Acute Rejection of the Allografted Human Heart

Transcription

1 THE ANNALS OF THORACIC SURGERY Journal of The Society of Thoracic Surgeons and the Southern Thoracic Surgical Association VOLUME 12 * NUMBER 2 AUGUST 1971 Acute Rejection of the Allografted Human Heart Diagnosis and Treatment Randall B. Griepp, M.D., Edward B. Stinson, M.D., Eugene Dong, Jr., M.D., David A. Clark, M.D., and Norman E. Shumway, M.D. ABSTRACT Twenty-six patients have received heart transplants at Stanford University Medical Center. Of these, 11 were alive at six months (42951, 10 at twelve and eighteen months (37%),,and 7 at twenty-four months (26%). Sixty episodes of acute allograft rejection were diagnosed in 21 patients. No correlation between histocompatibility match and rejection history was apparent. Emph.asis was placed on early diagnosis of rejection episodes and intermittent use of high-dose immunosuppressive therapy. Useful indexes of early graft rejection included electrocardiographic changes (decreasing QRS voltage, appearance of arrhythmias, right shift of the electrical axis, ST-T wave changes), clinical findings (appearance of gallop rhythm, decreased precordial activity, hypotension), and ultrasound echocardiographic findings (increased thickness of left ventricular wall, increased right ventricular diameter). Fifty-seven rejection episodes were reversed with increased immunosuppressive therapy, and 3 progressed to graft failure and the patient's death. In the cardiac transplant recipient, monitoring multiple indexes of allograft function allows the early diagnosis and successful treatment of most episodes of acute rejection. From the Departments of Surgery and Medicine, Stanford University School of Medicine, Stanford, Calif. Presented at the Seventh Annual Meeting of The Society of Thoracic Surgeons, Dallas, Tex., Jan , Supported in part by U.S. Public Health Service Grants HE and HE and by Research Grant FR-70, General Clinical Research Centers Branch. Address reprint requests to Dr. Griepp, Division of Cardiovascular Surgery, A.248, Stanford University Medical Center, Stanford, Calif

2 GRIEPP ET AL. F our years have passed since the first successful grafting of a human heart [l]. The dismal statistics of the world experience emphasize that control of graft rejection remains the major determinant of long-term survival. The observations that rejection is an episodic phenomenon [9, 101 and that limiting potent immunosuppressive therapy to periods of maximal immunological activity decreases infectious complications have focused attention on the precise diagnosis of rejection episodes. Using previous laboratory experience with canine cardiac transplantation [ll] as a guide, we have made the early diagnosis of rejection episodes and intermittent therapy our primary approaches to immunosuppression. This communication summarizes our experience with 60 episodes of acute cardiac rejection. Patients and Methods PATIENTS Twenty-six patients have received heart transplants at Stanford Medical Center. Twenty-three were men and 3, women. Their average age was 50 years. Twenty-one patients had arteriosclerotic heart disease and 5 had a primary cardiomyopathy. All patients had Class IV disability (New York Heart Association classification). Postoperative survival for all transplant patients, calculated by the life-table method [41, was 42% at six months (11 patients), 37% at twelve and eighteen months (10 patients), and 26% at twenty-four months (7 patients) (Fig. 1). Of the 26 patients who received heart grafts, 3 died within 72 hours following operation as a result of severe pulmonary hypertension and right heart failure. One patient suffered multiple metabolic and infectious complications and died two weeks following operation without having an episode of acute rejection. One patient was discharged from the hospital 40 days following transplantation, having had no evidence of acute rejection. In the 21 remaining patients 60 rejection episodes occurred. HISTOCOMPATIBILITY MATCHING ABO blood group compatibility between donor and recipient was assured in all cases, as was a negative cross-match of recipient sera and donor FZG. 1. Survii~al of 26 patients who received cardiac transplants, calculated from the time of operation, and of 13 patients who died before a donor became nvailable, calculated from the time of selection for transplantation I MONTHS 114 THE ANNALS OF THORACIC SURGERY

