Outcomes of patients with definite and suspected isolated cardiac ...

J Interv Card Electrophysiol (2015) 43:55–64 DOI 10.1007/s10840-015-9978-3

Outcomes of patients with definite and suspected isolated cardiac sarcoidosis treated with an implantable cardiac defibrillator Jordana Kron & William Sauer & Gisela Mueller & Joseph Schuller & Frank Bogun & Sinan Sarsam & Lynda Rosenfeld & Teferi Y. Mitiku & Joshua M. Cooper & Davendra Mehta & Arnold J. Greenspon & Matthew Ortman & David B. Delurgio & Ravinder Valadri & Calambur Narasimhan & Nalla Swapna & Jagmeet P. Singh & Stephan Danik & Steven M. Markowitz & Adrian K. Almquist & Andrew D. Krahn & Luke G. Wolfe & Shawn Feinstein & Kenneth A. Ellenbogen & Thomas Crawford

Received: 21 November 2014 / Accepted: 20 January 2015 / Published online: 13 February 2015 # Springer Science+Business Media New York 2015

Abstract Purpose Cardiac sarcoidosis (CS) patients are at increased risk for sudden death. Isolated CS is rare and can be difficult to diagnose. Methods In this multicenter retrospective review, patients with CS and an implantable cardiac defibrillator (ICD) were identified. Results Of 235 patients with CS and ICD, 13 (5.5 %) had isolated CS, including 7 (3.0 %) with definite isolated CS (biopsy or necropsy-proven) and 6 (2.6 %) with suspected

isolated CS based on a constellation of clinical, ECG, and imaging findings. Among 13 patients with isolated CS, 10 (76.9 %) were male, mean age was 53.8±7.6 years, and mean left ventricular ejection fraction was 38.3±16.5. Diagnosis was made by cardiac magnetic resonance (CMR) (n=2), biopsy (n=3), CMR and biopsy (n=2), CMR and positron emission tomography (PET) (n=2), PET (n=1), late enhanced cardiac CT (n=1), pathology at heart transplant (n=1), and autopsy (n=1). Eight of 13 (61.5 %) patients with isolated CS had a secondary prevention indication (VT in 6 and VF in 2)

J. Kron (*) : S. Feinstein : K. A. Ellenbogen Department of Cardiac Electrophysiology, Virginia Commonwealth University, P.O. Box 980053, Richmond, VA 23298-0053, USA e-mail: [email protected]

D. Mehta Department of Cardiology, Mount Sinai Hospital, New York, NY, USA

W. Sauer : J. Schuller Department of Cardiology, University of Colorado Denver, Denver, CO, USA G. Mueller Department of Radiology, University of Michigan, Ann Arbor, MI, USA F. Bogun : S. Sarsam : T. Crawford Department of Cardiology, University of Michigan, Ann Arbor, MI, USA

A. J. Greenspon Division of Cardiology, Thomas Jefferson University Hospital, Philadelphia, PA, USA M. Ortman Cooper University Hospital, Camden, NJ, USA D. B. Delurgio Department of Cardiology, Emory University, Atlanta, GA, USA R. Valadri Wright Center for Graduate Medical Education, Scranton, PA, USA

L. Rosenfeld Department of Cardiac Electrophysiology, Yale University, New Haven, CT, USA

C. Narasimhan : N. Swapna Department of Cardiology, CARE Hospital, Hyderabad, India

T. Y. Mitiku Wayne State University, Detroit, MI, USA

J. P. Singh Department of Cardiology, Massachusetts General Hospital, Boston, MA, USA

J. M. Cooper Department of Cardiology, Temple University, Philadelphia, PA, USA

S. Danik St. Luke’s Roosevelt Hospital, New York, NY, USA

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vs. 80 of 222 (36.0 %) with sarcoidosis in other organs (p= 0.04). Over a mean of 4.2 years, 9 of 13 (69.2 %) patients with isolated CS received appropriate ICD therapy, including antitachycardia pacing (ATP) and/or shock, compared with 75 of 222 (33.8 %) patients with cardiac and extracardiac sarcoidosis (p=0.0150). Six of 7 (85.7 %) patients with definite isolated CS received appropriate ICD intervention, compared with 78 of 228 patients (34.2 %) without definite isolated CS (p= 0.0192.) Conclusions In this retrospective study, patients with isolated CS had very high rates of appropriate ICD therapy. Prospective, long-term follow-up of consecutive patients with isolated CS is needed to determine the true natural history and rates of ventricular arrhythmias in this rare and difficult-to-diagnose disease.

arrhythmias. Isolated cardiac sarcoidosis (CS) can occur but is rare and mostly described in case reports and small series [2, 3]. Isolated CS can be difficult to diagnose and may be identified only at the time of cardiac transplantation or autopsy [4]. The prevalence and natural history of isolated cardiac sarcoidosis are not known. The purpose of this study was to evaluate the frequency of isolated CS in a large cohort of patients with CS and an implantable cardiac defibrillator (ICD). We tested the hypothesis that patients with isolated CS are at high risk for ventricular arrhythmias.

