- Email: [email protected]
Predictors of appropriate implantable defibrillator therapies in patients with arrhythmogenic right ventricular dysplasia
Predictors of appropriate implantable defibrillator therapies in patients with arrhythmogenic right ventricular dysplasia Jonathan P. Piccini, MD, Darshan Dalal, MD, MPH, Ariel Roguin, MD, PhD, Chandra Bomma, MD, Alan Cheng, MD, Kalpana Prakasa, MD, Jun Dong, MD, Crystal Tichnell, MGC, Cynthia James, PhD, ScM, Stuart Russell, MD, Jane Crosson, MD, Ronald D. Berger, MD, PhD, Joseph E. Marine, MD, Gordon Tomaselli, MD, Hugh Calkins, MD From the Division of Cardiology, Department of Medicine, The Johns Hopkins Hospital, Baltimore, Maryland. BACKGROUND Arrhythmogenic right ventricular dysplasia (ARVD) is an inherited cardiomyopathy characterized by ventricular arrhythmias and sudden cardiac death. The risk factors for sudden death and indications for implantable cardioverter-defibrillator (ICD) placement in patients with ARVD are not well defined. OBJECTIVES The purpose of this study was to determine which clinical and electrophysiologic variables best predict appropriate ICD therapies in patients with ARVD. Particular attention focused on whether the ICD was implanted for primary or second prevention. METHODS We enrolled 67 patients (mean age 36 ⫾ 14 years) with definite or probable ARVD who had undergone ICD placement. Appropriate ICD therapies were recorded, and Kaplan-Meier analysis was used to compare the event-free survival time between patients based upon the indication for ICD placement (primary vs secondary prevention), results of electrophysiologic testing, and whether the patient had probable or definite ARVD. RESULTS Over a mean follow-up of 4.4 ⫾ 2.9 years, 40 (73%) of 55 patients who met task force criteria for ARVD and 4 (33%) of 12 patients with probable ARVD had appropriate ICD therapies for ventricular tachycardia/ventricular fibrillation (VT/VF; P ⫽ .027). Mean time to ICD therapy was 1.1 ⫾ 1.4 years. Eleven of 28 patients who received an ICD for primary prevention (39%) and 33 of 35 patients who received an ICD for secondary prevention (85%) experienced appropriate ICD therapies (P ⫽ .001). Electrophysiologic testing did not predict appropriate ICD interventions in patients who received an ICD for primary prevention. Fourteen patients (21%) received ICD therapy for lifethreatening (VT/VF ⬎240 bpm) arrhythmias. There was no difference in the incidence of lifethreatening arrhythmias in the primary and secondary prevention groups (P ⫽ .29). CONCLUSION Patients who meet task force criteria for ARVD are at high risk for sudden cardiac death and should undergo ICD placement for primary and secondary prevention, regardless of electrophysiologic testing results. Further research is needed to confirm that a low-risk subset of patients who may not require ICD placement can be identified. KEYWORDS Arrhythmogenic right ventricular dysplasia; Arrhythmia; Cardiomyopathy; Sudden cardiac death; Implantable cardioverter-defibrillator (Heart Rhythm 2005;2:1188 –1194) © 2005 Heart Rhythm Society. All rights reserved.
Introduction The Johns Hopkins Arrhythmogenic Right Ventricular Dysplasia Program (ARVD.com) is supported by the Bogle Foundation, the Campanella family, the Wilmerding Endowments, NIH Grant 1 U01 HL65594-01A1, and the Donald W. Reynolds Foundation. Address reprint requests and correspondence: Dr. Hugh Calkins, Division of Cardiology, Department of Medicine, The Johns Hopkins Hospital, 600 N Wolfe Street, Carnegie 592, Baltimore, Maryland 21287. E-mail address: [email protected]. (Received July 12, 2005; accepted August 17, 2005.)
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD) is an inherited cardiomyopathy characterized by ventricular arrhythmias and right ventricular dysfunction.1– 4 Several studies have reported that patients with ARVD who undergo implantable cardioverter-defibrillator (ICD) placement have a high probability of receiving an appropriate ICD intervention for treatment of a sustained
1547-5271/$ -see front matter © 2005 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2005.08.022
Piccini et al Table 1
Predictors of ICD Therapies in ARVD
1189
Task force criteria for diagnosis of arrhythmogenic right ventricular dysplasia Major
Minor
Global and/or regional dysfunction and structural alterations Endomyocardial biopsy Repolarization abnormalities Depolarization/conduction abnormalities Arrhythmias
Severe dilation and reduction of RV ejection fraction, localized RV aneurysms Fibrofatty replacement of myocardium
Mild RV dilatation and/or reduced ejection fraction
Family history
Familial disease confirmed at necropsy or surgery
Epsilon waves or localized QRS prolongation (⬎110 ms) in leads V1–V3
T-wave inversion in leads V1–V3 or beyond Late potentials on signal-averaged ECG Left bundle branch block-type ventricular tachycardia (sustained and nonsustained) or frequent ventricular extrasystoles (⬎1,000/24 hours) Familial history of premature sudden death (⬍35 years) or clinical diagnosis based on present criteria
RV ⫽ right ventricular.
ventricular arrhythmia.5– 8 All of the patients in these studies met task force criteria for ARVD, and most of these patients had received an ICD for secondary prevention following a sustained ventricular arrhythmia. As a result, several questions concerning ICD therapy in patients with ARVD unanswered remain. First, the relative benefits of ICD therapy when used for primary rather than secondary prevention are unclear.9,10 Second, whether patients with probable ARVD, who do not meet the strict task force criteria for ARVD, benefit from ICD placement is unclear.11 The purpose of this study was to identify predictors of appropriate ICD interventions in a large series of patients with ARVD. Particular attention focused on defining the relative degree of benefit from ICD therapy in ARVD patients receiving an ICD for primary vs secondary prevention and for patients with probable vs definite ARVD.