3 Acute Rejection of Allografted Hum,an Heart lymphocytes. Although tissue-typing for ten HLA antigens [31 was carried out preoperatively in all but 1 patient, its outcome had little influence on the decision to proceed with transplantation. Eight donor-recipient pairs were mismatched for three antigens, 10 for two antigens, 5 for one antigen, and 2 were compatible for all antigens tested. No clear correlation between HLA compatibility and survival or rejection history has been apparent. DIAGNOSTIC STUDIES Standard twelve-lead electrocardiograms were taken one to three times daily using a Sanborn model 500 portable recorder. Consistent placement of precordial leads was assured by tattooing. A summation of the QRS voltage in leads I, 11,111, V,, and V, was used for all patients as an index of total electrical activity of the heart. A complete clinical cardiac examination was done at least twice daily, usually after the patient had rested quietly in bed for at least one-half hour but on occasion following standardized exercise. Phonocardiograms were taken at the bedside with a Sanborn twinbeam portable model 52 recorder or an Elema-Schonander Minograph 34 direct-writing recorder. Ultrasound echocardiograms were obtained with.a Smith Kline & French Ekoline 20. Polaroid photographs were made of the M display,* and measurements of left ventricle thickness and right ventricular diameter were taken from the photographs. Lactic dehydrogenase, lactic dehydrogenase fraction 1, and serum glutamic oxaloacetic transaminase (SGOT) were determined daily by standard clinical laboratory techniques. MAINTENANCE IMMUNOSUPPRESSION Azathioprine was administered to all patients in a dose of 4 mg. per kilogram of body weight immediately prior to operation. Early in the series, 7 patients received 1 mg. per kilogram for one to four weeks preoperatively. On the first postoperative day, maintenance azathioprine was begun with 2 mg. per kilogram per day and continued in the maximum tolerated dose as determined by studies of bone marrow and hepatic function. Most patients received between 1 and 3 mg. per kilogram daily. Methylprednisolone was administered intraoperatively in a dose of 4 to 10 mg. per kilogram. This amount was repeated during the first postoperative day in four divided doses. On the day following operation, prednisone was begun orally in a dose of 1.5 mg. per kilogram per day, tapering to an average of 1 mg. per kilogram per day by the end of the first postoperative month. Long-term maintenance dosage averaged 0.3 mg. per kilogram per day. In the first 16 patients, antilymphocyte globulin was administered intramuscularly daily in the immediate postoperative period and then with gradually decreasing frequency until two to six months postoperatively. The daily dose was 4 to 5 ml. of a preparation? having a leukocytotoxicity titer *Mitral valve motion. tsupplied in part by Prof. M. Carraz, Institut Pastcur de Lyon, Lyon, France. VOL. 12, NO. 2, AUGUST,

4 GRIEPP ET AL. of l/l,000 to l/s,000 and a protein content of 50 to 60 mg. per milliliter. In the last 8 patients a purified globulin preparation of horse antihuman thymocyte serum* was administered intravenously starting daily at the time of operation and continuing with gradually diminishing frequency or six to eight weeks. The cytotoxicity titer of this second preparation is 1165,000, the rosette formation-inhibition titer is 1 /50,000 to 1 / 150,000, and the protein content is 50 mg. per milliliter. Individual dosages of the purified preparation ranged from 2 to 5 ml. In 1 patient graft irradiation-450 rads given in three divided doses-was used. CLASSIFICATION OF REJECTION Rejection episodes were divided retrospectively into three major groups on the basis of clinical evaluation of cardiac function: Mild-No symptoms of congestive heart failure or diminished cardiac output either at rest or following moderate exercise; electrocardiographic findings frequently constituted the only indications of rejection, although in some cases a soft gallop sound may have been present Moderate-No evidence of impaired myocardial performance at rest, but moderate exercise resulted in weakness or shortness of breath Severe-Clinical evidence of impaired myocardial performance present at rest; weakness, anorexia, mental obtundation, as well as cool extremities, elevated venous pressure, mild to moderate hypotension, and decreased urinary output may have been present; performance of mild exercise accentuated the findings present at rest TREATMENT OF ACUTE RE JECTION EPISODES When the diagnosis of a rejection episode was established, methylprednisolone, 500 to 1,000 mg., and actinomycin D, 100 to 500 pg., were administered intravenously over an hour once or twice daily until evidence of rejection decreased or serious toxicity occurred. On occasion, antilymphocyte globulin was either increased in dosage or reinstituted. Sodium heparin was administered intravenously in a dose sufficient to double the clotting time just prior to administration of the subsequent dose (4,000 to 8,000 units every 6 hours). Vasopressor agents were administered intravenously in the presence of severe hypotension or marked impairment of cardiac output. *Supplied by Upjohn Co., Kalamazoo, Mich I16 THE ANNALS OF THORACIC SURGERY