Keywords Cardiac sarcoidosis . Isolated cardiac sarcoidosis . Implantable cardiac defibrillator . Ventricular tachycardia . Sudden cardiac death

2.1 Study population and diagnosis of cardiac sarcoidosis

Abbreviations ATP Anti-tachycardia pacing CMR Cardiac magnetic resonance CS Cardiac sarcoidosis DE Delayed enhancement ECG Electrocardiogram ICD Implantable cardiac defibrillator LVEF Left ventricular ejection fraction

1 Introduction Sarcoidosis is a multisystem disease characterized by noncaseating granulomas that most commonly develop in the lungs and lymph nodes, but may involve almost any organ system, including the liver, skin, eyes, and gastrointestinal tract. Microscopic evidence of cardiac involvement was found in 27 % of patients at autopsy in a series of patients with systemic sarcoidosis [1]. Cardiac sarcoidosis (CS) patients are at increased risk for sudden death from ventricular

S. M. Markowitz Department of Cardiology, Weill Cornell Medical Center, New York, NY, USA A. K. Almquist Department of Cardiology, Minneapolis Heart Institute, Minneapolis, MN, USA A. D. Krahn Division of Cardiology, University of British Columbia, Vancouver, BC, Canada L. G. Wolfe Department of General Surgery, Virginia Commonwealth University, P.O. Box 980053, Richmond, VA 23298-0053, USA

2 Methods

Clinical cardiac electrophysiologists at major medical centers in North America and India were asked to identify patients with cardiac sarcoidosis and an ICD [5]. The study was approved by the Institutional Review Board at Virginia Commonwealth University and the IRB at each participating center as required. This study is registered at clinicaltrials.gov (NCT01013311). Diagnosis of cardiac sarcoidosis was made based on: (1) biopsy-proven cardiac sarcoid, (2) MRI findings suggestive of cardiac sarcoid, (3) 18F-fluorodeoxyglucose positron emission tomography (18F FDG PET), (4) late enhancement cardiac CT, or (5) biopsy-proven sarcoidosis in another organ and presumptive cardiac involvement based on conduction system disease involving the AV node or His-Purkinje system and/or ventricular arrhythmias. For each patient, a questionnaire was completed by the electrophysiologist. The questionnaire included demographic information, history of extra-cardiac sarcoidosis, medical therapy, electrocardiogram (ECG) information, diagnostic cardiac studies, ICD therapy history, and device complications. The clinical electrophysiologist at the center made the determination of whether ICD therapy was appropriate or inappropriate. From the database, patients were identified who had no extracardiac sarcoidosis. Records including imaging studies were reviewed to make sure patients did not have extracardiac involvement. Patients who had biopsy or necropsy positive for noncaseating granulomas with no sarcoidosis in other organs were considered definite isolated CS. Patients who had suspected cardiac sarcoidosis based on a constellation of clinical, ECG, and imaging findings and no sarcoidosis in other organs were labeled suspected isolated CS. 2.2 Cardiac magnetic resonance Cardiac magnetic resonance (CMR) images of patients with isolated CS were collected. All available images were


analyzed offline (QMASS 7.2.26, Medis, Leiden, the Netherlands) by an experienced reader. Endocardial and epicardial borders were manually drawn in the short axis view (Fig. 1) to subsequently allow for the assessment of the left ventricular scar using a semiautomated threshold technique the Bfullwidth-half-maximum^ method (FWHM) [6]. Tissue with a signal intensity above 50 % of the maximum signal of the enhanced myocardium was quantified as scar tissue. The left ventricle was divided into 17 anatomic segments [7] and the right ventricle into 12 anatomic segments [8]. The presence or absence of delayed enhancement was determined for each segment by visual scoring. 2.3 Statistics All statistical analyses were performed using SAS 9.3. All tests were two-tailed with a significance level of 0.05. Categorical data were analyzed using Fisher’s exact test due to the sparseness of variables in individual cells in some of the tables. Continuous variables were compared using the Student’s t test.

