Outcome of patients with cardiac sarcoidosis undergoing cardiac transplantation—Single-center retrospective analysis

Journal of Cardiology 60 (2012) 407–410

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Original article

Outcome of patients with cardiac sarcoidosis undergoing cardiac transplantation—Single-center retrospective analysis Hirokazu Akashi (MD PhD) a , Tomoko S. Kato (MD PhD) a,∗ , Hiroo Takayama (MD PhD) b , Yoshifumi Naka (MD PhD) b , Maryjane Farr (MD) a , Donna Mancini (MD) a , P. Christian Schulze (MD PhD) a,∗ a b

Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, NY, USA Department of Surgery, Division of Cardiothoracic Surgery, Columbia University Medical Center, New York, NY, USA

a r t i c l e

i n f o

Article history: Received 26 April 2012 Received in revised form 20 June 2012 Accepted 4 July 2012 Available online 11 August 2012 Keywords: Heart failure Transplantation Prognosis Sarcoidosis

a b s t r a c t Background: Controversy exists whether heart transplantation (HTx) is an appropriate treatment option for patients with cardiac sarcoidosis due to its potential recurrence and multi-organ involvement. Recent data from the United Network for Organ Sharing dataset suggest that the clinical outcome of cardiac sarcoidosis patients is equivalent or even better than that of the general HTx population. Methods: We retrospectively reviewed the clinical course of 14 patients with cardiac sarcoidosis among a total of 825 patients who underwent HTx at Columbia University Medical Center between 1997 and 2010. Post-transplant survival of patients with sarcoidosis was compared with that of non-sarcoidosis patients. Results: More than half of cardiac sarcoidosis patients were initially diagnosed after HTx by tissue analysis of the explanted heart. While only 2/14 cases showed recurrence of cardiac sarcoidosis, the clinical outcome of sarcoid patients showed a trend toward higher mortality than that of non-sarcoidosis patients following HTx (1- and 5-year survival, 78.5 versus 87.2%, 52.4 versus 76.2%, respectively, p = 0.09). Conclusions: Although this is a single-center, retrospective analysis of a small number of cardiac sarcoidosis patients who underwent HTx, a concerning trend toward a higher mortality of patients with cardiac sarcoidosis was noted. A careful candidate selection in patients with known cardiac sarcoidosis should be discussed. © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Introduction Sarcoidosis is a multi-organ disease which can affect the heart leading to a progressive infiltrative cardiomyopathy. Heart transplantation (HTx) is an effective therapy for patients with end-stage heart failure (HF) and the outcome of patients with cardiac sarcoidosis has been reported to be identical to or even better than that in non-sarcoidosis patients [1–3]. However, multi-organ involvement of this disease and recurrence of sarcoidosis in a transplanted heart have been reported previously [4,5]. Therefore, debate exists regarding the appropriateness of HTx for patients with cardiac sarcoidosis due to the possibility of disease recurrence and involvement of other organs with potential development of multi-organ

∗ Corresponding authors at: Columbia University Medical Center, Department of Medicine, Division of Cardiology, 622 West 168th Street, PH 10, Room 203, New York, NY 10032, USA. Tel.: +1 212 305 6916; fax: +1 212 342 5355. E-mail addresses: [email protected] (T.S. Kato), [email protected] (P.C. Schulze).

dysfunction. We here review the post-transplant clinical course of HTx recipients with cardiac sarcoidosis at our institution. Methods Patients and study design Among a total of 825 patients undergoing HTx at Columbia University Medical Center, New York, USA, between March 1997 and May 2010, 14 patients were diagnosed with cardiac sarcoidosis as a primary cause of HF either pre-operatively or at the time of transplantation. Clinical course was reviewed retrospectively by chart review. Survival after heart transplantation of sarcoidosis patients was compared with the survival of non-sarcoidosis patients transplanted at our institution. Statistical analysis Data are presented as means ± SD. Normality was evaluated for each variable on the basis of normal distribution plots and

0914-5087/$ – see front matter © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jjcc.2012.07.013

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Table 1 Baseline characteristics. Sarcoidosis Recipient age (years) Gender, female (%) BMI (kg/m2 ) Hypertension (%) Diabetes mellitus (%) Pre-Op LVAD (%) Ethnicity (%) African American Caucasian Other Hispanic Asian UNOS status (%) Status 1A Status 1B Status 2 Laboratory values Hematocrit (%) BUN (mg/dL) Creatinine (mg/dL) AST (U/L) ALT (U/L) Total bilirubin (mg/dL) Total protein (g/dL) Albumin (g/dL) Glucose (mg/dL) HbA1c (%) Triglycerides (mg/dL) Cholesterol (mg/dL) HDL (mg/dL) LDL (mg/dL)