5 Acute Rejection of Allografted Human Heart 1.21 FIG. 2. Incidence of rejection episodes in 21 cardiac transplant recipients. V,** J Results INCIDENCE Sixty rejection episodes were diagnosed in 2 1 patients. Twenty-nine episodes were classified as mild, 16 as moderate, and 15 as severe. A single episode was diagnosed in 2 patients, 2 episodes in 6 patients, 3 episodes in 7 patients, 4 episodes in 5 patients, and 5 episodes in 1 patient. As can be seen in Figure 2, most episodes of rejection occurred during the first two months following grafting and tended to cluster into two populations around the tenth and thirtieth postoperative days. During the first 60 days following transplantation, the total incidence of rejection episodes is 1 episode per 20.5 patientdays. From 60 to 120 days the incidence decreases to 1 episode per 165 patient-days. ELECTROCARDIOGRAPHIC FINDINGS A decrease in QRS voltage was seen in all but 2 rejection episodes. The average decrease in the sum of I, 11, 111, V,, and V, was 1.14 millivolts per episode. As a percentage of the total QRS voltage immediately prior to the onset of rejection, this represents an average decrease of 30%. As can be seen in Table 1, in instances of mild and moderate rejection the electrocardio- TABLE 1. CHANGES IN QRS VOLTAGE AT ONSET OF REJECTION EPISODE AND WITH RECOVERY FOLLOWING TREATMENT Average Voltage Change Rejection (%) Classification Decrease Increase Mild Moderate Severe All rejection episodes VOL. 12, NO. 2, AUGUST,

6 GRIEPP ET AL. graphic voltage returned to the pretreatment level following therapy. Following a severe rejection episode, however, the QRS voltage returned only to approximately 70% of its value prior to the episode. There were 26 rejection episodes during which one or more arrhythmias occurred. In 19 episodes there was a single arrhythmia, in 5 episodes two arrhythmias, in 1 episode three arrhythmias, and in 1 episode four arrhythmias. In order of decreasing frequency, atrial premature contractions occurred ten times, ventricular premature contractions eight times, atrial flutter six times, atrial fibrillation four times, nodal rhythm and ventricular fibrillation each occurred twice, and sinus arrest, atrial tachycardia, premature nodal contractions, and ventricular tachycardia each occurred once. The average duration for all arrhythmias was 3.7 days. Classified according to level of origin, there were 22 atrial arrhythmias, 3 nodal arrhythmias, and 11 ventricular arrhythmias. As Table 2 demonstrates, the incidence of arrhythmias increased with the severity of the rejection episode. Indeed, in severe rejection there was an average of 1.33 arrhythmias per episode. Electrical cardioversion was required on one or more occasions during 6 rejection episodes. During 2 episodes quinidine was used, and during 1, xylocaine was required. A significant shift of the mean electrical axis in the frontal plane occurred during 28 rejection episodes. In 21 episodes this was a right shift of the axis with an average value of 37" (range 10" to go"), with a 26" (range 10" to 90 ) shift back to the left following treatment. During 7 episodes the axis shift was to the left, with a mean shift of 31" (range 15" to 50") and an average right shift of 23" (range 20" to 50") following treatment. ST-T wave changes occurred frequently throughout the early postoperative period and were often correlated with rejection episodes. Inversion of T waves in one or more limb or precordial leads coincided with the onset of 24 rejection episodes. ST depression of 1 mm. or more in one or more limb or precordial leads occurred at the onset of 10 rejection episodes. ST and T wave changes were most frequently seen with the first episode of rejection in a given patient and frequently did not revert to normal until 10 to 30 days following successful treatment. TABLE 2. INCIDENCE OF ARRHYTHMIAS DURING ACUTE REJECTION EPISODES Average Occurrence of Arrhythmias No. of (% of episodes) Arrhythmias Rejection Ventric- per Rejection Classification Atrial Nodal ular Episode Mild (29 episodes) 5 (17%) 1(3%) 3 (10%) 0.30 Moderate (16 episodes) 6 (37%)... 16%) 0.43 Severe (15 episodes) 11 (73%) 2 (13%) 7 (47%) 1.33 I 18 THE ANNALS OF THORACIC SURGERY

