Isolated Cardiac Sarcoidosis in Heart Transplantation

Isolated Cardiac Sarcoidosis in Heart Transplantation T.-I. Chang, N.-H. Chi, N.-K. Chou, C.-I. Tsao, H.-Y. Yu, Y.-S. Chen, and S.-S. Wang ABSTRACT Background. Heart transplantation is the ultimate treatment for end-stage heart failure. Cardiac sarcoidosis has rarely been reported in heart transplantation worldwide. Their long-term prognosis after heart transplantation is unknown. Herein we have presented clinical and pathological observations among heart transplantation patients with isolated cardiac sarcoidosis. Methods. From 1987 to 2011, we performed 411 heart transplantations including five patients retrospectively reviewed due to the presence of sarcoidosis and giant-cell cardiomyopathy in the recipient heart. Results. Among the heart transplantations from 2003 to 2011, the four male and one female patients were ages 31 to 40 years. None of them had extra-cardiac sarcoidosis. All five subjects presented with dilated cardiomyopathy with patent coronary arteries. The commonest clinical presentations were atrioventricular block, ventricular arrhythmia, electrocardiographic findings of ST elevations, and poor left ventricular ejection fractions (17%–23%). All patients survived without allograft heart failure to date with the longest survivor at 8 years postoperatively. No recurrence of sarcoidosis has been observed clinically or among the post– heart transplantation endomyocardial biopsies. Conclusion. Heart transplantation is a useful treatment for isolated cardiac sarcoidosis patients suffering end-stage heart failure. Often the diagnosis is difficult to establish before heart transplantation despite endomyocardial biopsy. No recurrence of sarcoidosis was observed among the allografted hearts. HE ETIOLOGY OF SARCOIDOSIS is still unknown. The disease may affect many organs. Pathological features include lymphocyte and phagocyte accumulation as well as noncaseating granulomas.1 These pathological changes destroy the normal tissue architecture causing variable degrees of organ dysfunction. Cardiac sarcoidosis is rare; there is almost no specific treatment to reverse it.2 It often presents with sudden death or a life-threatening arrhythmia.3 In the most severe cases, patients might present with end-stage heart failure. This retrospective analysis reviews the long-term outcomes among heart transplant patients with sarcoidosis.

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PATIENTS AND METHODS Patient Population From July 1987 to June 2010, we performed 411 orthotopic heart transplantations including five in patients diagnosed with sarcoidosis. Two of them were confirmed to have cardiac sarcoidosis in the explanted heart. We compared their outcomes with other the 406 patients without cardiac sarcoidosis. Pretransplant clinical and © 2012 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 44, 903–906 (2012)

demographic information, as well as pre- and posttransplant echocardiography reports, liver and renal function, cardiac output, central venous pressure, pulmonary artery pressure, pulmonary vascular resistance, and biopsy results were assessed.

Immunosuppression and Rejection Surveys All patients underwent immunosuppressive therapy including since 1995, rabbit antithymocyte globulin for induction and azathioprine (4 mg/kg) administered 1 hour before the operation with Solumedrol (1000 mg) infused upon release of the aortic cross-clamp. Rabbit antithymocyte globulin (1.5–2.5 mg/kg/d) was administered From the Department of Cardiovascular Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. T.-I. Chang and N.-H. Chi contributed equally to this manuscript. Address reprint requests to Professor Wang, Department of Cardiovascular Surgery, National Taiwan University Hospital, 7 Chung-Shan S Rd, 100 Taipei, Taiwan. E-mail: wangp@ntu. edu.tw 0041-1345/–see front matter doi:10.1016/j.transproceed.2012.01.087 903

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CHANG, CHI, CHOU ET AL

Table 1. Demographic Data of Sarcoidosis Patients and Nonsarcoidosis Patients Sarcoidosis

n Age Sex (M/F) Height (cm) Weight (kg) Pretransplant Mean PAP (mm Hg) LVEF (%) PVR (Wood unit) Ischemic time (min)

