Human Heart Transplantation: Current Status

Human Heart Transplantation: Current Status Randall B. Griepp, M.D., Edward B. Stinson, M.D.," Charles P. Bieber, M.D., Bruce A. Reitz, M.D., Jack G. Copeland, M.D., Philip E. Oyer, M.D., and Norman E. Shumway, M.D. ABSTRACT The overall survival rate for 97 heart transplant recipients operated on from 1968 to 1975 has been 49% at one year and 23% at five years. Progressive improvement in one-year survival has been achieved, from 22% in 1968 to 62% in 1974. The major factors responsible for increasing survival are better understanding and management of acute and chronic rejection. Current results suggest that heart transplantation deserves wider application in the treatment of selected patients with end-stage myocardial insufficiency. Considerable interest in cardiac transplantation has been maintained in our institution since 1968 and had resulted in the performance of 102 transplants in 97 patients by the end of 1975. The clinical experience accumulated in caring for these patients, coupled with input from studies carried out in the animal laboratory, has led to a progressive increase in patient survival and rehabilitation. Within the last few years, several important advances have been made in the treatment of acute and chronic rejection. This communication deals chiefly with the management of these two entities. Acute Rejection Maintenance Immunosuppression Azathioprine and corticosteroids remain the primary agents for maintenance immunosuppression following heart transplantation. An azathioprine loading dose of 5 mg per kilogram of body weight is given immediately preoperatively. Maintenance azathioprine is begun postoperatively as soon as the patient is able to take From the Department of Cardiovascular Surgery, Stanford University School of Medicine, Stanford, CA. *Established Investigator, American Heart Association. Presented at the Twelfth Annual Meeting of The Society of Thoracic Surgeons, Jan 26-28, 1976, Washington, DC. Address reprint requests to Dr. Griepp, Department of Cardiovascular Surgery, Stanford University Medical Center, 300 Pasteur Dr, Stanford, CA 94305. oral medications and is continued indefinitely at the highest dose compatible with adequate marrow function, usually 2 to 3 mglkg daily. Corticosteroid therapy consists of intravenous methylprednisolone, initially administered intraoperatively and then continued for 48 hours following operation. Subsequently oral prednisone is administered, beginning with 1.5 mglkg daily, then tapering to 1 mglkg by two months postoperatively and to 0.5 mglkg by six months. Thereafter, a continual effort is made to decrease prednisone to the lowest dose compatible with satisfactory allograft function. Longterm maintenance doses average 0.4 mglkg daily. Intramuscular rabbit anti-humanthymocyte globulin (RATG) is begun immediately after the operation and continued for the first ten postoperative days. Diagnosis Electrocardiographic evaluation and cardiac auscultation remain the two most important clinical surveillance techniques for detecting an acute rejection crisis [5]. Electrocardiographic correlates of rejection consist of an overall decrease in QRS voltage, the appearance of arrhythmias (usually atrial in origin), and in some instances a rightward shift of the mean QRS vector. At the time of operation an epicardial lead is attached to the donor atrium, and a decrease in the QRS voltage recorded from this lead may be the harbinger of an acute rejection crisis. The most useful physical finding in diagnosing an acute rejection crisis is the appearance of a ventricular filling sound, most frequently an S gallop. In the absence of acute rejection injury, gallop sounds are not characteristic of the human heart transplant, and the intensity of the gallop sound during an acute rejection crisis serves as a useful indicator of the severity of rejection. Endomyocardial biopsy has substantially in- 171

172 The Annals of Thoracic Surgery Vol 22 No 2 August 1976 creased the certainty with which the diagnosis of acute rejection can be made and also provides objective evidence of the efficacy of antirejection therapy [31. Cardiac biopsy is performed under local anesthesia by introducing a biopsy forceps into the internal jugular vein using a modified Seldinger technique. Under fluoroscopic control the biopsy forceps is guided into the right ventricle, and a 1 x 3 mm specimen of myocardium is removed from the intraventricular septum (Fig 1). Sufficient tissue can usually be obtained for staining with hematoxylin and eosin and with methylpyronine green. When it is important to determine the presence of rejection on an emergency basis, frozen sections have been helpful. To date, 470 endomyocardial biopsies have been performed in recipients of cardiac transplants. Satisfactory tissue for diagnosis has been obtained