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Objectives: To evaluate outcomes after heart retransplantation., Methods: From January 6, 1968, to June 2019, 123 patients (112 adult and 11 pediatric patients) underwent heart retransplantation, and 2092 received primary transplantation at our institution. Propensity-score matching was used to account for baseline differences between the retransplantation and the primary transplantation-only groups. Kaplan-Meier survival analyses were performed. The primary end point was all-cause mortality, and secondary end points were postoperative complications., Results: Retransplantation recipient age was 39.6 ± 16.4 years, and donor age was 26.4 ± 11.2 years. Ninety-two recipients (74.8%) were male. Compared with recipients who only underwent primary heart transplantation, retransplantation recipients were more likely to have hypertension (44/73.3% vs 774/53.3%, P = .0022), hyperlipidemia (40/66.7% vs 447/30.7%, P < .0001), and require dialysis (7/11.7% vs 42/2.9%, P = .0025). The indications for heart retransplantation were cardiac allograft vasculopathy (32/80%), primary graft dysfunction (6/15%), and refractory acute rejection (2/5%). After matching, postoperative outcomes such as hospital length of stay, severe primary graft dysfunction requiring intra-aortic balloon pump or extracorporeal membrane oxygenation, cerebral vascular accident, respiratory failure, renal failure requiring dialysis, and infection were similar between the 2 groups. Matched median survival after retransplantation was 4.6 years compared with 6.5 years after primary heart transplantation (log-rank P = .36, stratified log-rank P = .0063)., Conclusions: In this single-center cohort, the unadjusted long-term survival after heart retransplantation was inferior to that after primary heart transplantation, and short-term survival difference persisted after propensity-score matching. Heart retransplantation should be considered for select patients for optimal donor organ usage., (Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Aims: Since 1968, heart transplantation has become the definitive treatment for patients with end-stage heart failure. We aimed to summarize our experience in heart transplantation at Stanford University since the first transplantation performed over 50 years ago., Methods and Results: From 6 January 1968 to 30 November 2020, 2671 patients presented to Stanford University for heart transplantation, of which 1958 were adult heart transplantations. Descriptive analyses were performed for patients in 1968-95 (n = 639). Stabilized inverse probability weighting was applied to compare patients in 1996-2006 (n = 356) vs. 2007-19 (n = 515). Follow-up data were updated through 2020. The primary endpoint was all-cause mortality. Prior to weighting, recipients in 2007-19 vs. those in 1996-2006 were older and had heavier burden of chronic diseases. After the application of stabilized inverse probability weighting, the distance organ travelled increased from 84.2 ± 111.1 miles to 159.3 ± 169.9 miles from 1996-2006 to 2007-19. Total allograft ischaemia time also increased over time (199.6 ± 52.7 vs. 225.3 ± 50.0 min). Patients in 2007-19 showed superior survival than those in 1996-2006 with a median survival of 12.1 vs. 11.1 years., Conclusion: In this half-century retrospective descriptive study from one of the largest heart transplant programmes in the USA, long-term survival after heart transplantation has improved over time despite increased recipient and donor age, worsening comorbidities, increased technical complexity, and prolonged total allograft ischaemia time. Further investigation is warranted to delineate factors associated with the excellent outcomes observed in this study., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

We describe a simple and reproducible donor heart procurement technique in sequential steps. A detailed understanding of procurement and organ preservation techniques should be an essential part of a heart transplant training program.

Background: Allosensitization has been shown to negatively affect post-heart transplant (HTx) survival even with a negative crossmatch. Whether allosensitization related to mechanical circulatory support (MCS) is associated with worse post-HTx survival remains controversial., Methods: Adult HTx recipients listed in the United Network for Organ Sharing database (July 2006-December 2012) were identified. Multivariate Cox regression assessed the effect of allosensitization on survival. Propensity matching was performed to compare patients who were and were not allosensitized. Kaplan-Meier survival analysis compared matched and unmatched patients in the MCS and medically managed cohorts., Results: We identified 11,840 HTx recipients, of whom 4,167 had MCS. MCS was associated with allosensitization in multivariate logistic regression. Each different MCS device was associated with worse post-HTx survival in multivariate Cox regression. Allosensitization did not predict post-HTx mortality in MCS patients (hazard ratio, 1.07; 95% confidence interval, 0.89-1.28; p = 0.48. Among patients without MCS, allosensitization was associated with post-HTx mortality (hazard ratio, 1.19; 95% confidence interval, 1.03-1.39; p = 0.02). Kaplan-Meier analysis revealed equivalent survival in unmatched and matched cohorts when MCS patients who were allosensitized were compared with non-allosensitized MCS patients. Among non-MCS patients, allosensitization was associated with worse survival in unmatched and matched analysis., Conclusions: MCS was associated with allosensitization. For MCS patients, allosensitization did not independently predict worse post-HTx outcome. Among non-MCS patients, allosensitization was associated with worse post-HTx survival. Allosensitization appears to be a heterogeneous process influenced by presence of MCS., (Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Combined heart-liver transplant (HLT) is a viable therapy for patients with concomitant end-stage heart and liver failure. Using data from the United Network for Organ Sharing database, we examined the cumulative incidences of transplant and mortality in waitlisted candidates for HLT, isolated heart transplant (HRT) and isolated liver transplant (LIV) in the Model for End-Stage Liver Disease era. The incidence of waitlist mortality was higher in HLT candidates than in HRT candidates (p = 0.001, 26% vs. 12% at 1 year) or LIV candidates (p = 0.005, 26% vs. 14% at 1 year). These differences persisted after stratifying by disease severity. Posttransplant survival was not significantly different between HLT and HRT recipients or between HLT and LIV recipients. In a multivariable model, undergoing HLT was associated with enhanced survival for HLT candidates (hazard ratio, 0.41; confidence interval, 0.21-0.79; p = 0.008), but undergoing HRT alone was not. Interestingly, 90% of HLT recipients were allocated an organ locally, compared to 60% of HRT candidates and 73% of LIV candidates (both p < 0.001). These data suggest that the current cardiac and liver allocation systems may underestimate the risk of death for patients with concomitant end-stage heart and liver failure on the HLT waitlist., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

