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J Thorac Cardiovasc Surg 1999;117:543-555
© 1999 Mosby, Inc.

CARDIOTHORACIC TRANSPLANTATION

Long-Term Survival After Cardiac Retransplantation: A Twenty-Year Single-Center Experience

From the Divisions of Cardiothoracic Surgery^a and Cardiology,^b Columbia Presbyterian Medical Center, Columbia University, New York, NY.

Read at the Seventy-eighth Annual Meeting of The American Association for Thoracic Surgery, Boston, Mass, May 3-6, 1998.

Received for publication May 19, 1998. Revisions requested Aug 19, 1998. Revisions received Oct 3, 1998. Accepted for publication Oct 30, 1998. Address for reprints: Niloo M. Edwards, MD, Division of Cardiothoracic Surgery, Columbia Presbyterian Medical Center, Milstein Hospital Building 7-435, 177 Fort Washington Ave, New York, NY 10032.

	Abstract

Top Abstract Introduction Patients and methods Results Discussion Appendix: Discussion References

 
Objective: To identify risk factors for survival after cardiac retransplantation and compare the survival after retransplantation with that after primary cardiac transplantation.
Methods: A retrospective analysis of 952 patients undergoing cardiac transplantation for the treatment of end-stage heart disease at a single center between 1977 and October 1997. Of these, 43 patients (4.5%) underwent cardiac retransplantation for cardiac failure resulting from transplant-related coronary artery disease, rejection, and early graft failure.
Results: No significant difference in actuarial patient survival was found by Kaplan-Meier analysis at 1, 2, and 5 years between patients undergoing primary transplantation and those undergoing retransplantation—76%, 71%, and 60% versus 66%, 66%, and 51%, respectively (P = .2). Multivariable analysis identified a shorter interval between transplants and an initial diagnosis of ischemic cardiomyopathy as significant risk factors for death after retransplantation (P = .04 and .03, respectively). Since 1993, when our criteria for patient selection for retransplantation were revised on the basis of earlier experience to exclude patients with allograft dysfunction as a result of primary graft failure and those with intractable acute rejection occurring less than 6 months after transplantation, the survival has been significantly better (<1993 = 45%, 45%, and 33% versus 1993 = 94%, 94%, and 94% at 1, 2, and 4 years, respectively, P = .003).
Conclusion: The long-term outcome of cardiac retransplantation is comparable with that of primary transplantation, especially in patients with transplant-related coronary artery disease. Patient characteristics and other preoperative variables should assist in the rational application of retransplantation to ensure optimal use of donor organs.

	Introduction

Top Abstract Introduction Patients and methods Results Discussion Appendix: Discussion References

 
Cardiac transplantation is the only therapeutic modality to achieve long-term survival in the treatment of end-stage heart disease. ¹ Despite a growing insight into the pathogenesis of accelerated coronary artery disease in cardiac allograft recipients, the latter remains the major cause of late graft failure and death in patients undergoing cardiac transplantation. ² Primary graft failure and acute rejection account for the remainder of cases of myocardial dysfunction after cardiac transplantation. Therapeutic interventions for graft failure have included aggressive immunosuppressive therapy, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, and transmyocardial laser revascularization; however, these interventions provide only temporary benefit. The only therapeutic option that has been shown to obtain a satisfactory long-term outcome for a failing cardiac allograft is cardiac retransplantation. ³

Earlier studies have demonstrated poorer graft and patient survival after retransplantation than after primary transplantation. ^4-6 This poorer outcome coupled with the increasing donor shortage raises practical and ethical concerns regarding retransplantation. Accordingly, we performed a retrospective analysis of patients undergoing cardiac retransplantation at the Columbia Presbyterian Medical Center to analyze risk factors that predict the outcome after retransplantation and evaluate the survival benefit of cardiac retransplantation.