7 Acute Rejection of Allogl-afted Human Heart I v6 POD 5 POD 9 POD 12 FIG. 3. Serial electrocardiograms during successful treatment of a rejection episode. Note the decrease in QRS voltage from POD 5 (postoperative day 5) to POD 9 as well as the appearance of atrial putter. By POD 12, following 3 days of high-dase immunosuppressive therapy, the QRS voltage has increased and sinus rhythm has reappeared. Figure 3 is an example of the serial electrocardiographic findings occurring during a rejection episode. CLINICAL FINDINGS Diastolic filling sounds (gallops) corresponding in timing to a third or fourth heart sound occurred during 34 rejection episodes. Gallop rhythms persisted an average of 4.2 days (range 1 to 10 days). The gallop was protodiastolic in timing in 27 episodes and presystolic in 3, and both a protodiastolic and a presystolic gallop were heard in 4 episodes. The gallop was localized to the left sternal border in 14 episodes, at the apex in 11, and was heard in both locations in 9 episodes. The frequency with which abnormal diastolic sounds were heard increased with the severity of rejection, occurring in 41%, 56%, and 87% of mild, moderate, and severe rejection episodes, respectively. A significant fall in systolic blood pressure was seen during 20 rejection episodes and persisted an average of 2.8 days (range 1 to 7 days). The average fall was 23 mm. Hg, or 21%. The incidence of hypotension correlated well with the severity of rejection episodes, a significant drop occurring in 17% of mild, 31% of moderate, and 67% of severe rejection episodes. Precordial activity was clinically assessed in all episodes. Total precordial activity was decreased in 38% and a right ventricular lift occurred in 17%. Fever was a relatively uncommon finding during rejection episodes. An elevation in temperature ranging from 1" to 2 C. and lasting 4 to 5 days occurred during 4 episodes (7%). VoL. 12, NO. 2, AUGUST,

8 GRIEPP ET AL. ULTRASOUND ECHOCARDIOGRAPHIC FINDINGS Serial echocardiograms were obtained during 20 episodes of acute rejection. During 12 episodes (60%) an increase in left ventricle thickness was observed. The average increase in thickness was 3.4 mm. (range 2 to 11 mm.). An average increase in right ventricular diameter of 4.6 mm. (range 3 to 11 mm.) was detected during 9 episodes (45%). SEROLOGICAL FINDINGS Mild elevations in serum enzymes were occasionally seen during rejection episodes. An increase in SGOT of up to 50 units was seen in 22% of all episodes. An LDH increase of up to 100 units occurred in 13%, and an increase in LDH fraction 1 of up to 60 units was seen in 8% of episodes. TREATMENT OF REJECTION EPISODES Table 3 outlines the average duration of treatment of rejection episodes and the average total drug dosages used. The average length of treatment for all episodes was 3.4 days (range 1 to 6 days). The average total dose of methylprednisolone was 2,800 mg. (range 400 to 8,000 mg.), and the average dose of actinomycin D was 510 pg. (range 0 to 1,750 pg.). Antilymphocyte globulin was reinstituted or increased in dosage in 24 episodes (40%). Heparinization was used in 68%, and in 8% a vasopressor agent was utilized. Of the 60 episodes of acute rejection, 57 were successfully treated. In 3 instances, despite massive immunosuppressive therapy, rejection was unrelenting and resulted in graft failure and the patient's death. Figure 4 summarizes the course of a patient who underwent therapy for 3 rejection episodes. Table 4 lists the principal findings during rejection episodes and their frequency in this series. TABLE 5. TREATMENT OF ACUTE REJECTION EPISODES Average Methyl- Average Average prednis- Actino- Vaso- No.of olone mycind Hepa- pres- Rejection Days Dosage Do'sage ALG* rinb sorb Classification Treated (mg.) hpg.) (%) (%) (%) Mild 3.1 2, Moderate 3.3 3, Severe All rejection 4.0 3, episodes 3.4 2, *Percentage of episodes in which antilymphocyte globulin was either reinstituted or increased in dosage. bpercentage of episodes in which heparin or a vasopressor was used. 120 THE ANNALS OF THORACIC SURGERY