Without Sarcoidosis

P Value

5 34.93 ⫾ 8 4/1 160.06 ⫾ 4.2 59.23 ⫾ 11.5

406 44.0 ⫾ 16 288/108 163.8 ⫾ 4.9 63.30 ⫾ 9.1

.661 .732

33.56 ⫾ 7.5 20.13 ⫾ 12.7 2.8 ⫾ 1.9 136.6 ⫾ 58.4

40.05 ⫾ 6.3 19.85 ⫾ 6.87 3.55 ⫾ 3.21 126.3 ⫾ 69.5

.32 .75 .18 .27

.47

PAP, pulmonary artery pressure; LVEF, left ventricular ejection fraction; PVR, pulmonary vascular resistance.

for 5 days after transplantation. Oral cyclosporine was started within 5 days following transplantation or after renal functional recovery. Cyclosporine dosage was adjusted based on renal function and blood levels, which were maintained at trough levels of 300 to 500 ng/mL during the first 3 posttransplant months and 200 to 300 ng/mL at 1 year after transplantation. Azathioprine (1–2 mg/kg/d) was prescribed after transplantation at dosages adjusted to maintain a white blood cell count of 4000 to 6000/mm3. Prednisone (0.5 mg/kg/d) initiated on postoperative day 2 was gradually reduced to 0.2 mg/kg/d by the first month after transplantation. Tacrolimus (FK-506) and mycophenolate mofetil (Cellcept) were used in cases of recurrent rejection episodes or severe adverse reactions to cyclosporine and azathioprine, respectively. Since 2004, mycophenolate mofetil was substituted for azathioprine for primary immunosuppression. Coneomittantly, to prevent nephrotoxicity, the cyclosporine dose has been reduced to sustain a trough

Fig 1. (A) Grossly, all explanted hearts have patched fibrosis, which can be seen here in the subendocardium and extending to the epicardium. (B) Typically granulomatous inflammation can be detected in hematoxylin-cosin stain; the granulations destroy the normal arrangement of cardiomyocytes and cause ventricular dysfunction. (C) Multinucleated giant cells aggregated in the septum. (D) CD68 stain showed positive enhancement in those aggregated cells.

level of 250 to 350 ng/mL during the first 3 months after transplantation and 150 to 250 ng/mL at 1 year after transplantation. All patients were followed monthly in a specialized cardiac transplant clinic.

Pathology Examination Routine immune surveillance was performed at scheduled periodic endomyocardial biopsies; rejection episodes were treated with pulse steroids. Each follow-up endomyocardial biopsy was reviewed for recurrence of sarcoidosis. Rejection was defined as a biopsy-proven pathological finding and clinical event requiring specific immunosuppressive intervention.

Statistical Analysis Continuous data are expressed as mean values ⫾ SD (standard deviations). Comparisons between groups were determined by the two-tailed Student t test for differences in proportions and mean values. Follow-up times are described as medians using the inverse Kaplan-Meier estimator. Survival curves generated with the Kaplan-Meier method were compared using the log rank test. A difference of P ⬍ .05 was considered statistically significant.

RESULTS

We divided the 411 heart transplant patients into two groups: five cases of sarcoidosis versus the other 406 without sarcoidosis. The demographic data between these two groups are shown in Table 1 Both groups displayed similar ages: the mean for sarcoidosis patients was 34.93 ⫾ 8 versus without sarcoidosis, 44 ⫾ 16 years. Before transplantation, sarcoidosis patients seem to display lower pulmonary vascular resistance than the other patients (Wood

ISOLATED CARDIAC SARCOIDOSIS

905 Table 2. Summary of Cardiac Sarcoidosis Patients

Patient Number

Sarcoidosis Documented Before Transplantation

Extracardiac Involvement

Pretransplant Presentation ECG

Posttransplant EMB Times

Evidence of Recurrent Sarcoidosis

NYHA Functional Class

Latest Visit LVEF (%)

1

No

No

13

No

I

66

2 3

No Yes

No No

12 8

No No

I I

71 58

4

No

No

8

No

I

55

5

No

No

RBBB pattern with conduction delay Third-degree AV block Anteroseptal ST elevations, RBBB, AV block RBBB paten with conduction delay Anteroseptal ST elevation, inferior wall Q waves, ventricular tachycardia