	Patients and methods

Top Abstract Introduction Patients and methods Results Discussion Appendix: Discussion References

 
Patient selection
Between February 1977 and October 1997, 952 patients underwent cardiac transplantation at the Columbia Presbyterian Medical Center for the treatment of end-stage heart disease. Forty-three patients underwent cardiac retransplantation for cardiac allograft failure resulting from transplant-related coronary artery disease (n = 33), acute rejection (n = 7), primary graft failure (n = 2), and cardiac failure of unknown origin (n = 1). From 1993, our criteria for the selection of patients for cardiac retransplantation was revised on the basis of our earlier experience. Patients with allograft dysfunction resulting from primary graft failure and those with intractable acute rejection occurring less than 6 months after transplantation were not considered for retransplantation. Our current exclusion criteria for cardiac retransplantation are listed in Table I.Consequently, all patients undergoing retransplantation after 1993 (n = 19) had cardiac allograft failure as a result of transplant-related coronary artery disease, except 1 patient who underwent retransplantation for intractable acute rejection 10 years after the first transplant operation.

Immunosuppressive regimen
Since 1983 all patients undergoing transplantation at the Columbia Presbyterian Medical Center have received cyclosporine-based immunosuppression [INN: ciclosporin]. Changes in the immunosuppressive protocol have included the following: (1) progressive reduction in the administered dose of cyclosporine, (2) a change from double-therapy immunosuppression (cyclosporine and corticosteroids) to triple-therapy immunosuppression (cyclosporine, azathioprine, and corticosteroids) since 1985, (3) substitution of intravenous murine monoclonal antibody OKT3 (5 mg/day) for cyclosporine for the first 4 days after transplantation for patients who have severe renal dysfunction, and (4) use of mycophenolate mofetil instead of azathioprine since 1996.

Current dosing for standard triple-therapy immunosuppression consists of the following: (1) A preoperative dose of cyclosporine of 3 to 6 mg/kg is followed by intravenous cyclosporine (1-2 mg/kg in 24 hours) until oral intake is tolerated. Daily oral doses (3-6 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 intravenously until the patient can tolerate oral medications when azathioprine is changed to mycophenolate mofetil starting at a dose of 1000 mg twice daily. (3) Intravenous methylprednisolone (500 mg) is administered during the operation and followed in the postoperative period by 125 mg every 8 hours for 3 doses. Prednisone is then instituted at a daily oral dose of 1 mg/kg and gradually tapered over 4 months to 0.1 mg/kg per day.

Management of rejection
Rejection was diagnosed by endomyocardial biopsy and graded according to the International Society for Heart and Lung Transplantation (ISHLT) classification of acute rejection. ⁸ Routine treatment of rejection consisted of an increase in oral prednisone to 100 mg/day for 3 days followed by a taper for 1 week to the baseline dose. If rejection persisted after a course of oral prednisone therapy, as seen on endomyocardial biopsy, or if rejection was accompanied by altered hemodynamics, intravenous methylprednisolone (1 gm daily for 3 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. Other modalities attempted for repeated and persistent rejection have included methotrexate, total lymphoid irradiation, plasmapheresis, and photopheresis. Persistent rejection episodes less than 6 months after transplantation associated with hemodynamic instability, despite all attempted measures, were considered as an indication for retransplantation before 1993.

Angiography/diagnosis of coronary disease
All patients underwent annual coronary angiography. The diagnosis of transplant-related coronary artery disease was based on the following: (1) discrete lesions resulting in more than 50% obstruction of the proximal or midportions of major graft vessels or (2) diffuse, concentric narrowing of the whole vessels, including their branches. If transplant-related coronary artery disease was identified, the frequency of angiography was increased to a biannual regimen. Patients are not given routine vasodilators before coronary injections. All angiograms are reviewed by a cardiologist and compared with the previous year's films to detect the presence of luminal irregularities, discrete stenoses, and 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.

Immunologic studies
Human leukocyte antigen (HLA) typing. Serologic typing of HLA-A and HLA-B loci was performed by standard microcytotoxicity techniques. HLA-DR typing was performed by both serologic analysis and DNA techniques with sequence-specific oligonucleotide primers and the polymerase chain reaction.

