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Background Electrophysiological, imaging, and pathological studies have reported the presence of subtle structural abnormalities in hearts from patients with Brugada syndrome (BrS). However, data concerning disease involvement outside of the right ventricular outflow tract are limited. Objectives This study sought to characterize the presence and distribution of ventricular myocardial fibrosis in a cohort of decedents experiencing sudden cardiac death caused by BrS. Methods The authors evaluated 28 whole hearts from consecutive sudden cardiac death cases attributed to BrS and 29 hearts from a comparator group comprised of noncardiac deaths (control subjects). Cardiac tissue from 6 regions across the right and left ventricle were stained with Picrosirius red for collagen and tissue composition was determined using image analysis software. Postmortem genetic testing was performed in cases with DNA retained for analysis. Results Of 28 BrS decedents (75% men; median age of death 25 years), death occurred in sleep or at rest in 24 of 28 (86%). The highest proportion of collagen was observed in the epicardial right ventricular outflow tract of the BrS group (23.7%; 95% CI: 20.8%-26.9%). Ventricular myocardium from BrS decedents demonstrated a higher proportion of collagen compared with control subjects (ratio 1.45; 95% CI: 1.22-1.71; P < 0.001), with no significant interactions with respect to sampling location or tissue layer. There was insufficient evidence to support differences in collagen proportion in SCN5A-positive cases (n = 5) when compared with control subjects (ratio 1.23; 95% CI: 0.75-1.43; P = 0.27). Conclusions Brugada syndrome is associated with increased collagen content throughout right and left ventricular myocardium, irrespective of sampling location or myocardial layer., Central Illustration

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is a variably penetrant disease increasingly identified in young patients. OBJECTIVES: This study sought to describe the diverse phenotype, genotype, and outcomes in pediatric and adolescent patients. METHODS: Records from 1999 to 2016 were reviewed for individuals age

We read with interest the paper by Aquaro et al. ([1][1]) that evaluated the prognostic role of cardiac magnetic resonance (CMR) phenotypes of arrhythmogenic cardiomyopathy (ACM). The authors reported that left ventricular (LV) involvement and LV-dominant presentation (i.e., arrhythmogenic left

Background: Anterior T-wave inversion (ATWI) on electrocardiography (ECG) in young white adults raises the possibility of cardiomyopathy, specifically arrhythmogenic right ventricular cardi...

Cardiac sarcoidosis (CS) and arrhythmogenic right ventricular dysplasia (ARVD) are associated with ventricular arrhythmias and may have similar clinical presentations. We present a case initially diagnosed as ARVD, subsequently confirmed to be cardiac sarcoidosis. A 56 year old male was found

Arrhythmogenic right ventricular dysplasia (ARVD) is an inherited cardiomyopathy that can lead to heart failure and sudden cardiac death. This challenging diagnosis is based on clinical, electrocardiographic, and radiographic findings, along with suggestive genetic testing. A 72 year old man

Structural changes that occur in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) may predispose to tricuspid regurgitation developing or vice versa in the absence of significant left heart disease. There is little evidence to guide therapy such as tricuspid valve (TV) repair

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited cardiomyopathy that can lead to sudden cardiac death and heart failure. Our understanding of its pathophysiology and clinical expressivity is continuously evolving. The diagnosis of ARVC/D remains particularly challenging due to the absence of specific unique diagnostic criteria, its variable expressivity, and incomplete penetrance. Advances in genetics have enlarged the clinical spectrum of the disease, highlighting possible phenotypes that overlap with arrhythmogenic dilated cardiomyopathy and channelopathies. The principal challenges for ARVC/D diagnosis include the following: earlier detection of the disease, particularly in cases of focal right ventricular involvement; differential diagnosis from other arrhythmogenic diseases affecting the right ventricle; and the development of new objective electrocardiographic and imaging criteria for diagnosis. This review provides an update on the diagnosis of ARVC/D, focusing on the contribution of emerging imaging techniques, such as echocardiogram/magnetic resonance imaging strain measurements or computed tomography scanning, new electrocardiographic parameters, and high-throughput sequencing.

