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J Am Coll Cardiol, 2001; 37:189-194
© 2001 by the American College of Cardiology Foundation
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CLINICAL STUDY: HEART TRANSPLANT

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

Ranjit John, MD*, Hiranya A. Rajasinghe, MD*, Silviu Itescu, MD*, Sanjeev Suratwalla, BS*, Katherine Lietz, MD*, Alan D. Weinberg, MS*, Alfred Kocher, MD*, Donna M. Mancini, MD, FACC{dagger}, Ronald E. Drusin, MD, FACC{dagger}, Mehmet C. Oz, MD*, Craig R. Smith, MD, FACC*, Eric A. Rose, MD, FACC* and Niloo M. Edwards, MD*

* Department of Surgery, Columbia University College of Physicians and Surgeons, New York, New York, USA
{dagger} Department of Cardiology, Columbia University College of Physicians and Surgeons, New York, New York, USA

Manuscript received March 15, 2000; revised manuscript received July 24, 2000, accepted September 14, 2000.

Reprint requests and correspondence: Dr. Ranjit John, Division of Cardiothoracic Surgery, Columbia Presbyterian Medical Center, Milstein Hospital Building 7-435, 177 Fort Washington Avenue, New York, New York 10032
ranjitj{at}pol.net


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
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 2.9 l/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.

Abbreviations and Acronyms
  TRCAD = transplant-related coronary artery disease

Cardiac transplantation is the only therapeutic modality to achieve long-term survival in the treatment of end-stage heart disease (1,2). The feasibility of long-term survival is an important consideration, especially with the development of newer modalities of treatment for end-stage heart disease. The use of cyclosporine as part of the post-transplant immunosuppressive regime beginning in the early 1980s has significantly improved survival in heart transplant recipients (3,4). However, despite a growing insight into the pathogenesis of transplant-related coronary artery disease (TRCAD) in cardiac allograft recipients, it remains the major cause of late graft failure and death in cardiac transplant recipients (5). Thus, prevention of TRCAD remains essential to long-term survival after cardiac transplantation.

The opportunity to study graft function and survival in the second decade following cardiac transplantation has been limited to a few centers that were actively performing cardiac transplantation in the 1980s. This study aims to: 1) determine the long-term (>10 years) survival of patients after cardiac transplantation in the cyclosporine era, 2) evaluate the hemodynamic and functional parameters of cardiac allograft function in these long-term survivors and 3) identify risk factors adversely affecting long-term survival after cardiac transplantation.


   Methods
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 Methods
Results
 Discussion
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Patient selection.   Between April 1, 1983, and June 1988, 195 consecutive patients underwent orthotopic cardiac transplantation at the Columbia Presbyterian Medical Center for the treatment of end-stage heart disease. Selection of recipients was based on ABO compatibility and donor-recipient size matching. The reasons for choosing this period were twofold: 1) cyclosporine was introduced in 1983 and 2) patients transplanted during this era had a potential to survive >10 years (long-term survival after heart transplantation was the focus of this study).

Operative techniques.   Donor hearts were harvested from beating-heart brain-dead individuals. Graft procurement was performed either locally or distantly and preservation was done with cold cardioplegic arrest using Euro-Collin’s solution and topical hypothermia. Orthotopic cardiac transplantation was performed with the biatrial technique described by Lower and Shumway (6).