In patients with end-stage heart failure (ESHF) who are candidates for isolated heart transplant (HRT), dialysis dependence (DD) is considered an indication for combined heart-kidney transplantation (HKT). HKT remains controversial in ESHF transplant candidates with nondialysis-dependent renal insufficiency (NDDRI). Using United Network for Organ Sharing data, we examined the cumulative incidences of transplant and mortality in patients with DD and NDDRI waitlisted for HKT or HRT. In all groups, 3-month waitlist mortality was dismal: 31% and 21% for HRT- and HKT-listed patients with DD and 12% and 7% for HRT- and HKT-listed patients with NDDRI. Five-year posttransplant survival was improved in HKT recipients compared with HRT recipients for both patients with DD (73% vs. 51%, p<0.001) and NDDRI (80% vs. 69%, p<0.001). Likewise, multivariable analysis associated HKT with better outcomes than HRT in HKT-listed patients, although both improved survival. These data argue strongly for HKT in ESHF transplant candidates with DD. However, in patients with NDDRI, HKT must be weighed against the possibility of renal recovery with isolated HRT. Whether HRT (followed by a staged kidney transplant in patients who do not recover renal function after HRT), as opposed to HKT, maximizes organ benefit for patients with NDDRI and ESHF requires assessment. Nevertheless, given their dismal waitlist outcomes and excellent posttransplant results, we suggest that patients with DD and NDDRI with ESHF be considered for early listing and transplant., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Allosensitization in potential orthotopic heart transplant recipients is evaluated with the panel reactive antibody assay. Sensitized patients have prolonged wait times and increased waitlist and post-transplant mortality. Although low panel reactive antibody activity at the time of orthotopic heart transplantation is associated with improved outcomes, literature regarding the survival benefit of a panel reactive antibody reduction in the sensitized orthotopic heart transplant recipient remains limited., Methods: Adult orthotopic heart transplant recipients listed in the United Network for Organ Sharing database (October 1, 1987, to June 29, 2004) were stratified by peak panel reactive antibody activity and whether a substantial decline from peak to most recent panel reactive antibody activity occurred before transplant. Propensity matching adjusted for differences in recipient and donor characteristics. Graft survival was assessed with Kaplan-Meier analysis. Cox proportional hazards regression determined predictors of graft survival., Results: Pretransplant characteristics differed between sensitized patients who had a substantial decline in panel reactive antibody activity and those who did not. Propensity matching compensated for these differences. Kaplan-Meier survival analysis of matched groups showed that the median graft survival was 120 months in patients with a significant panel reactive antibody reduction and 103 months in patients with a trivial reduction (P = .007, log-rank). In Cox proportional hazards modeling, a significant reduction in panel reactive antibody activity had an independent protective effect on graft survival (hazard ratio, 0.88; confidence interval, 0.80-0.96; P = .006)., Conclusions: Sensitized patients who had a substantial reduction in panel reactive antibody activity had an associated decline in the incidence of graft failure compared with those without a panel reactive antibody activity reduction. These results support efforts to reduce panel reactive antibody activity before orthotopic heart transplantation in patients with high panel reactive antibody activity., (Copyright © 2013. Published by Mosby, Inc.)

Although invasive candidiasis (IC) causes significant morbidity and mortality in patients who undergo heart, lung, or heart-lung transplantation, a systematic study in a large cohort of thoracic organ transplant recipients has not been reported to date. Clinical and microbiological data were reviewed for 1305 patients who underwent thoracic organ transplantation at Stanford University Medical Center between 1980 and 2004. We identified and analyzed 76 episodes of IC in 68 patients (overall incidence 5.2% per patient).The incidence of IC was higher in lung (LTx) and heart-lung transplant (HLTx) recipients as compared with heart transplant (HTx) recipients (risk ratio [RR] 1.7, 95% confidence interval [CI] 1.1-2.7).The incidence of IC decreased over time in all thoracic organ transplant recipients, decreasing from 6.1% in the 1980-1986 time period to 2.1% in the 2001-2004 era in the HTx recipients, and from 20% in the 1980-1986 period to 1.8% in the 2001-2004 period in the LTx and HLTx recipients.The most common site of infection differed between the HTx and LTx cohorts, with bloodstream or disseminated disease in the former and tracheobronchitis in the latter. IC in the first year after transplant was significantly associated with death in both HTx (RR 2.9, 95% CI 1.8-4.6, P=0.001) and LTx and HLTx patients (RR 3.0, 95% CI 1.9-4.6, P<0.001). The attributable mortality from IC decreased during the 25-year period of observation, from 36% to 20% in the HTx recipients and from 39% to 15% in the LTx and HLTx recipients. There were a significant number of cases caused by non-albicans Candida species in all patients, with a trend toward higher mortality in the HTx group. In conclusion, the incidence and attributable mortality of IC in thoracic organ transplant recipients has significantly declined over the past 25 years.The use of newer antifungal agents for prophylaxis and treatment, the decrease in the incidence of cytomegalovirus disease, and the use of more selective immunosuppression, among other factors, may have been responsible for this change.

Human heart transplantation started 40 years ago. Medical records of all cardiac transplants performed at Stanford were reviewed. A total of 1446 heart transplantations have been performed between January 1968 and December 2007 with an increase of 1-year survival from 43.1% to 90.2%. Sixty patients who were transplanted between 1968 and 1987 were identified who survived at least 20 years. Twenty-year survivors had a mean age at transplant of 29.4 +/- 13.6 years. Rejection-free and infection-free 1-year survivals were 14.3% and 18.8%, respectively. At their last follow-up, 86.7% of long-term survivors were treated for hypertension, 28.3% showed chronic renal dysfunction, 6.7% required hemodialysis, 10% were status postkidney transplantation, 13.3% were treated for diabetes mellitus, 36.7% had a history of malignancy and 43.3% had evidence of allograft vasculopathy. The half-life conditional on survival to 20 years was 28.1 years. Eleven patients received a second heart transplant after 11.9 +/- 8.0 years. The most common causes of death were allograft vasculopathy (56.3%) and nonlymphoid malignancy (25.0%). Twenty-year survival was achieved in 12.5% of patients transplanted before 1988. Although still associated with considerable morbidity, long-term survival is expected to occur at much higher rates in the future due to major advances in the field over the past decade.

