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(Circulation. 1996;94:1815-1817.)
© 1996 American Heart Association, Inc.

Articles

Heart Transplantation in Chagas' Disease

10 Years After the Initial Experience

Valeria B. de Carvalho, MD; Eduardo F.L. Sousa, MD; Jose Henrique A. Vila, MD; Jose Pedro da Silva, MD; Marcio R. Caiado, MD; Sergio R. de R. Araujo, MD; Radi Macruz, MD; E.J. Zerbini

the Universidade de Sao Paulo (V.B.deC., R.M.); INTERCOR (V.B.deC., E.F.L.S., M.R.C., R.M.); Clinica Cardio Cirurgica J.P. da Silva (J.H.A.V., J.P.daS.); and Department of Pathology of Hospital da Real e Benemerita Sociedade Portuguesa de Beneficencia (S.R.deR.A.), Sao Paulo, Brazil.

	Abstract

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Background Heart transplantation (HT) as a therapeutic option for end-stage chronic Chagas' heart disease (CCHD) is controversial. Reactivation of Trypanosoma cruzi infection and recurrence of the disease in the allograft are likely to occur. Furthermore, active myocarditis has been reported to predispose patients to an increased incidence and severity of rejection.

Methods and Results We prospectively investigated the long-term follow-up of 10 patients with CCHD who underwent HT. Immunosuppression was based on cyclosporine A and azathioprine. T cruzi reactivation was prevented with benzonidazole. Besides allograft rejection surveillance, T cruzi infection was monitored through blood tests, myocardial biopsies, and serological tests. Over a mean follow-up period of 34±38 months (range, 73 to 124 months), 7 patients are alive and in NYHA functional class I. Life expectancy was 78% for the second year and 65% for 10 years. Rejection was less frequent in chagasic than in age- and sex-matched control patients (mean±SD, 1.60±1.26 versus 5.70±1.89 episodes per patient, respectively; P=.0001); decreased severity of rejection was also observed (P=.006). T cruzi parasitemias detected on three occasions were successfully treated with benzonidazole. There were no signs of recurrence of the disease in the allograft.

Conclusions These results suggest an important role of HT in the treatment of CCHD. There was a low frequency of T cruzi infection reactivation and no signs of recurrence of the disease in the allograft. The surprisingly decreased rejection incidence and severity require further studies for elucidation.

Key Words: Chagas' disease • transplantation • follow-up studies • myocarditis • rejection

	Introduction

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Heart transplantation is an effective treatment for patients with end-stage heart failure. Nevertheless, it is not indicated for patients with primary or secondary heart disease likely to recur in the allograft.¹ HT in Chagas' disease has raised important questions concerning infection reactivation related to immunosuppression and recurrence of the disease in the transplanted heart.²

CCHD is more prevalent in young people³ and presents high morbidity and mortality during the decompensation stage.⁴ On the other hand, treatment with specific drugs, such as benzonidazole, is satisfactory, at least during the acute phase of the disease.⁵ On the basis of these facts and of the results obtained with kidney transplantation in Chagas' disease,^{6 7} our group, under the leadership of Professor E.J. Zerbini, performed the first HT in a patient with CCHD on June 3, 1985.⁸ The present study prospectively investigated the follow-up of this patient and others with CCHD submitted to orthotopic HT in our institution. The main purpose of the study was not to determine the feasibility of HT in patients with CCHD but rather to investigate the follow-up features of these patients because of the systemic nature of the disease and the heart-specific immunoreactivity associated with active myocarditis.

	Methods

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Patients
Ten patients with NYHA functional class IV heart failure and positive serological tests for Chagas' disease who received orthotopic HTs as of 1985 were studied. Nine were men; the mean age was 44±11 years. Patients with megesophagus, megacolon, and classic contraindications were excluded.⁹ The mean value of LVEF by M-mode echocardiogram was 0.21±0.08.

Immunosuppression
The immunosuppression protocol was based on Yacoub et al.¹⁰ Cyclosporin A (CyA) was maintained in doses varying from 1 to 10 mg·kg^-1·d^-1 during the postoperative period, depending on values in total hemolyzed blood, seeking initial levels of 300 to 400 ng/mL and 100 to 150 ng/mL as of the third month. Azathioprine was maintained in doses varying from 0.5 to 1.5 mg·kg^-1·d^-1. Two patients also required steroids because of side effects of CyA, and in one of these, prednisone was continued on a long-term basis.