Immunosuppressive regimen.   Since 1983 all patients undergoing cardiac transplantation at the Columbia Presbyterian Medical Center have received cyclosporine-based immunosuppression. Between April 1, 1983, and April 3, 1985, patients received cyclosporine and steroid therapy (n = 35). After April 3, 1985, triple therapy has been administered to all patients with the addition of azathioprine to the immunosuppressive regimen (n = 135). Intravenous murine monoclonal antibody OKT3 (5 mg/day) has been used instead of cyclosporine for the first four days after transplantation for patients who have severe renal dysfunction. Current dosing for standard triple-therapy immunosuppression consists of: 1) Cyclosporine is administered in a preoperative dose of 3 to 6 mg/kg followed by intravenous cyclosporine (1 to 2 mg/kg/24 h) until oral intake is tolerated. Daily oral doses (3 to 6 mg/kg) are adjusted so that serum levels are maintained at 300 to 350 mg/dl. 2) Azathioprine is administered in a preoperative oral dose (4 mg/kg) followed by daily doses of 2 mg/kg with dosing adjusted according to the patient’s white blood cell count, platelet count and hepatic function. 3) Intravenous methylprednisolone (500 mg) is administered during the operation and followed in the postoperative period by 125 mg every 8 h for three doses. Prednisone is then instituted at a daily oral dose of 1 mg/kg and gradually tapered over four months to 0.1 mg/kg per day.

Management of rejection.   Rejection was diagnosed by routine endomyocardial biopsy, weekly for the first six weeks, then every two weeks for the next six months and then once monthly for the next one year. Routine treatment of rejection consisted of an increase in oral prednisone to 100 mg/day for three days followed by a taper for one week to the baseline dose. If rejection persisted, as seen on endomyocardial biopsy, after a course of oral prednisone therapy, or if rejection was accompanied by altered hemodynamics, intravenous methylprednisolone (1 g daily for three days) was used to reverse rejection. Intravenous OKT3 (5 mg/day) and antithymocyte globulin were used in hemodynamically unstable patients and in patients with rejection episodes refractory to intravenous steroid boost. Persistent rejection episodes post-transplant associated with hemodynamic instability, despite all attempted measures, were considered as an indication for retransplantation.

Angiography/diagnosis of coronary disease.   All patients underwent annual coronary angiography. The diagnosis of TRCAD was based on the following: 1) discrete lesions resulting in >50% obstruction of the proximal or mid-portions of major graft vessels or 2) diffuse, concentric narrowing of the whole vessels, including their branches. If TRCAD was identified, the frequency of angiography was increased to a biannual regimen. Patients were not given routine vasodilators before coronary injections. All angiograms were reviewed by a cardiologist and compared with the previous year’s films to detect the presence of luminal irregularities, discrete stenoses, loss of third-order branches or pruning of vessels. Explanted hearts and autopsy specimens were examined for evidence of vessel occlusion and irregularities, ischemic damage and presence of acute cardiac rejection.

HLA typing.   Serological typing of HLA-A and HLA-B loci was performed by standard microcytotoxicity techniques. HLA-DR typing was performed by serologic analysis.

Statistical analysis.   Data were examined univariately by the Student t test for continuous variables and Fisher’s exact test for discrete data. Actuarial survival of patients was estimated by Kaplan-Meier analysis, with p values calculated by log-rank statistics (7). For the multivariable survival analysis post-transplantation, variables with a univariate p value <0.25 were entered into a multiple logistic regression analysis model (8). This model is a multiple regression analysis for examining dichotomous outcomes and their potential associated risk factors by modeling a linearized function of a set of covariates. The interpretation of a risk factor allowed into the final model with a p value <0.05 is that it is an independent risk factor associated with the event, over and above other potential risk factors included in the equation. The risk ratio is the ratio of the estimated hazard for those with the characteristic variable in question to the estimated hazard for those without, controlling for other variables (or covariates).

For all statistical analysis, data was analyzed using SAS System software (SAS Institute, Inc., Cary, North Carolina).


   Results
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Demographic data.   The causes of end-stage heart disease in this population of 195 patients consisted of ischemic cardiomyopathy (n = 67), idiopathic cardiomyopathy (n = 97), congenital heart disease (n = 12) and others (n = 9). The mean age of patients at transplantation was 38.05 ± 15.98 years (range 10 to 64 years). There were 158 male and 37 female patients (male to female ratio 4.3:1).