Background: Several studies have shown a detrimental effect of female donor gender on the survival of solid-organ transplant recipients, including heart, kidney and liver. We evaluated our own experience in heart transplantation in the cyclosporine era, since 1980, to determine the effect of donor gender on survival., Methods: We retrospectively reviewed 869 consecutive patients who underwent primary heart transplantation at Stanford University Medical Center between December 1980 and March 2004. Actuarial life-table data were calculated for survival and freedom from rejection and compared between groups. Multivariate Cox proportional hazard analysis was used to identify predictors of reduced long-term survival., Results: One-year mortality in male recipients who received a female donor heart (24%) was higher than in male recipients who received male donor heart (13%) (p = 0.009). Actuarial survival rates for male recipients at 1, 5 and 10 years were 86%, 69% and 50% (with male donor), and 76%, 59% and 45% (with female donor) (p = 0.01), respectively. Donor gender had no effect on long-term survival in male recipients < 45 years of age and female recipients. Female donor gender was identified as an independent risk factor for death by multivariate analysis, with an odds ratio of 2.3 (95% confidence interval 1.5 to 3.4, p < 0.001)., Conclusions: In heart transplantation the detrimental effect of female donor gender on recipient survival is significant but limited to male recipients > 45 years of age. These findings should be considered in the process of donor-recipient matching.

Background: It has been suggested that the modality of brain death and time from brain death until harvest impact survival and rejection after heart transplantation., Methods: Donor files from 475 adult heart-transplant recipients were examined. From these files, a total management time (time from incident leading to brain death until aortic cross clamp) was determined, and the cause of brain death was noted. Recipient characteristics, details of postoperative course, as well as survival were obtained from the Stanford University Medical Center Heart Transplantation Database., Results: Two hundred and thirty (48.4%) donors sustained traumatic injuries, 112 (23.6%) suffered a subarachnoid hemorrhage, and 102 (21.4%) died of a gunshot wound to the head. The modality of brain death did not influence medium and long-term survival. A management time longer than 72 hours was associated with poorer outcome of the heart-transplant recipients. There were significantly more treated rejection episodes in recipients whose donor sustained traumatic injuries., Conclusion: Modality of brain death does not impact survival but appears to influence rejection. Increased management time is associated with adverse survival trends in heart-transplant recipients.

Background: Advanced age has been traditionally considered a relative contraindication for heart transplantation. Older patients are now considered as potential candidates for heart transplantation. The objective of this study was to evaluate the long-term results of heart transplantation in patients older than 60 years., Methods: Between 1986 and 2001, 81 patients aged between 60 and 70 years (mean, 63 +/- 2 years) underwent heart transplantation. These patients were compared with 403 adult recipients younger than 60 years (mean, 47 +/- 11 years) who underwent transplantation during the same period., Results: Thirty-day mortality was 6% (5/81) and 6% (25/403) in the older and younger patients, respectively (P = NS). Actuarial survival at 1, 5, and 10 years was 88% +/- 4% versus 83% +/- 2%, 75% +/- 5% versus 69% +/- 2%, and 50% +/- 9% versus 51% +/- 3% in the older and younger patients, respectively (P = NS). Older patients had significantly fewer rejection episodes (P =.003). Freedom from allograft coronary artery disease at 1, 5, and 10 years was 98% +/- 2% versus 92% +/- 2%, 85% +/- 6% versus 76% +/- 3%, and 81% +/- 7% versus 68% +/- 3% (P =.1). The incidences of infectious complication, cytomegalovirus infection, and posttransplant lymphoproliferative disorder were similar between the 2 groups, but older recipients were more likely to have a nonposttransplant lymphoproliferative disorder cancer (P =.002). Age at transplantation was not identified as an independent risk factor for early and late death., Conclusion: Heart transplantation in selected patients aged 60 years and older results in survival comparable with that of younger patients. Older patients have a lower risk of rejection but an increased risk of development of a nonposttransplant lymphoproliferative disorder cancer. Advanced age per se should not be considered as an exclusion criterion for transplantation.

Background: Post-transplantation lymphoproliferative disease (PTLD) is an important source of morbidity and mortality in transplant recipients, with a reported incidence of 0.8% to 20%. Risk factors are thought to include immunosuppressive agents and viral infection. This study attempts to evaluate the impact of different immunosuppressive regimens, ganciclovir prophylaxis and other potential risk factors in the development of PTLD., Methods: We reviewed the records of 1026 (874 heart, 152 heart-lung) patients who underwent transplantation at Stanford between 1968 and 1997. Of these, 57 heart and 8 heart-lung recipients developed PTLD. During this interval, 4 different immunosuppressive regimens were utilized sequentially. In January 1987, ganciclovir prophylaxis for cytomegalovirus serologic-positive patients was introduced. Other potential risk factors evaluated included age, gender, prior cardiac diagnoses, HLA match, rejection frequency and calcium-channel blockade., Results: No correlation of development of PTLD was found with different immunosuppression regimens consisting of azathioprine, prednisone, cyclosporine, OKT3 induction, tacrolimus and mycophenolate mofetil. A trend suggesting an influence of ganciclovir on the prevention of PTLD was not statistically significant (p = 0.12). Recipient age and rejection frequency, as well as high-dose cyclosporine immunosuppression, were significantly (p < 0.02) associated with PTLD development. The prevalence of PTLD at 13.3 years was 15%., Conclusions: The overall incidence of PTLD was 6.3%. It was not altered by sequential modifications in treatment regimens. Younger recipient age and higher rejection frequency were associated with increased PTLD occurrence. The 15% prevalence of PTLD in 58 long-term survivors was unexpectedly high.

Background: Multiple episodes of rejection following cardiac transplantation have been associated with an increased incidence of coronary atherosclerosis. Total lymphoid irradiation (TLI) has been shown to be a successful treatment for persistent allograft rejection, but its effect on coronary arterial disease has yet to be evaluated., Methods: From 1987 to 1999, 40 patients required TLI for persistent or recurrent allograft rejection following heart transplantation. Each patient's (Group 1, n = 31) post-transplant coronary angiograms were examined and compared with those of a control group (Group 2, (n = 32) matched for time of transplantation. Degree of coronary stenosis was assessed on a 6-point scale. All patients received induction therapy (rabbit anti-thymocyte globulin or OKT3) and standard triple immunosuppressive therapy. TLI (80 cGy x 10 fractions) was used for the treatment of recurrent or persistent rejection on the basis of clinical indications. Actuarial survival, number and treatment of rejection episodes, and severity of coronary artery disease were compared in each group., Results: Recipient gender, age, race and cytomegalovirus (CMV) status at time of transplant, along with donor gender, CMV status and graft ischemia time, were similar in both groups. Group 1 donor age was younger than that of Group 2 (22.2 +/- 11.2 vs 31.5 +/- 13.6 years, p = 0.004), and the indication for surgery in Group 1 patients was more likely to be ischemic heart disease (15 of 31 vs 6 of 32, p = 0.02). Mean follow-up was 5.7 +/- 3.5 years in Group 1 vs 6.9 +/- 3.8 in Group 2 (p = NS). Group 1 had more rejection episodes (4.4 +/- 2.2 vs 2.3 +/- 2.0, p = 0.0002) and more steroid treatments (9.78 +/- 4.0 g vs 5.14 +/- 4.7 g, p < 0.0001), but less coronary artery disease compared with Group 2 (p = 0.035)., Conclusions: Despite multiple episodes of rejection, patients treated with TLI after cardiac transplant appear to develop less coronary atherosclerosis than appropriately matched controls.