3 Results 3.1 Clinical characteristics of the study cohort Of 235 patients with CS and an ICD, 13 (5.5 %) had isolated CS, including 7 (3.0 %) patients with definite isolated CS (biopsy/necropsy proven) and 6 (2.6 %) with suspected isolated CS based on a constellation of clinical, ECG, and imaging findings. All other patients in the cohort (n = 222, 94.5 %) had extracardiac

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involvement, most commonly pulmonary involvement which occurred in 197 patients (83.8 %). Other common sarcoid involvement included systemic disease manifesting as weight loss, fevers, or sweats, n=24 (10.2 %); skin disease, n=24 (10.2 %); and ophthalmic disease, n=17 (7.2 %). Neurologic, liver, and renal sarcoidosis were less common. Demographic and clinical characteristics of patients with isolated CS are shown in Table 1. Demographic, clinical, and ECG data from patients with isolated CS are compared with patients with cardiac and extracardiac sarcoidosis in Table 2. Of 13 with isolated CS, 10 (76.9 %) were male, mean age was 53.8±7.6 years, and mean left ventricular ejection fraction was 38.3±16.5. Diagnosis was made by CMR (n=2), biopsy (n=3), CMR and biopsy (n=2), CMR and PET (n=2), PET (n=1), late enhanced cardiac CT (n=1), pathology at the time of heart transplant (n=1), and autopsy (n=1). Figure 2 shows 18F FDG PET of patient 2 with intense activity in the lateral wall, apex, septum, and basal inferior wall. Four (36.4 %) of the patients with isolated CS had class I NYHA heart failure, 5 (45.5 %) had class II, 1 (9.1 %) had class III, and 1 (9.1 %) had class IV. There was no significant difference in the distribution of heart failure class between patients with and without isolated CS. Twelve (92.3 %) had an abnormal ECG, including first degree AV block (n=2), third degree AV block (n=1), right bundle branch block with left anterior fascicular block (n=3), right bundle branch block with left posterior fascicular block (n= 1), left bundle branch block (n=1), and premature ventricular contractions (n=2). Some patients had more than one ECG abnormality, for example, first degree AV block and premature ventricular contractions.

Fig. 1 Short axis views. Manually drawn endocardial and epicardial borders in the left ventricular short axis and automated identification of delayed enhancement in patient 13

50

63

57

48 61 54

43

66

51 51 57

55

3

4

5 6 7

8

9

10 11 12

13

F

M M M

M

M

M F M

F

M

M

2 VT

2 VT 2 VT 1

1

2 VF

2 VT 1 1

1

2 VF

2 VT

1

CMR Autopsy Orthotopic heart transplant CMR and biopsy

Biopsy

CMR and biopsy

PET CMR and PET Cardiac CT

Biopsy

Biopsy

CMR and PET

CMR

55

33 30 12

27.5

46

15 60 53

30

52.5

35

20

Extensive DE

Multifocal DE No None

No

PET Yes and PET No (pacemaker); cardiac CT showed DE in noncoronary distribution DE in LV and RV

Not done

Scar in septum, inferior LV, RV Dilated LV, LA, RV, transmural scar in noncoronary distribution Not done

CMR

2

M

EF (%)

42

Diagnosis

1

Primary vs. secondary indication

Age

Patient

Gender

Demographic and clinical characteristics for patients with isolated cardiac sarcoidosis

Table 1

Noncaseating granulomas

Noncaseating granulomas Granulomatous myocarditis No Tissue at autopsy Tissue at OHT

Granulomatous myocarditis Noncaseating granulomas No No Normal

Normal

No

Biopsy

Definite

Suspected Definite Definite

Definite

Definite

Suspected Suspected Suspected

Definite

Definite

Suspected

Suspected

Definite vs. suspected isolated CS

Atrial fibrillation, ventricular pacing IVCD Ventricular pacing Atrial flutter, ventricular pacing RBBB, LAFB

First degree AVB, PVCs

LBBB RBBB, LPFB Third degree AVB, narrow escape

PVCs

RBBB, LAFB

RBBB, LAFB, first degree

Normal

ECG

1

2 14 5

2

5

12 0 2

0

3

0

0

Number of appropriate therapies (ATP and/or shocks)