Methods Patient population The Johns Hopkins Right Ventricular Dysplasia Program (http://ARVD.com) was established in 1995 to provide clinical care for patients with ARVD and to aid the study of this disease. At the initiation of the program, a registry was established that consists of the medical records of patients diagnosed with ARVD. All patients in the registry with complete medical records who had undergone ICD placement and a follow-up period of at least 3 months after device implantation were invited to participate in the study. All patients gave informed consent to participate in the study, which was approved by the institutional review board of the Johns Hopkins University.
Diagnosis of ARVD The diagnosis of ARVD is based on the presence of major and minor diagnostic criteria according to the
international task force definitions (Table 1).11 The diagnosis is established by the presence of two major criteria or one major criterion plus two minor criteria or four minor criteria. The patients were classified as having a diagnosis of definite ARVD when they met the full criteria. Probable ARVD was considered present when only partial fulfillment of the criteria was met (i.e., one major and one minor or three minor). Each of the patients with probable ARVD in this study had received an ICD following diagnosis of ARVD by their primary cardiologist and/or electrophysiologist. Data from 38 of the 67 subjects who participated in this study also were included in a prior study of ICD therapy in ARVD.7
Electrophysiologic testing Electrophysiologic testing was considered positive if programmed stimulation (without isoproterenol or atropine) induced sustained ventricular tachycardia, flutter, or fibrillation. Stimulation protocols were chosen by the patients’ clinical electrophysiologists.
Defibrillators Patients underwent ICD placement between February 1990 and February 2005. Implantation was performed through a thoracotomy with epicardial lead systems in four patients, all of whom later were implanted with transvenous systems. Decisions regarding programming of these devices were made by the patient’s clinical electrophysiologist. Stored data were reviewed after all discharges and interrogations were performed routinely every 3 to 6 months. ICD placement was defined as secondary prevention only in those patients with documented sustained ventricular arrhythmia or sudden cardiac death. All other patients, including those with a history of syncope or nonsustained ventricular arrhythmia, were classified as primary prevention.
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Classification of discharges and interpretation of intracardiac electrograms Electrograms obtained at the time of ICD therapy were analyzed to classify the arrhythmias responsible for precipitating defibrillator discharges, according to the following definitions.12 Ventricular fibrillation (VF) or flutter was defined as a ventricular arrhythmia with a cycle length ⱕ240 ms. Ventricular tachycardia (VT) was defined as a ventricular arrhythmia with a cycle length ⬎240 ms. The appropriateness of ICD therapies (shock or antitachycardia pacing) was deemed appropriate or inappropriate according to standard criteria.7 In cases where complete ICD interrogation data were not available for arrhythmia determination, we relied upon the interpretation of the treating electrophysiologist. Electrical or VT storm was defined according to Credner et al.13 as the occurrence of VT or VF which resulted in three or more ICD interventions (shock or antitachycardia pacing) in a 24-hour period.
Statistical analysis All data were entered in a database. Continuous data are expressed as mean ⫾ SD. The cumulative probability of survival was determined by the Kaplan-Meier method, and differences in survival between groups were evaluated with the log rank test. Categorical variables were compared between patients who received ICD therapy and those who did not via Chi-square analysis, and continuous variable were compared via unpaired t-test. Multivariate analysis was performed via conditional logistic regression using variables that were found to be statistically significant in univariate analysis. All statistical analyses were performed using STATA statistical software (version 8.2, College Station, TX, USA). P ⬍.05 was considered significant.
Results Patient population The patient population consisted of 67 patients who received an ICD as part of their treatment for ARVD (Figure 1). Fifty-five of these patients met the task force criteria for ARVD and were diagnosed with definite ARVD, and 12 patients did not meet strict task force criteria and were diagnosed with probable ARVD. Characteristics of the study population are given in Table 2. Thirty-five patients were male, and the mean age at the time of ICD placement was 36 ⫾ 14 years (range 2–78 years). Fifteen of these patients (22%) had a family history of ARVD. Sixty-six of these patients underwent electrophysiologic testing. A sustained ventricular arrhythmia was inducible in 49 patients (monomorphic VT in 35 and polymorphic VT/ VF in 14). Each of the 35 patients with a history of spontaneous sus-
Figure 1 Study design and outcome according to primary or secondary prevention. ARVD ⫽ arrhythmogenic right ventricular tachycardia; ICD ⫽ implantable cardioverter-defibrillator; VF ⫽ ventricular fibrillation; VT ⫽ ventricular tachycardia.
tained VT had inducible sustained ventricular arrhythmia at electrophysiologic study.
ICD placement Appropriate sensing was achieved in all patients at the time of device implantation, with a mean R-wave amplitude of 9.5 ⫾ 4.3 mV. The mean defibrillation threshold was 12.6 ⫾ 5.3 J. Forty-five patients (67%) had at least one generator change during follow-up, and 4 patients (6%) had two generator changes. Fourteen patients (21%) had devicerelated complications at the time of device implantation, replacement, or during long-term follow-up, including diaphragmatic sensing (n ⫽ 2), lead fracture (n ⫽ 3), lead repositioning (n ⫽ 2), lead dislodgment (n ⫽ 1), lead insulation defect (n ⫽ 1), reduced ventricular sensing requiring sensing from a coronary sinus lead (n ⫽ 1), a small pneumothorax that did not require chest tube placement (n ⫽ 1), pocket infection requiring device explantation (n ⫽ 1), pocket hematoma (n ⫽ 1), and generator exchange due to device recall (n ⫽ 1).