BackgroundPhysiological cardiac adaptation to regular exercise, including biventricular dilation and T-wave inversion (TWI), may create diagnostic overlap with arrhythmogenic right ventricular cardiomyopathy (ARVC).ObjectivesThe goal of this study was to assess the accuracy of diagnostic criteria for ARVC when applied to athletes exhibiting electrocardiographic TWI and to identify discriminators between physiology and disease.MethodsThe study population consisted of athletes with TWI (n = 45), athletes without TWI (n = 35), and ARVC patients (n = 35). Subjects underwent electrocardiography (ECG), signal-averaged electrocardiography (SAECG), echocardiography, cardiac magnetic resonance imaging (CMRI), Holter monitoring, and exercise testing.ResultsThere were no electrical, structural, or functional cardiac differences between athletes exhibiting TWI and athletes without TWI. When athletes were compared with ARVC patients, markers of physiological remodeling included early repolarization, biphasic TWI, voltage criteria for right ventricular (RV) or left ventricular hypertrophy, and symmetrical cardiac enlargement. Indicators of RV pathology included the following: syncope; Q waves or precordial QRS amplitudes 1,000 ventricular extrasystoles (or >500 non-RV outflow tract) per 24 h; and symptoms, ventricular tachyarrhythmias, or attenuated blood pressure response during exercise. Nonspecific parameters included the following: prolonged QRS terminal activation; ≤2 abnormal SAECG parameters; RV dilation without wall motion abnormalities; RV outflow tract ectopy; and exercise-induced T-wave pseudonormalization.ConclusionsTWI and balanced biventricular dilation are likely to represent benign manifestations of training in asymptomatic athletes without relevant family history. Diagnostic criteria for ARVC are nonspecific in such individuals. Comprehensive testing using widely available techniques can effectively differentiate borderline cases.

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with sudden cardiac death. However, the selection of patients for implanted cardioverter-defibrillators (ICDs), as well as programming of the ICD, is unclear. Objectives The objective of this study was to identify predictors, characteristics, and treatment of ventricular arrhythmias in patients with ARVC. Methods The Multidisciplinary Study of Right Ventricular Cardiomyopathy established the North American ARVC Registry and enrolled patients with a diagnosis of ARVC. Patients were followed prospectively. Results Of 137 patients enrolled, 108 received ICDs. Forty-eight patients had 502 sustained episodes of ventricular arrhythmias, including 489 that were monomorphic and 13 that were polymorphic. In the patients with ICDs, independent predictors of ventricular arrhythmias in follow-up included spontaneous sustained ventricular arrhythmias before ICD implantation and T-wave inversions inferiorly. The only independent predictor for life-threatening arrhythmias, defined as sustained ventricular tachycardia (VT) ≥240 beats/min or ventricular fibrillation, was a younger age at enrollment. Anti-tachycardia pacing (ATP), independent of the cycle length of the VT, was successful in terminating 92% of VT episodes. Conclusions In the North American ARVC Registry, the majority of ventricular arrhythmias in follow-up are monomorphic. Risk factors for ventricular arrhythmias were spontaneous ventricular arrhythmias before enrollment and a younger age at ICD implantation. ATP is highly successful in terminating VT, and all ICDs should be programmed for ATP, even for rapid VT.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by life-threatening ventricular arrhythmias and fibrous or fatty replacement of the myocardium, which can lead to congestive heart failure. Although there are recommendations based on high-risk characteristics, there