58 J Interv Card Electrophysiol (2015) 43:55–64

J Interv Card Electrophysiol (2015) 43:55–64 Table 2

59

Demographic, clinical, and ECG variables of patients with isolated CS compared with patients with cardiac and extracardiac sarcoidosis

Variable

Isolated CS (n=13)

Cardiac and extracardiac sarcoidosis (n=222)

p value

Male Age Ejection fraction NYHA class I Class II

10 (76.9 %) 53.8±7.6 38.3±16.5 4 (36.4 %) 5 (45.5 %)

142 (64.0 %) 55.7±11.2 45.4±15.6 85 (44.3 %) 63 (32.8 %)

0.5515 0.5762 0.1187 0.1939 for all NYHA classes

Class III Class IV Secondary prevention RBBB LBBB LAFB

1 (9.1 %) 1 (9.1 %) 8 (61.5 %) 4 (30.8 %) 1 (7.7 %) 3 (23.1 %)

41 (21.4 %) 3 (1.6 %) 80 (36.0 %) 60 (27.0 %) 10 (4.5 %) 24 (10.8 %)

Fig. 2 18F FDG PET of patient 2 showing intense concentration in the lateral wall, apex, septum, and basal inferior wall segments. Left ventricular cavity is dilated

0.0450 0.7542 0.4728 0.1765

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3.2 Definite isolated CS

Table 3 Medical therapy of patients with isolated CS compared with patients with cardiac and extracardiac sarcoidosis

Of the 7 patients with tissue-proven isolated CS, 5 (71.4 %) were male, mean age was 56.3±8.4 years, and mean left ventricular ejection fraction was 36.1±15.6.

Medication

Isolated CS Cardiac and extracardiac p value (n=13) sarcoidosis (n=232)

Any antiarrhythmic Sotalol Amiodarone Dofetilide Propafenone Quinidine Disopyramide Beta-blockers Immunosuppressants

11 (84.6 %) 4 (30.8 %) 8 (61.5 %) 1 (7.7 %) 0 (0 %) 0 (0 %) 0 (0 %) 7 (53.9 %)

91 (41.6 %) 54 (24.3 %) 37 (16.7 %) 15 (6.8 %) 7 (3.2 %) 5 (2.3 %) 2 (0.9 %) 143 (64.4 %)

0.0030 0.7406 0.0006 1.0000 1.0000 1.0000 1.0000 0.5542

6 (46.2 %) 2 (15.4 %) 0 (0 %) 1 (7.7 %)

136 (61.3 %) 44 (19.8 %) 15 (6.8 %) 14 (6.3 %)

0.3823 1.000 1.000 0.5856

3.3 Suspected isolated CS Of the 6 patients with suspected isolated CS, 5 (83.3 %) were male, mean age was 51.4±6.5 years, and mean left ventricular ejection fraction was 41.0±18.7. There was no statistical difference in gender, mean age, or left ventricular ejection fraction between the patients with definite and suspected isolated CS. The demographic and clinical findings of patient with suspected isolated CS are shown in Table 1. Patient 1 was 42 years old with a left ventricular ejection fraction (LVEF) of 20 % and delayed enhancement of the septum, inferior wall, and RV on CMR. Patient 2 presented with VT, first degree AV block, and bifascicular block and had a transmural scar on CMR and PET suggestive of CS. Patient 5 presented with VT and a left bundle branch block (LBBB) and had cardiac inflammation on PET. Patient 6 had right bundle branch block (RBBB) with left posterior fascicular block (LPFB) and had MRI and PET suggestive of CS. Patient 7 had complete heart block and late enhanced cardiac CT showing delayed enhancement in a noncoronary distribution. Patient 10 presented with VT and intraventricular conduction delay and had MRI showing multifocal delayed enhancement. 3.4 Cardiac biopsy results Five of 7 (71.4 %) patients with isolated CS who underwent endomyocardial biopsy had an abnormal biopsy and 2 (28.6 %) had negative biopsy (Table 1). One patient had tissue diagnosis made at the time of cardiac transplantation. 3.5 Medical therapy Patients with isolated CS were more likely to be on an antiarrhythmic medication, 11 of 13 (84.6 %) vs. those with concomitant extracardiac disease, 91 of 232 (41.6 %) (p=0.0030) (Table 3). Eight (61.5 %) patients with isolated CS were on amiodarone, 4 (30.8 %) were on sotalol, and 7 (53.9 %) were on beta-blockers. Patients with isolated CS were more likely to be on amiodarone than patients with both cardiac and extracardiac sarcoidosis (61.5 vs. 16.7 %, p=0.0006). Six (46.2 %) of the patients with isolated CS were on steroids, 2 (15.4 %) were taking methotrexate, and one (7.7 %) was taking hydroxychloroquine. There was no statistical difference between the immunosuppressants used to treat patients with and without isolated CS.