ICD therapies and follow-up Over a mean follow-up of 4.4 ⫾ 2.9 years, 44 (66%) of the 67 patients had an appropriate ICD therapy for treatment of a sustained ventricular arrhythmia. The mean time to ICD therapy was 1.1 ⫾ 1.4 years (Figure 2), and the mean number of appropriate ICD interventions during follow-up was 11.6 ⫾ 14.6 (range 1– 69). Thirty-eight patients (57%) received therapy for sustained VT ⱕ240 bpm, and 14 patients (21%) received therapy for life-threatening arrhyth-
Piccini et al Table 2
Predictors of ICD Therapies in ARVD
1191
Predictors of appropriate ICD therapy Total (n ⫽ 67)
Age (years) Male gender Definite arrhythmogenic right ventricular dysplasia Family history Diffuse right ventricular involvement Left ventricular dysfunction Syncope Right bundle branch block T-wave inversion in leads V1–V3 Abnormal late potentials (signal-averaged ECG) ⬎1,000 PVCs/24 hours (Holter) Spontaneous VT/VF Nonsustained VT Sustained VT/VF (secondary prevention) Inducible VT/VF at electrophysiologic study Monomorphic VT Polymorphic VT/VF Medications at ICD placement Membrane-active antiarrhythmic drug Class Ic Class III Amiodarone Sotalol Beta-blockers Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker
36 35 55 15 29 10 24 12 58 31 14
⫾ 14 (52) (82) (22) (43) (15) (36) (18) (87) (46) (21)
ICD therapy ⫹ (n ⫽ 44) 32 22 40 8 23 5 19 8 41 23 11
⫾ 14 (50) (91) (18) (52) (11) (43) (18) (93) (52) (25)
ICD therapy ⫺ (n ⫽ 23) 36 13 15 7 6 5 5 4 17 8 3
⫾ 15 (57) (65) (30) (26) (22) (22) (17) (74) (35) (13)
14 (21) 39 (58)
8 (18) 33 (75)
6 (26) 6 (26)
35 (52) 14 (21)
29 (66) 10 (23)
6 (26) 4 (17)
27 4 23 4 19 38 6
19 2 17 4 13 28 2
P value 0.30 .61 .01 .25 .04 .26 .08 .90 .03 .12 .06 ⬍.001 .02
(40) (6) (34) (6) (28) (57) (9)
(43) (5) (39) (9) (30) (64) (5)
8 2 6 0 6 10 4
(35) (9) (26) (26) (43) (17)
.51 .50 .30 .14 .77 .11 .08
ICD ⫽ implantable cardioverter-defibrillator; PVC ⫽ premature ventricular complex; VF ⫽ ventricular fibrillation; VT ⫽ ventricular tachycardia.
mia (VT/VF ⬎240 bpm). Sixteen patients (24%) had at least one episode of VT storm. Sixteen patients (24%) received inappropriate therapy for sinus tachycardia (n ⫽ 4), supraventricular tachycardia/atrial fibrillation (n ⫽ 8), or oversensing (n ⫽ 4). Twenty-three patients (34%) had no ICD interventions. At last follow-up, 64 patients were alive (96%), one patient died of progressive heart failure, one patient died of pneumonia while awaiting cardiac transplantation, and one patient died of a brain tumor. Two patients underwent cardiac transplantation because of end-stage heart failure.
Figure 2 Kaplan-Meier event-free analysis (appropriate implantable cardioverter-defibrillator [ICD] intervention) in the overall study population (n ⫽ 67).
Predictors of ICD therapy The clinical variables that were examined as potential predictors of an appropriate ICD discharge are given in Table 2. Variables associated with an appropriate ICD therapy included (1) those associated with the severity of structural right ventricular disease (definite ARVD, diffuse right ventricular involvement, and T-wave inversion in leads V1–V3) and (2) markers of arrhythmic risk (nonsustained VT, sustained VT [primary vs secondary prevention], and inducible sustained ventricular arrhythmia at electrophysiologic study). The incidence of appropriate ICD therapies was greater for patients with definite compared with probable ARVD (P ⫽ .027; Figure 3) and for patients with a positive electrophysiologic study (P ⫽ .002). Interestingly, none of the patients with probable ARVD who had a negative electrophysiology study experienced an appropriate ICD therapy (Figure 4). Another important predictor of an appropriate ICD intervention was whether the device was implanted for primary vs secondary prevention (Figure 5; P ⫽ .001). Although patients who underwent ICD placement for secondary prevention had a higher rate of appropriate ICD therapies, there was no difference in the occurrence of life-threatening arrhythmia (VT/VF ⬎240 bpm) between the primary and secondary prevention groups (Table 3, P ⫽ .29). Of note, the results of electrophysiologic testing were
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Figure 3 Kaplan-Meier event-free analysis (appropriate implantable cardioverter-defibrillator intervention) according to task force diagnosis (definite vs probable arrhythmogenic right ventricular tachycardia [ARVD]).
Figure 5 Kaplan-Meier event-free analysis (appropriate implantable cardioverter-defibrillator intervention) according to the indication for device implantation (primary vs secondary prevention).
unable to differentiate between primary prevention ARVD patients who did and those who did not receive an appropriate ICD intervention (P ⫽ .19). Multivariate analysis identified prior sustained VT/VF (secondary prevention) as an independent predictor of receiving an appropriate ICD intervention (odds ratio [OR] 11.44, confidence interval [CI] 1.61– 81.22, P ⫽ .015). Nonsustained VT showed a trend toward being predictive (OR 6.29, CI 0.99 – 40.02, P ⫽ .051).
their device for primary prevention. This study has four main findings. (1) The results of this study reveal a high rate of appropriate ICD therapies in this patient population. (2) There is a higher rate of appropriate ICD therapies among patients with definite ARVD as defined by the task force criteria compared with probable ARVD patients. Remarkably, no patient with probable ARVD who was noninducible at electrophysiologic testing received an appropriate ICD therapy. (3) The results of this study confirm that clinical variables associated with the severity of RV structural disease and ventricular arrhythmias predict appropriate ICD therapy. (4) The results of this study reveal that patients receiving an ICD for primary vs secondary prevention have a higher rate of appropriate ICD therapies but a similar rate of appropriate ICD therapy for rapid and potentially lifethreatening arrhythmias.
Medications The medications taken by the patients at the time of ICD placement are summarized in Table 2. Forty percent of patients were receiving class I or III antiarrhythmic agents. There was no association between antiarrhythmic drug use and appropriate ICD therapies (Table 2).
