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CLINICAL RESEARCH: HEART RHYTHM DISORDER

Efficacy of Antiarrhythmic Drugs in Arrhythmogenic Right Ventricular Cardiomyopathy

A Report From the North American ARVC Registry

Gregory M. Marcus, MD^_*,_*, David V. Glidden, PhD, Bronislava Polonsky, MS, Wojciech Zareba, MD, PhD, Lisa M. Smith, MPH^_*, David S. Cannom, MD, N.A. Mark Estes, III, MD^||, Frank Marcus, MD^¶, Melvin M. Scheinman, MD^_* for the Multidisciplinary Study of Right Ventricular Dysplasia Investigators

^_* Division of Cardiology, Electrophysiology Section, University of California, San Francisco, California
Department of Epidemiology and Biostatistics, University of California, San Francisco, California
Cardiology Division, Department of Medicine, University of Rochester Medical Center, Rochester, New York
Good Samaritan Hospital, Los Angeles, California
^|| Tufts University School of Medicine, Boston, Massachusetts
^¶ Sarver Heart Center, University of Arizona College of Medicine, Tucson, Arizona

Manuscript received February 23, 2009; revised manuscript received March 16, 2009, accepted April 3, 2009.

^_* Reprint requests and correspondence: Dr. Gregory M. Marcus, 500 Parnassus Avenue, MUE 434, San Francisco, California 94143-1354 (Email: marcusg{at}medicine.ucsf.edu).

	Abstract

Top Abstract Methods Results Discussion Conclusions Appendix References

 
Objectives: This study sought to examine the efficacy of empiric antiarrhythmic drugs in a rigorously characterized cohort of arrhythmogenic right ventricular cardiomyopathy (ARVC) patients.

Background: Antiarrhythmic drugs are important in protecting against ventricular arrhythmias in ARVC, but no studies have provided data in a group rigorously screened for the disease.

Methods: Antiarrhythmic medicines were examined in all subjects with implantable cardioverter-defibrillators (ICDs) enrolled in the North American ARVC Registry. A Cox proportional hazards model was used to account for time on each drug, and a hierarchical analysis was performed for repeated measures within individuals.

Results: Ninety-five patients were studied, with a mean follow-up of 480 ± 389 days. Fifty-eight (61%) received beta-blockers, and these medicines were not associated with an increased or decreased risk of ventricular arrhythmias. Sotalol was associated with a greater risk of any clinically relevant ventricular arrhythmia as defined by sustained ventricular tachycardia or ICD therapy (hazard ratio [HR]: 2.55, 95% confidence interval [CI]: 1.02 to 6.39, p = 0.045), but this was not statistically significant after adjusting for potential confounders. An increased risk of any ICD shock and first clinically relevant ventricular arrhythmia while on sotalol remained significant after multivariable adjustment. Those on amiodarone (n = 10) had a significantly lower risk of any clinically relevant ventricular arrhythmia (HR: 0.25, 95% CI: 0.07 to 0.95, p = 0.041), a finding that remained significant after multivariable adjustment.

Conclusions: In a cohort of well-characterized ARVC subjects, neither beta-blockers nor sotalol seemed to be protective. Evidence from a small number of patients suggests that amiodarone has superior efficacy in preventing ventricular arrhythmias.

Key Words: ARVC • ARVD • antiarrhythmic drugs • ventricular arrhythmias • ICD

Abbreviations and Acronyms   ARVC = arrhythmogenic right ventricular cardiomyopathy   CI = confidence interval   HR = hazard ratio   ICD = implantable cardioverter-defibrillator   IQR = interquartile range   VF = ventricular fibrillation   VT = ventricular tachycardia

Although an implantable cardioverter-defibrillator (ICD) is generally recommended as the best therapy to prevent death in the setting of ARVC in the U.S. (3), antiarrhythmic drugs also play a major role in the treatment of the disease. Implantable defibrillators are not as widely available in many other countries, and first-line therapy even for the highest-risk patients will often be antiarrhythmic medicines. Even in patients with ICDs, antiarrhythmic drugs are often required to reduce symptoms caused by premature ventricular contractions or ventricular tachycardia (VT) and are crucial in reducing the incidence of ICD shocks.