Rejection
AR was monitored through weekly endomyocardial biopsies during hospitalization, every 2 weeks during the first 2 months, monthly up to month 6, and every 2 or 3 months during the first year of follow-up and then every year or when AR was suspected. AR was diagnosed according to the criteria of the International Society of Heart Transplantation¹¹ ; grade 2 was treated with methylprednisolone at 0.5 or 1 g/d for 3 days. To analyze AR episodes, an age- and sex-matched control group of 10 patients who received HTs for other causes, with the same immunosuppressive regimen and followed through a similar period, was studied. The incidence and severity of treated AR episodes in chagasic (study group) and nonchagasic (control group) patients were compared.

Trypanosoma cruzi Infection Reactivation
Prevention of T cruzi infection reactivation was performed by administration of benzonidazole (10 mg·kg^-1·d^-1) during 60 days in the preoperative period to the 8 patients who tolerated it and to all patients during the immediate postoperative period. T cruzi infection was monitored during the preoperative and postoperative periods. In the latter, evaluation was performed along with endomyocardial biopsies, quarterly in the first year, and every 6 or 12 months thereafter. Tests to detect parasites in myocardial tissue and in blood were performed. Blood tests included direct examination, xenodiagnosis, and culture, as well as serological tests such as complement fixation, hemagglutination, and immunofluorescence assays.

Infection and Neoplasias
Episodes of infection that required treatment and the occurrence of neoplasias were included in the analysis.

Data Analysis
Data are expressed as mean±SD. Life expectancy curves were generated by the Kaplan-Meier method with ±95% CIs. The linearized rate for treated AR or infection was calculated by dividing the number of events per patient by the entire postoperative period. Patient and control data were compared by unpaired Student's t test. A value of P<.05 was accepted as significant. All patients were informed of study procedures, according to the ethical guidelines approved by our hospital's Ethics Committee.

	Results

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Outcome
The mean postoperative period was 34±38 months (range, 73 to 124 months). Seven patients are alive and in NYHA functional class I. Three patients died: 1 in the late postoperative period, of Lysteria monocytogenes septicemia, and 2 in the immediate postoperative period, of grade 4 rejection and fungal septicemia. Life expectancy was 78% for the second year and 65% for 10 years (Figure). During the long-term follow-up, mild arterial hypertension was observed in 2 patients, increased creatinine levels (maximum of 1.7 mg/dL) in 2, and hypercholesterolemia in 4; none developed diabetes. Seven patients underwent coronary angiography (9 to 96 months after surgery), which was normal in 6 and showed mild arterial stenosis and normal left ventricular function in 1 (month 14). The mean value of LVEF on the echocardiogram was 0.76±0.05 in survivors at the end of the postoperative period. All patients maintained positive serological tests for Chagas' disease.

View larger version (11K): [in this window] [in a new window]   Figure 1. Life expectancy curve for patients with CCHD after heart transplantation. Kaplan-Meier method and respective 95% CI.

Acute Rejection
Two patients did not present any episode of AR during a postoperative period of 50 and 43 months, as well as one who died on day 23. The others developed one to three episodes throughout the whole postoperative period. The mean of treated AR episodes per patient was lower in chagasic patients than in the control group (1.60±1.26 versus 5.70±1.89 episodes per patient, respectively; P=.0001) during the entire follow-up periods (P=NS), and the linearized rates for treated AR were 0.047 and 1.23 episodes per patient per month, respectively. AR was less severe in chagasic than in nonchagasic patients (P=.006).

T cruzi Infection Reactivation
Reactivation of T cruzi infection occurred in three patients, in whom the parasite was detected in blood during months 2, 17, and 23. Parasitemia was successfully treated with benzonidazole. There were no recurrences of infection for a postoperative period of 26 to 124 months. None of the patients presented signs of myocarditis or parasites in the allograft on these occasions. No parasites were found in myocardial or other tissues in the three autopsy studies.

Infection and Neoplasias
Seventeen episodes of infection required treatment during the postoperative period (1.70±1.57 episodes per patient). Eight events had bacterial origin, 6 viral, and 3 fungal. The linearized infection rate was 0.05 episode per patient per month. None of the patients developed neoplasias.