Prior studies of ICD therapy for ARVD
Discussion In this study, we report the outcome of 67 ARVD patients who underwent ICD placement. Forty-two percent received
Figure 4 Kaplan-Meier event-free analysis (appropriate implantable cardioverter-defibrillator intervention) according to task force diagnosis (definite vs probable arrhythmogenic right ventricular tachycardia [ARVD]) and the results of electrophysiologic testing. EPS(⫹) ⫽ sustained ventricular tachycardia/ventricular fibrillation induced at electrophysiologic study; EPS(⫺) ⫽ no inducible ventricular arrhythmia.
Four major studies of ICD use in patients with ARVD have been reported recently.5– 8 The first study by Corrado et al5 was a multicenter study of 132 patients with definite ARVD. Over 3-year follow-up, 48% of patients received an appropriate ICD therapy for ventricular arrhythmia, and 24% received life-saving therapy. The authors found that prior sustained VT/VF, younger age, and left ventricular dysfunction were independent predictors of appropriate ICD therapy. The second study by Wichter et al.6 was a single-center study of 60 patients with approximately 7 years of followup, during which 74% of the cohort had an appropriate ICD intervention and 40% had a life-saving ICD therapy. Right ventricular dysfunction was the sole predictor of ICD therapy. In the third study, we reported our single-center experience of 42 patients with 3.5 years of follow-up, during which 78% of patients received appropriate ICD therapy. We found that appropriate ICD discharges were associated with prior sustained VT/VF, inducible VT at electrophysiologic study, male gender, and diffuse RV involvement.7 The fourth and must current study by Hodgkinson et al8 described a genetically homogeneous cohort of 48 patients with chromosome 3-linked ARVD (ARVD5, chromosome
Piccini et al Table 3
Predictors of ICD Therapies in ARVD
1193
ICD therapy in primary and secondary prevention
Appropriate ICD therapy ICD Therapy for VT/VF ⬎240 bpm Time to first therapy (years)
Total (n ⫽ 67)
Primary prevention (n ⫽ 28)
Secondary prevention (n ⫽ 39)
P value
44 (66) 14 (21) 1.1 ⫾ 1.4
11 (39) 4 (15) 0.8 ⫾ 1.0
33 (85) 10 (26) 1.2 ⫾ 1.4
⬍.001 .29 .36
ICD ⫽ implantable cardioverter defibrillator; VF ⫽ ventricular fibrillation; VT ⫽ ventricular tachycardia.
3p25) who underwent ICD placement. Over 31 months, 70% had an appropriate ICD discharge, including 30% for VT ⬎240 bpm. Most importantly, there was no difference in the rate of ICD therapy in the primary and secondary prevention groups. Taken together, these studies suggest that ICD therapy has an important role in the management of patients with ARVD. However, two important areas were not well addressed. First, whether or not patients with probable ARVD require ICD placement is not clear. In our experience, patients in the United States not uncommonly receive an ICD for treatment of ARVD even though they do not fulfill the task force criteria for ARVD. Second, the relative benefit of ICD placement for primary vs secondary prevention in patients with ARVD requires further study.
Current results The results of the present study confirm and extend the previously published experience on the role of the ICD in patients with ARVD. As in prior studies, the incidence of appropriate ICD interventions in this cohort was high (66%), and markers of disease severity (e.g., diffuse right ventricular involvement) and prior ventricular arrhythmia also were associated with an increased frequency of receiving an appropriate ICD intervention.5–7 Furthermore, the incidence of life-threatening VT/VF in our population (21%) is similar to the 24% to 40% incidence reported in the prior studies. Given the 21% incidence of rapid VT/VF in this cohort, the presumed mortality benefit is comparable to that observed in the large ICD trials, including the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II; HR 0.69)14 and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT; Hazard ratio (HR) 0.77).15 This study has three important new findings. First, the results of this study demonstrate that patients who have definite ARVD who meet the task force criteria have a higher likelihood of receiving an appropriate ICD therapy compared with patients who have only probable ARVD (73% vs 33%). A second new finding of this study is that no patients with probable ARVD and a negative electrophysiologic study experienced an appropriate ICD discharge. This finding suggests that it may be possible to identify low-risk subgroups of ARVD patients who may not require ICD placement. The third new finding of this study is that there was no difference in the incidence of life-threatening VT/VF (VT/VF ⬎240 bpm) between the primary and secondary prevention groups.
Clinical implications The results of this study have several important clinical implications in the management of patients with ARVD. First, although patients who do not meet strict task force criteria for ARVD appear to be at lower arrhythmic risk than those with definite ARVD, nearly one third of patients with only probable ARVD received an appropriate ICD intervention. Based on this finding, we suggest that ICD placement not be restricted to only patients with definite ARVD. The fact that no patient with probable ARVD and a negative electrophysiologic study had an appropriate ICD intervention provides hope that low-risk subgroups of patients with probable ARVD can be identified. Second, the results of this study combined with the results of recently completed studies5,7,8 provide strong evidence of the important role of ICD therapy for primary prevention of sudden cardiac death in patients with ARVD.
References 1. Marcus FI, Fontaine GH, Guiraudon G, Frank R, Laurenceau JL, Malergue C, Grosgogeat Y. Right ventricular dysplasia: a report of 24 adult cases. Circulation 1982;65:384 –398. 2. Nava A, Bauce B, Basso C, Muriago M, Rampazzo A, Villanova C, Daliento L, Buja G, Corrado D, Danieli GA, Thiene G. Clinical profile and long-term follow-up of 37 families with arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol 2000;36:2226 –2233. 3. Corrado D, Fontaine G, Marcus FI, McKenna WJ, Nava A, Thiene G, Wichter T. Arrhythmogenic right ventricular dysplasia/cardiomyopathy: need for an international registry. Study Group on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy of the Working Groups on Myocardial and Pericardial Disease and Arrhythmias of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the World Heart Federation. Circulation 2000; 101:E101–E106. 4. Hulot JS, Jouven X, Empana JP, Frank R, Fontaine G. Natural history and risk stratification of arrhythmogenic right ventricular dysplasia/ cardiomyopathy. Circulation 2004;110:1879 –1884. 5. Corrado D, Leoni L, Link MS, Della Bella P, Gaita F, Curnis A, Salerno JU, Igidbashian D, Raviele A, Disertori M, Zanotto G, Verlato R, Vergara G, Delise P, Turrini P, Basso C, Naccarella F, Maddalena F, Estes NA 3rd, Buja G, Thiene G. Implantable cardioverter-defibrillator therapy for prevention of sudden death in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. Circulation 2003;108:3084 –3091. 6. Wichter T, Paul M, Wollmann C, Acil T, Gerdes P, Ashraf O, Tjan TD, Soeparwata R, Block M, Borggrefe M, Scheld HH, Breithardt G, Bocker D. Implantable cardioverter/defibrillator therapy in arrhythmogenic right ventricular cardiomyopathy: single-center experience of long-term follow-up and complications in 60 patients. Circulation 2004;109:1503–1508.