The mean follow-up period was 6.45 + 5.04 years, with a cumulative patient follow up time of 1,257 patient years.

A comparison of the demographic features between the long-term survival group and the non-long-term survival group is shown in Table 1.


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  		Table 1 Distribution of the Demographic Features Between Long-Term and Non-Long-Term Survivors After Cardiac Transplantation

 
Actuarial survival.   The actuarial survival of the 195 patients undergoing cardiac transplantation between 1983 and 1988 was 72%, 58% and 39% at one, five and ten years respectively by Kaplan-Meier analysis (Fig. 1). No differences in one-, five- and ten-year actuarial survival were found among patients who received triple immunosuppression (n = 159) compared with those on dual therapy (n = 36) (p = 0.9, Table 2). By comparison, one- and five-year actuarial survival increased to 81% and 70%, respectively, at our institution a decade later (1993 to 1997).



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  		Figure 1 Actuarial survival of patients undergoing primary cardiac transplantation between 1983 and 1988. The squares represent actual events, positioned along the horizontal axis by the time of the event and by the Kaplan-Meier method along the vertical axis.

 

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  		Table 2 Univariate Analysis of Factors Affecting Long-Term Survival After Cardiac Transplantation

 
Graft function in long-term survivors.   In patients with actuarial survival >10 years, 65 cardiac allografts maintained function beyond 10 years. Freedom from TRCAD in these allografts was 98% and 78% at 5 and 10 years respectively. Hemodynamic evaluation of the cardiac allograft function in long-term survivors revealed a mean cardiac index of 2.9 l/m2 and a mean ejection fraction of 58% (Table 3).


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  		Table 3 Hemodynamic Parameters in Long-Term Survivors at 10-Year Follow-Up

 
Univariate and multivariable analysis.   Univariate analysis revealed recipient age at transplant and underlying ischemic cardiomyopathy as statistically significant risk factors adversely affecting long-term survival after cardiac transplantation. Two other risk factors showed a trend toward significance: donor age at transplantation and donor ischemic time (Table 2). Other variables were not statistically significant. However, multivariable analysis by logistic regression analysis identified only an initial pretransplant diagnosis of ischemic cardiomyopathy (p = 0.04) as a statistically significant risk factor to adversely affect long-term survival following cardiac transplantation (Table 4). Among cardiac allograft recipients with a pretransplant diagnosis of ischemic cardiomyopathy, only 27% survived >10 years compared with 43% of those with other pretransplant diagnoses (p < 0.05).


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  		Table 4 Multivariate Analysis of Factors Affecting Long-Term Survival After Cardiac Transplantation

 

   Discussion
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 Results
 Discussion
References
 
Several improvements in the discipline of cardiac transplantation have allowed increasing survival in patients with end-stage heart disease. Cardiac transplantation remains the proven therapeutic modality to achieve long-term survival in these patients, despite the development of new surgical techniques for the treatment of end-stage heart failure such as partial left ventriculectomy, improved mechanical assist devices and further progress in the understanding of the immunological mechanisms in xenotransplantation (9–11). Survival and quality of life in these patients have steadily improved as a result of advancement in various fields, but the development of TRCAD continues to be an impediment to long-term survival. This study retrospectively evaluates a relatively earlier period in our large experience with cardiac transplantation. Given several changes and advances made in the treatment of patients with end-stage heart disease awaiting cardiac transplantation, several lessons can be learned from past experiences. The feasibility of long-term survival after cardiac transplantation with satisfactory hemodynamic function of the cardiac allografts over this duration is a major justification for the procedure’s continued use and applicability.