Despite the potentially important role of antiarrhythmic medicine in ARVC, a prospective study regarding the efficacy of different agents in a population rigorously determined to have ARVC has not yet been reported. Current practice is based largely on anecdote, extrapolation from other conditions, and studies that did not necessarily differentiate among different agents (4). One of the most cited reports was a European study involving serial programmed electrical stimulation testing in ARVC subjects, suggesting that sotalol therapy associated with acute prevention of VT/ventricular fibrillation (VF) induction may be particularly effective (5). To study the effectiveness of antiarrhythmic drugs in ARVC in a well-characterized population, we assessed the efficacy of antiarrhythmic drugs prescribed to patients participating in the North American ARVC study.

	Methods

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The Multidisciplinary Study of Right Ventricular Dysplasia established the North American ARVC Registry, which consists of 18 enrolling centers in the U.S. and Canada (Online Appendix), a clinical center at the University of Arizona, a data coordinating center at the University of Rochester, a genetic center at Baylor College of Medicine, 6 core laboratories in the U.S. and Europe, and a National Institutes of Health–appointed Data and Safety Monitoring Board (Online Appendix). Individuals with left bundle branch morphology ventricular arrhythmias or those who showed repetitive premature ventricular contractions (at least 1,000 during a 24-h Holter study) who also met task force criteria for the diagnosis of ARVC (6) were included: diagnostic tests, including copies of 12-lead electrocardiograms, signal-averaged electrocardiograms, magnetic resonance imaging, right ventricular angiograms, and right ventricular biopsies were sent to the study's core laboratories for blinded assessment. The diagnostic test results were sent to the Data Coordination Center and entered into a secure Web-based data management system. The data were monitored online, with error notices for items that did not match field requirements. Based on the interpretation of each test as affected, borderline, or nonaffected, the principal investigator (F.M.) performed final classification of the phenotype.

For the purposes of this analysis, only individuals who met the ARVC task force criteria for ARVC and who had an ICD placed were included. Task force major criteria include severe global or regional dysfunction and/or structural abnormality of the right ventricle such as dilation or aneurysm, fibrofatty replacement of the myocardium on biopsy, an epsilon wave on 12-lead electrocardiogram, and autopsy- or biopsy-confirmed family history of ARVC; minor criteria include minor regional or global dysfunction and/or structural abnormality of the right ventricle, inverted T waves in the right precordial leads in the absence of right bundle branch block, late potentials on signal-averaged electrocardiogram, left bundle branch block VT or more than 1,000 premature ventricular contractions in 24 h, and a family history of premature sudden death or ARVC; 2 major , 1 major and 2 minor, or 4 minor criteria are required for diagnosis (6). Each patient was assigned an ARVC score based on the diagnostic tests used to make the diagnosis, with 2 points for fulfilling a major criterion of a category and 1 point for meeting the minor criteria of a category. Those without an ICD were not included because follow-up data regarding medicine changes and arrhythmias were insufficiently complete. Also, the ICD subjects provided a uniform group with the ability to detect serial arrhythmias. Initially, patients were excluded if they had an ICD implanted before enrollment. Because patients and their personal physicians often became aware of this study after ICD implantation, this severely hampered referral for enrollment. During the second year of enrollment, the Data Safety Monitoring Board agreed to allow enrollment of patients whose ICDs were implanted within 6 months. In the last 2 years of the study, patients were permitted to be enrolled if they had an ICD implanted for fewer than 2 years.

Single- or dual-chamber ICDs were implanted according to customary practices at the discretion of the enrolling center, and referring electrophysiologists made all programming decisions regarding rate cutoff criteria for antitachycardia and shock therapy for ventricular tachyarrhythmias. Ultimately, 45% of the devices were dual-chamber and the remainder were single-chamber ICDs. All patients received defibrillators capable of recording and storing electrogram data for future collection and interpretation. Patients received routine ICD follow-up every 3 to 6 months as well as with any ICD shocks or symptomatic arrhythmias. Stored electrograms were reviewed after any device therapy and with each scheduled follow-up, and electrograms for all ICD therapies were sent to the ICD core laboratory (Tufts-New England Medical Center, Boston, Massachusetts), where all therapies were reviewed by expert electrophysiologists and classified as appropriate or inappropriate for sustained ventricular arrhythmias. All ICD therapies were considered, including antitachycardia pacing and shock therapy.