1194 7. Roguin A, Bomma CS, Nasir K, Tandri H, Tichnell C, James C, Rutberg J, Crosson J, Spevak PJ, Berger RD, Halperin HR, Calkins H. Implantable cardioverter-defibrillators in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol 2004; 43:1843–1852. 8. Hodgkinson KA, Parfrey PS, Bassett AS, Kupprion C, Drenckhahn J, Norman MW, Thierfelder L, Stuckless SN, Dicks EL, McKenna WJ, Connors SP. The impact of implantable cardioverter-defibrillator therapy on survival in autosomal-dominant arrhythmogenic right ventricular cardiomyopathy (ARVD5). J Am Coll Cardiol 2005;45:400 – 408. 9. Wichter T, Paul TM, Eckardt L, Gerdes P, Kirchhof P, Bocker D, Breithardt G. Arrhythmogenic right ventricular cardiomyopathy antiarrhythmic drugs, catheter ablation, or ICD? Herz 2005;30:91–101. 10. Wichter T, Breithardt G. Implantable cardioverter-defibrillator therapy in arrhythmogenic right ventricular cardiomyopathy: a role for genotyping in decision-making? J Am Coll Cardiol 2005;45:409 – 411. 11. McKenna WJ, Thiene G, Nava A, Fontaliran F, Blomstrom-Lundqvist C, Fontaine G, Camerini F. Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology. Br Heart J 1994;71:215–218.
Heart Rhythm, Vol 2, No 11, November 2005 12. Maron BJ, Shen WK, Link MS, Epstein AE, Almquist AK, Daubert JP, Bardy GH, Favale S, Rea RF, Boriani G, Estes NA 3rd, Spirito P. Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med 2000;342:365–373. 13. Credner SC, Klingenheben T, Mauss O, Sticherling C, Hohnloser SH. Electrical storm in patients with transvenous implantable cardioverterdefibrillators: incidence, management and prognostic implications. J Am Coll Cardiol 1998;32:1909 –1915. 14. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML, Multicenter Automatic Defibrillator Implantation Trial II Investigators. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346):877– 883. 15. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M, Troutman C, Anderson J, Johnson G, McNulty SE, Clapp-Channing N, Davidson-Ray LD, Fraulo ES, Fishbein DP, Luceri RM, Ip JH, Sudden Cardiac Death in Heart Failure Trial (SCDHeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225– 237.
Introduction The Johns Hopkins Arrhythmogenic Right Ventricular Dysplasia Program (ARVD.com) is supported by the Bogle Foundation, the Campanella family, the Wilmerding Endowments, NIH Grant 1 U01 HL65594-01A1, and the Donald W. Reynolds Foundation. Address reprint requests and correspondence: Dr. Hugh Calkins, Division of Cardiology, Department of Medicine, The Johns Hopkins Hospital, 600 N Wolfe Street, Carnegie 592, Baltimore, Maryland 21287. E-mail address: [email protected]. (Received July 12, 2005; accepted August 17, 2005.)
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD) is an inherited cardiomyopathy characterized by ventricular arrhythmias and right ventricular dysfunction.1– 4 Several studies have reported that patients with ARVD who undergo implantable cardioverter-defibrillator (ICD) placement have a high probability of receiving an appropriate ICD intervention for treatment of a sustained
1547-5271/$ -see front matter © 2005 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2005.08.022
Piccini et al Table 1
Predictors of ICD Therapies in ARVD
1189
Task force criteria for diagnosis of arrhythmogenic right ventricular dysplasia Major
Minor
Global and/or regional dysfunction and structural alterations Endomyocardial biopsy Repolarization abnormalities Depolarization/conduction abnormalities Arrhythmias
Severe dilation and reduction of RV ejection fraction, localized RV aneurysms Fibrofatty replacement of myocardium
Mild RV dilatation and/or reduced ejection fraction
Family history
Familial disease confirmed at necropsy or surgery
Epsilon waves or localized QRS prolongation (⬎110 ms) in leads V1–V3
T-wave inversion in leads V1–V3 or beyond Late potentials on signal-averaged ECG Left bundle branch block-type ventricular tachycardia (sustained and nonsustained) or frequent ventricular extrasystoles (⬎1,000/24 hours) Familial history of premature sudden death (⬍35 years) or clinical diagnosis based on present criteria
RV ⫽ right ventricular.
ventricular arrhythmia.5– 8 All of the patients in these studies met task force criteria for ARVD, and most of these patients had received an ICD for secondary prevention following a sustained ventricular arrhythmia. As a result, several questions concerning ICD therapy in patients with ARVD unanswered remain. First, the relative benefits of ICD therapy when used for primary rather than secondary prevention are unclear.9,10 Second, whether patients with probable ARVD, who do not meet the strict task force criteria for ARVD, benefit from ICD placement is unclear.11 The purpose of this study was to identify predictors of appropriate ICD interventions in a large series of patients with ARVD. Particular attention focused on defining the relative degree of benefit from ICD therapy in ARVD patients receiving an ICD for primary vs secondary prevention and for patients with probable vs definite ARVD.
Methods Patient population The Johns Hopkins Right Ventricular Dysplasia Program (http://ARVD.com) was established in 1995 to provide clinical care for patients with ARVD and to aid the study of this disease. At the initiation of the program, a registry was established that consists of the medical records of patients diagnosed with ARVD. All patients in the registry with complete medical records who had undergone ICD placement and a follow-up period of at least 3 months after device implantation were invited to participate in the study. All patients gave informed consent to participate in the study, which was approved by the institutional review board of the Johns Hopkins University.