Detection of anti-HLA antibodies. Sera were obtained from all patients on the day of transplantation and screened for the presence of lymphocytotoxic antibodies against separated T lymphocytes and B lymphocytes obtained from a panel of 70 individuals representative of all HLA class I and class II antigens found in the North American population. Sera were screened for complement-mediated lytic activity in the presence or absence of dithioerythritol (DTT). Total T cell panel reactive antibody was considered positive if serum, in the absence of DTT, reacted against greater than 10% of the T cell reference panel.

A prospective panel reactive antibody screen was performed on all patients who underwent transplantation. A negative prospective donor-specific lymphocyte crossmatch was required before transplantation when the panel reactive antibody titer was in excess of 20%.

Statistical analysis
Data were examined univariately by the Student t test for continuous variables and Fisher's exact test for discrete data (Table II).Actuarial survival of patients was estimated by Kaplan-Meier analysis, with P values calculated by log-rank statistics. ⁹ For the multivariable survival analysis after retransplantation, variables with a univariate P value < .25 were entered into a Cox proportional hazards model. ¹⁰ Any possible era effects (influence of year of transplantation) were corrected by stratification in the Cox model. This model is a multiple regression analysis for examining time-dependent outcomes and their potential associated risk factors by modeling a linearized function of a set of P covariates in the log hazard domain. The interpretation of a risk factor allowed into the model with a P value < .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 hazard 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). ¹⁰

	Results

Top Abstract Introduction Patients and methods Results Discussion Appendix: Discussion References

 
Demographic data
The cause of cardiac failure in this population of 909 patients consisted of idiopathic cardiomyopathy (n = 503), ischemic cardiomyopathy (n = 249), congenital heart disease (n = 66), tumor (n = 6), and others (n = 83). The mean age at transplantation was 43.4 ± 18.2 years (range 0.01-70.2 years). The population comprised 702 male and 207 female patients (male/female ratio 3.4:1). The mean follow-up period was 3.94 ± 3.5 years (range 0-15.1 years) with a cumulative patient follow-up time of 2762 patient-years.

In the study group, the mean age of patients at primary transplantation was 37.2 years (range 2-58 years, SD ± 16.7) and mean age at retransplantation was 41.6 years (range 5-64 years, SD ± 16.6). The original diagnosis of end-stage cardiac disease in these 43 patients was idiopathic cardiomyopathy (29, 66.7%), ischemic cardiomyopathy (11, 26.2%), and congenital heart disease (3, 7.1%). The indications for retransplantation included transplant-related coronary artery disease in 33 patients, rejection in 7 patients, acute graft failure in 2, and cardiac failure of unknown etiology in 1 patient. This group includes 1 patient who received a third graft 27.6 months after transplant-related coronary artery disease developed in the second graft (the first graft failed as a result of acute rejection). The mean follow-up period after retransplantation was 2.4 ± 2.7 years (range 0-9.5 years) with a cumulative patient follow-up time of 103.2 patient-years.

The time interval between the 2 transplants for all patients undergoing retransplantation ranged from 10 hours to 11.4 years (mean 4.4 years, SD ± 3.1 years). The mean intervals between transplants for patients undergoing retransplantation for acute graft failure, rejection, and transplant-related coronary artery disease were 0.06 months (SD ± 0.04 months), 33.1 months (SD ± 49.6 months), and 66.3 months (SD ± 31.8 months), respectively.

Actuarial survival
During the 20-year period, the actuarial survival of the 909 patients who received a primary transplant was 76%, 71%, and 60% at 1, 2, and 5 years, respectively. In the 43 patients undergoing retransplantation, the actuarial survival from the time of the second transplant was 66%, 66%, and 51% at 1, 2, and 5 years, respectively (Fig 1). The difference in the actuarial survival between these 2 groups was not statistically significant (P = .2).