Steroids Methotrexate Azathioprine Hydroxychloroquine

3.6 Primary vs. secondary prevention ICD indication Eight of 13 (61.5 %) patients with isolated CS had a secondary prevention indication (VT in 6 and VF in 2) vs. 80 of 222 (36.0 %) CS patients with systemic involvement (VT in 57, VF in 5, and syncope in 18) (p=0.04). Four patients (57.1 %) with definite isolated CS had an ICD implanted for secondary prevention. 3.7 CMR results CMR images of 5 patients were available for analysis. Delayed enhancement (DE) was found in all patients; it was unifocal in 3 and multifocal in 2 patients. The delayedenhanced tissue involved a mean of 8.8±13.8 % of the LV mass (range 3 to 36 %). DE was present in a mean of 8.8±6.3 segments in the 17-segment model of the LV, and in a mean of 2.6±3.1 right ventricular (RV) segments in the 12-segment model of the right ventricle. DE was found in the septum in 5 patients, in the inferior wall in 3 patients, in the lateral wall in 4 patients, and in the anterior wall in 5 patients. Two patients had additional right ventricular delayed enhancement. 3.8 Catheter ablation of arrhythmias Five of 13 (38.5 %) patients with isolated CS underwent one or more VT ablation compared with 30 of 222 (13.5 %) patients with extracardiac disease (p=0.0291). Three patients underwent one ablation, one of which was successful, one partially successful, and one unsuccessful. One patient underwent 2 ablations, the second of which was successful. One patient underwent 4 ablations, which were partially successful. All 5 (100 %) of the isolated CS patients who


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underwent VT ablation had appropriate ICD therapy compared with 4/8 (50 %) patients who did not undergo VT ablation (p=0.1049). Three of the 5 (60 %) who underwent VT ablation had ≥5 appropriate ICD therapies. 3.9 Appropriate ICD therapies Over a mean of 4.2±4.0 years (range 1 day to 20.5 years), 9 of 13 (69.2 %) patients with isolated CS received appropriate ICD therapy, including ATP and/or shock, compared with 75 of 222 (33.8 %) patients with cardiac and extracardiac sarcoidosis (p=0.0150) (Table 4). Eight of 13 (61.5 %) patients with isolated CS received an appropriate ICD shock vs. 59 of 222 (26.6 %) patients with cardiac and extracardiac sarcoidosis (p = 0.0110). Four (30.8 %) of patients with isolated CS received five or more appropriate therapies (ATP and/or shock) compared with 43 (19.4 %) of patients with cardiac and extracardiac sarcoidosis (p=0.2990.) For patients with a primary prevention indication, 3 of 5 (60.0 %) of patients with isolated CS received an appropriate therapy compared with 30 of 142 (21.1 %) of patients with cardiac and extracardiac sarcoidosis (p=0.0750) (Table 4). For patients with a secondary prevention indication, 6 of 8 (75.0 %) of patients with isolated CS received an appropriate therapy compared with 45 of 80 (56.2 %) of patients with cardiac and extracardiac sarcoidosis (p=0.4593). For patients with a primary prevention indication, 3 of 5 (60.0 %) of

Table 4 Appropriate ICD therapies and shocks in patients with isolated cardiac sarcoidosis compared with patients with cardiac and extracardiac sarcoidosis

Appropriate therapy (ATP and/or shocks) Appropriate shocks Appropriate therapy (ATP and/or shocks) in patients with primary prevention indication Appropriate therapy (ATP and/or shocks) in patients with secondary prevention indication Appropriate shocks in patients with primary prevention indication Appropriate shocks in patients with secondary prevention indication Five or more appropriate therapies (ATP and/or shock)

Isolated CS (n=13)

Cardiac and extracardiac sarcoidosis (n=222)

p value

9 (69.2 %)

75 (33.8 %)

0.0150

8 (61.5 %) 59 (26.6 %) 0.0110 3/5 (60.0 %) 30/142 (21.1 %) 0.0750

6/8 (75.0 %) 45/80 (56.2 %)