The Novacor left ventricular assist system is an implantable, electrically powered, wearable system that has been successfully used as a bridge to transplant since 1984. The pump is placed anterior to the left posterior rectus sheath with the percutaneous drive line positioned in the right lower abdominal wall. The seamless polyurethane blood sac is compressed by two solenoid-driven pusher plates. The inflow and outflow valves are porcine prostheses. The use of wearable external power packs facilitate patient mobility and rehabilitation before transplantation and may provide long-term support to selected patients as an alternative to transplantation.

Background: The experience with 30 years of cardiac transplantation at Stanford University Medical Center was reviewed. A total of 954 transplants were performed in 885 patients. Patients were divided into 3 groups based on immunosuppression received: group I, no cyclosporine (INN: ciclosporin) (n = 201) (January 1968-November 1980); group II, cyclosporine (n = 248) (December 1980-June 1987); and group III, cyclosporine + OKT3 (n = 436) (July 1987-March 1998)., Results: The 1-, 5-, and 10-year actuarial survivals were 68%, 41%, and 24% (group I); 80%, 57%, and 37% (group II); and 85%, 68%, and 46% (group III) (I vs II, P <.01; I vs III, P <.005; and II vs III, P <.005). The 1-, 5-, and 10-year actuarial death rates from rejection were 8%, 12%, and 14% (group I); 5%, 7%, and 7% (group II); and 2%, 5%, and 5% (group III) (I vs II, P = not significant; I vs III, P <.005; and II vs III, P <.005). The 1-, 5-, and 10-year actuarial death rates from infection were 25%, 43%, and 50% (group I); 8%, 17%, and 29% (group II); and 6%, 11%, and 16% (group III) (I vs II, P <.005; I vs III, P <.005; and II vs III, P <.05). The 1-, 5-, and 10-year actuarial death rates from graft coronary artery disease were 0%, 5%, and 13% (group I); 0%, 12%, and 19% (group II); and 1%, 6%, and 9% (group III) (I vs II, P <.01; I vs III, P <.005; and II vs III, P = not significant). There have been 69 retransplants in 67 patients with 1-, 5-, and 10-year actuarial survivals of 49%, 27%, and 15%, respectively., Conclusions: The evolution of 3 decades of experience with cardiac transplantation has resulted in improved overall survival. The incidence of rejection and of death from infection and graft coronary artery disease have decreased over time, primarily as a result of improvements in immunosuppression and in the prevention and treatment of infection. Continued advances in perioperative management and the development of more specific, less toxic immunosuppressive agents could further refine this initial experience and improve the survival and quality of life of patients after cardiac transplantation.

Background: The current critical shortage of cardiac allograft donors means that the decision to offer a patient repeat heart transplantation must be carefully considered. Since 1968, a total of 66 heart retransplantation procedures (63 first-time and three second-time) have been performed in 63 patients at Stanford., Methods: There were 52 male and 11 female patients, ranging in age from 3 to 62 years with a mean age of 41 years. Indications for retransplantation were primary allograft failure in nine patients, acute rejection in 17, graft atherosclerosis in 37, and constrictive disease in three. Six of the seventeen patients (35%) who underwent retransplantation before 1981 died in the hospital, and none are currently alive. Of the 46 patients who underwent retransplantation since 1981 treated with cyclosporine-based immunosuppression, 11 (24%) died in the hospital. Actuarial survival estimates for the whole retransplantation group at 1, 5, and 10 years were 55% +/- 8%, 33% +/- 8%, and 22% +/- 7%, respectively., Results: This survival was significantly worse (p < 0.05) than that in patients undergoing primary heart transplantation (81% +/- 2%, 62% +/- 2%, 44% +/- 13% at 1, 5, and 10 years). Those patients who underwent retransplantation for graft atherosclerosis since 1981 had a significantly better 1-year survival (p < 0.05) than those who underwent retransplantation for allograft rejection (69% +/- 10% versus 33% +/- 16%), but the 5-year survival was similar in both groups (34% +/- 11% versus 33% +/- 16%). Since 1981, actuarial freedoms from infection and rejection were 22% +/- 8% and 41% +/- 9%, respectively, at 1 year, and 7% +/- 7% and 36% +/- 9% at 5 years. Patients with cyclosporine-induced renal dysfunction (serum creatinine level of greater than 2.0 mg/dl) had a high probability of requiring postoperative dialysis and also of death after retransplantation. Three patients with significant cyclosporine-induced renal dysfunction underwent simultaneous kidney transplantation and heart retransplantation, and all were alive and well at the time this article was written. Sixteen patients were also currently alive at a mean follow-up of 44 months, and 15 were in New York Heart Association functional class I., Conclusions: We continue to list carefully selected candidates with good rehabilitation potential for heart retransplantation.

