Arrhythmogenic right ventricular dysplasia/cardiomyopathy. Original Article

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1 Original Article Arrhythmogenic Right Ventricular Dysplasia/ Cardiomyopathy and Cardiac Sarcoidosis Distinguishing Features When the Diagnosis Is Unclear Binu Philips, MD*; Srinivasa Madhavan, MD, MSPH*; Cynthia A. James, ScM, PhD; Anneline S.J.M. te Riele, MD; Brittney Murray, MS; Crystal Tichnell, MGC; Aditya Bhonsale, MD; Saman Nazarian, MD, PhD; Daniel P. Judge, MD; Hugh Calkins, MD; Harikrishna Tandri, MD; Alan Cheng, MD Background Cardiac sarcoidosis (CS) may show overlap in the clinical presentation with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). We sought to investigate patients with CS who were misdiagnosed with ARVD/C and identify clinical features to distinguish these 2 groups. Methods and Results Among patients enrolled in the Johns Hopkins ARVD/C registry, 15 patients with definite 2010 diagnostic criteria for ARVD/C were subsequently diagnosed with CS. Forty-two pathogenic desmosomal mutation carriers with definite ARVD/C based on the 2010 diagnostic criteria served as a control group. Patients with CS were older at the age of symptom onset, more likely to have comorbidities, and develop heart failure symptoms over time (P<0.05). Electrocardiographically, PR interval prolongation and high-grade atrioventricular block were exclusively associated with CS (P<0.05). HV interval prolongation and increased number of ventricular tachycardias induced were also associated with CS (P<0.05). Radiographically, significant left ventricular dysfunction, myocardial delayed enhancement of the septum, and mediastinal lymphadenopathy were more often see in those with CS (P<0.05). Conclusions The 2010 diagnostic criteria for ARVD/C have limited discrimination in distinguishing between ARVD/C and CS. Despite the overlay in clinical presentation, older age of symptom onset, presence of cardiovascular comorbidities, nonfamilial pattern of disease, PR interval prolongation, high-grade atrioventricular block, significant left ventricular dysfunction, myocardial delayed enhancement of the septum, and mediastinal lymphadenopathy should raise the suspicion for CS. (Circ Arrhythm Electrophysiol. 2014;7: ) Key Words: arrhythmogenic right ventricular dysplasia diagnosis sarcoidosis Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited desmosomal cardiomyopathy characterized by fibrofatty replacement of the right ventricular (RV) myocardium. Disease expression is variable and the spectrum of structural changes range from subtle basal RV involvement to diffuse biventricular involvement. 1 The broad spectrum of phenotypic manifestations makes the clinical diagnosis challenging. In the absence of histological evidence of myocardial fibrofatty replacement, the diagnosis is often established based on fulfilling various clinical criteria proposed by an International Task Force. 2 Unfortunately, other infiltrative myocardial diseases, such as cardiac sarcoidosis (CS), may show overlap in clinical presentation and meet the 2010 Task Force Criteria as well. 3 Being able to distinguish between the 2 is clinically important as the diagnostic and treatment strategies vary significantly and may involve genetic testing of family members or use of systemic immunosuppression. The ability of CS to present with clinical features similar to ARVD/C has been described previously. Despite their limited sample size, these reports suggest that there may be distinguishing features. 