0.4593

patients with isolated CS received an appropriate shock compared with 25 of 142 (17.6 %) of patients with extracardiac sarcoidosis (p=0.478). For patients with a secondary prevention indication, 5 of 8 (62.5 %) of patients with isolated CS received an appropriate shock compared with 34 of 80 (42.5 %) of patients with cardiac and extracardiac sarcoidosis (p=0.4578). 3.10 Appropriate ICD therapies in patients with definite isolated CS Six of 7 patients (85.7 %) with definite isolated CS received appropriate ICD intervention, including ATP and/or shock, compared with 78 of 228 patients (34.2 %) of patients without definite isolated CS (p=0.0192.) Five of 7 patients (71.4 %) with definite isolated CS received an appropriate ICD shock compared with 62 of 228 patients (27.2 %) without definite isolated CS (p=0.0213). Three of 7 patients (42.9 %) received five or more appropriate therapies (ATP and/or shock) compared with 44 of 228 (19.3 %) of the rest of the cohort (0.1450). 3.11 Inappropriate ICD shocks Two of 13 (15.4 %) patients with isolated CS received an inappropriate shock compared with 55 of 222 (24.7 %) patients with cardiac and extracardiac sarcoidosis (p = 0.7393). One patient (7.7 %) received three shocks for lead malfunction and one patient (7.7 %) received one shock for sinus tachycardia in the isolated CS group. Among 55 patients with concomitant extracardiac sarcoidosis, the most common identified reasons for inappropriate therapies were AF in 17 (30.1 %), supraventricular tachycardia in 7 (12.7 %), sinus tachycardia in 5 (9.1 %), P/QRS/T wave oversensing in 5 (9.1 %), and lead fracture in 3 (5.5 %). 3.12 Adverse events Two patients (15.4 %) with isolated CS had a defibrillator complication compared with 39 of 222 (17.6 %) patients with cardiac and extracardiac sarcoidosis (p=1.0). One patient with isolated CS had an infection of epicardial leads and patches, which had to be surgically removed. Another patient underwent ICD lead system extraction due to sepsis.

3/5 (60.0 %) 25/142 (17.6 %) 0.0478

5/8 (62.5 %) 34/80 (42.5 %)

0.4578

4 (30.8 %)

0.2990

4 Discussion 4.1 Study results

43 (19.4 %)

In this multicenter retrospective data review of 235 patients with cardiac sarcoidosis and an implantable cardiac

62


defibrillator seen at academic medical centers, 13 (5.5 %) patients had isolated CS. Over a mean of 4.2 years, 9 of 13 (69 %) patients with isolated CS received appropriate ICD therapy compared with 75 of 222 (34 %) of patients with cardiac and extracardiac sarcoidosis. Six of 7 (85.7 %) patients with definite isolated CS received appropriate ICD intervention, including ATP and/or shock, compared with 78 of 228 patients (34.2 %) of patients without definite isolated CS.

likely misses the diagnosis in some patients with isolated CS. While the diagnostic standard and guidelines for [cardiac] sarcoidosis [16] allowed for clinical evidence of extracardiac sarcoidosis for diagnostic purposes, the recently released Heart Rhythm Society guidelines rely on the availability of tissue diagnosis [17].

4.2 Prior reports of isolated CS

In our cohort of patients with CS and ICDs, 69 % of patients with isolated CS received appropriate therapy (ATP and/or shocks) for ventricular arrhythmia compared with 34 % of patients who had concomitant extracardiac sarcoidosis. Of the 7 patients with definite isolated CS, 86 % received an appropriate ICD therapy. Demographically, the patients with isolated CS were similar to the patients with extracardiac sarcoidosis with the exception that they were more likely to have a secondary prevention indication (62 vs. 36 %). The higher incidence of secondary prevention indication in the patients with isolated CS reflects the difficulty of establishing a diagnosis in these patients. Isolated cardiac involvement may present with symptoms of congestive heart failure or arrhythmia, either bradyrythmia or tachyarrhythmia. In contrast, patients with extracardiac sarcoidosis may present with either cardiac symptoms or a variety of nonlife-threatening symptoms related to other organs, for example, skin lesions or cough. A higher percentage of patients with isolated CS presented with syncope, ventricular tachycardia, or resuscitated sudden cardiac death. Interestingly, isolated CS patients with both primary prevention and secondary prevention indications had higher rates of appropriate ICD therapies than their counterparts with extracardiac sarcoidosis, though not statistically significant, likely due to the small number of patients. It is not known whether patients with isolated CS are a subset of CS patients more prone to ventricular arrhythmias or whether they are diagnosed with more advanced disease. Prospective studies are needed to further evaluate the reason for the extremely high rates of ventricular arrhythmias in isolated CS patients.

