CLINICAL STUDIES
Low incidence of transplant coronary artery disease in chinese heart recipients
Ron-Bin Hsu, MD*,
Shu-Hsun Chu, MD*,
Shoei-Shen Wang, MD*,
Wen-Je Ko, MD*,
Nai-Kuan Chou, MD*,
Chii-Ming Lee, MD ,
Ming-Fong Chen, MD and
Yuan-Teh Lee, MD
* Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
Manuscript received July 31, 1998;
revised manuscript received January 8, 1999,
accepted January 21, 1999.
Reprint requests and correspondence: Dr. Shu-Hsun Chu, National Taiwan University Hospital, No. 7, Chung-Shan S. Rd. Taipei, Taiwan 100, R.O.C
shchu{at}ha.mc.ntu.edu.tw
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Abstract
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OBJECTIVES
This study sought to assess the incidence of transplant coronary artery disease (CAD) in Chinese heart recipients.
BACKGROUND
The prevalence of transplant CAD detected by angiography at 1, 2 and 4 years after heart transplantation was 11%, 22% and 45%, respectively. The incidence of transplant CAD in Chinese heart recipients has not been reported.
METHODS
For those recipients surviving for more than 1 year after transplantation, coronary angiography was performed annually for surveillance of transplant CAD. The recipient characteristics, donor characteristics, rejection episodes, medication and human leukocyte antigen (HLA) mismatches were recorded.
RESULTS
Fifty patients were included in this study. Thirteen (26%) recipients had ischemic heart disease. Two patients (4%) had active cytomegalovirus (CMV) infection after transplantation. The mean number of rejection episodes in the 1st year after transplantation was 1.15. Among 47 patients with complete data of donor and recipient histocompatibility antigens, there were seven patients (14.9%) with two or fewer HLA mismatches. Among 74 angiograms of 50 patients reviewed, only one patient had discrete stenosis less than 50% in the middle portion of the left anterior descending artery at 1 year after transplantation. The cumulative incidence of transplant CAD was 2% at 1 year and 2% at 2 and 4 years after transplantation.
CONCLUSIONS
The incidence of transplant CAD was low in Chinese heart transplant recipients. Low percentage of ischemic heart disease in recipients, low occurrence of active CMV infection and rejection episodes after transplantation, less racial disparity, and lower HLA mismatches may be the important factors.
Advances in immunosuppressive therapy have reduced early mortality due to acute rejection and infection (1,2). However, transplant coronary artery disease (CAD) was still the major cause of mortality and morbidity in the long-term survivors of heart transplants (3–9). The prevalence of transplant CAD detected by angiography at 1, 2 and 4 years after transplantation was 11%, 22% and 45% (9). In Asia, the first clinical heart transplantation was performed by Wada in 1968. Because of poor result, no active heart transplantation program proceeded for two decades. In July 1987, the first heart transplantation was started in Taiwan (10). The aim of this study was to assess the incidence of transplant CAD in Chinese heart recipients.
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Methods
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Patients and treatment.
From October 1987 to June 1998, we had performed 92 cases of heart transplantation at the National Taiwan University Hospital. Eight-eight patients underwent orthotopic heart transplantation. Since 1997, we have used bicaval anastomosis, instead of standard midatrial anastomosis, for orthotopic transplantation especially in patients with high pulmonary vascular resistance. There were four cases of heterotopic heart transplantation for donor/recipient size mismatch in two (11), poor donor heart function in one and high pulmonary vascular resistance before transplantation in one patient. There were two cases of successful simultaneous heart and kidney transplantation. One case with Marfan syndrome had successful combined heart transplantation and resection of dissecting aortic aneurysm of ascending aorta and aortic arch. Three patients had mechanical bridge to heart transplantation successfully using the Thoratec ventricular assist device. Postoperatively, we used extracorporeal membrane oxygenation for acute allograft failure in eight patients. Three of eight patients were successfully weaned and discharged.
All patients received triple-drug immunosuppressive therapy according to our heart transplantation protocol. Since 1995, we have used rabbit antithymocyte globulins for induction therapy. Azathioprine (4 mg/kg) was given 1 h before the operation. Solumedrol (1,000 mg) was infused during release of the aortic cross clamp. Rabbit antithymocyte globulin 1.5 to 2.5 mg/kg/day was given after transplantation for 5 days. Cyclosporine was started orally within 5 days after transplantation or after the recovery of renal function. Cyclosporine dose was adjusted according to renal function and serum cyclosporine level, which was maintained at the trough level of 300 to 500 ng/ml during the first 3 months after transplantation and 200 to 300 ng/ml 1 year after transplantation. Azathioprine was given at 1 to 2 mg/kg/day after transplantation, with the dose adjusted to maintain a white blood cell count 4,000 to 6,000/mm3. Prednisone (0.5 mg/kg/day) was started on the second postoperative day and tapered to 0.2 mg/kg/day by the 1st month after transplantation. Endomyocardial biopsy was performed weekly in the first month, biweekly in the second month, monthly in the sixth month and yearly six months after transplantation. Tacrolimus (FK-506) and mycophenolate mofetil (Cellcept) were used for recurrent rejection or severe adverse reactions to cyclosporine and azathioprine.