3 6 Using a large observational database of patients with suspected ARVD/C, we sought to investigate patients with CS who were initially misdiagnosed with ARVD/C and identify clinical features to distinguish these 2 groups. Clinical Perspective on p 236 Methods Patient Registry and Diagnostic Evaluation Among 1140 patients enrolled, 15 patients who were initially diagnosed with definite ARVD/C before referral were ultimately diagnosed as having CS. The control group consisted of probands who were Received July 29, 2013; accepted February 11, From the Section of Cardiac Electrophysiology, Cardiovascular Institute, Warren Alpert Medical School of Brown University, Providence, RI (B.P.); Section of Cardiac Electrophysiology, Johns Hopkins Medical Institutes, Baltimore, MD (S.M., C.A.J., A.S.J.M.t.R., B.M., C.T., A.B., S.N., D.P.J., H.C., H.T., A.C.); and Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands (A.S.J.M.t.R.). *Drs Philips and Madhavan contributed equally. The Data Supplement is available at Correspondence to Alan Cheng, MD, Section of Cardiac Electrophysiology, Johns Hopkins Medical Institutes, 600 Wolfe St, Carnegie 568, Baltimore, MD acheng3@jhmi.edu 2014 American Heart Association, Inc. Circ Arrhythm Electrophysiol is available at DOI: /CIRCEP

2 Philips et al Differences Between ARVD/C and Cardiac Sarcoidosis 231 selected based on (1) harboring a pathogenic ARVD/C-associated desmosomal mutation, (2) fulfilling definite 2010 diagnostic criteria for ARVD/C, and (3) the availability of a comprehensive set of data for analysis. All individuals referred to the Johns Hopkins ARVD/C center for evaluation of possible ARVD/C were enrolled in a multicenter, observational registry after providing signed consent, which was approved by the Johns Hopkins School of Medicine Institutional Review Board. All patients underwent a comprehensive history and a cardiopulmonary-focused physical examination. Detailed family history was obtained for pedigree analysis and genotyping for desmosomal mutations performed in those with available serum. Additional diagnostic studies were collected including 12-lead and signal-averaged ECG, 24-hour Holter monitoring, exercise stress testing, chest roentgenogram, 2-dimensional (2D) echocardiography, cardiac computed tomography, and cardiac MRI. RV angiography and endomyocardial biopsy were performed at the discretion of the physician. Most individuals subsequently underwent a diagnostic electrophysiology study. A small subset of individuals with radiographic evidence of extracardiac abnormalities or those with ECG changes not typical of ARVD/C underwent whole body imaging with 18-fluorodeoxyglucose positron emission tomography. Diagnostic Criteria The 2010 diagnostic criteria were used to establish a diagnosis of ARVD/C. Definite ARVD/C was characterized by the presence of 2 major criteria, 1 major and 2 minor criteria or 4 minor criteria. 2 A borderline diagnosis of ARVD/C was made in the presence of 1 major and 1 minor criteria or 3 minor criteria. A diagnosis of possible ARVD/C was made if 1 major or 2 minor criteria were present. The diagnosis of CS was based on the Japanese guidelines revised in 2006 by the Japan Society of Sarcoidosis and Other Granulomatous Disorders. 7 The diagnosis was confirmed in the presence of an endomyocardial biopsy demonstrating noncaseating granulomas in the setting of evidence for systemic sarcoidosis. In the absence of endomyocardial histological evidence of disease, CS was diagnosed if there was radiographical, histological, or clinical evidence of extracardiac sarcoidosis in the setting of a series of major and minor criteria. 7 Of note, we considered cardiac 18-fluorodeoxyglucose uptake on positron emission tomography imaging to be equivalent to cardiac Gallium-67 uptake, which is not currently routinely performed. 8 Statistical Analysis All data analyses were performed using SAS version 9.2 (Cary, NC). Continuous variables were expressed as median and interquartile ranges and analyzed using the Wilcoxon rank-sum test. Categorical variables were expressed as frequency and analyzed using Fisher exact test. A P<0.05 was considered statistically significant. Results Patient Characteristics Among 1140 patients enrolled in the Johns Hopkins ARVD/C registry, 15 patients were subsequently diagnosed with CS. Forty-two probands harboring pathogenic ARVD/C-associated desmosomal mutations and fulfilling definite 2010 Diagnostic criteria for ARVD/C served as a control group (Table 1). Demographic Features and Clinical History The predominant presenting symptom for both groups was palpitations and 