ObjectivesThis study sought to determine how exercise influences penetrance of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) among patients with desmosomal mutations.BackgroundAlthough animal models and anecdotal evidence suggest that exercise is a risk factor for ARVD/C, there have been no systematic human studies.MethodsEighty-seven carriers (46 male; mean age, 44 ± 18 years) were interviewed about regular physical activity from 10 years of age. The relationship of exercise with sustained ventricular arrhythmia (ventricular tachycardia/ventricular fibrillation [VT/VF]), stage C heart failure (HF), and meeting diagnostic criteria for ARVD/C (2010 Revised Task Force Criteria [TFC]) was studied.ResultsSymptoms developed in endurance athletes (N = 56) at a younger age (30.1 ± 13.0 years vs. 40.6 ± 21.1 years, p = 0.05); they were more likely to meet TFC at last follow-up (82% vs. 35%, p < 0.001) and have a lower lifetime survival free of VT/VF (p = 0.013) and HF (p = 0.004). Compared with those who did the least exercise per year (lowest quartile) before presentation, those in the second (odds ratio [OR]: 6.64, p = 0.013), third (OR: 16.7, p = 0.001), and top (OR: 25.3, p < 0.0001) quartiles were increasingly likely to meet TFC. Among 61 individuals who did not present with VT/VF, the 13 subjects experiencing a first VT/VF event over a mean follow-up of 8.4 ± 6.7 years were all endurance athletes (p = 0.002). Survival from a first VT/VF event was lowest among those who exercised most (top quartile) both before (p = 0.036) and after (p = 0.005) clinical presentation. Among individuals in the top quartile, a reduction in exercise decreased VT/VF risk (p = 0.04).ConclusionsEndurance exercise and frequent exercise increase the risk of VT/VF, HF, and ARVD/C in desmosomal mutation carriers. These findings support exercise restriction for these patients.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically transmitted disease. However, the genetics are more complex than in other inherited conditions wherein a single gene abnormal mutation may be causative. In ARVC, 5 causative desmosomal genes have been identified, but because only 30% to 50% of patients with ARVC have 1 of these gene abnormalities, it is assumed that there are other genes not yet identified. Frequently, patients with ARVC have >1 genetic defect in the same gene (compound heterozygosity) or in a second complementary gene (digenic heterozygosity). In addition, a family member may have an ARVC gene defect and have development of the disease or have no or minimal manifestations of the disease. Clinical genetic testing is commercially available. It is beneficial for first-degree family members of a person with ARVC to have genetic testing but only if there is a known genetic abnormality in the affected person. If the affected family member (proband) with ARVC does not have a genetic defect identified, then it will not be identified in the family member. Genetic counseling is strongly advised for family members of the proband.

Anterior T-wave inversion (ATWI) on electrocardiography (ECG) in young white adults raises the possibility of cardiomyopathy, specifically arrhythmogenic right ventricular cardiomyopathy (ARVC). Whereas the 2010 European consensus recommendations for ECG interpretation in young athletes state that ATWI beyond lead VThis study investigated the prevalence and significance of ATWI in a large cohort of young, white adults including athletes.Individuals 16 to 35 years of age (n = 14,646), including 4,720 females (32%) and 2,958 athletes (20%), were evaluated by using a health questionnaire, physical examination, and 12-lead ECG. ATWI was defined as T-wave inversion in ≥2 contiguous anterior leads (VATWI was detected in 338 individuals (2.3%) and was more common in women than in men (4.3% vs. 1.4%, respectively; p 0.0001) and more common among athletes than in nonathletes (3.5% vs. 2.0%, respectively; p 0.0001). T-wave inversion was predominantly confined to leads VATWI confined to leads V

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a leading cause of sudden cardiac death, but its progression over time and predictors of arrhythmias are still being defined.This study sought to describe the clinical course of ARVC and occurrence of life-threatening arrhythmic events (LAE) and cardiovascular mortality; identify risk factors associated with increased LAE risk; and define the response to therapy.We determined the clinical course of 301 consecutive patients with ARVC using the Kaplan-Meier method adjusted to avoid the bias of delayed entry. Predictors of LAE over 5.8 years of follow-up were determined with Cox multivariable analysis. Treatment efficacy was assessed comparing LAE rates during matched time intervals.A first LAE occurred in 1.5 per 100 person-years between birth and age 20 years, in 4.0 per 100 person-years between ages 21 and 40 years, and in 2.4 per 100 person-years between ages 41 and 60 years. Cumulative probability of a first LAE at follow-up was 14% at 5 years, 23% at 10 years, and 30% at 15 years. Higher risk of LAE was predicted by atrial fibrillation (hazard ratio [HR]: 4.38; p = 0.002), syncope (HR: 3.36; p 0.001), participation in strenuous exercise after the diagnosis (HR: 2.98; p = 0.028), hemodynamically tolerated sustained monomorphic ventricular tachycardia (HR: 2.19; p = 0.023), and male sex (HR: 2.49; p = 0.012). No difference was observed in the occurrence of LAE before and after treatment with amiodarone, beta-blockers, sotalol, or ablation. A total of 81 patients received an implantable cardioverter-defibrillator, 34 were successfully defibrillated.The high risk of life-threatening arrhythmias in patients with ARVC spans from adolescence to advanced age, reaching its peak between ages 21 and 40 years. Atrial fibrillation, syncope, participation in strenuous exercise after the diagnosis of ARVC, hemodynamically tolerated sustained monomorphic ventricular tachycardia, and male sex predicted lethal arrhythmias at follow-up. The lack of efficacy of antiarrhythmic therapy and the life-saving role of the implantable cardioverter-defibrillator highlight the importance of risk stratification for patient management.