Non-sarcoidosis

51 ± 9 50 26.1 ± 1.3 42.9 28.6 50.0

53 ± 4 22.8 25.7 ± 2.0 38.8 28.4 31.76

50.0 28.6 14.3 7.1 0

13.9 62.9 10.5 9.8 3.0

35.7 50.0 14.3

45.9 38.4 15.7

p-Value 0.4748 0.0002 0.7240 0.8890 0.9243 0.1471 0.0034

0.4037

37.6 ± 5.3 23.4 ± 11.3 1.23 ± 0.3 25.9 ± 11.4 24.5 ± 13.7 0.8 ± 0.4 7.3 ± 0.7 3.6 ± 0.4 101.2 ± 21.0 6.0 ± 0.8 120.5 ± 67.8 157.4 ± 47.6 34.0 ± 6.1 98.7 ± 49.4

36.2 ± 6.2 29.0 ± 15.7 1.39 ± 0.8 34.8 ± 59.9 35.5 ± 72.3 1.1 ± 1.0 7.2 ± 0.9 3.9 ± 0.6 108.1 ± 44.8 6.0 ± 0.4 122.7 ± 78.8 150.8 ± 45.7 38.3 ± 14.1 87.3 ± 34.6

0.4542 0.1999 0.5020 0.609 0.615 0.229 0.552 0.057 0.6086 0.913 0.9266 0.5936 0.3576 0.3299

Data are means ± SD. BMI, body mass index; Pre-Op LVAD, pre-operative left ventricular assist device; UNOS, United Network for Organ Sharing; BUN, blood urea nitrogen; AST, aspartate aminotransferase; ALT, alanine aminotransferase; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

histograms and by the Kolmogorov–Smirnov test. Clinical characteristics and laboratory data were compared between groups using Student’s unpaired two-tailed t test or chi-square analysis. Survival after HTx was compared between the groups using Kaplan–Meier analysis and log-rank statistics. All statistical analyses were performed using the JMP 7.0 software (SAS Institute, Cary, NC, USA). Results Patients with sarcoidosis undergoing cardiac transplantation did not differ from non-sarcoidosis patients in regard to age, clinical history, pre-HTx left ventricular assist device (LVAD) requirement or United Network for Organ Sharing (UNOS) status at the time of HTx. The ethnic group of the patients included 7 African-American, 5 Caucasian, 1 Hispanic-American, and 1 other race. In patients with cardiac sarcoidosis, a significantly higher percentage of females and African-Americans was noted when compared to the nonsarcoidosis group (Table 1). Six patients (42.9%) were diagnosed with sarcoidosis before HTx with one patient diagnosed by right ventricular endomyocardial biopsy, one patient diagnosed on myocardial core tissue at the time of LVAD implantation, and 4 patients diagnosed by preexisting concomitant pulmonary sarcoidosis with end-stage HF. In these patients with pulmonary sarcoidosis, due to histologically confirmed extra-cardiac sarcoidosis accompanied by HF, their HF etiologies were considered as cardiac sarcoidosis [6]. The remaining 8 patients (57.1%) were eventually diagnosed with cardiac sarcoidosis at the time of HTx by the histological evaluation of the explanted hearts. Seven patients (50%) had concomitant pulmonary sarcoidosis, including one patient who developed abnormal findings on chest X-ray and pulmonary sarcoidosis was diagnosed after transplant. Among the 6 patients who received a diagnosis of pulmonary sarcoidosis before HTx, 3 patients (3/6, 50%) died at 9 days,

