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Background: A novel risk calculator based on clinical characteristics and noninvasive tests that predicts the onset of clinical sustained ventricular arrhythmias (VA) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) has been proposed and validated by recent studies. It remains unknown whether programmed ventricular stimulation (PVS) provides additional prognostic value. Methods: All patients with a definite ARVC diagnosis, no history of sustained VAs at diagnosis, and PVS performed at baseline were extracted from 6 international ARVC registries. The calculator-predicted risk for sustained VA (sustained or implantable cardioverter defibrillator treated ventricular tachycardia [VT] or fibrillation, [aborted] sudden cardiac arrest) was assessed in all patients. Independent and combined performance of the risk calculator and PVS on sustained VA were assessed during a 5-year follow-up period. Results: Two hundred eighty-eight patients (41.0 +/- 14.5 years, 55.9% male, right ventricular ejection fraction 42.5 +/- 11.1%) were enrolled. At PVS, 137 (47.6%) patients had inducible ventricular tachycardia. During a median of 5.31 [2.89-10.17] years of follow-up, 83 (60.6%) patients with a positive PVS and 37 (24.5%) with a negative PVS experienced sustained VA (PFunding Agencies|Leonie-Wild Foundation; Leyla Erkan Family Fund for ARVD Research; Hugh Calkins, Marvin H. Weiner, and Jacqueline J. Bernstein Cardiac Arrhythmia Center; Marvin H. Weiner, and Jacqueline J. Bernstein Cardiac Arrhythmia Center; Dr. Francis P. Chiramonte Private Foundation; Dr. Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins; Bogle Foundation; Healing Hearts Foundation; Campanella Family; Patrick J. Harrison Family; Peter French Memorial Foundation; Wilmerding Endowments; Fondation Leducq; National Center for Advancing Translational Sciences [UL1TR001079]; Philippa and Marvin Carsley cardiology research chair; Montreal Heart Institute Foundation; Georg und Bertha Schwyzer-Winiker Foundation; Baugarten Foundation; Swiss Heart Foundation [FF17019, FF21073]; Swiss National Science Foundation [160327]; Swedish Heart Lung Foundation [20200674]; Swedish state under the Avtal om lakarutbildning och forsknin (ALF)-agreement; Netherlands Cardiovascular Research Initiative; Dutch Heart Foundation [CVON201512/2018-30]

Aims Arrhythmogenic right ventricular cardiomyopathy (ARVC) patients have an increased risk of ventricular arrhythmias (VA). Four implantable cardioverter-defibrillator (ICD) recommendation algorithms are available The International Task Force Consensus (‘ITFC’), an ITFC modification by Orgeron et al. (‘mITFC’), the AHA/HRS/ACC guideline for VA management (‘AHA’), and the HRS expert consensus statement (‘HRS’). This study aims to validate and compare the performance of these algorithms in ARVC. Methods and results We classified 617 definite ARVC patients (38.5 ± 15.1 years, 52.4% male, 39.2% prior sustained VA) according to four algorithms. Clinical performance was evaluated by sensitivity, specificity, ROC-analysis, and decision curve analysis for any sustained VA and for fast VA (>250 b.p.m.). During 6.4 [2.8–11.5] years follow-up, 282 (45.7%) patients experienced any sustained VA, and 63 (10.2%) fast VA. For any sustained VA, ITFC and mITFC provide higher sensitivity than AHA and HRS (94.0–97.8% vs. 76.7–83.5%), but lower specificity (15.9–32.0% vs. 42.7%-60.1%). Similarly, for fast VA, ITFC and mITFC provide higher sensitivity than AHA and HRS (95.2–97.1% vs. 76.7–78.4%) but lower specificity (42.7–43.1 vs. 76.7–78.4%). Decision curve analysis showed ITFC and mITFC to be superior for a 5-year sustained VA risk ICD indication threshold between 5–25% or 2–9% for fast VA. Conclusion The ITFC and mITFC provide the highest protection rates, whereas AHA and HRS decrease unnecessary ICD placements. ITFC or mITFC should be used if we consider the 5-year threshold for ICD indication to lie within 5–25% for sustained VA or 2–9% for fast VA. These data will inform decision-making for ICD placement in ARVC.