The introduction of cyclosporine into widespread clinical use has resulted in improved patient survival following cardiac transplantation. As a result of increased numbers of cardiac transplants, the inherent nephrotoxicity of cyclosporine, and prolonged patient survival, cardiac transplant recipients commonly present with renal dysfunction. In the subgroup who ultimately develop end-stage renal disease (ESRD), therapeutic options include renal transplantation. However, the clinical course associated with this treatment modality is unknown. From 1980 to 1993, 430 cardiac transplants were performed with cyclosporine-based immunosuppression at the Standard University Medical Center. Fourteen (3.3%) patients developed ESRD, requiring chronic dialysis or renal transplantation. The cause of ESRD was cyclosporine nephropathy (13/14; 93%) and glomerulonephritis (1/14; 7%). The average time interval to the development of ESRD was 82 +/- 42 months. Nine patients underwent renal transplantation. During the period of followup (38 +/- 27 months; range 6-89 months) after renal transplantation, cardiac function remained stable. There were no episodes of primary nonfunction of the renal allograft. Patient and renal allograft survival was 89% at both 1 and 3 years after renal transplant. Average serum creatinine was 1.3 +/- 0.6 mg/dl at 1 year and 1.6 +/- 0.8 mg/dl at 3 years post-transplant. The incidence of infectious complications was not statistically different when compared to that of the heart transplant controls and that of a group of cadaveric renal transplant controls (n = 20). Surprisingly, the incidence of renal allograft rejection in the heart transplant patients was 10-fold less than that of the renal transplant controls (0.006 +/- 0.02/patient-year vs. 0.062 +/- 0.05/patient-year; p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Cardiac transplantation for children with endstage heart disease has become an accepted form of therapy and is being practiced with increasing frequency and improving short-term outcome., Methods and Results: To assess the medium-term outcome of pediatric cardiac transplantation, we analyzed our experience with 72 patients under the age of 18 (range, 0.1 to 17.7 years; mean, 9 +/- 6.4 [SD]) who underwent orthotopic cardiac transplantation at Stanford University between 1977 and 1993. There were 38 male and 34 female patients. Preoperative diagnoses included congenital heart disease in 24 (33%), idiopathic cardiomyopathy in 27 (37%), viral cardiomyopathy in 12 (17%), and familial cardiomyopathy in 7 (10%) patients. Immunosuppressive management has evolved over time and has included a tapering schedule of steroids, azathioprine, rabbit antithymocyte globulin, cyclosporine in all patients after 1980, and induction with OKT3 since 1987. Operative mortality rate was 12.5 +/- 4.0% (mean +/- 70% confidence intervals). Actuarial survival estimates at 1, 5, and 10 years are 75 +/- 7.1%, 60 +/- 6.4%, and 50 +/- 8.1% (mean +/- 1 SEM), respectively. Causes of death included infection in 8 (28% of deaths), rejection in 7 (24%), graft coronary disease in 5 (17%), pulmonary hypertension in 4 (14%), and nonspecific graft failure in 2 (7%) patients. Survival rates were similar for patients over and those under age 10 years (including the infant cohort of 18 patients transplanted since 1986). Currently, there are 43 patients alive, all in New York Heart Association functional class I. Only 22 +/- 5.6% of patients were free of rejection at 1 year, but 86 +/- 5.4% were free of rejection-related death at 10 years. At 1 year, only 37 +/- 6% of patients were free from any infection, but 88 +/- 4.2% remained free of infection-related death at 5 years. Actuarial freedom from graft coronary artery disease (angiographic or autopsy proven) was 85 +/- 6.6% at 5 years and from coronary artery disease-related death was 91 +/- 4.7%., Conclusions: These data demonstrate satisfactory medium-term outcome of cardiac transplantation in selected pediatric patients with end-stage heart disease, but further progress is necessary to more effectively control rejection, infection, and graft coronary disease.

We analyzed our experience with 496 patients who underwent primary cardiac transplantation since the introduction of cyclosporine immunosuppression (Dec. 16, 1980, to Jan. 7, 1993). There were 388 male and 108 female patients. Mean recipient age was 40 +/- 16 years (range 0.1 to 70 years, median 44 years). Recipient diagnoses included coronary disease in 188, idiopathic cardiomyopathy in 196, viral cardiomyopathy in 35, and congenital heart disease in 28 patients. Donor age was 25 +/- 10 years (range 1 to 53 years, median 24 years). Graft ischemic time was 148 +/- 57 minutes (range 38 to 495 minutes, median 149 minutes). Operative mortality (hospital death) rate was 7.9% +/- 1.3% (70% confidence intervals). Multivariate logistic regression analysis revealed that (higher) pulmonary vascular resistance and gender (female) were the only independent predictors of hospital death (p < 0.05). Actuarial survival estimates for all patients at 1, 5, and 10 years are 82% +/- 1.7% (83% +/- 1.8% adult, 77% +/- 5.2% pediatric), 61% +/- 2.5% (65% +/- 2.5% adult, 64% +/- 6.6% pediatric), and 41% +/- 3.7% (40% +/- 4% adult, 54% +/- 8.6% pediatric), respectively. For 232 patients treated with triple-drug immunosuppression and induction with OKT3 since 1987, survival estimates at 1 and 5 years are 82% +/- 2.6% and 67% +/- 3.7%, respectively. Causes of death for the entire group were rejection in 29 (14% of deaths), infection in 69 (34%), graft coronary disease in 36 (18%), nonspecific graft failure in 6 (3%), malignancy in 19 (10%), stroke in 6 (3%), pulmonary hypertension in 6 (3%), and other causes in 30 (15%) patients. Actuarial freedom from rejection at 3 months, 1 year, and 5 years was 21% +/- 1.9%, 14% +/- 1.7%, and 7.2% +/- 1.5%, respectively (+/- 1 standard error of the mean). Estimates of freedom from rejection-related death at 1, 5, and 10 years were 96% +/- 1%, 93% +/- 1.4%, and 93% +/- 1.4%, respectively. Actuarial freedom from any infection at 3 months and at 1 and 5 years was 40% +/- 2.3%, 27% +/- 2.1%, and 15% +/- 2.0% and from infection-related death, 95% +/- 1.0%, 93% +/- 1.2%, and 85% +/- 1.9%, respectively. Actuarial freedom from (angiographic or autopsy proved) graft coronary artery disease at 1, 5, and 10 years was 95% +/- 1.2%, 73% +/- 2.7%, and 65% +/- 3.6% and from coronary disease-related death or retransplantation 98% +/- 0.7%, 84% +/- 2.2%, and 66% +/- 4.3%, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

To assess survival after the development of transplant coronary artery disease, annual angiography reports from 353 heart transplant recipients were reviewed. Fifty-four patients who survived beyond 1 year and in whom moderate-to-severe proximal or midvessel coronary artery disease developed were identified. Moderate-to-severe proximal or midvessel coronary disease was defined for this study as a 40% or more stenosis in 1 or more primary or secondary epicardial arteries. Actuarial survival (Kaplan-Meier) from the time of disease detection in those 54 patients was 67% at 1 year, 44% at 2 years, and 17% at 5 years. Actuarial survival was reduced proportionate to disease severity. Survival for single-vessel disease (> or = 40% stenosis) was 64% at 1 year, 36% at 2 years, and 22% at 5 years. Survival was significantly worse with triple-vessel disease (13% at 2 years; p = 0.01) and intermediate for double-vessel disease (41% at 2 years; p = 0.01). Of 19 patients who underwent retransplantation for coronary artery disease, 13 patients (68%) died at a mean of 24 +/- 20 months (range, 1 to 59), and of 15 patients from whom postmortem or angiographic data were available, 11 patients (73%) showed recurrence of significant coronary artery disease in the new graft. Identification of moderate or severe proximal or midvessel coronary disease at angiography predicts an overall mortality rate of more than 50% at 2 years. The poor survival rate in those who underwent retransplantation (around 50% at 4 years) and the high rate of redevelopment of coronary disease suggest that retransplantation should be reserved for selected candidates with angiographically severe disease, if used at all.