	Discussion

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Data presented through long-term follow-up show that heart transplants for treatment of heart failure due to CCHD lead to good results. A life expectancy of 65% in 10 years seems promising, considering the unfavorable natural history of decompensated CCHD; life expectancy of patients with clinical signs of heart failure is 47% for year 2, 19% after 5 years, and 9% after 10 years.⁴ Overall mortality was lower than that reported in another series¹² but similar to a more recent one.¹³ No death was directly related to the disease itself. The favorable 10-year follow-up of the first chagasic patient who underwent HT, who is still in NYHA functional class I and has a normal LVEF, as well as of the remaining survivors should be emphasized. Even though the mean length of follow-up of the whole sample is only 34±38 months, it may be in some way substantial, considering the poor natural history of the severely symptomatic chagasic patients and the lack of reports about any other longer follow-ups on HT in CCHD. The incidence of coronary artery disease and other usual post-HT complications was not unusual.

An important and unprecedented finding was the lower incidence and severity of AR, unlike the data reported in patients with a diagnosis of myocarditis.¹⁴ This unexpected finding supports the view that the pathogenesis of CCHD is somewhat unknown, despite the evidence of autoimmune mechanisms. Recent findings once again suggest the fundamental role of the parasite, not only during the acute but also in the chronic stage, leading to changes in immunodepression, hypersensitivity reactions, increased fibrinogenesis, microthrombi, microspasm, and microinfarctions.¹⁵ Thus, the eradication of the parasite through antiparasitic drugs must be emphasized.^{15 16} Conversely, studies on CCHD have demonstrated an immunological imbalance, with intense immunodepression, depletion of CD4+ cells and interleukin 2, and other alterations in cytokines.^{15 17 18} A hypothesis to be investigated is how much this immunodepression would contribute to the decreased incidence and severity of AR found in the chagasic patient. Further studies are necessary to validate this hypothesis.

Reactivation of infection by T cruzi was unusual, and there were no concomitant clinical signs of the disease or myocarditis. No recurrence of the disease in the allograft or deterioration of LVEF suggesting clinically silent myocardial damage was observed in any patient. Our data are in accordance with the uncommon reactivation of infection after kidney transplantation.^{6 7 19 20} They differ, however, from the reported high incidence of disease reactivation and myocarditis after HT,¹² which could be linked to overimmunosuppression or use of steroids. The effect of immunosuppressive drugs in T cruzi infections has not been completely elucidated. Experimentally, the increase in the severity of disease in T cruzi–infected and immunodepressed mice by association of CyA and prednisone has been reported.²¹ However, CyA could be useful for controlling autoimmune reactivity without inducing infection reactivation.^{2 22} The exceptional use of steroids in this study may have favored the results. Besides, the eventual beneficial influence of administration of benzonidazole in the immediate preoperative and postoperative periods cannot be disregarded.

The prevalence of infection was not outstanding. The absence of neoplasias in this study, despite prophylactic and systematic use of benzonidazole, does not support the view that damage to the T-cell function by benzonidazole treatment and T cruzi infection could be responsible for the high incidence of neoplasias observed in another study.¹² These findings might be related to other factors, among them overimmunosuppression.

A limitation to this study is the number of patients, which is small, given that chagasic patients have high morbidity and mortality, a very low socioeconomic status, and limited access to adequate private health facilities. This limitation must be considered in the interpretation of the collected results; hence the relatively large CIs observed in life expectancy analysis. However, the long period between inclusions of patients into the study does not invalidate its findings, because there were no changes in relation to surgical procedures, immunosuppression therapy, or infection surveillance.

In conclusion, the present study suggests that HT is an effective option for treating heart failure in CCHD. Reactivation of T cruzi infection may occur, but it can be controlled when identified early. Recurrence of disease in the allograft was not observed. The low incidence and severity of AR were unexpected findings, but they require further studies for elucidation. The future of these patients is unpredictable, but since chronic Chagas' myocarditis takes many years to evolve, current data encourage us to suppose that HT may change the natural history of the decompensated chronic heart disease.

	Selected Abbreviations and Acronyms

 

AR = acute rejection CCHD = chronic Chagas' heart disease HT = heart transplantation LVEF = left ventricular ejection fraction

	Footnotes

 
Reprint requests to R. Bahia, 70, 13° A. Higienopolis CEP 01244000, Sao Paulo, Sao Paulo, Brazil.

E.J. Zerbini, Emeritus Professor of Cardiovascular Surgery of the Universidade de Sao Paulo, died October 23, 1992.

Received February 14, 1996; revision received August 14, 1996; accepted August 14, 1996.

	References

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