Each patient was contacted at least once yearly, and interim data related to medications, symptoms, documented arrhythmias, events determined by interrogation of ICDs, and medication changes were entered into the database. Medication prescriptions were not standardized and were determined by the treating physician.

All subjects signed informed consent approved by the institutional review board of their enrolling center.

Statistical analysis.   Normally distributed continuous variables are presented as mean ± SD and were compared using Student t tests. Continuous variables that were not normally distributed are expressed as median and interquartile range (IQR) and were compared using the Wilcoxon rank sum test. Categorical variables were compared using the chi-square test. Medicines and potential confounders were examined as time-dependent covariates in a Cox proportional hazard model (7) to examine 1 of 4 different outcomes: any clinically relevant arrhythmia (defined as sustained VT or VT/VF requiring ICD antitachycardia pacing therapy or ICD shock), any ICD shock (defined as an appropriate ICD discharge for a ventricular arrhythmia), first clinically relevant arrhythmia, or first ICD shock. Using outcomes of any clinically-relevant arrhythmia or any ICD shock, the same patient remained in the model and could contribute repeated data and potentially multiple outcomes—in these circumstances, a Cox model with a robust standard error was used to account for clustering within individuals (8). The comparisons were primarily between time on drug versus time not on drug; for example, for amiodarone, the comparison would be between all subjects during the time they were receiving amiodarone versus all subjects during the time they were not receiving amiodarone. Therefore, the same subject could be in both groups. Potential confounders (see the Results section) were added to the regression model based on previously demonstrated associations or those typically deemed to be clinically important, or having associations with both the predictor and outcome with values of p < 0.1, or changing the regression coefficient by >10%.

Analyses were performed using Stata version 9.2 (Stata Corp., College Station, Texas). Two-sided p values <0.05 were considered statistically significant.

	Results

Top Abstract Methods Results Discussion Conclusions Appendix References

 
Ninety-five ARVC patients with ICDs were included in the analysis and were followed up for a mean 480 ± 389 days. The median ARVC score (2 points for fulfilling a major criterion and 1 point for fulfilling a minor criterion) was 4, with an IQR of 4 to 5. Over the follow-up period, 235 clinically relevant arrhythmias (either sustained VT or ICD therapy for VT/VF) were observed in 32 patients, with a mean tachycardia cycle length of 302 ± 45 ms; 49 of these events resulted in an appropriate ICD shock. The mean tachycardia cycle length of ventricular arrhythmias resulting in an ICD shock was 256 ± 43 ms. There were no deaths. Patient characteristics of those with and without clinically relevant ventricular arrhythmias are shown in Table 1. Those with a previous history of sustained VT, aborted sudden death, or syncope (when examined as a group) more commonly exhibited a clinically relevant ventricular arrhythmias during the study period (p = 0.022).

In an exploratory analysis, the effects of each individual beta-blocker were examined. Only atenolol showed a statistically significant association: 20 subjects received atenolol for a median of 665 days (IQR 188 to 930 days) throughout the study; while on atenolol, subjects were 75% less likely to have a clinically relevant ventricular arrhythmia throughout the duration of the study (95% CI: 37% to 90% less likely, p = 0.003), a finding that remained significant after adjusting for the same confounders listed in the above paragraph (adjusted HR: 0.25, 95% CI: 0.08 to 0.80, p = 0.018). This did not seem to be caused by an especially high dose of atenolol because the median dose was 25 mg daily (IQR 25 to 50 mg). However, none of the individual beta-blockers (including atenolol) were significantly associated with any ICD shock (i.e., ICD shock throughout the study duration), first clinically relevant arrhythmia, or first ICD shock.

Sotalol.   Thirty-eight patients were treated with sotalol at some point during study follow-up, for a median 644 days (IQR 464 to 1,091 days). Association between sotalol use and the outcomes of any clinically relevant arrhythmia, any ICD shock, first clinically relevant arrhythmia, and first ICD shock are shown in Table 2. The median daily dose of sotalol was 240 mg (IQR 160 to 320 mg). The mean tachycardia cycle length of those with ventricular arrhythmias while taking sotalol was significantly slower: 311 ± 41 ms versus 292 ± 46 ms in those not taking sotalol (p = 0.0009). Although not all associations were statistically significant, the HRs consistently showed no effect or favored a detrimental effect of sotalol, whether compared with no sotalol or compared with no other antiarrhythmic agents and whether or not potential confounders are taken into account (Table 2). Adjusting for ARVC score did not meaningfully change any of these results.