in more than 95% of these biopsies. Complications have been relatively minor and consisted of premature ventricular contractions in approximately 20%, supraventricular arrhythmias in 3%, and pneumothorax caused by trauma to the apical pleura during introduction of the biopsy forceps in 2%. Using a combination of clinical and histological findings, it has been possible to standardize the diagnosis and management of acute rejection. A drop of 20% or more in the QRS voltage Fig I. Technique of endomyocardial biopsy. (from either the standard electrocardiographic leads or the atrial wire), the development of a new arrhythmia, or the appearance of a gallop sound are considered presumptive evidence of acute rejection injury, and an endomyocardial biopsy is obtained within several hours. If the clinical findings argue strongly for the presence of acute rejection or if there is reason to believe that the presumptive episode is likely to be a severe one, antirejection therapy is begun immediately after obtaining the biopsy. If the clinical findings are equivocal, therapy is delayed for approximately twelve hours until permanent histological sections can be obtained. Antirejection therapy involves increasing the dosage of corticosteroids, and occasionally RATG, and beginning administration of actiriomycin D and heparin. The complete treatment regimen consists of the following: 1. Methylprednisolone, 1.0 gmivdaily for2 to4 days. 2. Actinomycin D, 200 pg IV daily for 1 to 3 days. 3. Antithymocyte globulin IM for 3 to 5 days. 4. Prednisone increased for 10 to 14 days. 5. Heparin IV for 5 to 7 days. Rabbit Antithymocyte Globulin (IIATG) During the first two years following the inception of clinical cardiac transplantation we used heterologous antisera producedl from horses, against either thoracic duct lymphocytes or splenocytes, as an immunosuppressive adjunct. Subsequently we found horse anti-humanthymocyte globulin (HATG) to be somewhat more efficacious than the earlier preparations [6]. In late 1973 we made a further change and began using antithymocyte globulin raised in rabbits. The procedures for immunization and harvesting of the rabbit antiserum are similar to the protocol used by Davis and colleagues [41. The purified globulin fraction is administered intramuscularly in a dose of 3 to 15 mglkg on postoperative days 1, 2,3, 5, 7,,and 9. Doses of individual batches are adjusted on the basis of the sheep red blood cell rosette inhibition titers. Serum levels of rabbit globulin in the cardiac recipients are assayed serially utilizing a modified Farr technique [ll.

173 Griepp et al: Human Heart Transplantation Table I. Comparison of the Efficacy of RATG and HATG in Preventing Rejection Factola RATG HATG p Value Rejection onset 23.8 f 0.5 12.6 f 0.5 0.01 Rejection frequency 2.9 f 0.07 5.0 f 0.1 0.002 Rejection score 4.7 f 0.6 7.5 f 0.3 0.05 'Rejection onset is the postoperative day on which the first rejection crisis is diagnosed. Rejection frequency is the number of rejection episodes per 100 patient-days occurring in the first two postoperative months. Rejection score is computed similarly to rejection frequency except that each episode is graded mild, moderate, or severe and weighted accordingly in the calculation of score. Mean values are shown with standard errors. Factors indicative of rejection in the first 29 patients receiving RATG were compared with those in the last 20 patients receiving HATG. In all patients, episodes of acute rejection were confirmed by cardiac biopsy. As shown in Table 1, by each of the three variables assayed, rejection was significantly less severe in patients who were given RATG than in those receiving HATG. Serial determination of rabbit globulin levels allowed the patients receiving RATG to be divided into two distinct groups as determined by the kinetics of rabbit globulin elimination from the serum. In 19 patients rabbit globulin was rapidly eliminated, with a mean half life of 1.4 k 0.4 days. In 10 patients the serum rabbit globulin half-life was prolonged, with values ranging from 4 to 18 days and averaging 9.0 f 4.3 days. Table 2 compares rejection indicators in these two groups of patients. It is readily apparent that in patients in whom rabbit globulin was eliminated in a slow and presumably nonimmune fashion, the incidence and severity of acute rejection were substantially diminished. Thus it is apparent not only that RATG is a more potent immunosuppressive agent than HATG, but also Table 2. Comparison of Rejection in Patients with Rapid versus Slow RATG Clearance from the Serum Slow Rapid Factola Elimination Elimination p Value Rejection onset 32.3 k 1.7 19.3 f 0.6 0.001 Rejection frequency 1.9 f 0.1 3.9 f 0.2 0.001 Rejection score 2.5 f 0.2 5.8 f 0.3 0.001 "See Table 1 for explanation. that more effective immunosuppression is obtained in patients in whom RATG is not