This study shows that long-term survivors of cardiac transplantation maintain good cardiovascular hemodynamic function in the absence of TRCAD. Notably, the five-year incidence of TRCAD in these long-term survivors is significantly lower than that reported in the overall transplant population. Therefore, it appears that prevention of TRCAD is central in allowing long-term survival and good hemodynamic function. This result is in agreement with other studies of long-term survivors where hemodynamic parameters determined at five years after cardiac transplantation were normal. DeCampli et al. (12) from Stanford reported on a group of long-term survivors with adequate graft function in the second decade after heart transplantation. In a group of 71 patients followed up to seven years after cardiac transplantation, no evidence was found of systolic dysfunction or dilated or restrictive cardiomyopathy (13). Similarly, no evidence of impairment of graft hemodynamic function was reported in 174 patients followed for a period of 5 years (14).

Several nonimmunological and immunological risk factors have been implicated in the development of TRCAD after cardiac transplantation (15). Traditional risk factors for atherosclerosis such as hypertension, smoking and elevated plasma triglycerides have also been described as predisposing factors for TRCAD. Similar to earlier studies, our study demonstrated that the principal risk factor for poor survival due to TRCAD is a pretransplant diagnoses of ischemic heart disease (16). This further emphasizes the need to monitor and prevent the known risk factors for atherosclerosis in the post-transplant period. These risk factors and consequently the incidence of TRCAD may be reduced by the use of lipid-lowering agents and calcium channel blockers (17–19). Additional risk factors for TRCAD include prolonged ischemic time and older donor age (20). These were also identified as risk factors in our study population.

The relationship between prolonged ischemic time and TRCAD may reflect release of endothelial-derived factors such as nitric oxide and endothelin, which are known to exert significant negative influence on myocardial function (21). In addition, damaged endothelium may be a better target for immune attack. The possibility of allograft endothelial dysfunction contributing to TRCAD gained impetus from the recognition that endothelial dysfunction is linked to the development of atherosclerosis in nontransplanted individuals. Donor hearts from older individuals may be at increased risk for myocardial dysfunction as well as for the earlier development of TRCAD because of underlying atherosclerosis. Immunological risk factors that have been implicated include elevated pretransplant panel reactive antibody level, number of episodes of acute rejection, HLA mismatches, steroid dosage and CMV infection (22–24). Thus, it is likely that a combination of immunological and nonimmunological factors contribute to the development of TRCAD. Transplant-related coronary artery disease may be related to the recipient’s continuing immune response against donor major-histocompatibility complex antigens, because long-term allograft survival correlated directly with the number of donor-recipient HLA matches and inversely with the development of circulating antibodies against donor HLA-DR molecules (25,26). Because donor-recipient HLA-DR mismatching is associated with increased cardiac allograft rejection episodes, TRCAD may be the end result of recurrent or persistent allograft rejection (27–29).

Study limitations.   The limitations of this study include those related to a retrospectively performed study. There is also a possibility of underreporting of TRCAD, especially with the recent use of intravascular ultrasound that has improved the detection of TRCAD. Moreover, identification of risk factors for the development of TRCAD was beyond the scope of this study. Many of the short-term survivors died within one year and many did not have autopsy studies. Thus, any data commenting on the prevalence of TRCAD in non-long-term survivors would be erroneously applied to this population. Further, several advances in the field of cardiac transplantation have significantly changed the overall management of these patients from that in use a decade ago (30). Despite these disadvantages, the ability to study a cohort of patients from a previous decade provides a unique opportunity to study the influence of several variables on long-term survival after cardiac transplantation.

Conclusions.   Long-term survival with normally functioning cardiac allografts well into the second decade after heart transplantation is feasible in a subset of patients with end-stage heart disease. The major obstacle for achieving this status in more patients appears to be the risk for the recurrence of ischemic cardiomyopathy due to atherosclerosis and TRCAD. These results are even more encouraging when considering the tremendous advances that have occurred in the past several years in the prevention and management of both immunologic and nonimmunologic risk factors for TRCAD. Strict attention to the avoidance of known risk factors for CAD, as well as increased use of lipid lowering and anti-hypertensive agents in the post-transplant period for patients receiving cardiac allografts, is essential to allow long-term survival in these patients.


   References
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