Accurate knowledge of causes of sudden cardiac death (SCD) in athletes and its precipitating factors is necessary to establish preventative strategies.This study investigated causes of SCD and their association with intensive physical activity in a large cohort of athletes.Between 1994 and 2014, 357 consecutive cases of athletes who died suddenly (mean 29 ± 11 years of age, 92% males, 76% Caucasian, 69% competitive) were referred to our cardiac pathology center. All subjects underwent detailed post-mortem evaluation, including histological analysis by an expert cardiac pathologist. Clinical information was obtained from referring coroners.Sudden arrhythmic death syndrome (SADS) was the most prevalent cause of death (n = 149 [42%]). Myocardial disease was detected in 40% of cases, including idiopathic left ventricular hypertrophy (LVH) and/or fibrosis (n = 59, 16%); arrhythmogenic right ventricular cardiomyopathy (ARVC) (13%); and hypertrophic cardiomyopathy (HCM) (6%). Coronary artery anomalies occurred in 5% of cases. SADS and coronary artery anomalies affected predominantly young athletes (≤ 35 years of age), whereas myocardial disease was more common in older individuals. SCD during intense exertion occurred in 61% of cases; ARVC and left ventricular fibrosis most strongly predicted SCD during exertion.Conditions predisposing to SCD in sports demonstrate a significant age predilection. The strong association of ARVC and left ventricular fibrosis with exercise-induced SCD reinforces the need for early detection and abstinence from intense exercise. However, almost 40% of athletes die at rest, highlighting the need for complementary preventive strategies.

Catheter ablation of hemodynamically unstable ventricular tachycardia (VT) relies on substrate mapping of sites critical for reentry. Late potentials (LP), commonly seen in post-infarction scars, reflect areas of myocardium where conduction is slowed and interrupted by fibrosis (1,2). Although LPs are not specific for critical isthmuses, they are highly sensitive as a guide for targeting ablation in patients with ischemic cardiomyopathy (ICM) (3–5). The prevalence and value of LPs as ablation targets in patients with nonischemic cardiomyopathy (NICM) remains unknown. Analysis of human explanted hearts with dilated cardiomyopathy has revealed fibrosis, myocyte disarray, and membrane abnormalities.(6,7) Fractionated electrograms in patients with NICM have been attributed to lines of activation block from fibrosis, resulting in nonuniform conduction.(8) However, scar in NICM differs from infarct scar with less confluence, a basal predilection, and less endocardial involvement.(9–11) The purpose of this study was to compare the characteristics and prevalence of LPs within scar tissue in patients with NICM and ICM and to assess their value as ablation targets.

Therapeutic options for ventricular tachycardia due to structural heart disease in peripartum cases are limited by teratogenic risk. A 22-year-old female presented with 3 days of palpitations and dizziness. She was found to be in an unstable monomorphic ventricular tachycardia requiring

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a major cause of sudden cardiac death in young, previously asymptomatic athletes. However in highly trained athletes the diagnosis is challenging because of overlapping features (elevated right ventricular end-diastolic volume

Infiltrative cardiomyopathies have overlapping features by conventional imaging criteria; Precise diagnosis requires a multimodality approach and has important implications for treatment. A 49 year old male presented in ventricular tachycardia which terminated with lidocaine. Baseline EKG was

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.

