Charles P. Bieber

Cardiac Transplantation in Man VII. Cardiac Allograft Pathology

To date, 12 of 18 patients receiving cardiac allografts at the Stanford Medical Center have died. Five of these died with some degree of graft failure resulting from rejection injury. The remaining seven demonstrated some morphologic evidence of rejection, but death was due to other causes including pulmonary hypertension in two, hemorrhage and sepsis in one, infection in two, cerebral embolism in one, and hepatic failure in one. Acute rejection injury was defined in 10 allografts, accelerated acute rejection in one, and chronic rejection in nine.The clinical signs of allograft rejection and their morphologic correlates were essentially as predicted from the study of orthotopic canine cardiac allografts. The clinical features and most of the anatomic lesions of acute rejection were usually reversible by current methods of immunosuppressive therapy. Chronic rejection, manifested primarily by obliterative intimal proliferation in coronary arteries, was present in most allografts obtained from patients surviving at least 1 month. Its severity was apparently not related to the quality of the host-donor leukocyte antigen match, and it was not routinely detectable clinically. This intimal thickening may limit long survival of patients undergoing cardiac transplantation.

Defective in vitro suppressor cell function in idiopathic congestive cardiomyopathy.

Because abnormalities of the immune system may be involved in the pathogenesis of idiopathic congestive cardiomyopathy (ICCM), we studied suppressor cell function in patients with ICCM. Previously described in vitro techniques were modified for optimal demonstration of concanavalin A (con A)-inducible suppressor activity by peripheral blood mononuclear cells (PBM). Baseline responses in the mixed leukocyte reaction (MLR) were similar for PBM from 16 normal subjects, eight patients with end-stage coronary artery disease (CAD), and 18 patients with ICCM. In the presence of autologous, con A-treated PBM, MLR responses were significantly suppressed for normals (geometric mean disintegrations/min decreasing from 36,308 to 4677; p < 0.001) and for CAD patients (25,703 decreasing to 50l1;p < 0.001). In contrast, autologous, conc A-treated PBM from patients with ICCM failed to suppress MLR responses (30,902 increasing to 44,688; p < 0.005). Similar results were observed in mitogen stimulation experiments. Con A-treated PBM from a normal subject suppressed the MLR response of PBM from an ICCM patient. The failure of con A-treated PBM to inhibit in vitro immune responses may reflect an in vivo defect in suppressor cell function in patients with ICCM.

Infectious Complications After Cardiac Transplantation in Man

Abstract Infectious complications developed postoperatively in 12 of 20 patients undergoing cardiac transplantation. In five, infection was considered to have caused or contributed directly to deat...

TREATMENT OF CADAVERIC RENAL TRANSPLANT RECIPIENTS WITH TOTAL LYMPHOID IRRADIATION, ANTITHYMOCYTE GLOBULIN, AND LOW-DOSE PREDNISONE

The ability of preoperative total lymphoid irradiation (TLI) to reduce the need for chronic immunosuppression after cadaveric renal transplantation was examined in 25 recipients who were given a brief course of antithymocyte globulin (ATG) postoperatively with daily low-dose prednisone (0.1-0.2 mg/kg) as the sole maintenance immunosuppressive drug. Patients were selected for the study on the basis of their low levels of cytotoxic antibodies. Grafts were not HLA-matched, and the mean interval between completion of TLI and transplantation was 9 days. During an observation period of up to 25 months, 2 grafts were lost because of rejection. There were two deaths due to disseminated viral infections and two to late cardiovascular complications. At the last observation point, the mean serum creatinine of the 19 patients with functioning grafts was 1.5 mg/dl, and the mean dose of prednisone was 10.2 mg/day. 10 of these patients did not have a rejection episode. Comparison of patients given TLI with a group given cyclosporin at the same institution showed similar graft survival but better graft function in the TLI group.

Use of rabbit antithymocyte globulin in cardiac transplantation. Relationship of serum clearance rates to clinical outcome.

SUMMARY Serum rabbit globulin (RG) clearance rates were determined in 30 consecutive cardiac transplant recipients by radioimmune assay of serum RG levels after completion of an initial postoperative course of rabbit anti-human antithymocyte globulin (RATG). Twenty patients, who exhibited rapid RG elimination rates (average half-life, 1.6 days), had a rejection onset time of 16.2 days, rejectition frequency of 3.9 episodes/100 patient days, and a 1-year survival rate of 59%, respectively, as compared with 28.3 days, 1.9 episodes/100 patients days, and 80%, respectively, for the 10 patients with more prolonged initial RG elimination rates (average half-life, 11.4 days). Nineteen patients received one or more repeat courses of RATG. In 16 of these a progressive increase in RG half-life during subsequent RATG administration could be demonstrated. A close correlation was observed between total RATG doses given in the initial course and peak serum levels of RG obtained (r = 0.82) and between onset of rejection and initial t1/2 RG (r = 0.69). This latter correlation was improved by the elimination of one of the 30 patients (r = 0.81) or by considering only those patients treated from a single RATG batch (r = 0.85; n = 15). No significant relationship was detected between any of the parameters assayed and (1) total RATG dose, or (2) rosette inhibition titers of RATG administered. Survival and rejectin parameters of the first 30 patients receiving RATG were compared with the previous 20 receiving equine antithymocyte globulin; these 50 comprising the entire population in which rejection was confirmed by cardiac biopsy. Rejection onset was 20 versus 12 days, rejection frequency was 3.1 versus 5.0 episodes/100 patient days, and graft survival at 1 year was 66 versus 41% for the RATG-equine antithymocyte globulin-treated patients, respecctively. From these data it was concluded that (1) RATG administration favorably affects transplantation outcome; (2) RATG half-life, as reflected by RG clearance rates, was the most important variable governing RATG effectiveness, (3) variation in rosette inhibition titers within RATG batches made in the same fashion from large rabbit pools were of minimal clinical importance; and (4) monitoring of serum RG levels provided a necessary and rational basis for effective modulation of immunosuppressive therapy.

