Factors affecting long-term survival (>10 years) after cardiac transplantation in the cyclosporine era.

OBJECTIVES: The aim of this study was to determine long-term survival (>10 years) after cardiac transplantation in the cyclosporine era and identify risk factors influencing long-term survival. BACKGROUND: Despite the availability of newer modalities for heart failure, cardiac transplantation remains the treatment of choice for end-stage heart disease. METHODS: Between 1983 and 1988, 195 patients underwent heart transplantation at a single center for the treatment of end-stage heart disease. Multivariable logistic regression analysis of pretransplant risk factors affecting long-term survival after cardiac transplantation included various recipient and donor demographic, immunologic and peritransplant variables. RESULTS: Among the group of 195 cardiac transplant recipients, actuarial survival was 72%, 58% and 39% at 1, 5 and 10 years respectively. In the 65 patients who survived >10 years, mean cardiac index was 2.91/m2 and mean ejection fraction was 58%. Transplant-related coronary artery disease (TRCAD) was detected in only 14 of the 65 patients (22%). By multivariable analysis, the only risk factor found to adversely affect long-term survival was a pretransplant diagnosis of ischemic cardiomyopathy (p = 0.04). CONCLUSIONS: Long-term survivors maintain normal hemodynamic function of their allografts with a low prevalence of TRCAD. It is possible that similar risk factors that lead to coronary artery disease in native vessels continue to operate in the post-transplant period, thereby contributing to adverse outcomes after cardiac transplantation. Aggressive preventive and therapeutic measures are essential to limit the risk factors for development of coronary atherosclerosis and enable long-term survival after cardiac transplantation.

Enhanced cardiac effect of digoxin during quinidine treatment.

Quinidine causes an increase in the serum digoxin concentration. Three patients were studied to determine if the increase in serum concentration is paralleled by an increase in the cardiac effect of digoxin. Each patient's clinical condition and serum digoxin concentration were stable when quinidine administration was begun. In all three patients, serum digoxin concentrations increased significantly after beginning quinidine, and decreased when quinidine was discontinued. While taking quinidine, all three patients had ECG findings that suggested enhanced digitalis effect and one patient had clinical evidence of an increased hemodynamic effect. These effects paralleled the increases in serum digoxin concentration. Our findings suggest that the increase in serum digoxin concentration, which occurs after beginning quinidine, is associated with an increase in the effect of digoxin on the heart.

Idiopathic cardiomyopathy and panic disorder: clinical association in cardiac transplant candidates.

Patients under evaluation for cardiac transplant surgery were seen for routine psychiatric diagnosis and treatment. Of 35 patients with idiopathic cardiomyopathy, 83% (N = 29) had definite or probable panic disorder. Of 25 patients with postinfarction cardiac failure, rheumatic heart disease, or congenital heart disease, only 16% (N = 4) had definite or probable panic disorder. The authors suggest that autonomic mechanisms may underlie the association of cardiomyopathy and panic disorder and that increased cardiac sympathetic tone or circulating catecholamines may cause myocarditis and cardiomyopathy.

A previously unrecognized drug interaction between quinidine and digoxin.

Following the development of digoxin radioimmunoassay, we noted that serum digoxin concentrations appeared to rise in patients given quinidine. To further evaluate this important possible interaction between digoxin and quinidine, charts from 863 cardiology patients were reviewed. Ninety two patients received both drugs after having been on digoxin alone; 38 were ineligible for the study because of insufficient data and 27 were excluded because of changing renal function and/or concomitant antiarrhythmic drug therapy, leaving 27. Serum digoxin increased in 25 of the 27 study patients (93%) during quinidine therapy; mean serum digoxin rose from 1.4 ng/ml before quinidine to 3.2 ng/ml during quinidine. Anorexia, nausea and/or vomiting developed in 16 patients (59%) during quinidine therapy, but disappeared in all 10 patients in whom digoxin alone was reduced in dose, suggesting that digoxin had a causative role in the appearance of these symptoms although they developed only after quinidine had begun. Three of thirteen patients with only atrial arrhythmias on digoxin prior to quinidine developed new ventricular premature depolarizations (VPD) after starting quinidine; two of these three as well as four patients with prior VPDs developed new ventricular tachycardia, ventricular fibrillation, asystole, or sudden death. When starting quinidine in patients who are taking digoxin, the clinical course, ECG and serum digoxin should be followed closely.

Cardiac transplantation. Changing patterns in evaluation and treatment.

This study reports the authors' experience with 66 heart transplants in 64 patients done over an 8-year period (1977-1985). In the early series, a high frequency of complications involving serious infections was noted. In April 1983, the immunosuppressive regimen was changed to cyclosporine and low-dose steroids. Patients were monitored with frequent myocardial biopsies and determinations of serum cyclosporine levels. Although this is not a controlled study, the authors believe that the improved results, including reduced frequency and severity of infections, are related to altered immune suppression. They speculate that patients with successful cardiac grafts develop a form of specific unresponsiveness and now are studying the mechanisms of this adaptation.

Dobutamine in the rejecting transplanted heart.