2.6 months, and 30.8 months post-transplant (Table 2). One of these patients experienced recurrence of cardiac sarcoidosis, which was histologically diagnosed at the time of autopsy. The remaining 3 patients who had prior pulmonary-involvement of sarcoidosis did not have recurrence or worsening of pulmonary/cardiac sarcoidosis and their post-transplant course was uneventful. Nine patients (64.3%) developed post-operative renal dysfunction with creatinine > 2.0 mg/dL. Length of hospitalization after HTx also showed no significant differences between the groups. Five patients (35.7%) died after HTx at 9–1236 days (mean survival duration 41.0 ± 18.7 months). Two patients died in the hospital (14.3%). Causes of death were pneumonia, sepsis, recurrence of cardiac sarcoidosis, primary graft failure, and malignancy as listed in Table 2. The mean follow-up after transplant for all patients with sarcoidosis in this cohort was 55.1 ± 51.3 months. Two patients, including those with pre-existing lung sarcoidosis, had been treated with maintenance steroid therapy prior to HTx. Following HTx, all patients received triple immunosuppressive regimen using calcineurin inhibitors, mycophenolate, and steroids. Allograft cellular rejection occurred in 4 patients (28.5%) at grade 3A. In 3 patients it occurred within 6 months after HTx and in 1 patient 18 months post-HTx. The 4 patients were treated with pulse steroid therapy and 2 of the 4 patients were also treated with muromonab-CD3 therapy in addition to pulse steroid therapy. Two patients (14.3%) were diagnosed with recurrence of cardiac sarcoidosis within 3 years after HTx. One patient died secondary to ventricular fibrillation after developing progressive cardiomyopathy because of sarcoidosis recurrence and rejection. A second patient who also developed biopsy-confirmed recurrence of cardiac sarcoidosis did not show signs of rejection or cardiac failure and it was assumed that this recurrence had healed when subsequent biopsies were negative for sarcoidosis (Table 2).

2/14 (14.3%) 4/14 (28.5%) 55.1 ± 51.3 9/14 (64.3%) 7/14 (50.0%) 6/14 (42.9%) 6/14 (42.9%) 51 ± 9

M F M F M F M M M 6 7 8 9 10 11 12 13 14

Diagnosed by core biopsy at the time of LVAD implantation. b Diagnosed by myocardial biopsy during cardiac transplant evaluation. c Diagnosed after cardiac transplant. Data are means ± SD. F, female; M, male; Pre-OP, preoperative; Dx, diagnosis; LVAD, left ventricular assist device; Post-OP, postoperative; HTx, heart transplantation; 3A, International Society of Heart and Lung Transplantation conventional rejection grade 3A; m, months; OKT3, muromonab-CD3.

46 63 60 46 44 F F F M F 1 2 3 4 5

a

OKT3

Pulse steroid

No No Yes No No No No No No OKT3

No 3A (3 m) No 3A (2 m) No 3A (6 m) No No No Pneumonia Pneumonia Cervical cancer 74.9 alive 3.7 died 36.8 died 40.6 died 53.5 alive 81.4 alive 81.9 alive 141.9 alive 171.6 alive No Yes No Yes Yes Yes No Yes Yes No No No No Yes No Yes No Yes Yes No No No No No No No No 67 42 44 46 49 55 49 64 43

Yes No No No No No No Yesc No

Pulse steroid Recurrent rejections/cardiac sarcoidosis

No No No No 3A (18 m) Graft failure Sepsis

0.3 died 2.6 died 21.7 alive 29.0 alive 30.8 died Yes No Yes Yes No Yesa Yes Yesb Yes Yes

Yes Yes Yes Yes Yes

No Yes Yes No Yes

Cause of death Follow-up after HTx (months) Post-OP renal dysfunction Pulmonary sarcoidosis Pre-OP LVAD use Pre-OP Dx of sarcoidosis Age (years) Sex No.

Table 2 Clinical course following cardiac transplantation.

No No No No Yes

Therapy for rejection Rejection > grade 2 (after HTx)

Recurrence

H. Akashi et al. / Journal of Cardiology 60 (2012) 407–410

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Fig. 1. Kaplan–Meier survival curves of sarcoidosis patients and non-sarcoidosis patients. Blue line indicates patients with sarcoidosis as a primary heart disease for transplant and red line indicates patients with other heart disease. Pts, patients. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

Kaplan–Meier analysis revealed that overall survival of sarcoidosis patients tended to be lower than that of non-sarcoidosis patients (Fig. 1). The overall survival rate of patients with sarcoidosis compared to non-sarcoidosis patients was 78.5% versus 87.2% at 1 year and 58.9% versus 76.2% at 5 years (p = 0.09). The analysis of survival showed that the 6 patients with known sarcoidosis before HTx tended to have higher mortality post-HTx compared to patients diagnosed at the time of HTx (1-year mortality: 87.5% versus 66.7% and 5-year mortality: 72.9% versus 33.3%, p = 0.08, Fig. 2) likely due to a more generalized disease process with additive peripheral end-organ involvement and damage. Causes of death were pneumonia, sepsis, recurrence of cardiac sarcoidosis, primary graft failure, and malignancy. Discussion There has been debate as to whether HTx is an appropriate treatment option for patients with cardiac sarcoidosis, because of the possibility of recurrence of cardiac sarcoidosis in a transplanted heart and involvement of other organs such as the lung which could even occur after successful HTx. Further, a number of patients develop multi-organ involvement although the death rate due to