subject to immune elimination. Chronic Rejection Although survival immediately following transplantation depends upon the management of acute rejection episodes and infections, it became apparent relatively early in our experience that the major determinant of long-term survival of the cardiac allograft recipient was development of arteriosclerosis in the transplanted heart. Our first long-term survivor died at twenty-one months of an acute myocardial infarction, and extensive coronary artery lesions were evident at postmortem examination. Similar findings were present postmortem in Barnard's first long-term survivor [lo]. Based on the histological appearance of the lesions and the rapidity with which they developed, a tentative hypothesis for the pathogenesis of graft arteriosclerosis was formulated. It seems probable that the initial event is immune injury to the tunica intima of the coronary vessel, resulting in endothelial slough and exposure of a thrombogenic surface. Microthrombi, consisting predominantly of platelets, accumulate and undergo organization, forming a small intimal lesion. Repetition of this process, compounded by the infiltration of plasma lipids into the hypertrophied tunica intima, which elicits additional inflammation, results in continuous formation of intimal lesions and consequent luminal narrowing. A schema of the proposed pathogenic mechanism is shown in Figure 2. On the basis of this hypothesis and studies performed by Kincaid-Smith [9] in renal allo- Fig2. Proposed pathogenesis ofgraft arteriosclerosis. IMMUNE INJURY TO VESSEL WALL J MICROTHROMBOSIS PRoLIFERATIVE REPAIR ORGANIZATION \ / HYPERLlPlDEMlA INFILTRATION OF INTIMAL PROLIFERATION HYPERTROPHIED \?IMA GRAFT ARTERIOSCLEROSIS

174 The Annals of Thoracic Surgery Vol 22 No 2 August 1976 graft recipients, we thought that a combination of antithrombotic therapy and a sustained attempt to lower plasma lipid levels might be effective in reducing the severity of graft arteriosclerosis. Accordingly, after January, 1970, all patients receiving cardiac allografts were placed on a continuous regimen of warfarin and dipyridamole following transplantation and were given a diet low in cholesterol and saturated fat, with calorie restriction designed to maintain normal body weight. The incidence of graft arteriosclerosis has subsequently been assayed by annual coronary arteriography or postmortem examination [8]. Figure 3 depicts the time-related incidence of graft arteriosclerosis in all patients in our series who have survived beyond three months. Group I consists of 9 three-month survivors operated on prior to 1970 (before initiation of the regimen designed to prevent graft arteriosclerosis), and group I1 consists of 40 three-month survivors in whom the regimen was utilized. It is clear that the incidence of graft arteriosclerosis has been substantially reduced, and it no longer appears to be a significant cause of late mortality from three to five years postoperatively [71. Tissue Typing Complete histocompatibility antigen (HL-A) typing of both donor and recipient has been obtained in 89 of our 97 allograft recipients [2]. In 10 patients with 0 or 1 HL-A antigen incompatibilities the one-year survival was 24% (2 Fig3. Incidence of graft arteriosclerosis in two groups of heart transplant patients: Group 1-9 patients not on the prophylactic regimen for graft arteriosclerosis; Group 1140 patients on the prophylactic regimen (see text forfull explanation). The probability that the difference between these two populations is due to chance is less than 0.002. 1.00, I 1 2 3 4 POSTOP YEARS patients); in 19 patients with 2 mismatches it was 53% (10 patients); in 37 patients with 3 mismatches, 48% (18 patients); and in 23 patients with4 mismatches, 55% (13 patients). No significant differences in survival have occurred between any of the groups, and in addition, no correlation between the number of HL-A mismatches and history of rejection has been evident. In the last two years one of us has devised a technique for calculating match score in which specific HL-A incompatibilities are weighted by the frequency with which antibo'dies are formed during pregnancy in the face of known maternal-offspring HL-A incompatibilities. Utilizing this statistic, a significant correlation emerges between match score and survival [71. At present, however, this correlation does not appear strong enough to justify using match score to determine suitable cardiac donors preoperatively. Retransplantation Cardiac retransplantation has been carried out 5 times in our series. In 1 patient successful retransplantation was accomplished 24 hours following placement of the initial graft, which had an extremely unstable rhythm with resultant compromise of hemodynamic function. In 2 patients retransplantation was carried out during the first two postoperative months because