All patients discharged received 100 mg aspirin daily and 25 mg dipyridamole three times per day for prevention of transplant CAD. Hyperlipidemia was treated with dietary modification and body weight control first. Hypertriglyceridemia was treated with bezafibrate. Hypercholesterolemia was treated with pravastatin and acipimox. Hyperuricemia was treated with probenecid and allopurinol. Hyperglycemia was treated with oral hypoglycemic agent and insulin. Hypertension was treated with angiotensin-converting enzyme inhibitors and calcium antagonists. All patients were followed at a special cardiac transplant clinic.
Data collection.
For those patients surviving for more than six months after transplantation, coronary angiography and endomyocardial biopsy were performed annually for surveillance of transplant CAD. The coronary angiogram performed 1 month after transplantation was used for baseline data. Cineangiograms were recorded at 60 frames/s through a lens with a focal length of 135 mm and with an X-ray field of 15 cm. Multiple pairs of perpendicular views of the left and right coronary arteries were taken. All coronary angiograms were reviewed by two cardiologists in a blinded fashion. Coronary lesions were evaluated by on-line digital quantitative coronary angiograms (DCI System, Philips, Best, The Netherlands) (12). The intraobserver and interobserver variations were 5% and 8%, respectively. The diagnosis of transplant CAD was made from the evidence of any coronary artery irregularity or diffuse narrowing in proximal and distal vessels. Transplant CAD was classified as localized atherosclerotic lesions or diffuse concentric narrowing. Endomyocardial biopsy was examined for ischemic myocardial pathology. Cardiac events including myocardial infarction, left ventricular dysfunction, arrhythmia and sudden death were recorded. The recipient characteristics (age, gender, body weight, smoking, hypertension, diabetes, cholesterol level, triglyceride level and viral infection), donor characteristics (age, gender, preexisting coronary artery disease and allograft ischemic time), rejection episodes, medications and human leukocyte antigen (HLA) match were recorded. Cytomegalovirus (CMV) infection was defined as a fourfold rise in antibody, CMV inclusion body or positive culture. Rejection was defined as biopsy-proven pathologic finding and clinical event leading to specific immunosuppressive intervention.
Statistical analysis.
Comparisons between groups were determined by the two-tailed t test for difference in proportion and means. A difference of p < 0.05 was considered statistically significant.
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Results
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Among these 92 heart transplant recipients, seven patients died within the first month after transplantation because of bleeding in 3, acute rejection in 2, arrhythmia in 1 and cerebral injury in 1 patient. Another 10 patients died within the first year after transplantation because of infection in 5, rejection in 3 (two for medical noncompliance) and arrhythmia and gastrointestinal bleeding each in one patient. The operative mortality rate was 7.6%. The one-year survival rate was 81.5%. Twenty-five of 92 cardiac transplant patients are alive less than 1 year after transplantation and could not be evaluated for this study. At the time of this study, obesity was present in 17, hypertension in 21, hyperuricemia in 27, diabetes in 17, renal dysfunction in 21 and hyperlipidemia in 34 of 50 patients. No patients used diltiazem. Pravastatin was used in 12 patients for hyperlipidemia.
Fifty patients survived for more than one year and were included in this study. Among these 50 patients, there were 42 men and 8 women. The clinical diagnosis of end-stage heart failure was idiopathic dilated cardiomyopathy in 31 (62%), ischemic heart disease in 13 (26%), valvular heart disease in 4 (8%), congenital heart disease and postpartum cardiomyopathy in 1 patient. The mean recipient age was 44.1 ± 13.6 years at the time of transplantation. The mean donor age was 29.4 ± 10.8 years (range 15 to 55). Positive CMV antibody was present in 44 of 48 recipients (91.7%) and 27 of 30 donors (90%) at the time of transplantation. The allograft ischemic time was 45 to 223 min (mean 101.1).
Rejection.