9 GAUOP SOUND ARRHYTHMIAS '1 VOLTAGE ORS (rnv) 5 - Acute Rejection of Allografted Human Heart 00 a *%+as i"c: 10.. :::hiiiiiii = I FIG. 4. Summary of diagnostic findings and immunosuppressive therapy during the hospital course of a cardiac transplant recipient. QRS voltage is the sum of leads Z, ZZ, IZI, V,, and V6. The solid arrows indicate treatment with 250 pg, of actinomycin D; the cross-hatched arrow, treatment with 100 pg. (APC's = atrial premature contractions; PAT = paroxysmal atrial tachycardia; ALG = antilymphocyte globulin.) TABLE 4. INCIDENCE OF DIAGNOSTIC FINDINGS IN ACUTE REJECTION Finding Electrocardiographic QRS voltage decrease Axis shift Arrhythmias T wave inversion ST depression Clinical Gallop sounds Decreased precordial impulse Hypo tension Right ventricular lift Fever Ultrasound echocardiographic Left ventricle thickness increased Right ventricular diameter increased Serological Increase in SGOT Increase in LDH Increase in LDH fraction 1 Percent of Episodes VOL. 12, NO. 2, AUGUST,

10 GRIEPP ET AL. Comment On the basis of our 16 patient-years of experience in cardiac transplantation, we believe that several points merit emphasis. The phenomenon of acute cardiac rejection is an episodic one that occurs with maximal frequency and severity during the first two months following operation. During this period, extremely close surveillance of graft function is necessary to detect and treat rejection episodes as early as possible. If the patient survives this critical period without evidence of ongoing rejection or serious infectious complications, he has an 80% chance of surviving one or more years following operation [6]. It is noteworthy that within this series, mismatching for one, two, or three HLA antigens did not preclude long-term survival; indeed, no correlation of survival and rejection history with histocompatibility matching is yet apparent. In our first few patients the diagnosis of allograft rejection was rarely made until unequivocal evidence of congestive heart failure or low cardiac output appeared. As experience accumulated, however, it became evident that a number of subtle findings such as electrocardiographic voltage decrease, appearance of arrhythmias, and gallop rhythm frequently appeared before more obvious evidence of cardiac dysfunction. Prompt initiation of immunosuppressive therapy not only reversed these findings but also prevented the development of severe graft dysfunction. The smoother postoperative course and long-term survival of the patients treated on the basis of the factors described in this communication validate their usefulness. A balance must be struck, however, between making an early diagnosis and establishing the diagnosis with certainty, in order to avoid unnecessary administration of toxic immunosuppressive agents. Despite, or perhaps because of, the numerous aspects of cardiac function that are monitored, arriving at a diagnosis of rejection is not always straightforward. In establishing the diagnosis, it has been found useful to place diagnostic findings in two groups. The first includes findings that may have been found to accompany acute rejection but may also recur as a result of other factors. Included in this group are diminution in QRS voltage, right shift of the electrical axis, ST-T wave changes, changes in serum enzymes, and mild hypotension. Although each of these factors may be present because of circumstances other than graft rejection, the coincident occurrence of several increases the likelihood that rejection is present. In some patients a diagnosis of rejection has been made on the basis of these criteria alone. A diagnosis of cardiac rejection can be made with greater certainty, however, if one or more findings from a second group are present. This confirmatory group includes observations that may not occur with every rejection episode but do not appear secondary to any other causes in this setting. Included are arrhythmias, the appearance of diastolic filling sounds, 122 THE ANNALS OF THORACIC SURGERY