ObjectivesThis study sought to investigate the prevalence and mechanisms underlying right ventricular (RV) dyssynchrony in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) using tissue Doppler echocardiography (TDE).BackgroundAn ARVD/C is characterized by fibrofatty replacement of RV myocardium and RV dilation. These pathologic changes may result in electromechanical dyssynchrony.MethodsEchocardiography, both conventional and TDE, was performed in 52 ARVD/C patients fulfilling Task Force criteria and 25 control subjects. The RV end-diastolic and -systolic areas, right ventricular fractional area change (RVFAC), and left ventricular (LV) volumes and function were assessed. Mechanical synchrony was assessed by measuring differences in time-to-peak systolic velocity (TSV) between the RV free wall, ventricular septum, and LV lateral wall. An RV dyssynchrony was defined as the difference in TSVbetween the RV free wall and the ventricular septum, >2 SD above the mean value for control subjects.ResultsThe mean difference in RV TSVwas higher in ARVD/C compared with control subjects (55 ± 34 ms vs. 26 ± 15 ms, p < 0.001). Significant RV dyssynchrony was not noted in any of the control subjects. Based on a cutoff value of 56 ms, significant RV dyssynchrony was present in 26 ARVD/C patients (50%). Patients with RV dyssynchrony had a larger RV end-diastolic area (22 ± 5 cm2vs. 19 ± 4 cm2, p = 0.02), and lower RVFAC (29 ± 8% vs. 34 ± 8%, p = 0.03) compared with ARVD/C patients without RV dyssynchrony. No differences in QRS duration, LV volumes, or function were present between the 2 groups.ConclusionsAn RV dyssynchrony may occur in up to 50% of ARVD/C patients, and is associated with RV remodeling. This finding may have therapeutic and prognostic implications in ARVD/C.

Objectives: The purpose of this study was to determine the extent of left ventricular (LV) involvement in individuals predisposed to developing arrhythmogenic right ventricular dysplasia/cardiomyop...

Objectives We evaluated the diagnostic contribution and the therapeutic and prognostic implications of 3-dimensional electroanatomic mapping (EAM)-guided endomyocardial biopsy (EMB) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Background ARVC is a frequent cause of life-threatening ventricular arrhythmias and sudden death in young people. The value of current diagnostic criteria and the role of imaging techniques and EMB are still debated. Methods We studied 30 consecutive patients (17 male, mean age 43 ± 17 years) with a noninvasive diagnosis of ARVC according to current criteria. All patients underwent 3-dimensional EAM-guided EMB. Results Twenty-nine (97%) of 30 patients presented an abnormal voltage map. Histology and immunohistochemistry confirmed the diagnosis of ARVC in 15 patients, and showed active myocarditis according to Dallas criteria in the remaining 15 patients. Patients with ARVC were not distinguishable on the basis of clinical features, presence, and severity of structural and functional right ventricular abnormalities and 3-dimensional EAM findings. On the basis of clinical and histological features, a cardioverter-defibrillator was implanted in 13 patients with biopsy-proven ARVC and in 1 patient only with myocarditis. At a mean follow-up of 21 ± 8 months, 7 (47%) patients with ARVC experienced a recurrence of symptomatic sustained ventricular arrhythmias with appropriate defibrillator intervention in all cases. All patients with myocarditis remained asymptomatic and free from arrhythmic events. Conclusions Right ventricular myocarditis frequently mimics ARVC. Three-dimensional EAM-guided EMB is a safe and effective tool in differential diagnosis and in the selection of the most appropriate therapeutic strategy.

ObjectivesWe tested whether 3-dimensional electroanatomical voltage mapping (EVM) may help in the differential diagnosis between idiopathic right ventricular outflow tract (RVOT) tachycardia and arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D).BackgroundRight ventricular EVM has been demonstrated to reliably identify low-voltage regions (“electroanatomical scar”), which in patients with ARVC/D correspond to areas of fibrofatty myocardial replacement.MethodsThe study population comprised 27 patients (15 men and 12 women, age 33.9 ± 8 years) with RVOT tachycardia and no echocardiographic/angiographic evidence of right ventricular (RV) dilation/dysfunction, who underwent EVM and endomyocardial biopsy (EMB) for characterization of ventricular tachycardia (VT) substrate before catheter ablation.ResultsElectroanatomical voltage mapping was normal in 20 of 27 patients (74%, group A), with electrogram voltage >1.5 mV throughout the RV. The other 7 patients (26%, group B) showed ≥1 (1.4 ± 07) RV electroanatomical scar area(s) (bipolar voltage