The majority of patients with CS have extracardiac sarcoid involvement, with pulmonary and lymph node disease being the most common [5, 9]. CS can be difficult to diagnose and requires a high index of suspicion by the treating physician. The literature describes case reports of isolated CS presenting with acute systolic heart failure [10], progressive dyspnea [11], unexplained syncope due to ventricular arrhythmia [2], and being diagnosed intraoperatively at the time of surgery for severe mitral regurgitation [12]. In one surgical series of 411 heart transplantations from 1987 to 2011, 5 patients were found to have unexpected cardiac sarcoidosis at the time of transplantation [3]. These patients did not have extracardiac involvement. 4.3 Prevalence of isolated CS The prevalence of isolated CS is not known. In this cohort of 235 patients with CS and an ICD, the prevalence was 5.5 %. Because all patients in this study had ICDs, they may represent a higher-risk population, with high rates of both ventricular arrhythmias and high-degree heart block. In an unselected group of CS patients, the prevalence of isolated CS may be even lower, as the denominator would be larger, including patients with multiorgan sarcoidosis who have mild or subclinical cardiac involvement. The incidence of tissue-proven isolated CS was 3 % in this cohort. The remaining patients had suspected isolated CS based on a constellation of clinical, ECG, and imaging findings. Isolated CS is notoriously difficult to diagnose. In a recent report of 10 patients who underwent cardiac transplantation for severe chronic systolic heart failure, none had the diagnosis of sarcoidosis prior to transplant except for 3, who had noncaseating granulomas in LV wall tissue excised for LVAD implantation [13]. Based on the Japanese Ministry of Health and Welfare guidelines, isolated CS can only be diagnosed with biopsy or necropsy showing noncaseating granulomas [14]. These guidelines have not been prospectively validated in patients with extracardiac or isolated CS. Furthermore, given the low diagnostic yield of endomyocardial biopsy, particularly without imaging or electroanatomic guidance, patients with isolated CS can have false-negative cardiac biopsies [15]. The requirement for confirmatory cardiac biopsy

4.4 Appropriate ICD therapies

4.5 Diagnosis and natural history of isolated CS Diagnosing isolated CS can be clinically challenging. One case report describes a woman who presented with sustained VT and intermittent AV block [18]. She fulfilled criteria for arrhythmogenic right ventricular cardiomyopathy; however, CS was suspected and electroanatomic mapping-guided endomyocardial biopsy was performed. After standard endomyocardial biopsy was inconclusive, tissue samples from a low-voltage region of the RV septum confirmed a diagnosis of isolated CS. CMR supported the diagnosis of 6 patients in our cohort. CMR with delayed enhancement has been shown to be useful in the diagnosis of cardiac sarcoidosis in patients with


pulmonary sarcoidosis [19]. In patients with extracardiac sarcoidosis, CMR with delayed enhancement was more than twice as sensitive for cardiac involvement as the 1993 Japanese Ministry of Health criteria [7, 14]. The utility of CMR in the diagnosis of isolated cardiac sarcoidosis has not been systematically studied, although CMR has yielded the diagnosis of isolated CS [11]. It is also unknown whether isolated CS is a distinct clinical entity or whether it is merely a stage in more widespread multisystem disease that develops over time. In one case series, two of three patients presented with conduction abnormalities that preceded other clinical or radiographic evidence of sarcoidosis by several years [20]. Our retrospective study examined patients at only one time point and thus was not able to look at patients with isolated CS longitudinally. The Cardiac Sarcoidosis Consortium, an ongoing international prospective registry, will include yearly data points on patients with CS and will hopefully provide insight into the true frequency of isolated CS and whether it remains isolated to the heart or develops into multiorgan system disease.