30% had syncope. The majority of patients in both groups presented initially with ventricular arrhythmias and among these patients, the morphology was predominantly left bundle branch block for both groups. Twenty-nine percent of patients with ARVD/C had a history of ventricular tachycardia (VT) storm, defined as 3 episodes of VT within Table 1. Clinical Characteristics ARVD/C (N=42) Cardiac Sarcoidosis (N=15) P Value Age at onset of symptoms, y 23 [18 29] 45 [40 47] < Men 28 (67) 12 (80) 0.51 Comorbidity Hypertension 2 (5) 6 (40) Atrial flutter/fibrillation 1 (2) 4 (27) Coronary artery disease 0 5 (33) <0.001 Predominant presenting symptom Palpitations/chest discomfort 21 (50) 5 (33) 0.37 Dyspnea 2 (5) 2 (13) 0.28 Near syncope 6 (14) 4 (27) 0.43 Syncope 13 (31) 4 (27) 0.99 VT/VF at initial presentation 28 (67) 9 (60) 0.76 VT storm 12 (29) 5 (33) hour PVC count [ ] [ ] Heart failure symptoms (NYHA 0 (0) 5 (33) <0.001 class II IV) Family history of disease 17 (39.5) 0 (0) Family history of premature SCD 8 (19) 0 (0) 0.10 Discrete data shown with percentages in parentheses. Values are median and first and third quartiles are shown in brackets. ARVD/C indicates arrhythmogenic right ventricular dysplasia/cardiomyopathy; NYHA, New York Heart Association; PVC, premature ventricular complex; SCD, sudden cardiac death; and VT/VF, ventricular tachycardia/ventricular fibrillation. a 24-hour period at any point in the patient s history, as compared with 33% with CS (P=0.75). Although there was no statistical difference in ventricular premature beats between the 2 groups, there was a trend toward more ventricular premature beats in the group with ARVD/C (2375 [ ] versus 596 [ ]; P=0.05). Patients with CS were older at the age of symptom onset (45 [40 47] versus 23 [18 29] years; P<0.001) and more likely to have comorbidities including hypertension, coronary artery disease, and atrial arrhythmias. Heart failure symptoms were present only in patients with CS. Family history of disease (39.5% versus 0%; P=0.003) and premature sudden cardiac death (19% versus 0%; P=0.10) were present only in ARVD/C patients. Electrocardiographic Characteristics The electrocardiographic characteristics of the study population are shown in Table 2. T wave inversions beyond lead V3 were common in the majority of subjects in both groups and epsilon waves were present in a minority of patients in both groups. There were no significant differences in the presence of late potentials on signal-averaged ECG between the groups. With respect to atrioventricular conduction, first degree atrioventricular block (Figure 1) was exclusively seen among patients with CS (53% versus 0% in ARVD/C; P<0.001). The median PR interval in patients with CS was 211 ( ) ms versus 159 ( ) ms for ARVD/C (P<0.001). Third degree atrioventricular block was also exclusively seen among

3 232 Circ Arrhythm Electrophysiol April 2014 Table 2. Electrocardiographic Characteristics ARVD/C (N=42) Cardiac Sarcoidosis (N=15) P Value PR interval prolongation 0 (0) 8 (53) <0.001 Second degree AV block 0 (0) 2 (13) 0.07 Third degree AV block 0 (0) 5 (33) <0.001 Any AV block* 0 (0) 10 (67) <0.001 Interventricular conduction delay Any 7 (17) 9 (60) LBBB 0 (0) 0 (0) RBBB 7 (17) 5 (33) 0.27 NIVCD 0 (0) 4 (27) PR interval, ms 159 [ ] 211 [ ] <0.001 QRS interval, ms 89 [85 102] 132 [ ] <0.001 TWI V1, V2, or V3 only 15 (36) 3 (20) 0.34 TWI>V3 24 (57) 8 (53) 0.99 Epsilon wave 3 (7) 2 (13) 0.60 Atrial pacing 0 (0) 4 (27) Ventricular pacing (0) 6 (40) <0.001 Late potentials on SAECG 28 (67) 8 (53) 0.26 Discrete data shown with percentages in parentheses. Values are median and first and third quartiles are shown in brackets. ARVD/C indicates arrhythmogenic right ventricular dysplasia/cardiomyopathy; AV, atrioventricular; LBBB, left bundle branch block; NIVCD, nonspecific interventricular conduction delay; RBBB, right bundle branch block; SAECG, signal-averaged ECG; and TWI, T wave inversion. *It should be noted that some patients had a history of intermittent second degree and third degree AV block but only