The status of cardiac transplantation, 1975.

Since December 1967, 263 human cardiac transplant operations have been performed throughout the world. Eighty-two of these were performed at Stanford University Medical Center. In 1974, 27 such operations were performed, 15 at Stanford. Survival rates for the entire Stanford series are 48% at one year and 25% at three years; survival rates at one and three years for patients surviving the first three critical months after transplantation are 77% and 42%, respectively. Recipients under the age of 55 years, with New York Heart Association Class IV cardiac disability, are selected for transplant procedures according to criteria dictated by experience over the past seven years. A routine immunosuppressive regimen for organ transplantation, incorporating prednisone, azathioprine, and antithymocyte globulin is employed early postoperatively, and prednisone and azathioprine are used for indefinite maintenance therapy. Acute cardiac graft rejection in nearly all recipients is diagnosed by clinical signs, electrocardiographic changes, and percutaneous transvenous endomyocardial biopsy. Ninety-five percent of acute rejection episodes are reversible with appropriate immunosuppressive treatment, but infectious complications are common and have accounted for 56% of all postoperative deaths. The Stanford experience in cardiac transplantation has demonstrated the potential therapeutic value of this procedure. Maximum survival now extends beyond five years. Satisfactory graft function has been documented in long-term surviving patients, the majority of whom have enjoyed a high degree of social and physical rehabilitation.

Survival of primates following orthotopic cardiac transplantation treated with total lymphoid irradiation and chemical immune suppression

Fractionated total lymphoid irradiation (TLI) has been used for attempts at induction of a donor-specific tolerant-like state in allograft recipients and for immunosuppressive effects. Cyclosporin A (Cy A) has been shown to suppress rejection of organ grafts in many species including man. The present study was designed to test the effectiveness of TLI in combination with either CY A or rabbit anticynomolgus thymocyte globulin (ATG) and azathioprine. Thirty-one orthotopic cardiac allografts were performed using surface cooling and total circulatory arrest in outbred cynomolgus monkeys. TLI was administered preoperatively in fractions of 100 rad until a total of 600 or 1800 rad was achieved. Cy A was administered 17 mg/kg/day. All treatment groups demonstrated extended survival. Myocardial biopsies as early as 4 weeks were consistent with mild rejection in all treatment groups. No significant synergistic effect upon survival could be demonstrated utilizing TLI plus Cy A when compared with using Cy A alone. TLI (1800 rad) plus ATG and azathioprine was associated with a high incidence of early death attributable to leukopenia and infection. Cy A alone or in combination with TLI was associated with the development of lymphoid malignancy.

Pathology of the Conduction System in Cardiac Rejection

Correlation of electrocardiographic abnormalities occurring postoperatively with lesions of the conduction system found at autopsy was done in 20 dogs which had received cardiac homografts. The incidence of arrhythmias closely paralleled the severity of rejection injury found within the heart and specifically within the conduction system. Severe pathological changes in the conduction system (grade D) were uniformly associated with arrhythmias. These disturbances, as well as decrease in electrocardiographic voltage, have consistent anatomic correlates in acute rejection of cardiac homografts and are of primary importance in the clinical diagnosis of acute rejection.

Long-term survival and function after cardiac transplantation.

Cardiac transplantation now permits prolonged survival for some patients with otherwise fatal heart disease. This report summarizes the hemodynamic and clinical characteristics of 25 patients who have survived five or more years after cardiac replacement. The average age of the patients at the time of operation was 40 ± 10 (SD) years; 23 were men. The average duration of survival is 6.7 years, and ranges from five to 10.5 years. Annual cardiac catheterization and clinical follow-up were performed to assess systolic cardiac function, coronary anatomy, and quality of extended rehabilitation. We found that among these long-term survivors, the left ventricular ejection fraction remained constant (0.59 ± 0.08 one year postoperatively, 0.57 ± 0.09 at most recent study, p = ns). Segmental wall motion measured by fluoroscopic examination of midwall intramyocardial markers also remained normal. Four of 21 (19%) patients with complete longitudinal studies developed significant graft coronary artery disease. Clinical evaluation revealed that the long-term survivors required fewer than one unscheduled admission to the hospital per year. Sixteen of 25 patients (64%) were gainfully employed, and 22 of 25 (88%) enjoyed substantial benefit in terms of extended rehabilitation. These 25 long-term survivors represent 27% of 92 patients transplanted between 1968 and 1975. The actuarial survival rate at five years, of patients transplanted since 1975, is 40 ± 5%. This increase in survival rate reflects improved techniques of early postoperative management. Cardiac transplantation now offers prolonged survival with good quality of life for selected patients with terminal heart disease

Human Heart Transplantation: Current Status

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.