View larger version (26K): [in this window] [in a new window]   Fig. 1 Actuarial survival of patients undergoing primary cardiac transplantation (PCT) versus patients undergoing retransplantation from the time of the second transplant (RETX). The squares and triangles represent actual events positioned along the horizontal axis at the time of the event and by the Kaplan-Meier method along the vertical axis. CI, Confidence interval.

The actuarial survival of primary cardiac allograft recipients undergoing transplantation before 1993 at 1 and 5 years was 72% and 58%, respectively, as compared with actuarial survival of 46% and 33% at 1 and 5 years, respectively, for patients undergoing cardiac retransplantation before 1993 (P = .004, Fig 2).The actuarial survival at 1 and 4 years of patients undergoing primary cardiac transplantation since 1993 was 81% and 77%, respectively, as compared with 94% and 94%, respectively, for patients undergoing retransplantation since 1993 (P = .09, Fig 3).

View larger version (26K): [in this window] [in a new window]   Fig. 2 Actuarial survival of patients undergoing primary cardiac transplantation (PCT) before 1993 versus patients undergoing cardiac retransplantation (from the time of the second transplant, RETX) before 1993. The squares and triangles represent actual events, positioned along the horizontal axis at the time of the event and by the Kaplan-Meier method along the vertical axis. CI, Confidence interval.

View larger version (22K): [in this window] [in a new window]   Fig. 3 Actuarial survival of patients undergoing primary cardiac transplantation (PCT) since 1993 versus patients undergoing cardiac retransplantation (from the time of the second transplant, RETX) since 1993. The squares and triangles represent actual events, positioned along the horizontal axis at the time of the event and by the Kaplan-Meier method along the vertical axis. CI, Confidence interval.

Comparison with 1997 ISHLT registry ¹¹

Mortality
Nineteen patients undergoing cardiac retransplantation died during the period of the study. The 2 patients undergoing retransplantation for acute graft failure died as a result of severe cardiovascular hemodynamic instability, 11 patients died of sepsis of varying origins, 1 patient died of lung cancer, and the rest died of cardiovascular instability as a result of severe rejection, transplant coronary artery disease, and arrhythmia. The causes of death of these patients, as well as the indications for primary and retransplantation, interval between transplants, and the time to death, are shown in Table III.

View larger version (22K): [in this window] [in a new window]   Fig. 4 Actuarial survival of patients undergoing cardiac retransplantation at an interval less than 24 months after the first transplant versus patients undergoing cardiac retransplantation at an interval more than 24 months after the first transplant. The squares and triangles represent actual events, positioned along the horizontal axis at the time of the event and by the Kaplan-Meier method along the vertical axis. CI, Confidence interval.

View larger version (21K): [in this window] [in a new window]   Fig. 5 Actuarial survival of patients with underlying ischemic cardiomyopathy (CAD) undergoing cardiac retransplantation versus patients undergoing cardiac retransplantation without underlying ischemic cardiomyopathy (no CAD). The squares and triangles represent actual events, positioned along the horizontal axis at the time of the event and by the Kaplan-Meier method along the vertical axis. CI, Confidence interval.

	Discussion

Top Abstract Introduction Patients and methods Results Discussion Appendix: Discussion References

 
Despite the development of new surgical techniques for the treatment of end-stage heart failure, such as partial left ventriculectomy, ¹² improved mechanical assist devices, ¹³ and further progress in the understanding of the immunologic mechanisms in xenotransplantation, ¹⁴ cardiac transplantation remains the proven therapeutic modality to achieve long-term survival in these patients. The survival and the quality of life in these patients has been steadily improving as a result of advancement in various fields, but the development of transplant-related coronary artery disease and intractable acute rejection continues to be an impediment to long-term survival. Further, the occurrence of cardiac allograft failure in these patients often poses a therapeutic dilemma to the transplant team because of the scarcity of donor organs. So far, since first reported by Copeland and associates ¹⁵ in 1977, cardiac retransplantation has been shown to be the only way to prolong survival. However, earlier results with cardiac retransplantation have not always been encouraging enough to justify its routine use. The recent ISHLT registry identified retransplantation as the single most important risk factor for both 1- and 5-year mortality after adult heart transplantation. ¹¹ We reviewed patients undergoing cardiac retransplantation to evaluate survival, as well as to identify risk factors affecting the outcome after retransplantation in these patients.