Fig. 2. Kaplan–Meier survival curves of sarcoidosis patients, whose diagnosis was made before and at the time of transplant, and non-sarcoidosis patients. Black line indicates patients with other heart disease and gray line indicates patients with sarcoidosis, of whom survival of patients with diagnosis of sarcoidosis was made before transplant are shown in dashed-red line, and that of patients diagnosed at the time of transplant are shown in dotted-red line. Pts, patients; HTx, heart transplantation. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

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sarcoidosis was reported to be less than 5% [7,8]. The largest published experience of post-HTx outcome of patients with sarcoidosis comes from a retrospective analysis of the UNOS database with a total of 65 patients (mean age 46 years) with sarcoidosis who underwent HTx [3]. In contrast to our single center experience, Zaidi et al. stated that one-year post-HTx survival was better for sarcoidosis patients than for patients receiving transplantation for all other diagnoses (87.7% versus 84.5%, p = 0.03). The diagnosis of cardiac sarcoidosis in their study based on the UNOS database was the pre-transplant diagnostic code listed in the Heart Transplant Recipient Registration Form of the UNOS; therefore, detailed pretransplant clinical information and/or the histological evaluation was not available. It is difficult to differentiate cardiac sarcoidosis from non-ischemic cardiomyopathy prior to the transplant. In our study, the diagnosis of sarcoidosis was based on histological confirmation at the time of transplant. We speculate that this discordance of diagnostic criteria between the UNOS database and our cohort may contribute to the different results of post-transplant prognosis between the studies. Indeed, our present observation revealed that patients who were diagnosed with sarcoidosis prior to transplant showed worse survival than those with diagnosis after transplant, although it was not statistically significant. We speculate that patients who received a diagnosis of sarcoidosis prior to transplant were more prone to be in a systemic pro-inflammatory condition, regardless of the presence or absence of clinically problematic co-morbidities related to sarcoidosis while on the waiting list. Pro-inflammatory state before transplant would persist after transplant, and may contribute to a poor post-transplant outcome. In addition, patients with known sarcoidosis were already treated with steroids before transplant and we tried not to completely wean them off steroids after transplant, which may also contribute to their susceptibility to infection. The clinical manifestations of cardiac sarcoidosis are largely nonspecific. As a result, diagnostic testing such as endomyocardial biopsy or imaging may be required, particularly in patients without other manifestations of the disease [1,6,7,9,10]. A definitive histological diagnosis of cardiac sarcoidosis can be challenging because the sarcoidosis granulomas can be missed by endocardial biopsy and even serial biopsy might not always prove the diagnosis [11,12]. Endomyocardial biopsy has a low sensitivity approaching 20% in a series of 26 patients [12], which commonly leads to the diagnosis of idiopathic dilated cardiomyopathy in those patients [10,13]. Some of our patients with sarcoidosis were successfully bridged-to-transplant by LVAD, which has evolved into a promising therapy for patients with advanced HF [14,15]. Histological evaluation of LVAD core tissue would further help to diagnose the etiology of HF. The definite diagnosis of cardiac sarcoidosis can often be a surprising finding at the time of HTx on the explanted heart [11]. Diagnostic accuracy could be improved by additional tools such as magnetic resonance imaging with gadolinium enhancement or radiocardiography including fluorodeoxyglucose positron emission tomography, which may be helpful in the identification and follow-up of cardiac sarcoidosis but so far has not been fully established [16]. In addition, recurrence of cardiac sarcoidosis after transplant should be carefully observed, not only by the use of endomyocardial biopsy but also using imaging modalities including serial echocardiograms to detect any change over the post-operative period compared to the findings immediately after transplant [17]. In this single-center, retrospective analysis of a small number of cardiac sarcoidosis patients who underwent HTx, a concerning

