the animals were elevated.(ABSTRACT TRUNCATED AT 250 WORDS)

Experimental evaluation of the mitroflow pericardial heart valve prosthesis. Part II. Pathologic examination.

The results of the morphologic and histopathologic examination of 37 bovine pericardial heart valve prostheses that were retrieved after experimental implantation in Chacma baboons for periods of one to twelve months are presented in this study. The implanted prostheses consisted of 33 Mitroflow valves, size 21 mm, that belonged to four different groups according to the method of preparation of the pericardium (process I to IV) and 4 commercially available Ionescu-Shiley valves, size 19 mm. All implantations were in the mitral position, except 1 Mitroflow and 1 Ionescu-Shiley prosthesis, which were implanted in the tricuspid position. Moderate or abundant noninfected thrombotic deposits were found on the cusps of 13 of the 33 Mitroflow valves (39%). The Ionescu-Shiley valves shared this tendency, perhaps to a lesser extent, for the formation of thrombus on the valve cusps. Results of transmission electron microscopy, scanning electron microscopy, and calcification analysis are also presented. In this experimental study, the authors did not identify any significant characteristics in the Mitroflow bovine pericardial heart valve prosthesis that would lead to improved or extended durability of this device over the commercially available Ionescu-Shiley bovine pericardial heart valve prosthesis and probably over any other glutaraldehyde-treated bioprosthesis. They would suggest, therefore, that any clinical investigations of the prosthesis be undertaken very cautiously.

Valve replacement in children.

The performance of the St. Jude prosthetic valve is reviewed in 81 patients aged 3 to 15 years. All 66 mitral (2 re-replacements), 8 aortic and 9 double valve replacements between February 1979 and August 1984 are included. The early mortality was 3.7% and actuarial analysis shows a 90% event free survival up to 5 years. Anticoagulant therapy was used in most patients, but comparison between groups receiving warfarin or aspirin or no therapy reveals no differences in the complication rate. The valve is well suited for use in children since the early degeneration seen with heterograft valves does not occur, and anticoagulation is not essential.

Necrotizing enterocolitis in pulmonary atresia with intact ventricular septum.

Necrotizing enterocolitis (NEC) occurred in 2 neonates with pulmonary atresia and intact ventricular septum. Both infants underwent open heart surgery for the insertion of a right ventricular outflow tract patch under profound hypothermia, surface cooling and a fibrillating heart, without circulatory arrest. In both patients the development of NEC preceded both the cardiac catheterization study and open heart surgery. Urgent repair of the cardiac lesion was undertaken in an attempt at improving the critical bowel wall ischemia. Postoperatively, exacerbation of the NEC reached an advanced stage rapidly leading to the death of the patients. Recommendations regarding the management of future cases exhibiting this potentially lethal combination of disease are presented.

Left atrial myxoma in a 13-month-old infant.

The presentation, diagnosis and management of a 13-month-old child with a left atrial myxoma is described. The value of echocardiography in confirming the diagnosis is emphasized.

Surgical management of congenital heart disease. A review of 7 years' experience.

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 surgical treatment of tetralogy of Fallot.

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.

Heterotopic cardiac transplantation. A 7-year experience at Groote Schuur Hospital, Cape Town.

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.

Valve replacement in patients over 70 years of age.

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.

Changes in indications for heart transplantation. An additional argument for the preservation of the recipient's own heart.

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.

Technique, complications, and clinical value of endomyocardial biopsy in patients with heterotopic heart transplants.

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.

Tricuspid atresia corrected by the Fontan method.

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.

Orthotopic transplantation of the baboon heart after 20 to 24 hours' preservation by continuous hypothermic perfusion with an oxygenated hyperosmolar solution.

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.

The present status of heterotopic cardiac transplantation.

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.