Several important studies related to the treatment of atrial fibrillation (AF) were published in the past year. In addition, building on recent data, the American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), and the Heart Rhythm Society (HRS) provided updates to the

Hypertrophic cardiomyopathy (HCM)1,2 is a major focus of this document given that it is the single most common cause of sudden death in young competitive athletes in the United States, responsible for at least one-third of these events.3 HCM is the most frequent nontraumatic cause of sudden death in the young1,2 and a common genetic heart disease, occurring in at least 1 in 500 people in the general population.4 HCM is a clinically and genetically heterogenous disease, associated with >1500 mutations in ≥11 major genes (and a variety of other susceptibility genes with lesser evidence for pathogenicity), encoding proteins of the cardiac sarcomere, adjacent Z disk, and calcium handling.5 Although HCM is associated with substantial diversity in morphological expression,6 clinical diagnosis usually occurs with recognition of the characteristic disease phenotype, that is, left ventricular (LV) hypertrophy without chamber dilatation in the absence of another cardiac or systemic disease capable of producing the magnitude of hypertrophy evident.1,6 Neither systolic anterior motion of the mitral valve, hyperdynamic LV function, or identification of pathogenic sarcomere mutations is obligatory for the clinical diagnosis of HCM.2 Atrial fibrillation is a common cause of morbidity in HCM, occurring in ≈20% of patients, although usually after 30 years of age.1,2 Notably, the clinical presentation and course are diverse, with unexpected sudden death in the young the most visible disease complication. A major impetus in HCM has been the identification of those patients at increased risk for sudden death. Indeed, a risk-stratification algorithm has been largely effective in identifying those people at highest risk who are eligible for primary prevention of sudden death with an implantable cardioverter-defibrillator (ICD),7–10 thereby markedly reducing HCM-related mortality to 0.5% per year.7 …

Late gadolinium enhancement (LGE) in cardiovascular magnetic resonance imaging (CMR) has emerged as an in vivo marker of myocardial fibrosis. The purpose of our study was to evaluate the prognostic significance of LGE in patients with arrhythmogenic right ventricular dysplasia/ cardiomyopathy (ARVD/

OBJECTIVES The purpose of this study was to determine interobserver agreement for interpretation of magnetic resonance imaging (MRI) examinations of arrhythmogenic right ventricular dysplasia (ARVD) and to determine sensitivity and specificity of fat detection versus functional parameters measured by MRI. BACKGROUND The interobserver variability of MRI and the relative importance of different MRI parameters (fat detection, regional and global right ventricular [RV] function) for ARVD diagnosis is unknown. METHODS Two experienced observers blinded to the clinical history independently analyzed MRI datasets obtained from 40 patients evaluated for ARVD. Twenty normal subjects underwent MRI and served as control subjects. The MRI scans were performed according to a standard protocol on a 1.5-T scanner. The observers reported on fat infiltration, global and regional RV function, myocardial thinning, and chamber dilatation qualitatively. The RV volumes were measured on the cine sequences. RESULTS Interobserver kappa scores for fat infiltration, global and regional RV function, wall thinning, and RV outflow dilatation were 0.74, 0.94, 0.89, 0.93, and 0.93, respectively. Correlation coefficients between observers for RV end-diastolic volume, end-systolic volume, and ejection fraction were 0.93, 0.94, and 0.95, respectively (p < 0.001). Fifteen patients were diagnosed with ARVD using Task Force criteria. Sensitivity of fat infiltration, RV enlargement, and regional RV dysfunction for diagnosing ARVD was 84%, 68%, and 78%, and specificity was 79%, 96%, and 94%, respectively. CONCLUSIONS Qualitative assessment of RV structure and function is highly reproducible for experienced observers. Among the qualitative parameters, fat infiltration is less reproducible and lacks specificity compared with RV kinetic abnormalities.