Seventeen infants less than 1 year of age have undergone heart (12), heart-lung (3), and lung (2) transplantation for end-stage cardiopulmonary disease. The infants undergoing heart transplantation had a mean age of 4.5 months (range, 19 days to 12 months) with the diagnosis of cardiomyopathy in 4 and congenital heart disease in 8. Four of the 8 patients (50%) had hypoplastic left heart syndrome. Actuarial survival at 1 and 2 years was 74% and compared favorably with the survival of older children at 1 and 2 years of 82% and 69%. The linearized rejection rate was less in infants as compared with children more than 1 year of age (0.61 versus 1.48 episodes per 100 patient days). In intermediate follow-up, no graft atherosclerosis has been noted. Immunosuppression has included a three-drug protocol of cyclosporine, azathioprine, and prednisone. A steroid taper to alternate day steroids or off completely by 6 months has been the goal and has been accomplished in 6 of 12 infants. Heart-lung and lung transplantation has been performed in 5 infants. One infant in each group died: 1 infant secondary to airway complications and sepsis and another due to pulmonary sepsis. A pulmonary lobe from a larger and older donor was transplanted into a 4-week-old infant as a single-lung transplant with good outcome. The 3 surviving infants are well 24, 18, and 2 months after transplantation. Obliterative bronchiolitis has not been clinically apparent in this group. These data support the clinical efficacy of heart, heart-lung, and lung transplantation in the first year of life.

At Stanford University, a Novacor left ventricular assist system (Baxter Healthcare Corporation, Novacor Division, Oakland, Calif.) was placed as a bridge to heart transplantation in 13 patients. During the hospitalization preceding device implantation, all patients were receiving inotropic support for biventricular failure, 11 had pulmonary edema, 6 had life-threatening ventricular arrhythmias, 5 had liver dysfunction with coagulopathy, and 2 had renal failure necessitating artificial support. The mean cardiac index before implantation of the Novacor system was 1.5. All survivors with the Novacor device had a dramatic increase in cardiac output (mean cardiac index = 3.1). One patient with cardiac allograft rejection died during implantation of the left ventricular assist system. Two patients died of pulmonary sepsis and multiorgan failure after the device was implanted. All patients who had the Novacor device implanted for more than 7 days were able to walk and ride stationary bicycles while awaiting transplantation. Ten patients (77%) underwent successful heart transplantation after a mean of 18 days' support with the Novacor device. One patient died of presumed sepsis 2 days after transplantation. Nine patients (90%) are alive 4 months to 6 years after transplantation. In the overall United States experience, 68 patients (as of May 1990) have had a Novacor left ventricular assist device implanted. Five were still being supported, 39 had received a transplant (62%), and 35 patients (90%) survived the transplant hospitalization (1 died later). No instances of device failure have occurred. Overall, the Novacor assist system provided effective bridging to transplantation, with posttransplant survival similar to results after routine transplantation. Modifications and improvements based on this clinical experience have been made in the areas of patient selection, techniques of operative placement, postoperative management, and design of the assist system. Isolated left heart support with a fully implantable left ventricular assist system will be offered as an alternative to heart transplantation for selected patients by 1992.

Increased rejection incidence in female heart transplant recipients receiving immunosuppressive therapy with cyclosporine and azathioprine has been reported and a possible role for gender-mismatched grafting (male donor into female recipient) has been suggested. To test the hypothesis that rejection is more frequent in female patients receiving male hearts, we analyzed the results of heart transplantation in gender-matched and -mismatched grafts in 313 recipients maintained with either double therapy with cyclosporine and prednisone (group 1, n = 104) or triple therapy with cyclosporine, azathioprine, and prednisone (group 2, n = 209). There were 21 female recipients in group 1 and 41 in group 2. The variables studied were 90-day total methylprednisolone sodium succinate requirements, 90-day linearized rejection rate, 90-day event-free actuarial rejection, 6-month actuarial infection-free survival, overall actuarial survival, and median day to first rejection. Statistical analyses included two-tailed t or Cox-Mantel testing as appropriate. In group 1, transplantation of a male heart into a female recipient (M/F grafting) was associated with a 40% higher 90-day cumulative steroid requirement (5008 +/- 3400 mg for M/F vs 3600 +/- 2977 mg for F/F), reflecting a higher rate of rejection in M/F recipients. Linearized rejection rates (90-day) were higher (1.6 +/- 0.4 vs 1.3 +/- 0.5 episodes per patient), and consequent 6-month event-free infection rates were lowest in these patients, although not significantly so. Actuarial survival did not differ significantly between the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

A retrospective review was undertaken to determine the clinical features, outcome, and impact on survival of nontuberculous mycobacterial infections in 14 (of 502) heart transplant recipients. The prevalence of these infections was significantly higher (p less than 0.05) during the precyclosporine than during the cyclosporine era. The mean interval from transplantation to diagnosis was 3.5 +/- 0.7 years (+/- SEM). The 14 patients had a higher (p less than 0.05) linearized rejection rate than did other transplant patients during postoperative years 1, 2, and 4 to 6, and had received 7.3 +/- 2 gm of methylprednisolone as bolus treatment of rejection before diagnosis. Eight patients were initially seen with disseminated disease, four had localized pulmonary infection, one had subcutaneous infection in the previous site of a left ventricular assist device, and in one the organism was cultured from a fluid collection adjacent to a hip prosthesis. Twelve patients were first given 3 +/- 1 antimycobacterial drugs; the infections were usually controlled, but in 75% of patients the therapeutic regimen was prematurely stopped or altered because of drug toxicity. Mycobacterial infection was a contributory cause of death in only one patient. Actuarial survival in the 14 patients was not significantly different from the entire transplant population at 4 to 7 years. We conclude that nontuberculous mycobacterial infections occur late after heart transplantation, that drug treatment is usually successful (although difficult), and that long-term survival is not adversely affected if the infection is successfully controlled.