Diagnosis of ARVD The diagnosis of ARVD is based on the presence of major and minor diagnostic criteria according to the
international task force definitions (Table 1).11 The diagnosis is established by the presence of two major criteria or one major criterion plus two minor criteria or four minor criteria. The patients were classified as having a diagnosis of definite ARVD when they met the full criteria. Probable ARVD was considered present when only partial fulfillment of the criteria was met (i.e., one major and one minor or three minor). Each of the patients with probable ARVD in this study had received an ICD following diagnosis of ARVD by their primary cardiologist and/or electrophysiologist. Data from 38 of the 67 subjects who participated in this study also were included in a prior study of ICD therapy in ARVD.7
Electrophysiologic testing Electrophysiologic testing was considered positive if programmed stimulation (without isoproterenol or atropine) induced sustained ventricular tachycardia, flutter, or fibrillation. Stimulation protocols were chosen by the patients’ clinical electrophysiologists.
Defibrillators Patients underwent ICD placement between February 1990 and February 2005. Implantation was performed through a thoracotomy with epicardial lead systems in four patients, all of whom later were implanted with transvenous systems. Decisions regarding programming of these devices were made by the patient’s clinical electrophysiologist. Stored data were reviewed after all discharges and interrogations were performed routinely every 3 to 6 months. ICD placement was defined as secondary prevention only in those patients with documented sustained ventricular arrhythmia or sudden cardiac death. All other patients, including those with a history of syncope or nonsustained ventricular arrhythmia, were classified as primary prevention.
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Classification of discharges and interpretation of intracardiac electrograms Electrograms obtained at the time of ICD therapy were analyzed to classify the arrhythmias responsible for precipitating defibrillator discharges, according to the following definitions.12 Ventricular fibrillation (VF) or flutter was defined as a ventricular arrhythmia with a cycle length ⱕ240 ms. Ventricular tachycardia (VT) was defined as a ventricular arrhythmia with a cycle length ⬎240 ms. The appropriateness of ICD therapies (shock or antitachycardia pacing) was deemed appropriate or inappropriate according to standard criteria.7 In cases where complete ICD interrogation data were not available for arrhythmia determination, we relied upon the interpretation of the treating electrophysiologist. Electrical or VT storm was defined according to Credner et al.13 as the occurrence of VT or VF which resulted in three or more ICD interventions (shock or antitachycardia pacing) in a 24-hour period.
Statistical analysis All data were entered in a database. Continuous data are expressed as mean ⫾ SD. The cumulative probability of survival was determined by the Kaplan-Meier method, and differences in survival between groups were evaluated with the log rank test. Categorical variables were compared between patients who received ICD therapy and those who did not via Chi-square analysis, and continuous variable were compared via unpaired t-test. Multivariate analysis was performed via conditional logistic regression using variables that were found to be statistically significant in univariate analysis. All statistical analyses were performed using STATA statistical software (version 8.2, College Station, TX, USA). P ⬍.05 was considered significant.
Results Patient population The patient population consisted of 67 patients who received an ICD as part of their treatment for ARVD (Figure 1). Fifty-five of these patients met the task force criteria for ARVD and were diagnosed with definite ARVD, and 12 patients did not meet strict task force criteria and were diagnosed with probable ARVD. Characteristics of the study population are given in Table 2. Thirty-five patients were male, and the mean age at the time of ICD placement was 36 ⫾ 14 years (range 2–78 years). Fifteen of these patients (22%) had a family history of ARVD. Sixty-six of these patients underwent electrophysiologic testing. A sustained ventricular arrhythmia was inducible in 49 patients (monomorphic VT in 35 and polymorphic VT/ VF in 14). Each of the 35 patients with a history of spontaneous sus-
Figure 1 Study design and outcome according to primary or secondary prevention. ARVD ⫽ arrhythmogenic right ventricular tachycardia; ICD ⫽ implantable cardioverter-defibrillator; VF ⫽ ventricular fibrillation; VT ⫽ ventricular tachycardia.
tained VT had inducible sustained ventricular arrhythmia at electrophysiologic study.
ICD placement Appropriate sensing was achieved in all patients at the time of device implantation, with a mean R-wave amplitude of 9.5 ⫾ 4.3 mV. The mean defibrillation threshold was 12.6 ⫾ 5.3 J. Forty-five patients (67%) had at least one generator change during follow-up, and 4 patients (6%) had two generator changes. Fourteen patients (21%) had devicerelated complications at the time of device implantation, replacement, or during long-term follow-up, including diaphragmatic sensing (n ⫽ 2), lead fracture (n ⫽ 3), lead repositioning (n ⫽ 2), lead dislodgment (n ⫽ 1), lead insulation defect (n ⫽ 1), reduced ventricular sensing requiring sensing from a coronary sinus lead (n ⫽ 1), a small pneumothorax that did not require chest tube placement (n ⫽ 1), pocket infection requiring device explantation (n ⫽ 1), pocket hematoma (n ⫽ 1), and generator exchange due to device recall (n ⫽ 1).