3

No

I

63

ECG, electrocardiogram; AV, arterioventricular; EMB, endomyocardial biopsy; NYHA, New York Heart Association; LVEF, left ventricular ejection fraction.

unit 2.8 vs 3.55); however, due to the few cases, there was no significant difference. Only one of the sarcoidosis patients was diagnosed before heart transplantation by endomyocardial biopsy. All of them were documented to show scattered fibrosis, noncaseating granulations, and mononuclear cell aggregations, that is, typical pathological findings in the explanted heart (Fig 1). All of them displayed nonspecific electrocardiogram findings (Table 2). After heart transplantation, all of the cases were examined for extracardiac sarcoidosis: chest computed tomography on all five patients was negative. They were followed

periodically with endomyocardial biopsies. Although it is known that the positive yield rate of a biopsy is low, we performed 41 examinations. The biopsy specimens showed no evidence of granulomata. During the follow-up, left ventricular function was checked every 3 months, of which showed good results. The New York Heart Association (NYHA) functional class of each was class I. The long-term survival among sarcoidosis patients was good. No one died over the 7-year follow-up (Fig 2). To compared with the nonsarcoidosis group, the long-term survival seemed better in the sarcoidosis cohort albeit not significantly.

Fig 2. Kaplan-Meier actuarial survival curve for two groups. Solid line: patients with sarcoidosis; dotted line: patients without sarcoidosis. There was no patient loss in the sarcoidosis group compared with nonsarcoidosis patients; they had better survival within 7-year follow-up.

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DISCUSSION

Cardiac biopsy is frequently negative because of the patchy distribution of the disease.4 Thus we only had one patient diagnosed before transplantation. According to the literature, the areas most often affected by the disease are the basal and lateral left ventricular wall.5 In our patients, scar tissue was distributed over the entire myocardium conduction and arrhythmia ECG abnormalities are common in cardiac sarcoidosis. All of our subjects showed interventricular conduction delay with QRS widening. Two of them also had a history of malignant arrhythmia. The scanty scar distribution in the myocardium not only destroys the normal arrangement of cardiomyocytes but also influences the conduction system. Most people with end-stage cardiac sarcoidosis die because of severe heart failure and a lethal arrhythmia.6 During the follow-up, left ventricular function was good in all patients with normal functional classes. Their long-term survival was not inferior to subjects without sarcoidosis, even showing a better trend. However, due the small case number, there was no significant difference. Follow-up biopsies failed to reveal pathological evidence of recurrent sarcoidosis. Clinically, all patients showed good ventricular function and NYHA class.

CHANG, CHI, CHOU ET AL

In conclusion, isolated cardiac sarcoidosis is rare. Heart transplantation is still the standard treatment for end-stage disease. The long-term results in those patients are good. Their survival is not inferior to nonsarcoidosis patients; ventricle function is good.3 Our study failed to detect, evidence of recurrence in the follow-up period. Heart transplantation in end-stage sarcoidosis patients is lifesaving and effective, possibly providing better long-term survival than observed in nonsarcoidosis patients. REFERENCES 1. Iannuzzi MC, Rybicki BA, Teirstein AS: Sarcoidosis. N Engl J Med 357:2153, 2007 2. Silverman KJ, Hutchins GM, Bulkley BH: Cardiac sarcoid: a clinicopathologic study of 84 unselected patients with systemic sarcoidosis. Circulation 58:1204, 1978 3. Zaidi AR, Zaidi A, Vaitkus PT: Outcome of heart transplantation in patients with sarcoid cardiomyopathy. J Heart Lung Transplant 26:714, 2007 4. Donsky AS, Escobar J, Capehart J, et al: Heart transplantation for undiagnosed cardiac sarcoidosis. Am J Cardiol 89:1447, 2002 5. Milman N, Andersen CB, Mortensen SA, et al: Cardiac sarcoidosis and heart transplantation: a report of four consecutive patients. Sarcoidosis Vasc Diffuse Lung Dis 25:51, 2008 6. Abeler V: Sarcoidosis of the cardiac conducting system. Am Heart J 97:701, 1979