To elucidate the long-term effects of cyclosporine, we retrospectively studied 310 consecutive patients who have undergone cardiac transplantation at our institution since December 1980 and in whom immunosuppression has been maintained with cyclosporine. The ages of recipients ranged from 1 month to 64 years and of donors from 1 month to 48 years. The actuarial survival rates for cyclosporine-treated patients were 80.7% at 1 year and 59.7% at 5 years and were significantly greater than those for previous patients not treated with cyclosporine (p less than 0.005). Their actuarial prevalence of rejection was 60.0% at 1 month and 86.9% at 1 year; 206 patients are living. The actuarial prevalence of lymphoma development was 4.6% at 5 years but has been significantly lower with the current immunosuppression protocol of lower doses of cyclosporine, and OKT3 in place of rabbit anti-thymocyte globulin (p less than 0.005). Infection remains the most common cause of death. Recipients less than 50 years of age had a significantly higher actuarial survival than older recipients (p less than 0.01). Male and female recipients had similar overall prevalence of survival and rejection, but men died of graft atherosclerosis significantly more frequently (p less than 0.005). Rehabilitation has been successful in 85% of patients surviving 1 year after transplantation. Of those surviving 1 year, 96.5% were in New York Heart Association class I. Thus the results of orthotopic cardiac transplantation have improved since the introduction of cyclosporine and have allowed measured liberalization of the criteria for recipient selection.

Combined heart and lung transplantation was carried out in ten patients at Stanford University Medical Center between March, 1981, and December, 1982. All patients had end-stage pulmonary hypertension. 7 of them had Eisenmenger's syndrome and 3 primary pulmonary hypertension. 3 patients died within a month of operation, but the remaining recipients are well 2 months to 2 years after transplantation. The hospital stay of the survivors ranged from 38 to 85 days. All survivors have returned to normal activity. The results of heart and lung transplantation have thus been considerably superior to those reported previously for lung transplantation. It is suggested that cardiopulmonary replacement is suitable treatment for end-stage pulmonary hypertension with or without associated congenital heart disease and that its application to other forms of advanced pulmonary failure may be warranted.

Combined heart and lung transplantation was carried out in 17 patients at Stanford University between March, 1981, and December, 1983. The recipients were between 22 and 45 years old. All patients had end-stage pulmonary hypertension; 10 had Eisenmenger's syndrome and the remaining 7, primary pulmonary hypertension. Five patients died within the first few postoperative weeks. The remainder are well between four weeks and 33 months from operation. The immunosuppressive protocol has consisted of cyclosporine with an initial course of rabbit antithymocyte globulin. Azathioprine also was given for the first two weeks and then was replaced with prednisone. Rejection, as diagnosed by cardiac biopsy, was treated with high doses of methylprednisolone. Modifications of technique that have developed include the removal of the recipient heart and lungs separately, and preservation of the lungs with a modified Collins' solution instead of a cardioplegic solution. Rejection occurred in 6 of the 12 survivors. Infections developed in 9 patients, but only one resulted in a fatal outcome (Legionella). Thus, the results of clinical heart-lung transplantation have been considerably superior to clinical efforts in lung transplantation. It is suggested that the combined operation is preferable for the following reasons: (1) all diseased tissue is removed, thus eliminating recurrent infection and ventilation/perfusion disparity; (2) transplantation of the entire heart-lung block preserves coronary-bronchial vascular anastomoses and makes airway dehiscence less likely; and (3) to date, diagnosis of rejection by cardiac biopsy has appeared to be a satisfactory method of diagnosing and treating pulmonary rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in the management of cardiac transplant recipients over the past 10 years have resulted in a substantial improvement in the outlook for survival. Imuran and prednisone remain the primary immunosuppressive agents, but rabbit antihuman thymocyte globulin is used initially and reinstituted during rejection. Endomyocardial biopsy has allowed more precise diagnosis and management of rejection, and more recently immunological monitoring has been introduced to provide more frequent assessment of the host immune response. Infection is the major cause of death, and its diagnosis and treatment is managed aggressively. Current survival figures justify the use of cardiac transplantation, by an experienced team, when other measures have been exhausted.

Clinical cardiopulmonary transplantation is currently limited by the availability of suitable heart-lung donors. Distant graft procurement, with pretreatment, of the donor by intravenous prostaglandin E1 and cooling of the graft with pulmonary artery perfusion, is now clinically established and should increase the number of available donors. Between March 1981 and September 1986, 40 heart-lung transplantations were performed. The characteristics of the donor pool were analyzed. Gram stain of the donor tracheal aspirate revealed gram-positive bacteria in 80% and gram-negative organisms in 35%. Yeast was present on stain in 25% of the patients. Donor arterial oxygen tension was less than 100 torr inspired oxygen concentration 40%) repeatedly in one patient; this recipient died of lung failure at operation. Severe deterioration of allograft lung function was seen in 11 (27.5%) recipients. The causes of deterioration were substantial postoperative bleeding in six patients, sepsis in two, and acute rejection, poor lung function, and allograft heart failure in one patient each. HLA-A locus mismatch, poor donor alveolar-capillary gas exchange, tracheal colonization with heavy polymorphonuclear cells, and heavy bacteria and fungus resulted in increased operative mortality. Donor pretreatment with prostaglandin E1 was associated with improved survival. Recipient selection, emphasizing adequate liver function and absence of previous thoracic operation, careful surgical technique with minimal bleeding, and brief perfusion time were factors associated with improved survival. Early morbidity and mortality were principally related to recipient risk factors, and the strict criteria observed for selection of heart-lung donors were valid. The importance of appropriate recipient selection is underscored.

Between December 1980, when immunosuppression with cyclosporine was introduced, and May 1988, 288 patients underwent primary transplantation for end-stage cardiac disease (group TX). Fourteen patients underwent retransplantation for accelerated graft atherosclerosis (group RTXAGA), and 9 underwent retransplantation for intractable acute allograft rejection (group RTXREJ). Cumulative patient follow-up was 724 patient-years (range, 1 month to 7.5 years; mean, 2.3 years). Within the first 3 postoperative months, no differences were noted between groups for linearized rates of infection or rejection except between the rate of rejection for group TX (1.69 +/- 0.09 events/100 patient-days) and group RTXAGA (0.94 +/- 0.3 events/100 patient-days) (p less than 0.02). No significant differences existed between groups for actuarial rates of remaining rejection-free or infection-free for more than 7.5 years. No significant differences in actuarial survival existed except between group TX (81% +/- 2% at 1 year and 58% +/- 4% at 5 years) and group RTXREJ (44% +/- 17% at 1 year and 44% +/- 0% at 5 years) (p less than 0.05). We conclude that patients who undergo retransplantation for accelerated graft atherosclerosis experience a lower rate of early rejection and similar rates of infection and survival compared with patients who receive primary transplants. Cardiac retransplantation for rejection incurs rejection and infection at rates similar to those of primary procedures. However, patients who undergo retransplantation for rejection survive these complications significantly less often than do patients who receive primary transplants. This information should be considered when scarce donor hearts become available and retransplantation is contemplated.