Our early experience at the Columbia Presbyterian Medical Center showed no difference in outcome between those undergoing primary transplantation and retransplantation. ¹⁶ However, the initial number of patients undergoing retransplantation was relatively small in that study, and we have since more than tripled our experience. Further, we have since changed our selection criteria for retransplantation based on our initial results, as well as those of others. This study indicates that cardiac retransplantation is an effective therapy for patients with cardiac allograft failure, especially that resulting from transplant-related coronary artery disease. Long-term 5-year graft survival can be expected in more than 50% of all patients undergoing retransplantation, and patient survival has exceeded 50% at 10 years.

An analysis of the risk factors affecting outcome after cardiac retransplantation showed that the interval between transplants and an initial diagnosis of ischemic cardiomyopathy are the main determinants of survival. Patients undergoing retransplantation after a short interval have a high mortality, in contrast to patients undergoing transplantation after longer intervals. These findings are consistent with the data previously reported for patients undergoing cardiac retransplantation both by other centers ³ and by the ISHLT registry report. ¹⁰ A possible explanation for the poor outcome after retransplantation in patients with a primary diagnosis of ischemic cardiomyopathy is that these patients are more likely than other cardiac allograft recipients to have other end-organ dysfunction owing to generalized atherosclerosis.

A likely explanation for the relationship between shorter interval between transplants and survival after retransplantation is that the same risk factors for shorter survival of the first allograft are operating to limit survival of the second allograft. We have recently shown that the presence of pre-formed immunoglobulin G antibodies against allogeneic major histocompatibility complex class II molecules in retransplant candidates is a major risk factor for earlier and more frequent episodes of high-grade rejection after retransplantation. ¹⁷ Moreover, we have also shown that a high cumulative frequency of high-grade rejections is directly correlated with significantly earlier onset of transplant-related coronary artery disease. ¹⁸ Since the freedom from development of transplant-related coronary artery disease after retransplantation was 50% at 5 years, similar to that with the primary grafts in these patients, this entity remains a major concern ¹⁹ and may be the end result of persistent donor-specific alloreactivity. Therefore it is very likely that in those individuals with active antidonor immune responses while the primary allograft is in place, graft failure occurs earlier, and, in the absence of modification of the immunosuppressive regimen, graft failure of the second allograft is also likely to occur sooner. Modification of donor-specific immune responses by means of intravenous immunoglobulin or cyclophosphamide, or both, may have a significant impact on survival of the second allograft. ^20,21 As for primary transplant patients, it is important that aggressive lowering of cholesterol levels, as well as avoidance of other risk factors such as cigarette smoking, be pursued in the posttransplantation period for the prevention of transplant-related coronary artery disease. ²² This comparison of the relationship between primary transplant time-related survival and that after retransplantation is limited by the fact that it is a risk-unadjusted comparison, except for date.

The Stanford group reported that patients undergoing retransplantation with a creatine level of 2.0 mg/dL or more have a significantly higher risk of postoperative dialysis and death than do patients with a creatinine level less than 2.0 mg/dL. ⁶ As mentioned in Table I, our exclusion criteria for retransplantation include a creatinine level above 2.0 mg/dL. However, simultaneous kidney transplantation and heart retransplantation is a possible approach in cardiac retransplant candidates with elevated creatinine levels.