had PR prolongation at the time of enrollment in the study. These patients were counted as having PR prolongation as well as having second and third degree AV block as appropriate. subjects with CS as compared with ARVD/C patients (33% versus 0%; P 0.001). In this cohort, the sensitivity and specificity of having any atrioventricular block for the diagnosis of sarcoidosis were 66.7% and 100%, respectively. Interventricular conduction delay was observed more commonly in patients with CS as compared with those with ARVD/C. Nine of 15 patients with CS demonstrated a QRS duration >120 ms including 5 with a right bundle branch block (RBBB) pattern and 4 with nonspecific interventricular conduction delay. Seven of 42 patients with ARVD/C demonstrated a QRS duration >120 ms and all 7 had a RBBB pattern. The median QRS duration in patients with CS was significantly greater than in ARVD/C patients (132 [ ] ms versus 89 [85 102] ms; P<0.001). Electrophysiological Characteristics During electrophysiology study (Table 3), VT inducibility was observed in both groups (80% sarcoidosis versus 64% ARVD/C; P=0.34). There were no significant differences in the mean cycle lengths or the morphology/axis of the induced VTs. The HV interval was significantly longer in patients with CS (50 [50 55] ms versus 44 [40 45] ms; P 0.001). The median number of VTs induced per patient was significantly greater among patients with CS (2.0 [1 4] versus 1.0 [1 2]; P=0.007). Imaging Characteristics The RV ejection fraction was moderately reduced for both groups with no significant difference in the RV end-diastolic volume (Table 4). The presence of major RV structural abnormality was present in 45% of ARVD/C patients and 33% of patients with CS (P=0.55). Among 37 ARVD/C patients and 12 patients with CS who underwent cardiac MRI and had adequate image quality, 49% of patients with ARVD/C had evidence of delayed enhancement, whereas 58% of patients with CS had delayed myocardial enhancement (P=0.74). Patients with CS had lower left ventricular (LV) ejection fractions (57 [35 60]% versus 63 [55 65]%; P<0.001). Furthermore, intramyocardial fat was significantly more Figure 1. Representative 12-lead ECG obtained from a patient with cardiac sarcoidosis who was initially misdiagnosed with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). The ECG illustrates the characteristic T wave inversions associated with ARVD/C in leads V1 through V5. The ECG also illustrates PR interval prolongation, which is not present in patients with ARVD/C.

4 Philips et al Differences Between ARVD/C and Cardiac Sarcoidosis 233 Table 3. common in ARVD/C patients (67% versus 8%; P<0.001). Septal involvement of gadolinium delayed enhancement (Figure 2) was more commonly associated with CS (42% versus 11%; P=0.004). Mediastinal lymphadenopathy noted on standard chest roentgenogram, computed tomography, and MRI images was also seen more often in patients with CS (27% versus 0%; P=0.004). Phenotypic Classification All of the patients with CS met definite 2010 diagnostic criteria for ARVD/C criteria (Table 5). 2 Using the 1994 diagnostic Table 4. Electrophysiological Characteristics Imaging Characteristics ARVD/C (N=42) ARVD/C (N=42) Cardiac Sarcoidosis (N=15) Cardiac Sarcoidosis (N=15) P Value AH interval, ms 100 [84 130] 116 [82 130] 0.18 HV interval, ms 44 [40 45] 50 [50 55] <0.001 Patients with inducible VT 27 (64) 12 (80) 0.34 Median number of VTs induced 1.0 [1 2] 2.0 [1 4] per patient Percentage of LBBB superior axis Percentage of LBBB inferior axis Percentage of RBBB superior axis Percentage of RBBB inferior axis Median VT cycle length, ms 277 [ ] 310 [ ] 0.61 Discrete data shown with percentages in parentheses. Values are median with first and third quartiles shown in brackets. ARVD/C indicates arrhythmogenic right ventricular dysplasia/cardiomyopathy; LBBB, left bundle branch block; ms, milliseconds; RBBB, right bundle branch block; and VT, ventricular tachycardia. P Value Major RV structural abnormality 19 (45) 5(33) 0.55 LV dysfunction (EF<50%) 3 (7) 8 (53) <0.001 RVEF* 45 [30 