Amiodarone.   Ten participants took amiodarone for a median of 545 days (IQR 190 to 583 days). The primary predictor in the amiodarone analyses was time receiving amiodarone, without special consideration (such as blanking of outcomes) during either amiodarone loading or withdrawal. While taking amiodarone, participants had a 75% lower risk of any clinically relevant ventricular arrhythmia (HR: 0.25, 95% CI: 0.07 to 0.95, p = 0.041); after adjustment for age, sex, New York Heart Association functional class, left ventricular ejection fraction, a family history of sudden death, and a previous history of sustained VT or aborted sudden death, participants had a 97% decreased risk (HR: 0.03, 95% CI: 0.01 to 0.64, p = 0.025). Comparing only with those not taking other antiarrhythmic drugs, amiodarone was also significantly associated with a lower risk of any clinically relevant ventricular arrhythmia (HR: 0, p < 0.001); after adjustment for potential confounders, this remained significant. Those taking amiodarone before a first event had an HR of 0 for either any ICD shock, first clinically relevant arrhythmia, or first ICD shock (of note, an HR of 0 means that all the first events occurred in those not taking amiodarone before they occurred in those taking amiodarone). Figure 1 provides a timeline of the 10 patients receiving amiodarone, with data on each antiarrhythmic medicine used for those patients included.

View larger version (14K): [in this window] [in a new window] [Download PPT slide]   Figure 1 Timeline of Antiarrhythmic Medicine Use in the 10 ARVC Patients Who Received Amiodarone at Any Time During Study Follow-Up Each patient is represented by a different number (1 to 10). Vertical gray lines represent episodes of either sustained ventricular tachycardia or implantable cardioverter-defibrillator (ICD) therapy. *ICD shock. ARVC = arrhythmogenic right ventricular cardiomyopathy.

	Discussion

Top Abstract Methods Results Discussion Conclusions Appendix References

 
In this evaluation of antiarrhythmic agents in a cohort of rigorously characterized ARVC patients, we found that beta-blockers were neither harmful nor protective against clinically relevant ventricular arrhythmias, that sotalol was not effective, and that amiodarone, although only received by a relatively small number of patients, had the greatest efficacy.

As exemplified by this study and by the fact that no deaths occurred in these high-risk patients over an average of more than 1 year of follow-up, ICDs seem to be effective in preventing death in ARVC patients.

Despite the importance of pharmacologic therapy in ARVC, a study of antiarrhythmic efficacy in a rigorously characterized ARVC population has not previously been reported. The only other study to previously examine specific antiarrhythmic agents first determined acute efficacy of drugs by response to serial testing with programmed ventricular stimulation (5). This European study of originally 81 patients and more recently updated to 191 patients (9) suggested that sotalol was the most effective agent, and amiodarone did not seem to be particularly useful; however, a critical difference is that this study determined selection of antiarrhythmic therapy based on suppression of VT in the electrophysiology laboratory. In contrast, ours is the first study to describe the outcome of different antiarrhythmic drugs chosen empirically by practicing physicians. The acute nature of assessing drug efficacy in the previous study may have been insufficient to allow for full amiodarone loading and consequently full antiarrhythmic effect of the drug. One limitation of this previous study was that subjects were included if they had either "proven or highly suspected" ARVC. They did prospectively follow up these patients, again finding that sotalol was the most effective agent, but the predictor was the antiarrhythmic agent they were on when discharged and did not take into account duration of therapy or the possibility that medicines may have been changed. Finally, ascertainment of the outcome depended largely on clinical presentation because very few of these subjects had ICDs, making the detection of VT incomplete. Despite this limitation and because it was previously the only study that evaluated antiarrhythmic drugs in ARVC, this study is frequently referenced as an indication for sotalol as a first-line antiarrhythmic agent in ARVC (2,9). In fact, it may be that electrophysiology-guided antiarrhythmic therapy is useful in identifying ARVC patients who are good candidates for sotalol.