Thirty-two patients had a biopsy-proven episode of acute rejection within the 1st year after transplantation, with an incidence of rejection of 64% within 1 year after transplantation. The mean number of rejection episodes in the 1st year after transplantation was 1.15. Among the ninety-two cases of heart transplantation, two patients had acute vascular rejection and died in spite of mechanical circulatory support, plasmapheresis and immunoadsorption therapy. Rejection rarely occurred in patients more than one year after transplantation. Only two recipients had late acute rejection.
Infection.
During the follow-up period, eight patients had major infection. Among these 50 recipients, seven patients (14%) were hepatitis B carriers. Three of seven carriers had liver failure due to hepatitis B reactivation. Two patients were treated successfully with lamivudine. One patient had liver cirrhosis at eight years after transplantation. Two patients (4%) had active CMV infection and were treated with ganciclovir therapy. One patient had Aspergillus infection and was cured by amphotericin infusion and wedge resection of infected lung (13). There was one patient with malignant lymphoma of small intestine. No patient had solid organ tumor or Kaposi sarcoma after transplantation.
Cardiac event.
Cardiac events occurred in three patients. One patient had atrial arrhythmia. One patient had biopsy-negative left ventricular dysfunction and the coronary angiogram was patent. Another patient with heterotopic heart transplantation had sudden arrest of donor heart. The coronary artery was patent and the pathology was massive coagulation necrosis. The patient was doing well for improved native heart function due to prolonged unloading of native heart after heterotopic heart transplantation.
Human leukocyte antigen mismatch.
Complete HLA information on the A, B and DR loci was available for both donor and recipient in 47 patients. Seven patients (14.9%) had two or fewer HLA mismatches, whereas three patients (6.4%) had mismatches of all six HLA loci (Table 1).
Transplant CAD.
Coronary angiography was reviewed by at least two cardiologists at the time of study. Among 74 angiograms of 50 patients reviewed, only one patient had discrete stenosis less than 50% in the middle part of the left anterior descending artery at one year after transplantation. This patient, a 39-year old man, was a case of ischemic heart disease and received heart transplantation for end-stage heart failure. He had two rejection episodes in the first year after transplantation. No coronary angioplasty was performed then, because he was free of angina and left ventricular dysfunction. No patient had diffuse narrowing of coronary artery. The cumulative incidence of transplant CAD was 2% (1/50) at 1 year and 2% at 2 years (30 cases) and 4 years (10 cases) after transplantation. In all specimens of endomyocardial biopsy after 1 year posttransplant, there was no evidence of ischemic myocardial pathology including subendocardial myocyte vacuolization and coagulative myocyte necrosis as described by Winters and Schoen (14).
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Discussion
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Transplant CAD.
Heart transplantation has become a highly effective therapy for patients with end-stage heart diseases. With advances in management of infectious complications and immunosuppressive therapy, the survival after heart transplantation continues to improve. In the 1993 Registry of the International Society for Heart and Lung Transplantation, the one-year and five-year survival rates after heart transplantation were 79.1% and 67.8% (15). Although modern immunosuppressive therapy has reduced death caused by acute rejection and infection, late mortality as a result of transplant CAD remains an unresolved problem (3–8). In a multi-institutional study (9), the prevalence of transplant CAD detected by angiography was 11%, 22% and 45% at 1, 2 and 4 years after transplantation, respectively. Transplant CAD is an accelerated form of atherosclerosis, characterized by rapid development of intimal hyperplasia and smooth muscle cell proliferation (16). It accounts for 36% of deaths in patients who survive 1 year after transplantation and for 60% of retransplantation (17,18). Myocardial revascularization procedures, including coronary angioplasty (19), coronary artery bypass (20) and transmyocardial laser revascularization (21), have limited role in the management of transplant CAD for diffuse narrowing of distal coronary artery. Retransplantation is also associated with higher mortality and morbidity (18). It is imperative to understand the risk factors and pathogenesis of transplant CAD and to prevent its development and progression.
Heart transplantation in Asia.
Asia has more than 50% of the world’s population, but the number of heart transplantation up to December 1996 was only 380 cases. This number is quite small in contrast to the huge number performed in America and Europe. The major problem has been that the acceptance of the concept of brain death as the definition of death of the patient is difficult for Oriental people due to cultural and religious reasons. Most Chinese people want to keep the whole body buried after death. Although Taiwan is a small island with a population of 22 million, about half the number of heart transplantations in Asia have been performed in Taiwan. This provided us a chance to evaluate the incidence of transplant CAD in Chinese heart recipients. In this study, the incidence of transplant CAD in our patients was only 2% at 1 year and none at 2 and 4 years after transplantation. This was much lower compared with the Western series (3,9).