45] 38 [28 45] 0.47 RVEDV, ml* 223 [ ] 261 [ ] 0.85 LVEF 63 [55 65] 57 [35 60] <0.001 Any scar* 18 (49) 7 (58) 0.18 RV scar* 10 (27) 3 (25) 0.99 Septal scar* 4 (11) 5 (42) LV free wall scar* 14 (38) 6 (50) 0.16 Intramyocardial fat* 28 (67) 1 (8) <0.001 Mediastinal lymphadenopathy 0 (0) 4 (27) Discrete data shown with percentages in parentheses. Values are median with first and third quartiles shown in brackets. ARVD/C indicates arrhythmogenic right ventricular dysplasia/cardiomyopathy; LV, left ventricle; LVEF, left ventricle ejection fraction; RV, right ventricle; RVEDV, right ventricle end-diastolic volume; and RVEF, right ventricle ejection fraction. *Data obtained from 12 patients with cardiac sarcoidosis and 37 patients with ARVD/C who underwent cardiac MRI and adequate image quality. criteria, 8 patients met definite criteria. 9 Table I in the Data Supplement shows the diagnostic criteria met for CS based on the revised Japanese guidelines. 7 Among the CS group, 12 patients underwent endomyocardial biopsies. Six patients had evidence of interstitial fibrosis but noncaseating granulomas were evident only in 1. Three patients underwent orthotopic heat transplantation for refractory heart failure. Noncaseating granulomas were present in all 3 explanted hearts. Immunohistochemistry showed evidence of CD68 staining in the granulomas. Acid fast bacilli, Grocott s methenamine silver stain, periodic acid-schiff, and Gram staining were negative. A clinical diagnosis of CS was made on the basis of the revised criteria in the remaining 11. Extra-CS was observed via lung biopsy in 4 patients, mediastinal lymph node biopsy in 1 patient, and conjuctival biopsy in 1. The remainder of patients had radiographic and clinical evidence of extracardiac sarcoidosis with symptom resolution with corticosteroid therapy. Among the 11 patients without myocardial biopsies demonstrating CS, 10 patients met 1 major and 3 minor criteria for diagnosis of CS. One patient met only 3 minor criteria for diagnosis of CS but had histological evidence of extracardiac sarcoidosis and delayed enhancement of the myocardium. Among the 42 control patients, each patient had a pathogenic ARVD/C-associated desmosomal mutation and met diagnostic criteria for definite ARVD/C (Table II in the Data Supplement). The vast majority (76%) had a pathogenic mutation affecting the PKP2 gene. Application of the diagnostic criteria for CS to this group revealed that only 1 patient met criteria for CS. Among this group, 15 patients (36%) underwent endomyocardial biopsies and 3 patients had fibrofatty infiltration meeting major tissue criteria based on the 1994 diagnostic criteria. Treatment and Follow-up Eighty-seven percent (13/15) of patients with CS underwent implantable cardioverter-defibrillator implantation, whereas 98% (41/42) patients with ARVD/C had an implantable cardioverter-defibrillator implanted. Seventy-three percent (11/15) of patients with CS were treated with β-blockers as compared with 57% (24/42) of patients with ARVD/C (P=0.36). Antiarrhythmic use between the 2 groups was 53% for patients with CS and 29% for ARVD/C patients (P=0.12). All patients with CS were treated with steroids at some point in their history. The median follow-up for the CS group was 17 (6 36) months compared with 49 (25 74) months in the ARVD/C group (P=0.01). As noted above, 3 (20%) patients with CS underwent heart transplantation compared with none with ARVD/C (P=0.02). There were no deaths observed in this cohort. Discussion Our study identified several important observations. First, ARVD/C patients present with symptoms at a younger age often are without cardiovascular comorbidities and more commonly have a family history of disease. Second, atrioventricular conduction abnormalities were seen exclusively in patients with CS. Third, LV dysfunction and heart failure symptoms were more commonly observed in patients with CS. Finally, MRI delayed enhancement of the septum was more commonly associated with CS along with extracardiac abnormalities such as mediastinal lymphadenopathy.