The optimal timing of retransplantation in patients with cardiac allograft failure is not always an easy decision for the transplant team. In cases of primary graft failure and allograft failure resulting from severe rejection with its accompanying hemodynamic instability, retransplantation often offers the last hope for survival and is thus used as a salvage procedure. This accounts for the poorer survival in these subgroups of patients, both in our experience and in that of others. ²³ Retransplantation for primary graft failure is still accompanied by a dismally high mortality (100%) in our experience. On this basis we have revised our selection criteria so that patients with transplant-related coronary artery disease are almost the only ones undergoing retransplantation. Since 1993, we have not performed cardiac retransplantation for cardiac allograft recipients with acute graft failure and resistant acute rejection, except in 1 pediatric cardiac transplant recipient who underwent retransplantation for rejection resistant to treatment 10 years after the primary transplantation. Retransplantation for transplant-related coronary artery disease should be performed before the development of noncardiac organ dysfunction denies the patient an opportunity for retransplantation. However, for transplant-related coronary lesions amenable to interventions other than retransplantation, such as angioplasty and coronary artery bypass grafting, it is important that the latter be attempted together with aggressive immunosuppressive therapy before retransplantation is attempted. ^24-26

Despite the conclusions derived from this study, the limitations are primarily related to the relatively small number of retransplant patients as compared with the primary transplant patients. Although we and others have shown that immunologic factors such as the presence of pretransplant anti-HLA immunoglobulin G antibodies are associated with adverse outcomes after transplantation, ^17,18,27 immunologic variables were not determinants of patient survival after retransplantation in this study. Again, a small sample size limits the strength of the statistical analysis performed. Multicenter-based studies such as the ISHLT registry are the obvious solutions to this limitation, although the problem with this is the varied criteria for selection for retransplantation among different cardiac transplant centers.

In conclusion, this study shows that cardiac retransplantation appears to be a viable option in view of the encouraging long-term survival achieved, except in cases of acute graft failure and resistant acute rejection. However, it seems that with larger numbers of patients undergoing retransplantation, one would be able to identify additional subgroups of patients in whom the outcome is so poor as to make retransplantation unjustifiable. The satisfactory long-term outcome in patients with cardiac allograft failure caused by transplant-related coronary disease, especially after a longer retransplant interval, warrants retransplantation. This approach appears valid so long as limited alternate therapy for the treatment of end-stage heart disease exists. Studies investigating mechanisms as well as possible therapeutic solutions for transplant-related coronary artery disease and rejection must continue to make early and premature cardiac allograft failure a preventable entity.

	Appendix: Discussion

Top Abstract Introduction Patients and methods Results Discussion Appendix: Discussion References

 
Dr William A. Baumgartner (Baltimore, Md). I congratulate Dr John and his colleagues on their retrospective analysis of the results with cardiac retransplantation. Over a 21-year period, 43 patients or 4.5% of their total series underwent cardiac retransplantation for cardiac failure resulting from transplant-related coronary artery disease, rejection, and early graft failure. They have demonstrated the futility of retransplantation less than 6 months after the primary transplantation, in particular in patients with rejection and early graft failure. Actuarial survival in patients undergoing retransplantation greater than 6 months after primary transplantation compares favorably with their overall patient survival statistics. Multivariate analysis demonstrated that only the interval between transplantation and an initial diagnosis of ischemic cardiomyopathy were significant risk factors for poor outcome.

The issue of cardiac retransplantation is controversial within the transplant community. It was a subject of debate at one of the recent meetings of the ISHLT. In addition, the registry supported by this society identified retransplantation as the single most important risk factor for both 1- and 5-year mortality after adult heart transplantation. At the most recent ISHLT meetings, the registry report included a further analysis of retransplantation.

According to the registry, which comprises thousands of patients, the 1-year retransplantation survival increases as the time from the primary transplantation increases. The 1-year transplant survival approaches 80%, similar to that of primary transplantation.

With the scarcity of donor organs, retransplantation often poses a treatment dilemma. This dilemma of which patient should receive the donor organ is reenacted in all of our individual programs. Our policy of retransplantation is similar to the authors' current one. We have performed 16 retransplants or 6% of the total number of our transplant procedures. Our 5- and 10-year actuarial survivals are 94% and 73%, respectively. Our only indication for retransplantation has been accelerated coronary arteriosclerosis. These findings support the authors' conclusions.