Dopamine is commonly used to improve cardiac output and to maintain peripheral perfusion after myocardial injury. It has several advantages over other catecholamines. At effective inotropic dose levels, dopamine produces less peripheral vasoconstriction than norepinephrine. Dopamine also causes fewer arrhythmias than isoproterenol. This is a case report of a heart transplant patient who began rejecting and developed heart failure. In addition to the immunosuppressive agents, dopamine was used initially as the vasopressor with marked deterioration in the patient's condition. Dobutamine, a new inotropic agent, was substituted for dopamine with subsequent improvement in cardiac function. The authors concluded that dobutamine may be the most appropriate agent to use in the rejecting transplanted heart because of the former's direct action on the heart. Dobutamine may also be preferred for support of the cardiac outputs of patients with chronic heart failure.

Reduced infection in cardiac transplant recipients.

Despite the introduction of cyclosporine immunosuppression, infectious morbidity and mortality in cardiac transplant recipients has remained high. To decrease infectious complications, lower doses of cyclosporine and oral prednisone than previously reported were used for maintenance immunosuppression in 22 operative survivors of orthotopic cardiac transplantation. Twelve infections occurred in 10 patients followed 8 +/- 5 months. Fifty-five percent of patients had no infectious complications. There were no deaths. Seven infections required hospitalization for a mean of 12 days. Infection rate per patient for the first 3 months after transplantation was 0.23 compared with a range of 0.82 to 1.06 in series previously reported in which higher doses of steroids were used. Lowered doses of steroid can be used for maintenance immunosuppression and treatment of rejection with acceptable short-term results. With such a protocol, a low incidence of controllable infectious complications with no deaths has been observed.

Diagnosis and classification of myocarditis by endomyocardial biopsy.

Myocarditis was diagnosed by endomyocardial biopsy in 34 patients with otherwise unexplained heart failure. On the basis of both clinical and histologic findings these patients were divided into three groups. Seven patients had acute myocarditis (mean age, 20 years; mean ejection fraction, 22 per cent) characterized by an interstitial inflammatory infiltrate and extensive, acute cell damage. Five of these patients died after a mean duration of illness of eight weeks. Eighteen patients had rapidly progressive myocarditis (mean age, 35 years; mean ejection fraction, 19 per cent) characterized by patchy acute and healing cell damage and fibrosis; 17 of them died after a mean duration of illness of 23 months. Nine patients had chronic myocarditis (mean age, 31 years; mean ejection fraction, 31 per cent) characterized by focal inflammation and cell damage. All nine were alive after a mean follow-up period of 39 months. In four of these nine, clinical and hemodynamic improvement occurred after one month of immunosuppressive therapy. Our study suggests that a clinically useful classification of myocarditis can be accomplished by endomyocardial biopsy.

Interaction between quinidine and digoxin.

The serum digoxin concentration increased in 25 of 27 study patients (93%), and the mean serum digoxin concentration rose from 1.4 ng/ml to 3.2 ng/ml during quinidine therapy. Anorexia, nausea, or vomiting developed in 16 patients (59%) but disappeared in all ten patients for whom the digoxin dose alone was reduced, suggesting that digoxin excess caused these symptoms. Ventricular premature depolarizations developed in three patients after starting quinidine therapy; ventricular tachycardia developed in one patient, and another died suddenly. When starting quinidine therapy in patients who are taking digoxin, the clinical course, ECG, and serum digoxin level should be followed closely.

High-risk reparative surgery. A neglected alternative to heart transplantation.

The selection of patients for either high-risk reparative operations on the heart or for transplantation has become increasingly difficult as a result of improved results with both modalities. A retrospective review was done of patients referred for heart transplantation who were not considered candidates for conventional cardiac surgery, yet instead underwent reparative procedures rather than transplantation. Of 23 adult patients referred during a 7-year period, 18 had coronary artery disease, and five had valvular heart disease. All had New York Heart Association class IV symptoms. Preoperative left ventricular ejection fractions were in the range 0.08-0.63 (mean, 0.28). Ten of 18 patients with coronary artery disease required insertion of an intra-aortic balloon pump for hemodynamic support perioperatively. Seven patients had primary coronary artery bypass grafts, and 10 had reoperative coronary bypass procedures. One patient had a left ventricular aneurysmectomy, and one had endocardial stripping in addition to myocardial revascularization procedures. Of the patients with valvular disease, three had aortic valve replacement, of which two were reoperations, and two others had mitral valve replacements with tricuspid annuloplasties. With a mean follow-up of 25 months, 1-, 3-, 12-, and 24-month actuarial survival rates were 91%, 87%, 82%, and 76%, respectively. One patient who underwent aortic valve replacement in this study successfully received heart transplantation 19 months postoperatively. These results compare favorably with the current results for patients undergoing first-graft heart transplantation. All survivors enjoy New York Heart Association class I or II functional capacity.(ABSTRACT TRUNCATED AT 250 WORDS)

Reversal of cardiac transplant rejection without massive immunosuppression.