5 234 Circ Arrhythm Electrophysiol April 2014 Figure 2. Representative delayed enhancement MRI in patients with cardiac sarcoidosis and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). A, A short-axis delayed enhanced image from a patient with sarcoidosis. B, An axial delayed enhanced image from a patient with sarcoidosis. Arrow depicts right ventricular (RV) myocardial enhancement including enhancement of the septum. Of note, transbronchial needle aspiration from the left upper lobe revealed lung parenchyma with noncaseating granulomatous inflammation in this patient. C, A short-axis delayed enhanced image from a patient with ARVD/C. D, An axial delayed enhanced image from a patient with ARVD/C. Arrow depicts RV myocardial enhancement. There is no septal myocardial enhancement. Clinical Presentation and Diagnostic Task Force Criteria Although our ARVD/C patients presented more often at a younger age with less comorbidities, this study is generally in agreement with earlier reports suggesting that clinical features alone have poor discriminatory power between these 2 entities. 6 More importantly, our findings suggest that the revised diagnostic criteria for ARVD/C lacked the ability to distinguish ARVD/C from CS. In fact, all patients with CS fulfilled definite criteria for ARVD/C. Conversely, the diagnostic criteria for CS seem to have better specificity against ARVD/C because only 1 of 42 ARVD/C patients would have been diagnosed with CS. Diagnostic Tests: ECG and Electrophysiology Study Findings The ECG signatures associated with ARVD/C were present in the majority of patients with CS. Among patients with CS, T wave inversions in at least leads V1 through V4 were present in 53% patients, similar to the ARVD/C group. Among patients with CS and RBBB, 4 of 5 patients had T wave inversions in at least leads V1 through V4 and the majority had terminal Table 5. Phenotypic Classification of Cardiac Sarcoidosis Patients Based on the 2010 Diagnostic Criteria for Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy 2 Patient Structural Depolarization Repolarization Arrhythmia Tissue Family History Classification 1 Minor Minor None Major None None Definite 2 Minor Minor Major Minor None None Definite 3 Major Minor Major None None None Definite 4 Major None Major Minor None None Definite 5 Minor Minor Minor Major None None Definite 6 Minor Minor Major Major None None Definite 7 Major Minor Major Minor None None Definite 8 Minor Minor None Major None None Definite 9 Minor Minor Minor Minor None None Definite 10 Major Minor Minor None None None Definite 11 Major Minor Minor Major None None Definite 12 Minor Minor Minor Major None None Definite 13 Minor Major Major None None None Definite 14 Minor Major Major Minor None None Definite 15 Minor Minor None Major None None Definite

6 Philips et al Differences Between ARVD/C and Cardiac Sarcoidosis 235 activation delay and an r /s ratio <1 in V1, both characteristic of ARVD/C In addition, 10% of patients in both groups had epsilon waves. However, PR interval prolongation and atrioventricular conduction abnormalities were unique features associated only with CS. Furthermore, interventricular conduction disturbances were more common in patients with CS. Among those with a wide QRS complex, ARVD/C patients always had RBBB, whereas those with CS had both RBBB and nonspecific interventricular conduction delay. Schuller et al 13 have noted that the presence of QRS fragmentation in 2 contiguous leads or bundle branch block was associated with cardiac involvement in pulmonary sarcoidosis patients. Interestingly, PR interval prolongation was not associated with cardiac involvement in their study. This discrepancy may be partly related to differences in the cohorts studied. Our cohort consisted of patients with CS who had predominant myocardial involvement and mimicked many of the clinical findings present in ARVD/C patients, whereas their cohort consisted of patients with biopsy-proven pulmonary sarcoidosis and minimal overlay in the clinical presentation with ARVD/C. In addition, our findings from the electrophysiology study complement those reported previously. 14 Patients with CS had longer HV intervals and a greater number of VTs induced. However, the characteristics of the induced VT were less helpful in discriminating between CS and ARVD/C. Diagnostic Tests: Cardiac Imaging RV structure and function abnormalities constitute one of the diagnostic criteria for ARVD/C and prior reports suggest that RV structural differences exist in ARVD/C patients and patients with CS. 15 Our findings suggest that they have limited ability to discriminate one entity from another. In fact, differences in RV size and function were indistinguishable between ARVD/C patients and patients with CS. However, LV dysfunction was significantly more likely in subjects with CS as noted previously. 6,15 In addition, intramyocardial fat infiltration was more common in ARVD/C. We have previously shown that although intramyocardial fat infiltration is sensitive for the diagnosis of ARVD/C, it is the least specific and reproducible MRI parameter. 16 Importantly, the most distinguishing MRI feature was delayed enhancement of the septum, which was seen almost exclusively in patients with CS. Although imaging shows relative sparing of the septum in ARVD/C, a multicenter clinical pathological study showed macroscopic and histological evidence of septal involvement. 