11 Acute Rejection of Allografted Human Heart a significant increase in left ventricle thickness or right ventricular diameter as determined by ultrasound, the presence of a right ventricular lift, or a significant decrease in total precordial activity. Unequivocal signs of low cardiac output or congestive heart failure, such as cool, moist extremities, severe hypotension, a soft pulse, decreased urine output, fluid accumulation, hepatomegaly, dyspnea, and orthopnea, are infrequently seen but are also included in this latter group. The fact that most of these findings are based on clinical evaluation reemphasizes the importance of a careful examination of the heart at least twice daily. A concept of the pathology of cardiac rejection and the resulting changes in cardiac physiology is helpful in understanding the significance of clinical and laboratory findings. In the dog and in man, the pathological findings in early rejection consist primarily of perivascular and interstitial infiltration with mononuclear cells and edema fluid as well as mild vascular changes consisting of endothelial cell swelling and slough with platelet and fibrin deposition. Grossly, the myocardium is red and rubbery with increases in the thickness of the ventricular walls [Z, 81. The primary physiological effect of these changes is myocardial restriction with decreased ventricular compliance, resulting in diastolic filling sounds, elevated venous pressure, and increased thickness of the ventricular wall as measured by ultrasound echocardiography. In man, clinical and electrocardiographic evidence suggests that some early indications of acute rejection are in reality subtle signs of right ventricular failure. A right shift of the electrical axis occurs as well as an increase in right ventricular diameter. Fluid accumulation and hepatomegaly frequently precede any manifestations of left ventricular failure. It has been suggested that the thin right ventricle may be more sensitive to rejection injury [El, but a more likely explanation is that in man, the work load imposed on the transplanted right ventricle is relatively greater than that on the left ventricle owing to the substantial degree of elevated pulmonary vascular resistance that is almost invariably present in patients who are candidates for cardiac transplantation. Histopathological studies of rejected canine and human hearts reveal marked mononuclear cell infiltration [21 in conduction tissue, which may in part account for the arrhythmias frequently seen during rejection. An additional factor may be increased levels of circulating catecholamines that are present secondary to mild diminution in cardiac output. With increasing experience in the treatment of rejection, it has become apparent that antilymphocyte globulin is a potent immunosuppressive agent in this setting and should be regarded as a primary modality of antirejection therapy rather than as an adjunct. Its lack of toxicity to bone marrow and liver makes it a particularly useful agent for treating rejection episodes during periods when leukopenia or hepatic dysfunction militate against the use VOL. 12, NO. 2, AUGUST,

12 GRIEPP ET AL. of actinomycin D or increased azathioprine. To date, 2 episodes of acute rejection have been successfully reversed with antilymphocyte globulin alone. Heparinization during acute rejection episodes has been shown by Kahn and his associates [7] to prolong the survival of porcine heterotopic cardiac allografts. Pathological examination of rejected canine as well as human hearts demonstrates deposition of platelets and fibrin throughout the microvasculature [2, 81. It seems reasonable that heparin may retard or prevent this deposition, and we now use systemic heparinization for 5 to 7 days during rejection episodes. The successful treatment of 95% of all rejection episodes sounds an optimistic note that is not entirely warranted since it does not take into account a significant number of infectious and other serious complications [13]. Continuing efforts are necessary to refine the criteria for diagnosing rejection and for determining the minimal drug dosages necessary to reverse these episodes. Finally, it must be noted that all the indexes of graft rejection herein enumerated are related to changes in graft performance. Although some tentative beginnings have been made [5], the other half of the picturenamely, the monitoring of host immunological activity-remains largely unexplored. It is perhaps in this area that the next advances in diagnosing allograft rejection will be made. References 1. Barnard, C. N. The operation. S. Afr. Med. J. 41:1271, Bieber, C. P., Stinson, E. B., Shumway, N. E., Payne, R., and Kosek, J. Cardiac transplantation in man: Cardiac allograft pathology. Circulation 41:753, Bodmer, W., Tripp, M., and Bodmer, J. Application of a Fluorochromatic Cytotoxicity Assay to Human Leukocyte Typing. In E. S. Curtoni, P. L. Mattiuz, and R. M. Tosi (Eds.), Histoconzpatibzlity Testing. Copenhagen: Munksgaard, P Cutler, S. J., and Ederer, F. Maximum utilization of the life table method in analyzing survival. J. Chronic Dis. 8:699, Ellis, R. J., Lillehei, C. W., and Zabriskie, J. B. The significance of heartbinding antibody in human cardiac rejection. Ann. Thorac. Surg. 10:432, Griepp, R. B., Stinson, E. B., Dong, E., Jr., Clark, D. A., and Shumway, N. E. Determinants of operative risk in human heart transplantation. Amer. J. Surg. In press. 7. Kahn, D. R., Carr, E. A., Oberman, H. A., Kirsh, M. M., Dufek, J. H., Moores, W. Y., Carroll, M., Gago, O., and Sloan, H. Effect of anticoagulants on the transplanted heart. J. Thorac. Cardiovasc. Surg. 60:617, Kosek, J. C., Hurley, E. J., and Lower, R. R. Histopathology of orthotopic canine cardiac homografts. Lab. Invest. 19:97, Lower, R. R., Dong, E., Jr., and Glazner, F. S. Electrocardiograms of dogs with heart homografts. Circulation 33:455, Lower, R. R., Dong, E., Jr., and Shumway, N. E. Long-term survival of cardiac homografts. Surgery 58: 110, THE ANNALS OF THORACIC SURGERY