ICD therapies and follow-up Over a mean follow-up of 4.4 ⫾ 2.9 years, 44 (66%) of the 67 patients had an appropriate ICD therapy for treatment of a sustained ventricular arrhythmia. The mean time to ICD therapy was 1.1 ⫾ 1.4 years (Figure 2), and the mean number of appropriate ICD interventions during follow-up was 11.6 ⫾ 14.6 (range 1– 69). Thirty-eight patients (57%) received therapy for sustained VT ⱕ240 bpm, and 14 patients (21%) received therapy for life-threatening arrhyth-
Piccini et al Table 2
Predictors of ICD Therapies in ARVD
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Predictors of appropriate ICD therapy Total (n ⫽ 67)
Age (years) Male gender Definite arrhythmogenic right ventricular dysplasia Family history Diffuse right ventricular involvement Left ventricular dysfunction Syncope Right bundle branch block T-wave inversion in leads V1–V3 Abnormal late potentials (signal-averaged ECG) ⬎1,000 PVCs/24 hours (Holter) Spontaneous VT/VF Nonsustained VT Sustained VT/VF (secondary prevention) Inducible VT/VF at electrophysiologic study Monomorphic VT Polymorphic VT/VF Medications at ICD placement Membrane-active antiarrhythmic drug Class Ic Class III Amiodarone Sotalol Beta-blockers Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker
36 35 55 15 29 10 24 12 58 31 14
⫾ 14 (52) (82) (22) (43) (15) (36) (18) (87) (46) (21)
ICD therapy ⫹ (n ⫽ 44) 32 22 40 8 23 5 19 8 41 23 11
⫾ 14 (50) (91) (18) (52) (11) (43) (18) (93) (52) (25)
ICD therapy ⫺ (n ⫽ 23) 36 13 15 7 6 5 5 4 17 8 3
⫾ 15 (57) (65) (30) (26) (22) (22) (17) (74) (35) (13)
14 (21) 39 (58)
8 (18) 33 (75)
6 (26) 6 (26)
35 (52) 14 (21)
29 (66) 10 (23)
6 (26) 4 (17)
27 4 23 4 19 38 6
19 2 17 4 13 28 2
P value 0.30 .61 .01 .25 .04 .26 .08 .90 .03 .12 .06 ⬍.001 .02
(40) (6) (34) (6) (28) (57) (9)
(43) (5) (39) (9) (30) (64) (5)
8 2 6 0 6 10 4
(35) (9) (26) (26) (43) (17)
.51 .50 .30 .14 .77 .11 .08
ICD ⫽ implantable cardioverter-defibrillator; PVC ⫽ premature ventricular complex; VF ⫽ ventricular fibrillation; VT ⫽ ventricular tachycardia.
mia (VT/VF ⬎240 bpm). Sixteen patients (24%) had at least one episode of VT storm. Sixteen patients (24%) received inappropriate therapy for sinus tachycardia (n ⫽ 4), supraventricular tachycardia/atrial fibrillation (n ⫽ 8), or oversensing (n ⫽ 4). Twenty-three patients (34%) had no ICD interventions. At last follow-up, 64 patients were alive (96%), one patient died of progressive heart failure, one patient died of pneumonia while awaiting cardiac transplantation, and one patient died of a brain tumor. Two patients underwent cardiac transplantation because of end-stage heart failure.
Figure 2 Kaplan-Meier event-free analysis (appropriate implantable cardioverter-defibrillator [ICD] intervention) in the overall study population (n ⫽ 67).
Predictors of ICD therapy The clinical variables that were examined as potential predictors of an appropriate ICD discharge are given in Table 2. Variables associated with an appropriate ICD therapy included (1) those associated with the severity of structural right ventricular disease (definite ARVD, diffuse right ventricular involvement, and T-wave inversion in leads V1–V3) and (2) markers of arrhythmic risk (nonsustained VT, sustained VT [primary vs secondary prevention], and inducible sustained ventricular arrhythmia at electrophysiologic study). The incidence of appropriate ICD therapies was greater for patients with definite compared with probable ARVD (P ⫽ .027; Figure 3) and for patients with a positive electrophysiologic study (P ⫽ .002). Interestingly, none of the patients with probable ARVD who had a negative electrophysiology study experienced an appropriate ICD therapy (Figure 4). Another important predictor of an appropriate ICD intervention was whether the device was implanted for primary vs secondary prevention (Figure 5; P ⫽ .001). Although patients who underwent ICD placement for secondary prevention had a higher rate of appropriate ICD therapies, there was no difference in the occurrence of life-threatening arrhythmia (VT/VF ⬎240 bpm) between the primary and secondary prevention groups (Table 3, P ⫽ .29). Of note, the results of electrophysiologic testing were
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Figure 3 Kaplan-Meier event-free analysis (appropriate implantable cardioverter-defibrillator intervention) according to task force diagnosis (definite vs probable arrhythmogenic right ventricular tachycardia [ARVD]).
Figure 5 Kaplan-Meier event-free analysis (appropriate implantable cardioverter-defibrillator intervention) according to the indication for device implantation (primary vs secondary prevention).
unable to differentiate between primary prevention ARVD patients who did and those who did not receive an appropriate ICD intervention (P ⫽ .19). Multivariate analysis identified prior sustained VT/VF (secondary prevention) as an independent predictor of receiving an appropriate ICD intervention (odds ratio [OR] 11.44, confidence interval [CI] 1.61– 81.22, P ⫽ .015). Nonsustained VT showed a trend toward being predictive (OR 6.29, CI 0.99 – 40.02, P ⫽ .051).
their device for primary prevention. This study has four main findings. (1) The results of this study reveal a high rate of appropriate ICD therapies in this patient population. (2) There is a higher rate of appropriate ICD therapies among patients with definite ARVD as defined by the task force criteria compared with probable ARVD patients. Remarkably, no patient with probable ARVD who was noninducible at electrophysiologic testing received an appropriate ICD therapy. (3) The results of this study confirm that clinical variables associated with the severity of RV structural disease and ventricular arrhythmias predict appropriate ICD therapy. (4) The results of this study reveal that patients receiving an ICD for primary vs secondary prevention have a higher rate of appropriate ICD therapies but a similar rate of appropriate ICD therapy for rapid and potentially lifethreatening arrhythmias.
Medications The medications taken by the patients at the time of ICD placement are summarized in Table 2. Forty percent of patients were receiving class I or III antiarrhythmic agents. There was no association between antiarrhythmic drug use and appropriate ICD therapies (Table 2).
Prior studies of ICD therapy for ARVD
Discussion In this study, we report the outcome of 67 ARVD patients who underwent ICD placement. Forty-two percent received
Figure 4 Kaplan-Meier event-free analysis (appropriate implantable cardioverter-defibrillator intervention) according to task force diagnosis (definite vs probable arrhythmogenic right ventricular tachycardia [ARVD]) and the results of electrophysiologic testing. EPS(⫹) ⫽ sustained ventricular tachycardia/ventricular fibrillation induced at electrophysiologic study; EPS(⫺) ⫽ no inducible ventricular arrhythmia.