17 Therefore, lack of imaging evidence of septal fibrosis does not necessarily imply lack of histological evidence of septal involvement. Finally, extracardiac manifestations, such as mediastinal lymphadenopathy, were incidentally noted in 27% of sarcoidosis patients and in no patients with ARVD/C. Its presence should raise the suspicion for sarcoidosis. Clinical Course In our study, ARVD/C and CS had distinct natural histories. Although electric instability was uniformly present in both groups, patients with CS were more likely to develop progressive heart failure symptoms with some requiring heart transplantation. 18 Although heart failure was not present among this cohort of ARVD/C patients, some ARVD/C patients do require heart transplantation. 19 Mechanistic Links and Clinical Implications Inflammation is a common feature of CS 20 and recently has been reported to be present in patients with ARVD/C also. 21 It has been shown that certain inflammatory mediators can promote intracellular translocation of junctional plakoglobin and lead to disruption of desmosomal proteins. This may provide a mechanistic link between granulomatous myocarditis and ARVD/C. Unfortunately, immunohistochemical testing for changes in the distribution of desmosomal proteins will not accurately discriminate ARVD/C from CS. 22 CS showed significant overlap in clinical presentation with ARVD/C and unfortunately using the revised diagnostic criteria for ARVD/C did not adequately discriminate between the 2 entities. Isolated forms of ARVD/C with presentation of symptoms at an older age, heart failure symptoms, atrioventricular conduction abnormalities, significant LV dysfunction and septal involvement, and extracardiac radiographic abnormalities should prompt further investigation to exclude CS. A timely and accurate diagnosis is critical given the vastly different diagnostic and therapeutic approaches for these 2 entities. Limitations Several limitations affected this analysis. Our data were obtained as part of a large registry using a cohort of referred patients, which may result in bias. Second, although this study represents the largest cohort studied on this issue to date, the limited cohort size prevents us from definitively validating the discriminatory power of these discriminatory variables or controlling for confounding. Finally, many patients with CS did not have electroanatomic mapping at the time of electrophysiology study. Therefore, we could not adequately address the role of electroanatomic mapping in distinguishing between ARVD/C and CS. Conclusions This study identifies several clinically useful variables which can be easily obtained to distinguish between ARVD/C and CS. Presentation of symptoms at an older age, presence of cardiovascular comorbidities, nonfamilial pattern of disease, atrioventricular conduction abnormalities, significant LV dysfunction, myocardial delayed enhancement of the septum, and mediastinal lymphadenopathy should raise the suspicion for CS. Although these findings may suggest the need for modification of the Task Force Criteria, further studies are needed to determine whether and how the Task Force Criteria should be modified to provide greater discrimination between ARVD/C and sarcoidosis. Acknowledgments We are grateful to the ARVD/C patients and families who have made this work possible. Sources of Funding We wish to acknowledge funding from the National Heart, Lung, and Blood Institute (K23HL to Dr Tandri), the Dr Francis P. Chiaramonte Private Foundation, St. Jude Medical Inc, and Medtronic Inc. The Johns Hopkins Arrhythmogenic Right Ventricular Dysplasia/ Cardiomyopathy Program is supported by the Dr Satish, Rupal, and Robin Shah ARVD/C Fund at Johns Hopkins, the Bogle Foundation, the Healing Hearts Foundation, the Campanella Family, the Patrick J. Harrison Family, the Peter French Memorial Foundation, and the Wilmerding Endowments.

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A new diagnostic test for arrhythmogenic right ventricular cardiomyopathy. N Engl J Med. 2009;360: CLINICAL PERSPECTIVE Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited infiltrative myocardial condition associated with a broad spectrum of phenotypic manifestations and an increased risk for sudden cardiac death. Although histological evidence of fibrofatty replacement is the gold standard for diagnosis, the yield of myocardial biopsies is often low. Hence, the diagnosis is currently established by fulfilling a series of clinical criteria proposed by an International Task Force. Unfortunately, many of the metrics used for the clinical diagnosis of ARVC/D have limited specificity and can also be seen in other infiltrative myocardial conditions such as cardiac sarcoidosis. Distinguishing between these 2 entities in a timely and accurate manner is critical given the vastly different diagnostic and therapeutic approaches for these 2 diseases. Using the Johns Hopkins ARVD/C registry of 1140 patients, we studied 15 patients who were initially misdiagnosed with ARVD/C but later confirmed as having cardiac sarcoidosis. All of these patients met the 2010 Task Force Criteria for definite ARVD/C. Presentation of symptoms at an older age, presence of cardiovascular comorbidities, nonfamilial pattern of disease, atrioventricular conduction abnormalities, significant left ventricular dysfunction, myocardial delayed enhancement of the septum, and mediastinal lymphadenopathy was more commonly associated with cardiac sarcoidosis. The presence of these clinical features in patients presumed to have ARVD/C should raise the suspicion for cardiac sarcoidosis.