of unremitting, drug-resistant, acute rejection injury. In 1 of these patients the second graft was rejected within two weeks, but acute rejection in the other patient was relatively easy to control, and the patient is at present a long-term survivor. Cardiac retransplantation was required in 2 patients because of the develo.pment of severe coronary artery lesions in the original graft after two to five years. One of them died postoperatively of a fungal infection that had been present at the time of retransplantation. The second patient continued to do well more than one year following placement of his seccind graft. Survival and Rehabilitation Figure 4 depicts the survival curve of the 97 patients who have received heart transplants. The majority of deaths occurred within the first year following transplantation, so that if an individual reaches his first anniversary, he has approximately a 50% chance of continuing to

175 Griepp et al: Human Heart Transplantation 1.20 I \,+NOT TRANSPLANTED I34 PTS) POSTOP YEARS -.- Fig4. Survival of 97 patients who received heart transplants and34 patients selected for transplantation who died before a donor became available. 2 5 0.60 0.40 E Y z 0.20 68 69 70 71 12 13 74 YEAR Fig5.One-year survival by calendar year in the Stanford University series. survive for five years following operation. Also shown in Figure 4 is the survival curve for 34 patients who were selected for transplantation but who died before a suitable donor became available; all had died by one year following selection. Figure 5 depicts one-year survival by calendar year from 1968 through 1974, the last year in which a complete one-year survival can be ascertained. Progressive improvement in one-year survival is apparent; 1974 one-year survival was 62%. The statistics for rehabilitation, which is as important as survival, are equally encouraging. Of the 37 patients in our series who have survived for one year or more, 32 (86%) have been rehabilitated to New York Heart Association Functional Class I. References 1. Bieber CP, Lydick E, Griepp RB, et al: Radioimmune assay of heterologous serum gamma globulin in patients receiving rabbit antihuman thymocyte globulin. Transplantation 20:393,1975 I 2. 3. 4. 5. 6. 7. 8. 9. 10. Bodmer W, Tripp M, Bodmer J: Application of a fluorochromatic cytotoxicity assay to human leukocyte typing, Histocompatibility Testing. Edited by ES Curtoni, PL Mattiuz, RM Tosi. Copenhagen: Munksgaard, 1967, p 341 Caves PK, Stinson EB, Billingham ME, et al: The diagnosis of human cardiac allograft rejection by serial cardiac biopsy. J Thorac Cardiovasc Surg 66:461, 1973 Davis RC, Glasgow AH, Williams LF Jr, et al: Trial of rabbit antihuman ALG in cadaver kidney transplantation. Transplant Proc 3:766, 1971 Griepp RB, Stinson EB, Dong E Jr, et al: Acute rejection of the allografted human heart. Ann Thorac Surg 12:113, 1971 Griepp RB, Stinson EB, Dong E Jr, et al: The use of antithymocyte globulin in human heart transplantation. Circulation 45:Suppl 2:147, 1972 Griepp RB, Stinson EB, Oyer PE, et al: Management of long-term survivors of heart transplantation. Transplant Proc 7:Suppl 1:595, 1975 Griepp RB, Wexler L, Stinson EB, et al: Coronary arteriography following cardiac transplantation. JAMA 221:147, 1972 Kincaid-Smith P: Modification of the vascular lesions of rejection in cadaveric renal allografts by dipyridamole and anticoagulants. Lancet 2:920, 1969 Thomson JG: Production of severe atheroma in a transplanted human heart. Lancet 2:1088, 1969 Discussion DR. GRIEPP: It is always a pleasure to present these data, but sometimes I wonder whether a paper on heart transplantation is accepted on its merits or because it saves time during the discussion period. I should like to present some additional information as an encouragement to others contemplating initiation of a program in heart transplantation. We have plotted the cost of heart transplantation over the years compared with the cost of aortic valve replacement in our hospital. In 1970 the average cost of heart transplantation was about $20,000, approximately six times the cost of an aortic valve replacement. In the past year the average cost of a heart transplant was just under $30,000, but this now represents only four times the cost of aortic valve replacement. Thus, the cost of heart transplantation is decreasing in comparison to more standard types of cardiac operations. With respect to long-term survival and rehabilitation, 5 patients have currently lived beyond five years. Our longest survivor is a man who is alive and active more than six years following operation. Most of our long-term survivors are doing quite well and leading close to normal lives. More than 85% of the one-year survivors are in New York Heart Association Functional Class I, and of these patients, greater than 80% have returned to gainful employment.