4.6 Potential limitations The potential limitations of observational research must be considered in our study. Data was collected retrospectively at one time point, and therefore, longitudinal data about disease progression was not evaluated. The number of patients with isolated CS was small, and larger numbers of patients are needed to support the findings in our study. Patients were seen at tertiary care centers with an interest in sarcoidosis. Referral bias may have led to more severe or complex cases being included in the cohort. Patients were evaluated and treated at the discretion of their primary electrophysiologist and may have had extracardiac sarcoidosis that was not identified. All patients had ICDs and may not be representative of an unselected group of isolated CS patients, including patients with pacemakers or no cardiac rhythm devices. ICD programming was left to the discretion of the treating physician and strategies to reduce appropriate but unnecessary ATP or shocks may not have been consistently employed. Analysis of ICD therapy to determine whether shocks were appropriate or not was performed by the enrolling center physician rather than an independent core lab. The patients with suspected isolated CS did not have tissue confirming the diagnosis and may not have had cardiac sarcoidosis. The net effect of the potential biases in our methodology is likely an overestimation of the frequency of appropriate ICD therapies in patients with isolated CS. Our cohort likely includes a high-risk population that is not representative of a typical cohort of isolated CS patients. However, isolated CS is a rare disease and to our knowledge, this is one of the largest cohorts reported in the literature.

63

4.7 Conclusions In this retrospective study, patients with isolated CS and an ICD had very high rates of ventricular arrhythmias, with 69 % receiving an appropriate shock over 4 years. Our methodology is limited by potential biases, the net effect of which is likely an overestimation of the frequency of appropriate ICD therapies in patients with isolated CS. Prospective, long-term follow-up of consecutive patients with isolated CS is needed to determine the true natural history and rates of ventricular arrhythmias in this rare and difficult-to-diagnose disease.

Conflict of interest Dr. Kron has reported that she has no relationships relevant to the contents of this paper to disclose. Dr. Sauer has reported that he received education grants for EP fellowship and consulting fees from Medtronic Inc., St. Jude Medical, and Boston Scientific Corp. Dr. Mueller has reported that she has no relationship relevant to the contents of this paper to disclose. Dr. Schuller has reported that he has no relationships relevant to the contents of this paper to disclose. Dr. Bogun has reported that he has no relationships relevant to the contents of this paper to disclose. Dr. Sarsam has reported that he has no relationships relevant to the contents of this paper to disclose. Dr. Rosenfeld has reported that she has received fellowship support from Medtronic Inc., Boston Scientific, and St. Jude Medical. Dr. Mitiku has reported that he has no relationships relevant to the contents of this paper to disclose. Dr. Cooper has received honoraria from Medtronic Inc., Boston Scientific, Biotronik, St. Jude Medical, and Spectranetics. Dr. Mehta has reported that he has no relationships relevant to the contents of this paper to disclose. Dr. Greenspon has received honoraria from Medtronic Inc., Boston Scientific, and St. Jude Medical. Dr. Ortman has received speaking fees from St. Jude Medical and Boston Scientific. Dr. Delurgio has reported that he has no relationships relevant to the contents of this paper to disclose. Dr. Valadri has reported that he has no relationships relevant to the contents of this paper to disclose. Dr. Narasimhan has reported that he has no relationships relevant to the contents of this paper to disclose. Dr. Swapna has reported that she has no relationships relevant to the contents of this paper to disclose. Dr. Singh has reported that he received research grants from St. Jude Medical, Medtronic Inc., Boston Scientific Corp., and Biotronik; consultant fees from Boston Scientific Corp., Biotronik, St. Jude Medical, Medtronic Inc., CardioInsight Inc., Thoratec Inc., and Biosense Webster; honoraria from Medtronic Inc., Biotronik, Guidant Corp., St. Jude Medical, and Sorin Group. Dr. Danik has reported consultant fees from St. Jude Medical, Boston Scientific. Dr. Markowitz has reported that he has no relationships relevant to the contents of this paper to disclose. Dr. Almquist has reported that he has no relationships relevant to the contents of this paper to disclose. Dr. Krahn has reported that he has no relationships relevant to the contents of this paper to disclose. Mr. Wolfe has reported that he has no relationships relevant to the contents of this paper to disclose.

64 Mr. Feinstein has reported that he has no relationships relevant to the contents of this paper to disclose. Dr. Ellenbogen has received honoraria from Medtronic Inc., Boston Scientific, and Cameron Medical; speaking fees from Medtronic Inc., Boston Scientific, St. Jude Medical, Biotronik, and Sanofi; research grants from Medtronic Inc., Boston Scientific, Biosense Web, and Sanofi; fellowship support from Medtronic Inc., Boston Scientific, and Biosense Web. Dr. Crawford has received grant support from Cardiovascular Center at the University of Michigan and Boston Scientific, Inc. for the development and maintenance of cardiac sarcoidosis registry.

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