Six patients received heart-lung transplants between March, 1981, and January, 1982. There were four women and two men between 26 and 45 years of age, three with primary pulmonary hypertension and three with congenital heart disease and pulmonary hypertension (Eisenmenger's syndrome). Immunosuppression was primarily with cyclosporin-A, with additional corticosteroid, azathioprine, and rabbit antihuman thymocyte globulin. Six episodes of allograft rejection in four patients (10, 11, 21, 24, 53, and 86 days after transplantation) were detected by means of transvenous endomyocardial biopsy. All patients experienced pulmonary edema early after transplantation (reimplantation response), and two patients required mechanical ventilatory support for allograft rejection at 10 and 11 days. Treatment of rejection consisted of intravenous methylprednisolone (four episodes) or augmented oral prednisone (two episodes), with resolution. No episode thought to be pulmonary rejection has occurred in the absence of cardiac findings. Four patients are alive from 6 to 15 months after transplantation and are functionally normal. Early experience with heart-lung transplantation suggests (1) that allograft rejection can be detected by cardiac findings and successfully treated by augmented corticosteroids, (2) that lung rejection does not occur in the absence of cardiac findings, (3) that the frequency and severity of rejection episodes are not greater than with standard cardiac transplantation, and (4) that the frequency of rejection episodes is highest within the first 60 days after transplantation.

Two thirds of the 114 patients undergoing heart transplantation at Stanford (Calif) Medical Center have had atherosclerotic cardiac disease. Two of these patients have been found in the late posttransplant period to have symptomatic abdominal aortic aneurysms requiring resection. We present the clinical course and successful operative treatment of these two patients, with emphasis on the prophylaxis of infection and maintenance of hemodynamic, metabolic, and immune stability. Close surveillance of the long-term cardiac transplant survivor should be directed towards other manifestations of atheroscleortic disease.

A 17-year-old girl presented with an enlarged cardiac silhouette on routine chest roentgenogram. After clinical evaluation, echocardiography, and pericardiocentesis failed to provide a diagnosis, exploratory thoracotomy and biopsy revealed an unresectable left ventricular fibroma. The tumor continued to enlarge and began causing ventricular arrhythmia. Therefore, she underwent cardiac transplantation 2 years after the initial diagnosis was made. She is now alive nd well 18 months following transplantation.

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 rejection 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 patient 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 rejection 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, respectively. 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.

We report our initial experience with three patients who received heart-lung transplants. The primary immunosuppressive agent used was cyclosporin A, although conventional drugs were also administered. In the first patient, a 45-year-old woman with primary pulmonary hypertension, acute rejection of the transplant was diagnosed 10 and 25 days after surgery but was treated successfully; this patient still had normal exercise tolerance 10 months late. The second patient, a 30-year-old man, underwent transplantation for Eisenmenger's syndrome due to atrial and ventricular septal defects. His graft was not rejected, and his condition was markedly improved eight months after surgery. The third patient, a 29-year-old woman with transposition of the great vessels and associated defects, died four days postoperatively of renal, hepatic, and pulmonary complications. We attribute our success to experience with heart-lung transplantation in primates, to the use of cyclosporin A, and to the anatomic and physiologic advantages of combined heart-lung replacement. We hope that such transplants may ultimately provide an improved outlook for selected terminally ill patients with pulmonary vascular disease and certain other intractable cardiopulmonary disorders.

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.

Integration of data derived from immunologic monitoring techniques and endomyocardial biopsy currently permits more precise administration of immunosuppressive medications for the treatment of acute cardiac allograft rejection than was formerly possible, resulting in a substantially improved outlook for long-term survival. Indeed, the probability of survival for 5 years postoperatively of 50% exceeds that for several categories of cardiac patients currently undergoing other more common forms of heart surgery. The continuing demonstration of the potential for cardiac transplantation clearly warrants further application of this procedure for the treatment of appropriate patients with end-stage cardiac disease.

During the first 31/2 years of the Stanford heart-lung transplant program, 23 transplants have been carried out in 22 patients with severe pulmonary vascular disease. Actuarial survival curves predict 1 and 2 year survival rates of 71% and 57%, respectively, for all patients. As a result of increasing experience, the early mortality of 26% has been reduced, with only one early death occurring in the last eight patients; prior cardiac surgery was a contributing factor in three of the six patients suffering early deaths. Two late deaths occurred in the series 14 and 15 months after operation. One patient died suddenly as a result of an acute myocardial infarct and the other patient died because of respiratory failure. At autopsy, both patients had severe proliferative coronary atherosclerosis with obliterative bronchiolitis affecting the lungs. An additional patient required a retransplant for obliterative bronchiolitis 37 months after the initial procedure, and he too was found to have severe coronary artery disease. Hemodynamics and left ventricular function were normal in patients studied 1 and 2 years after undergoing the transplantation procedure. Thus, the early mortality and morbidity of combined heart and lung transplantation has been significantly reduced, but the long-term complications, particularly graft atherosclerosis and obliterative bronchiolitis, are yet to be fully controlled.

Seventeen patients received combined heart and lung transplants at Stanford University between March 1981 and December 1983. All recipients were suffering from end-stage pulmonary hypertension. Five patients died within the first few postoperative weeks, but the remainder were well between 2 and 35 months after operation. Immunosuppression consisted of cyclosporine with an initial course of rabbit antithymocyte globulin, and azathioprine was given for the first 2 postoperative weeks. Maintenance immunosuppression was achieved with cyclosporine and prednisone. Rejection, as diagnosed by cardiac biopsy, was treated with intravenous methylprednisolone. The functional status of the survivors has been good, and upon discharge from the hospital, all returned to normal activity. Our preliminary experience indicates that cardiopulmonary transplantation represents a realistic therapeutic approach for patients with end-stage pulmonary disease.