I have 4 questions. Limiting retransplantation to those patients who have survived for more than 6 months after their primary procedure still causes occasional disagreements. In regard to criteria, we believe strongly that patients considered for retransplantation should meet all the selection criteria imposed on patients undergoing a primary transplant procedure. Dr John, would you mind expanding on your criteria for retransplantation?

Can you provide information regarding the extent of coronary artery disease in your entire patient population? What is the freedom from development of coronary artery disease at 10 years?

Similarly, how many of your patients have died of coronary artery disease? In our own series, several of the patients are not candidates for retransplantation by the time significant or advanced coronary artery disease develops, with its associated left ventricular dysfunction.

Finally, you have shown a relationship of rejection with development of transplant-related coronary artery disease. We have shown a relationship between the extent of ischemic injury seen on the first cardiac biopsy specimen and the subsequent development of coronary artery disease. Have you seen any similar correlation?

Dr John. Thank you, Dr Baumgartner, for your kind and very relevant comments.

The two main indications for cardiac retransplantation (since our selection criteria were revised in 1993) are as follows: (1) the presence of diffuse accelerated graft atherosclerosis with concomitant left ventricular dysfunction that is not amenable to angioplasty or coronary artery bypass grafting and (2) graft failure as a result of acute rejection occurring more than 6 months after transplantation. The exclusion criteria for cardiac retransplantation are similar to those for primary cardiac transplantation but, if anything, are more stringent. These include, for example, an upper age limit of 55 years (as compared with 65 years for primary transplantation) and the presence of severe pulmonary hypertension (cutoff for retransplant candidates is 3 Wood units as compared with 6 Wood units for primary transplants). The other exclusion criteria include those that we apply to primary transplant candidates, such as the presence of active infection, recent or active malignancy, human immunodeficiency virus disease, and other factors.

Regarding the development of coronary artery disease, in our experience the freedom from transplant-related coronary artery disease at 10 years is approximately 30% to 40%.

I do not have a specific answer for your third question concerning the number of deaths from transplant-related coronary artery disease. Deaths related to transplant-related coronary artery disease fall into 3 major groups. One includes patients who die before obtaining their first annual coronary angiogram, and the postmortem examination reveals transplant-related coronary artery disease. The second group includes patients who are listed for retransplantation because of transplant-related coronary artery disease and die while awaiting a donor organ. The third group of deaths includes patients with transplant-related coronary artery disease who are ineligible for retransplantation on the basis of our exclusion criteria.

Finally, as you mentioned, our most significant association with transplant-related coronary artery disease are immunologic factors such as an earlier onset of high-grade rejection and an increased cumulative frequency of high-grade rejection. We have not observed any relationship between ischemic injury and transplant-related coronary artery disease. However, in our experience, the incidence of ischemic injury on the first cardiac biopsy is relatively uncommon, in the range of 5% of first cardiac biopsies.

Dr Robert W. Emery (Minneapolis, Minn). I am curious about the fact that you found ischemic cardiomyopathy to be a risk factor for retransplantation because you removed the end-organ. This would imply an ongoing, underlying, untreated disease process. Do you think that the new heart will be subject to this ongoing process? Do we need to look further into why patients with ischemic cardiomyopathy have retransplantation, or are there other comorbid risk factors that would contribute to problems with retransplantation?

Dr John. Thank you, Dr Emery. The concern regarding heart transplantation for ischemic cardiomyopathy is that even though the end-organ is replaced, the basic risk factors for the primary pathogenesis of the disease, namely, atherosclerosis, persists. It is important to be aggressive with modification of risk factors for atherosclerosis after heart transplantation, such as the avoidance of cigarette smoking, control of hypertension, and the use of lipid-lowering agents. Otherwise, progressive atherosclerosis, both in the retransplanted heart and in other organs such as the kidney, will contribute to a relatively poorer survival.

	References

Top Abstract Introduction Patients and methods Results Discussion Appendix: Discussion References

 

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