Because the same ARVC patient can have multiple events (i.e., multiple episodes of ventricular arrhythmias and/or ICD therapies) and because medicines can be changed in the same patient, assessment of individual drug efficacy is difficult and complex. By studying prospectively collected data in this well-characterized cohort of ARVC patients with ICDs using a Cox proportional hazards model in a hierarchical structure, we were able to report on the efficacy of a given drug while accounting for the time patients were taking a particular drug and the fact that there were repeated measures within individuals.

Beta-blockers are generally recommended for ARVC patients (3,10). Although these agents are likely safe, we found no evidence that they were protective. Because more than half of all participants were taking a beta-blocker at some point during follow-up (61%), it is unlikely that insufficient power to detect a meaningful beta-blocker effect was responsible for this negative finding. However, there may be differences among beta-blockers. Notably, atenolol was significantly associated with a reduced risk of any clinically relevant arrhythmia. Although multiple hypothesis testing could be responsible for this positive finding, it is unlikely to fully explain a robust p value of 0.003: even using the conservative Bonferroni correction for testing 4 beta-blockers, the threshold p value for statistical significance would be 0.05 divided by 4 (or 0.0125). Finally, we cannot exclude confounding by indication that was not sufficiently addressed with our measured potential confounders in our regression model; in other words, perhaps healthier or lower-risk individuals (as determined by some unknown/unmeasured factor) were more likely to receive atenolol.

Although previous data have suggested that sotalol might be especially effective for ARVC patients (5), our data suggest that it may have no significant protective effect and may even be harmful. In general, even after adjusting for potential confounders, those patients on sotalol were at higher risk for any clinically relevant ventricular arrhythmia or ICD shock throughout the study and at higher risk for the first clinically relevant arrhythmia (whether compared with those not on sotalol or those on no antiarrhythmic drug). Although the point estimate also suggested a higher risk of first ICD shock, this association was not statistically significant; however, because first ICD shock was the least common outcome, we may have had insufficient power to detect a statistically significant difference for this particular outcome. Those taking sotalol had a statistically significantly slower VT cycle length, suggesting that any proarrhythmia (if present) was unlikely to be caused by torsades de pointes, which would be expected to be faster than the mean 192 beats/min observed. In fact, this slower rate shows that the sotalol had some effect on the ventricular myocardium and suggests that it might make arrhythmias more tolerable. Although serial QTc measurements may also have helped to determine the true potassium-blocking effect of sotalol, these measurements were not available for each patient every time a medicine or dose was changed. Once again, there is the possibility that confounding by indication played a role: for confounding to explain an apparent harmful effect of sotalol, one would have to posit that those who were more likely to have arrhythmias were more likely to receive sotalol. Although this is possible, it would seem unlikely to explain the finding that those receiving sotalol were at higher risk for their first clinically relevant ventricular arrhythmia. It is also possible that the therapies other than sotalol (such as amiodarone) were simply more efficacious; however, even when compared with no therapy, sotalol did not seem to be protective. Finally, although we could not detect a protective effect of the higher doses of sotalol in this study (320 mg or higher, based on the highest quartile), the doses of sotalol given (median 240 mg/day, IQR 160 to 320 mg/day) may have been insufficient, particularly as the successful sotalol experience described in Europe involved doses of 320 to 480 mg/day and up to 640 mg/day in some cases (9).

Although amiodarone was only taken by 10 patients during the study, it seemed to have a consistent protective effect regardless of the outcome examined or whether or not potential confounders were taken into account. Because those most likely to be at risk for sustained VT or VF would more likely be treated with amiodarone, confounding by indication would not seem to be responsible for these positive findings, particularly because amiodarone reduced the risk of any clinically relevant arrhythmia (i.e., if anything, confounding by indication would have been expected to make amiodarone appear less effective than it actually was). For example, it might generally be thought that amiodarone would be reserved for those at the highest risk of requiring ICD therapy or sustained VT, therefore resulting in a false association between amiodarone and higher risk of arrhythmias. However, even when examining all significant ventricular arrhythmias (including those who had a change in therapy after an arrhythmic event), amiodarone was still significantly associated with a lower risk. Notably, we do not have data on medicine-related toxicities other than proarrhythmia. Given the relatively small number of patients on amiodarone, the superior efficacy observed should be viewed with some caution; in particular, when considering applying these findings to clinical practice, the possibility of long-term toxicities, particularly when treating younger and otherwise healthy individuals, must still be guided by clinical judgment.