13 Acute Rejection of Allografted Human Heart 11. Lower, R. R., Dong, E., Jr., and Shumway, N. E. Suppression of rejection crises in the cardiac homograft. Ann. Thorac. Surg. 1:645, Schroeder, J. S., Popp, R. L., Stinson, E. B., Dong, E., Jr., Shumway, N. E., and Harrison, D. C. Acute rejection following cardiac transplantation: Phonocardiographic and ultrasound observations. Circulation 40: 155, Stinson, E. B., Bieber, C. P., Griepp, R. B., Clark, D. A., Shumway, N. E., and Remington, J. S. Infectious complications after cardiac transplantation in man. Ann. Intern. Med. 74:22, Discussion DR. C. WALTON LILLEHEI (New York, N.Y.): I believe that this excellent paper and the superb results described by Dr. Griepp in the treatment of rejection represent a historic turning point in the brief but rather turbulent history of cardiac transplantation. Personally, I have never had any doubt about the feasibility of cardiac replacement for that small but important group of patients who have terminal irreversible heart failure. Certainly, the results reported today fully justify that faith. It is pleasing to me likewise to see this decisive comeback after several years of rather dismal survival results. Undoubtedly, cardiac transplantation will now assume its proper role in our therapeutic armamentarium. I think that it is particularly appropriate to have this significant advance come from Dr. Shumway and his Stanford group, because they were the ones who first worked out the methods for cardiac transplantation and applied them successfully in animals some ten years ago. I think, too, that another point is worthy of emphasis in this presentation-something that has come up many, many times in the past and will be repeated many, many times in the future-since it portrays a most instructive lesson. That is the fact that success did not come to this group because they sat back in their armchairs puffing on their pipes and waiting for someone to discover a cure for rejection, as many critics have stridently recommended. This accomplishment came about because of their hard, dedicated work in the clinical arena-on the firing line, daily taking care of patientsbuttressed with appropriate, well-conceived laboratory work, and finally topped off with a great deal of determination. The last point I should like to make today is, the fact that the authors have been 95% successful in their treatment of rejection is indeed wonderful news! However, it may lead to unwarranted optimism in the minds of some who fail to appreciate that they have achieved this success with entirely conventional methods-the ECG, auscultation, clinical examination-because they virtually lived with their patients. Not all will find that feasible. So, for the future certainly we do need more sensitive indexes for monitoring allograft rejection, ones that do not depend upon mechanical damage to the heart as do all these conventional methods. At present, there is considerable optimism that this goal can be realized. Some may recall that last VOL. 12, NO. 2, AUGUST,

14 GRIEPP ET AL. year, at this meeting, my associates Dr. Ellis and Dr. Zabriskie and I presented our results (Ann. Thoruc. Surg. 10:432, 1970) with tracing of circulating antibody as an earlier and more reliable test for detecting impending rejection of cardiac allografts. Considerable additional work has been done this year which I can summarize by stating that the test results have been confirmed not only in man but have been reproduced consistently in animals (rabbit and dog). Also, it is encouraging that at least two other groups have confirmed these findings. I refer to the work of Goldman and his associates in Toronto and Rossen and colleagues in Houston. So while these current results in the detection and treatment of rejection are excellent, for the immediate future I believe that we can look forward to even more sophisticated tests, based upon host immunological activity, as the next important advance in this field. DR. GRIEPP: It is a great honor to have had Dr. Lillehei discuss this paper. I should like to emphasize one of his points, namely, that techniques for monitoring host immunological activity are badly needed in this field. At present we are detecting very subtle changes in graft function as an index of rejection, while the wide variations in host reactivity are only crudely estimated. NOTICE FROM THE AMERICAN BOARD OF THORACIC SURGERY The 1972 spring examinations will be given as follows: Written Examination. To be held at various centers throughout the country on February 11, Final date for filing ap lication is December 1, Oral Examination. To be given April 2 i; -30, 1972, in Los Angeles, Calif. Final date for filing application is December 1, Effective January 1, 1972, the fees will be as follows: registration fee, $50; examination fee, $350; and reexamination fee, $250. Please address all communications to the American Board of Thoracic Surgery, Inc., East Seven Mile Road, Detroit, Mich THE ANNALS OF THORACIC SURGERY