Although cyclosporine has decreased the severity of acute cardiac transplant rejection, most centers have continued to use high-dose intravenous steroids to treat acute rejection. To minimize the morbidity of antirejection therapy, acute rejection episodes in 37 cardiac transplant recipients were treated prospectively with only a boost of oral prednisone. Cyclosporine was continued at the same maintenance dose while oral prednisone was increased to 100 mg/day for 3 days, then rapidly tapered over 1 week to the maintenance dose. Seventy-six of 85 acute rejection episodes (90%) showed histologic resolution of mycocyte necrosis on repeat biopsy. Three acute rejection episodes (3.5%) resolved only after "rescue therapy" with intravenous steroid, and an additional three episodes (3.5%) required the combination of intravenous steroid and rabbit antithymocyte globulin to effect resolution. In addition, three acute rejection episodes (3.5%) resulted in graft loss. This was fatal in two patients and one patient underwent successful retransplantation. Oral steroid therapy alone is adequate therapy for most acute rejection episodes in cyclosporine-treated heart transplant recipients, and low infectious morbidity and mortality has been associated with this antirejection protocol.

Elevated pulmonary vascular resistance and cardiac transplantation.

Severe elevation of pulmonary vascular resistance has been considered a contraindication to cardiac transplantation. Most centers exclude patients with pulmonary vascular resistance greater than 6 Wood units. Wood units, however, do not correct for variations in body size and therefore may not be the best measure for use in comparison of patients. We performed a retrospective analysis of 82 cardiac transplant recipients and compared preoperative pulmonary vascular resistance (PVR) calculated in two ways to the incidence of right ventricular failure and death. Our data show that the PVR index unit (PVRI) identifies those patients that are at risk for right heart failure better than the Wood unit, which does not correct for body size. Four patients died of right heart failure with resistance less than 6 Wood units, but had PVRI greater than 6 units. High resistance is not an absolute contraindication to cardiac transplantation; 28 of 33 patients operated on with a PVRI greater than 6 survived. The degree of elevation of PVR did not correlate with survival. Ten of 12 patients with a PVRI greater than 9 survived. Testing with nitroprusside at cardiac catheterization was helpful in determining reversibility of pulmonary vascular obstruction. No patients with a PVRI less than 6 developed right heart failure.

Present status of human cardiac allografts and prospects for xenografts.

Cardiac allotransplantation is no longer experimental. It is the standard by which all other methods of cardiac replacement must be judged. The dramatic improvement in survival and the quality of life of cardiac transplant recipients reflects many factors including refined criteria for patient and donor selection, as well as the clinical introduction of cyclosporine. Current contraindications to the procedure include: 1) age greater than 65 years, 2) active infection, 3) active malignant neoplastic disease, 4) recent pulmonary embolus or infarction, 5) irreversible renal or hepatic failure, and 6) fixed elevation of pulmonary vascular resistance. The introduction of cyclosporine has been accompanied by an increase in the 1 year survival. While the use of cyclosporine has not decreased the incidence of rejection episodes, it has dramatically decreased their severity. In addition, the incidence and severity of infectious complications, as well as the length of hospitalization, have been decreased with the introduction of cyclosporine. Despite the progress made, several problems remain in the management of transplant recipients. Chronic cyclosporine therapy has been associated with a disturbingly high incidence of hypertension and renal impairment, and a low, yet significant, incidence of malignant neoplasms. However, the most significant obstacle to successful clinical cardiac transplantation is the scarcity of donor organs. Many centers now report that the mortality rate for patients awaiting transplantation exceeds the mortality associated with the procedure itself. Donor scarcity has led to renewed interest in the development of mechanical cardiac devices and investigation into cross-species transplantation (xenotransplantation).

Posttransplantation lymphoproliferative disorders treated with cyclophosphamide-doxorubicin-vincristine-prednisone chemotherapy.

BACKGROUND: Posttransplantation lymphoproliferative disorders after solid organ transplantation are a serious complication occurring in 1-10% of patients. Different therapies have been used, but the optimal treatment is unknown. There is relatively little information in the literature on the experience with cytotoxic chemotherapy. METHODS: The disease stage of patients with biopsy-documented posttransplantation lymphoproliferative was determined with standard methods to establish the extent of the disease. Patients in whom the disease failed to regress after initial management, which included reduction in immunosuppression, were treated with a combination chemotherapy regimen consisting of six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Response to therapy was determined by following previously defined sites of disease with appropriate tests. Patients were maintained on a reduced dose of immunosuppressants. RESULTS: In the four patients studied, lymphoproliferative disorders developed after heart (three cases) or lung (one case) transplantation, which did not regress after immunosuppression was reduced. All four experienced a complete remission with CHOP chemotherapy, which continued at 3, 13+, 20 and 30+ months after completion of treatment. One patient died of sepsis after completing therapy at a point when his leukocyte count was normal, and no evidence of posttransplantation lymphoproliferative disorder was found at autopsy. A second patient died of liver failure with no clinical evidence of lymphoproliferative disorder. CONCLUSION: Although this is a small series, it demonstrates that patients with posttransplantation lymphoproliferative disorders may respond to cytotoxic chemotherapy. The duration of response is undetermined.