trend toward a higher mortality in patients with cardiac sarcoidosis was noted in the absence of significant difference in end-organ damage or other clinical risk factors. These results of our present observation contrast with prior reports that have shown comparable or even better outcomes of this population compared to non-sarcoidosis patients following HTx, although the diagnosis of sarcoidosis in the previous study was made prior to transplant at the time of listing and the diagnosis of our patients was confirmed according to the histological evaluation of explanted heart. Our observations would argue for a careful candidate selection in patients with known cardiac sarcoidosis. Further investigation would be required to evaluate an appropriate post-transplant immunosuppressive regimen for patients with sarcoidosis, including the continuation or withdrawal of steroid therapy in the chronic phase. Acknowledgments Akashi H. and Kato T.S. contributed equally to this work. References [1] Sekiguchi M, Yazaki Y, Isobe M, Hiroe M. Cardiac sarcoidosis: diagnostic, prognostic, and therapeutic considerations. Cardiovasc Drugs Ther 1996;10:495–510. [2] Valantine HA, Tazelaar HD, Macoviak J, Mullin AV, Hunt SA, Fowler MB, Billingham ME, Schroeder JS. Cardiac sarcoidosis: response to steroids and transplantation. J Heart Transplant 1987;6:244–50. [3] Zaidi AR, Zaidi A, Vaitkus PT. Outcome of heart transplantation in patients with sarcoid cardiomyopathy. J Heart Lung Transplant 2007;26:714–7. [4] Oni AA, Hershberger RE, Norman DJ, Ray J, Hovaguimian H, Cobanoglu AM, Hosenpud JD. Recurrence of sarcoidosis in a cardiac allograft: control with augmented corticosteroids. J Heart Lung Transplant 1992;11:367–9. [5] Yager JE, Hernandez AF, Steenbergen C, Persing B, Russell SD, Milano C, Felker GM. Recurrence of cardiac sarcoidosis in a heart transplant recipient. J Heart Lung Transplant 2005;24:1988–90. [6] Hiraga H, Yuwai K, Hiroe M. Guidelines for the diagnosis of cardiac sarcoidosis: study report on diffuse pulmonary disease. Tokyo: Japanese Ministry of Health and Welfare; 1993. p. 23–4. [7] Chapelon-Abric C, de Zuttere D, Duhaut P, Veyssier P, Wechsler B, Huong DL, de Gennes C, Papo T, Blétry O, Godeau P, Piette JC. Cardiac sarcoidosis: a retrospective study of 41 cases. Medicine (Baltimore) 2004;83:315–34. [8] Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med 2007;357:2153–65. [9] Pandya C, Brunken RC, Tchou P, Schoenhagen P, Culver DA. Detecting cardiac involvement in sarcoidosis: a call for prospective studies of newer imaging techniques. Eur Respir J 2007;29:418–22. [10] Yoshida Y, Morimoto S, Hiramitsu S, Tsuboi N, Hirayama H, Itoh T. Incidence of cardiac sarcoidosis in Japanese patients with high-degree atrioventricular block. Am Heart J 1997;134:382–6. [11] Donsky AS, Escobar J, Capehart J, Roberts WC. Heart transplantation for undiagnosed cardiac sarcoidosis. Am J Cardiol 2002;89:1447–50. [12] Uemura A, Morimoto S, Hiramitsu S, Kato Y, Ito T, Hishida H. Histologic diagnostic rate of cardiac sarcoidosis: evaluation of endomyocardial biopsies. Am Heart J 1999;138:299–302. [13] Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL, Baughman KL, Kasper EK. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000;342: 1077–84. [14] Sasaoka T, Kato TS, Komamura K, Takahashi A, Nakajima I, Oda N, Hanatani A, Mano A, Asakura M, Hashimura K, Niwaya K, Funatsu T, Kobayashi J, Kitamura S, Shishido T, et al. Improved long-term performance of pulsatile extracorporeal left ventricular assist device. J Cardiol 2010;56:220–8. [15] Kyo S, Minami T, Nishimura T, Gojo S, Ono M. New era for therapeutic strategy for heart failure: destination therapy by left ventricular assist device. J Cardiol 2012;59:101–9. [16] Smedema JP, White L, Klopper AJ. FDG-PET and MIBI-Tc SPECT, as follow-up tools in a patient with cardiac sarcoidosis requiring a pacemaker. Cardiovasc J Afr 2008;19:309–10. [17] Hashimoto S, Kato TS, Komamura K, Hanatani A, Niwaya K, Funatsu T, Nakatani T, Kobayashi J, Sumita Y, Tanaka N, Hashimura K, Asakura M, Kanzaki H, Kitakaze M. The utility of echocardiographic evaluation of donor hearts upon the organ procurement for heart transplantation. J Cardiol 2011;57:215–22.