Four major studies of ICD use in patients with ARVD have been reported recently.5– 8 The first study by Corrado et al5 was a multicenter study of 132 patients with definite ARVD. Over 3-year follow-up, 48% of patients received an appropriate ICD therapy for ventricular arrhythmia, and 24% received life-saving therapy. The authors found that prior sustained VT/VF, younger age, and left ventricular dysfunction were independent predictors of appropriate ICD therapy. The second study by Wichter et al.6 was a single-center study of 60 patients with approximately 7 years of followup, during which 74% of the cohort had an appropriate ICD intervention and 40% had a life-saving ICD therapy. Right ventricular dysfunction was the sole predictor of ICD therapy. In the third study, we reported our single-center experience of 42 patients with 3.5 years of follow-up, during which 78% of patients received appropriate ICD therapy. We found that appropriate ICD discharges were associated with prior sustained VT/VF, inducible VT at electrophysiologic study, male gender, and diffuse RV involvement.7 The fourth and must current study by Hodgkinson et al8 described a genetically homogeneous cohort of 48 patients with chromosome 3-linked ARVD (ARVD5, chromosome
Piccini et al Table 3
Predictors of ICD Therapies in ARVD
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ICD therapy in primary and secondary prevention
Appropriate ICD therapy ICD Therapy for VT/VF ⬎240 bpm Time to first therapy (years)
Total (n ⫽ 67)
Primary prevention (n ⫽ 28)
Secondary prevention (n ⫽ 39)
P value
44 (66) 14 (21) 1.1 ⫾ 1.4
11 (39) 4 (15) 0.8 ⫾ 1.0
33 (85) 10 (26) 1.2 ⫾ 1.4
⬍.001 .29 .36
ICD ⫽ implantable cardioverter defibrillator; VF ⫽ ventricular fibrillation; VT ⫽ ventricular tachycardia.
3p25) who underwent ICD placement. Over 31 months, 70% had an appropriate ICD discharge, including 30% for VT ⬎240 bpm. Most importantly, there was no difference in the rate of ICD therapy in the primary and secondary prevention groups. Taken together, these studies suggest that ICD therapy has an important role in the management of patients with ARVD. However, two important areas were not well addressed. First, whether or not patients with probable ARVD require ICD placement is not clear. In our experience, patients in the United States not uncommonly receive an ICD for treatment of ARVD even though they do not fulfill the task force criteria for ARVD. Second, the relative benefit of ICD placement for primary vs secondary prevention in patients with ARVD requires further study.
Current results The results of the present study confirm and extend the previously published experience on the role of the ICD in patients with ARVD. As in prior studies, the incidence of appropriate ICD interventions in this cohort was high (66%), and markers of disease severity (e.g., diffuse right ventricular involvement) and prior ventricular arrhythmia also were associated with an increased frequency of receiving an appropriate ICD intervention.5–7 Furthermore, the incidence of life-threatening VT/VF in our population (21%) is similar to the 24% to 40% incidence reported in the prior studies. Given the 21% incidence of rapid VT/VF in this cohort, the presumed mortality benefit is comparable to that observed in the large ICD trials, including the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II; HR 0.69)14 and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT; Hazard ratio (HR) 0.77).15 This study has three important new findings. First, the results of this study demonstrate that patients who have definite ARVD who meet the task force criteria have a higher likelihood of receiving an appropriate ICD therapy compared with patients who have only probable ARVD (73% vs 33%). A second new finding of this study is that no patients with probable ARVD and a negative electrophysiologic study experienced an appropriate ICD discharge. This finding suggests that it may be possible to identify low-risk subgroups of ARVD patients who may not require ICD placement. The third new finding of this study is that there was no difference in the incidence of life-threatening VT/VF (VT/VF ⬎240 bpm) between the primary and secondary prevention groups.
Clinical implications The results of this study have several important clinical implications in the management of patients with ARVD. First, although patients who do not meet strict task force criteria for ARVD appear to be at lower arrhythmic risk than those with definite ARVD, nearly one third of patients with only probable ARVD received an appropriate ICD intervention. Based on this finding, we suggest that ICD placement not be restricted to only patients with definite ARVD. The fact that no patient with probable ARVD and a negative electrophysiologic study had an appropriate ICD intervention provides hope that low-risk subgroups of patients with probable ARVD can be identified. Second, the results of this study combined with the results of recently completed studies5,7,8 provide strong evidence of the important role of ICD therapy for primary prevention of sudden cardiac death in patients with ARVD.
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1194 7. Roguin A, Bomma CS, Nasir K, Tandri H, Tichnell C, James C, Rutberg J, Crosson J, Spevak PJ, Berger RD, Halperin HR, Calkins H. Implantable cardioverter-defibrillators in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol 2004; 43:1843–1852. 8. Hodgkinson KA, Parfrey PS, Bassett AS, Kupprion C, Drenckhahn J, Norman MW, Thierfelder L, Stuckless SN, Dicks EL, McKenna WJ, Connors SP. The impact of implantable cardioverter-defibrillator therapy on survival in autosomal-dominant arrhythmogenic right ventricular cardiomyopathy (ARVD5). J Am Coll Cardiol 2005;45:400 – 408. 9. Wichter T, Paul TM, Eckardt L, Gerdes P, Kirchhof P, Bocker D, Breithardt G. Arrhythmogenic right ventricular cardiomyopathy antiarrhythmic drugs, catheter ablation, or ICD? Herz 2005;30:91–101. 10. Wichter T, Breithardt G. Implantable cardioverter-defibrillator therapy in arrhythmogenic right ventricular cardiomyopathy: a role for genotyping in decision-making? J Am Coll Cardiol 2005;45:409 – 411. 11. McKenna WJ, Thiene G, Nava A, Fontaliran F, Blomstrom-Lundqvist C, Fontaine G, Camerini F. Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology. Br Heart J 1994;71:215–218.
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