Risk factors.
Numerous studies have investigated the possible risk factors for the development of transplant CAD (3–8). Controversies still exist regarding donor and recipient factors which promote the development and progression of CAD after transplantation. Both immunologic and nonimmunologic factors could contribute to the occurrence of transplant coronary artery disease. Older recipient age, older donor age, male recipient, female donor, recipient with ischemic heart disease, allograft ischemic time, CMV infection, hyperlipidemia, obesity, immunosuppression, acute rejection, prophylactic diltiazem use, HLA mismatches and racial disparity have been recognized as the risk factors (3–9,22–25). In Table 2, we compare the donor and recipient characteristics between our patients and Western patients (3–8,24). The donor age, recipient age and percentage of male gender were the same. Pretransplant diagnosis of recipients in our study was less due to ischemic heart disease. The prevalence of ischemic heart disease is low in Oriental countries possibly due to low fat and high vegetable diet.
Cytomegalovirus infection.
Human CMV infection has been recognized as a significant risk factor of transplant CAD, and prophylactic ganciclovir therapy may protect against the development of transplant CAD (3,22). In this study, more than 90% of donors and recipients had positive CMV antibody before transplantation. The incidence of CMV mismatches between donors and recipients was also low. The percentage of CMV seronegative recipients was only 8.3% in this study. Thus the chance of primary CMV infection after transplantation was reduced. In fact, people in Taiwan usually had CMV infection by airborne transmission before adulthood. This accounts for the high incidence of past CMV infection before transplantation.
Human leukocyte antigen mismatch.
Previous studies have shown that HLA mismatches are associated with a higher incidence and severity of transplant CAD (3,23). The pathogenic mechanism of transplant CAD is thought to be primarily immune-mediated. Both cellular and humoral immunities are involved. Besides, race and donor/recipient race mismatch may influence the development of transplant CAD. African-Americans have increased early mortality due to transplant CAD (24). In this study, the donors and recipients were all Chinese except one white donor from Ireland. Thus the race mismatch was only one of 50 recipients. The HLA mismatch was also low in this study. The incidence of HLA mismatches two or less in A, B and DR loci was 14.9%, compared with 6% in Western series (26).
Rejection.
Previous studies have shown that the risk of transplant CAD may be increased by acute graft rejection (6,25). In this study, we used antithymocyte globulin for induction and higher doses of cyclosporine for maintenance immunosuppression. The incidence of rejection within one year after transplantation was the same between this study and Western series (26). But the mean number of rejection episodes in the first year after transplantation was 1.15. Low number of rejection episodes after transplantation may be the causative factor of low incidence of transplant CAD in this study.
Several nonimmunologic factors could contribute to the development of transplant CAD. In this study, the prevalence of diabetes mellitus, renal dysfunction and hyperlipidemia in recipients after one year posttransplant was higher than in the Western series (8). It further indicated that the low incidence of transplant CAD in Chinese heart recipients was significant, and that the development of transplant CAD is genetic/immunologic.
Study limitation.
The major limitation of this study was relatively short follow-up (30 patients at 2 years and 10 patients at 4 years). It is important to continue this study and see if these preliminary observations hold up.
Conclusions.
This study confirms the low incidence of transplant CAD in Chinese heart transplant recipients in comparison with Western transplant patients. Low percentage of ischemic heart disease in recipients, low occurrence of active CMV infection and rejection episodes after transplantation, less racial disparity and lower HLA mismatches may be the important factors.
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Footnotes
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This study was supported in part by grant 88N108 from National Taiwan University Hospital.