OBJECTIVES We sought to assess the utility of cardiovascular magnetic resonance (CMR) in the evaluation of arrhythmogenic right ventricular cardiomyopathy (ARVC) in relation to diagnostic criteria and genotype. BACKGROUND Timely diagnosis of ARVC is difficult as clinical findings may be subtle and nonspecific in early disease. The role of CMR is controversial owing to the absence of a standardized protocol, insufficient experience with the modality, and inherent difficulties in imaging the right ventricle. METHODS Comprehensive CMR examination was performed in 232 patients undergoing evaluation for suspected ARVC. CMR outcomes were compared with: 1) prospective clinical diagnosis using Task Force guidelines, with and without the proposed modifications for familial ARVC; and 2) gene-carrier status in 35 individuals from genotyped families. RESULTS CMR studies were positive in all 64 patients who prospectively fulfilled Task Force criteria, resulting in 100% sensitivity. Specificity in relation to Task Force criteria was low (29%). Of the 119 apparent false positives detected by CMR, however, 63 fulfilled modified diagnostic criteria for familial ARVC and 7 were obligate gene carriers, suggesting that CMR frequently identifies individuals with early disease, in whom Task Force criteria are relatively insensitive. This was borne out by evaluation of genotyped individuals (26 gene-positive and 9 gene-negative), in whom CMR had a sensitivity of 96% and a specificity of 78%. CONCLUSIONS CMR is a valuable component of the diagnostic workup for ARVC when performed with a dedicated protocol by specialists with experience in analysis of volumes, right ventricular wall motion, and delayed-enhancement imaging.

OBJECTIVES The purpose of our study was to characterize the penetrance of PKP2 mutations among family members of people with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) and to examine clinical features and predictors of disease among PKP2 mutation carriers. BACKGROUND Arrhythmogenic right ventricular dysplasia/cardiomyopathy is an inherited cardiomyopathy characterized by fatty-fibrous myocardial replacement of the right ventricle, ventricular arrhythmias, and right ventricular dysfunction. Mutations in PKP2, the gene encoding plakophilin-2, are found in 11% to 43% of ARVD/C probands. METHODS The study population was composed of 64 individuals in 9 families with an ARVD/C proband previously shown to carry a pathogenic PKP2 mutation. The diagnosis of ARVD/C was established based on task force criteria (TFC) set by the European Society of Cardiology. RESULTS In addition to the probands, PKP2 mutations were present in 52% of relatives screened. Forty-nine percent of PKP2 mutation carriers met TFC. Among mutation carriers who did not meet full TFC, 50% met at least some TFC criteria besides family history. Pedigrees showed wide intra-familial variability, ranging from severe disease with early death to individuals who were completely asymptomatic late in life. Male PKP2 mutation carriers were more likely to have structural and conduction abnormalities as determined by imaging studies, signal-averaged electrocardiography, and 24-h ambulatory electrocardiography (p < 0.05). CONCLUSIONS PKP2 mutations in a group of North American families with ARVD/C have both reduced penetrance and variable expressivity. Gender may have an influence on penetrance of PKP2 mutations, with male mutation carriers more likely to develop specific phenotypic manifestations of this disease.

Objectives The purpose of this study was to quantify the echocardiographic abnormalities in probands who were newly diagnosed with arrhythmogenic right ventricular dysplasia (ARVD). Background The diagnosis of ARVD remains challenging. The Multidisciplinary Study of Right Ventricular Dysplasia was initiated to characterize the cardiac structural, clinical, and genetic aspects of ARVD. Methods Detailed echocardiograms were performed in 29 probands and compared with echoes from 29 normal control patients matched for age, gender, body size, and year of echo. Right atrial (RA) and right ventricular (RV) chamber dimensions, RV regional function, and the presence of morphologic abnormalities (hyper-reflective moderator band, trabecular derangement, and sacculations) were assessed. The RV systolic function was calculated as RV fractional area change (FAC). Results The RV dimensions were significantly increased, and RV FAC was significantly decreased in probands versus control patients (27.2 ± 16 mm vs. 41.0 ± 7.1 mm, p = 0.0003). The right ventricular outflow tract (RVOT) was the most commonly enlarged dimension in ARVD probands (37.9 ± 6.6 mm) versus control patients (26.2 ± 4.9 mm, p 30 mm occurred in 89% of probands and 14% of controls. The RV morphologic abnormalities were present in many probands (trabecular derangement in 54%, hyper-reflective moderator band in 34% and sacculations in 17%) but not in controls. Conclusions Probands with ARVD have significant RA and RV enlargement and decreased RV function, which can be easily assessed on standard echocardiographic imaging. These parameters should be measured when ARVD is suspected and compared with normal values.