Study limitations.   As eluded to above, confounding is certainly a possibility when dealing with this observational data, particularly because the choice of antiarrhythmic agents was not standardized and was determined by the discretion of the treating physician. Confounding by indication may have played an important role; however, as mentioned previously, it is unlikely that this is sufficient to explain all of our findings related to either sotalol or amiodarone. Other unmeasured confounders may be present, and only randomization in a prospective experimental study can adequately address this. Although the use of ICDs to detect arrhythmias increased our sensitivity in ascertainment of the outcome, we cannot exclude the possibility that some of the arrhythmias resulting in ICD therapy may ultimately have spontaneously terminated and therefore may not have led to lethal or potentially even symptomatic tachycardias if the ICD had not been in place. However, in individuals with ICDs, the most clinically relevant outcome is often avoidance of therapies, particularly avoidance of ICD shocks. Because ICD programming was determined by the treating providers rather than by a uniformly adopted protocol, it is possible that some ICD therapies may have differed among participants receiving different drugs, primarily as a result of differences in ICD programming. Although all rhythms resulting in ICD therapies were reviewed by the ICD core laboratory, we also cannot exclude the possibility that some arrhythmias may have been misclassified, particularly in subjects with single-chamber devices. Although our exclusion of ARVC subjects without ICDs allowed for study of a uniform group and a sensitive and specific method of detecting ventricular arrhythmia, this may have limited generalizability to lower-risk ARVC patients without ICDs; importantly, because all comparisons were performed within this group, this limitation should not have caused any bias (i.e., there is no limitation to internal validity). Finally, some of the subgroup analyses (such as outcomes involving first-occurrence events) involved smaller sample sizes that may have been prone to over-fitting in the multivariate models; however, the consistent findings for each drug across adjusted and unadjusted analyses as well as across different outcomes (any event or first event) suggests that the smaller sample sizes likely did not cause substantial error. Despite these limitations, the data from this study are uniquely robust in that they included only well-characterized ARVC patients and sensitive and specific outcome data obtained from continuous monitoring via implantable devices.

	Conclusions

Top Abstract Methods Results Discussion Conclusions Appendix References

 
In this rigorously characterized North American ARVC population, in which individual empirically prescribed antiarrhythmic agents were analyzed as time-dependent covariates, we found that beta-blockers were neither protective nor harmful, that sotalol (at doses generally lower than those given in Europe) was not effective, and that amiodarone, although only given to 10 patients, showed superior efficacy in preventing sustained VT and ICD therapies.

	Appendix

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For participating centers, please see the online version of this article.

	Footnotes

 
Dr. Scheinman has received speaker's fees from Medtronic, Boston Scientific, and St. Jude. This study is supported by grant number KL2 RR024130 (Dr. Gregory M. Marcus) from the National Center for Research Resources, a component of the National Institutes of Health; the American Heart Association Western States Affiliate Beginning Grant-in-Aid Award (Dr. Gregory M. Marcus); and grants UO1-HL65594 and HL65691 from the National Heart, Lung, and Blood Institute.

	References

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3. Calkins H. Arrhythmogenic right-ventricular dysplasia/cardiomyopathy Curr Opin Cardiol 2006;21:55-63.[Web of Science][Medline]

4. Marcus FI, Fontaine GH, Frank R, Gallagher JJ, Reiter MJ. Long-term follow-up in patients with arrhythmogenic right ventricular disease Eur Heart J 1989;10(Suppl D):D68-D73.

5. Wichter T, Borggrefe M, Haverkamp W, Chen X, Breithardt G. Efficacy of antiarrhythmic drugs in patients with arrhythmogenic right ventricular disease. Results in patients with inducible and noninducible ventricular tachycardia. Circulation 1992;86:29-37.[Abstract/Free Full Text]

6. McKenna WJ, Thiene G, Nava A, et al. 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 Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy Br Heart J 1994;71:215-218.[Free Full Text]

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This Article Abstract Figures Only Full Text (PDF) Online Appendix Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Marcus, G. M. Search for Related Content PubMed PubMed Citation Articles by Marcus, G. M. Related Collections Related Articles