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References
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1. Kahan BD. Immunosuppressive therapy with cyclosporine for cardiac transplantation. Transplant Heart. 1987;75:40–55
2. Sarris GE, Moore KA, Schroeder JS, et al. Cardiac transplantation: the Stanford experience in the cyclosporine era. J Thorac Cardiovasc Surg. 1994;108:240–252[Abstract/Free Full Text]
3. Weis M, von-Scheidt W. Cardiac allograft vasculopathy: a review. Circulation. 1997;96:2069–2077[Abstract/Free Full Text]
4. Sharples LD, Caine N, Mullins P, et al. Risk factor analysis for the major hazards following heart transplantation—rejection, infection, and coronary occlusive disease. Transplantation. 1991;52:244–252[Medline]
5. Gao SH, Schroeder JS, Alderman EL, et al. Prevalence of accelerated coronary artery disease in heart transplant survivors. Circulation. 1989;80(Suppl III):100–105
6. Olivari MT, Homans DC, Wilson RF, et al. Coronary artery disease in cardiac transplant patients receiving triple-drug immunosuppressive therapy. Circulation. 1989;80(Suppl III):111–115
7. Labarrere CA, Nelson DR, Faulk WP. Endothelial activation and development of coronary artery disease in transplanted human hearts. JAMA. 1997;278:1169–1175[Abstract/Free Full Text]
8. Brann WM, Bennett LE, Keck BM, Hosenpud JD. Morbidity, functional status, and immunosuppressive therapy after heart transplantation: an analysis of the joint International Society for Heart and Lung Transplantation/United Network for Organ Sharing Thoracic Registry. J Heart Lung Transplant. 1998;17:374–382[Medline]
9. Costanza MR, Naftel DC, Pritzker MC, et al. Heart transplant coronary artery disease detected by angiography: a multi-institutional study (abstr). J Heart Lung Transplant. 1996;15:S39
10. Wang SS, Chu SH, Ko WJ. Clinical outcome in heart transplantation: experience at the National Taiwan University Hospital. Transplant Proc. 1996;28:1735–1736[Medline]
11. Chu SH, Wang SS, Tsai CH, et al. Monitoring of two hearts in one chest. J Cardiovasc Surg. 1995;36:449–454[Medline]
12. Lee TM, Chu CC, Hsu YM, et al. Exaggerated luminal loss a few minutes after successful percutaneous transluminal coronary angioplasty in patients with recent myocardial infarction compared with stable angina: an intracoronary ultrasound study. Cathet Cardiovasc Diagn. 1997;41:32–39[CrossRef][Medline]
13. Wang SS, Chu SH, Lee YC, et al. Successful treatment of invasive pulmonary aspergillosis in heart transplantation. Transplant Proc. 1994;26:2329–2332[Medline]
14. Winters GL, Schoen FJ. Graft arteriosclerosis-induced myocardial pathology in heart transplant recipients: predictive value of endomyocardial biopsy. J Heart Lung Transplant. 1997;16:985–993[Medline]
15. Kaye MP. The Registry of the International Society for Heart and Lung Transplantation: Tenth Official Report—1993. J Heart Lung Transplant. 1993;12:541–548[Medline]
16. Dressler FA, Miller LW. Necropsy versus angiography: how accurate is angiography? J Heart Lung Transplant. 1992;11:S56–S59[Medline]
17. Uretsky BF, Murali S, Reddy PS, et al. Development of coronary artery disease in cardiac transplant patients receiving immunosuppressive therapy with cyclosporine and prednisone. Circulation. 1987;76:827–834[Abstract/Free Full Text]
18. Gao SH, Schroeder JS, Hunt SA, Stinson EB. Retransplantation for severe accelerated coronary artery disease in heart transplant recipients. Am J Cardiol. 1988;62:876–881[CrossRef][Medline]
19. Christensen BV, Meyer SM, Iacarella CL, et al. Coronary angioplasty in heart transplant recipients: a quantitative angiographic long-term follow-up study. J Heart Lung Transplant. 1994;13:212–220[Medline]
20. Halle AA III, DiSciascio G, Massin EK, et al. Coronary angioplasty, atherectomy and bypass surgery in cardiac transplant recipients. J Am Coll Cardiol. 1995;26:120–128[Abstract]
21. March RJ, Guynn T. Cardiac allograft vasculopathy: the potential role for transmyocardial laser revascularization. J Heart Lung Transplant. 1995;14:S242–S246[Medline]
22. Valantine HA, Gao SH, Gopinathan SK, et al. Impact of prophylactic immediate post-transplant ganciclovir on development of transplant atherosclerosis: a randomized placebo-controlled study. J Heart Lung Transplant. 1996;15:S72
23. Stempfle HU, Klauss V, Mudra H, et al. The influence of HLA compatibility on the incidence of cardiac allograft vasculopathy detected by intravascular ultrasound (abstr). J Heart Lung Transplant. 1996;15:S72
24. Dumas-Hicks D, Ripoll M, Ventura HO, Mehra MR. Does racial disparity influence clinical outcomes in adult women undergoing heart transplantation (abstr)? J Heart Lung Transplant. 1998;17:S78
25. Bann CC, Holweg CT, Niesters GM, et al. The nature of acute rejection is associated with development of graft vascular disease after clinical heart transplantation. J Heart Lung Transplant. 1998;17:363–373[Medline]
26. Jarcho J, Naftel DC, Shroyer TW, et al. Influence of HLA mismatch on rejection after heart transplantation: a multi-institutional study. J Heart Lung Transplant. 1994;13:583–596[Medline]
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Abstract
Methods