Objectives The aim of this study was to assess the outcome of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) patients treated with an implantable cardioverter-defibrillator (ICD). Background Arrhythmogenic right ventricular dysplasia/cardiomyopathy is associated with tachyarrhythmia and an increased risk of sudden death. Methods This study included 42 ARVD/C patients with ICDs (52% male, age 6 to 69 years, median 37 years) followed at our center. Results Mean follow-up was 42 ± 26 months (range 4 to 135 months). Complications associated with ICD implantation included need for lead repositioning (n = 3) and system infection (n = 2). During follow-up, one patient died of a brain malignancy and one had heart transplantation. Lead replacement was required in six patients as a result of lead fracture and insulation damage (n = 4) or change in thresholds (n = 2). During this period, 33 of 42 (78%) patients received a median of 4 (range 1 to 75) appropriate ICD interventions. The median period between ICD implantation and the first firing was 9 months (range 0.1 to 66 months). The ICD firing storms were observed in five patients. Inappropriate interventions were seen in 10 patients. Predictors of appropriate firing were induction of ventricular tachycardia (VT) during electrophysiologic study (EPS) (84% vs. 44%, p = 0.024), detection of spontaneous VT (70% vs. 15%, p = 0.001), male versus female gender (91% vs. 65%, p = 0.04), and severe right ventricular dilation (39% vs. 0%, p = 0.013). Using multivariate analysis, VT induction during EPS was associated with increased risk for firing in ARVD/C patients; odds ratio 11.2 (95% confidence interval 1.23 to 101.24, p = 0.031). Conclusions Patients with ARVD/C have a high arrhythmia rate requiring appropriate ICD interventions. The ICD therapy appears to be well tolerated and important in the management of patients with ARVD/C.

Sudden cardiac death (SCD) is responsible for more premature loss of life than any individual disease [(1)][1]. Although the proportion of SCD occurring during exercise is low (∼5%) [(2–4)][2], it plays a prominent role in the perceived mortality risk for athletes and generates substantial

We read with great interest the recent paper by Zaidi et al. [(1)][1] demonstrating that T-wave inversion (TWI) in the precordial leads is a nonspecific finding in asymptomatic athletes and that other parameters have to be evaluated before diagnosing arrhythmogenic right ventricular cardiomyopathy

Background: The purpose of this study was to determine cardiac magnetic resonance (CMR) impact in diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). We also studied how intramyocardial fat or fibrofatty infiltration imaged by CMR might influence diagnostic

Background Exercise has been proposed as a trigger for arrhythmogenic right ventricular cardiomyopathy (ARVC) phenotype manifestation; however, research is hampered by the limited availability of animal models in which disease-associated mutations can be tested. Objectives This study evaluated the impact of exercise on ARVC cardiac manifestations in mice after adeno-associated virus (AAV)–mediated gene delivery of mutant human PKP2 , which encodes the desmosomal protein plakophilin-2. Methods We developed a new model of cardiac tissue–specific transgenic-like mice on the basis of AAV gene transfer to test the potential of a combination of a human PKP2 mutation and endurance training to trigger an ARVC-like phenotype. Results Stable cardiac expression of mutant PKP2 (c.2203C>T), encoding the R735X mutant protein, was achieved 4 weeks after a single AAV9-R735X intravenous injection. High-field cardiac magnetic resonance over a 10-month postinfection follow-up did not detect an overt right ventricular (RV) phenotype in nonexercised (sedentary) mice. In contrast, endurance exercise training (initiated 2 weeks after AAV9-R735X injection) resulted in clear RV dysfunction that resembled the ARVC phenotype (impaired global RV systolic function and RV regional wall motion abnormalities on cardiac magnetic resonance). At the histological level, RV samples from endurance-trained R735X-infected mice displayed connexin 43 delocalization at intercardiomyocyte gap junctions, a change not observed in sedentary mice. Conclusions The introduction of the PKP2 R735X mutation into mice resulted in an exercise-dependent ARVC phenotype. The R735X mutation appears to function as a dominant-negative variant. This novel system for AAV-mediated introduction of a mutation into wild-type mice has broad potential for study of the implication of diverse mutations in complex cardiomyopathies.