Background: The arrhythmogenic right ventricular cardiomyopathy (ARVC) risk calculator stratifies risk for incident sustained ventricular arrhythmias (VA) at the time of ARVC diagnosis. However, included risk factors change over time, and how well the ARVC risk calculator performs at follow-up is unknown. Methods: This was a retrospective analysis of patients with definite ARVC and without prior sustained VA. Risk factors for VA including age, nonsustained ventricular tachycardia, premature ventricular complex burden, T-wave inversions on electrocardiogram, cardiac syncope, right ventricular function, therapeutic medication use, and exercise intensity were assessed at the time of 2010 Task Force Criteria based ARVC diagnosis and upon repeat evaluations. Changes in these risk factors were analyzed over 5-year follow-up. The 5-year risk of VA was predicted longitudinally using (1) the baseline ARVC risk calculator prediction, (2) the ARVC risk prediction calculated using updated risk factors, and (3) time-varying Cox regression. Discrimination and calibration were assessed in comparison to observed VA event rates. Results: Four hundred eight patients with ARVC experiencing 132 primary VA events were included. Matched comparison of risk factors at baseline versus at 5 years of follow-up revealed decreased burdens of premature ventricular complexes (−1200/day) and nonsustained ventricular tachycardia (−14%). Presence of significant right ventricular dysfunction and number of T-wave inversions on electrocardiogram were unchanged. Observed risk for VA decreased by 13% by 5 years follow-up. The baseline ARVC risk calculator’s ability to predict 5-year VA risk worsened during follow-up (C statistics, 0.83 at diagnosis versus 0.68 at 5 years). Both the updated ARVC risk calculator (C statistics of 0.77) and time-varying Cox regression model (C statistics, 0.77) had strong discrimination. The updated ARVC risk calculator overestimated 5-year VA risk by an average of +6%. ConclusionS: Risk factors for VA in ARVC are dynamic, and overall risk for incident sustained VA decreases during follow-up. Up-to-date risk factor assessment improves VA risk stratification.

Background Implantable cardioverter-defibrillators (ICDs) are an effective treatment in some patients with inherited heart disease, including inherited channelopathies, yet they have also been shown to impact patients' psychological health. Objective We sought to improve understanding of the level of anxiety and depression as well as device acceptance among inherited channelopathy patients with an ICD. Methods Eligible patients seen at Johns Hopkins Hospital were sent a survey, which included the Hospital Anxiety and Depression Scale (HADS), Cardiac Anxiety Questionnaire (CAQ), and the Florida Patient Acceptance Survey (FPAS). Student t tests and χ2 tests were used to identify associations with abnormal anxiety and depression scores. Results Among eligible patients (n = 65), 32 individuals (49%) completed the survey. The rate of device-related complications was 34%, and 41% of patients experienced 1 or more ICD shocks. Twelve patients (38%) had an abnormal HADS anxiety subscore and 5 patients (16%) had an abnormal HADS depression subscore (score ≥ 8). Secondary-prevention ICDs were associated with an abnormal HADS anxiety subscore (P = .03). Experiencing ICD shock(s), device complications, age, sex, and family history of sudden cardiac death were not statistically associated with anxiety or depression. Overall, respondents demonstrated high device acceptance by FPAS (79.9 ± 2.9, maximum total score 100) and moderately high cardiac-specific anxiety by CAQ total score (1.53 ± 0.12). Conclusion A high prevalence of generalized anxiety was identified among inherited channelopathy patients with ICDs. High device acceptance and lack of association with ICD shocks or complications indicate that further research is necessary to understand this increased incidence.

Supplemental Digital Content is available in the text., Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease characterized by ventricular arrhythmias and progressive ventricular dysfunction. Genetic testing is recommended, and a pathogenic variant in an ARVC-associated gene is a major criterion for diagnosis according to the 2010 Task Force Criteria. As incorrect attribution of a gene to ARVC can contribute to misdiagnosis, we assembled an international multidisciplinary ARVC Clinical Genome Resource Gene Curation Expert Panel to reappraise all reported ARVC genes. Methods: Following a comprehensive literature search, six 2-member teams conducted blinded independent curation of reported ARVC genes using the semiquantitative Clinical Genome Resource framework. Results: Of 26 reported ARVC genes, only 6 (PKP2, DSP, DSG2, DSC2, JUP, and TMEM43) had strong evidence and were classified as definitive for ARVC causation. There was moderate evidence for 2 genes, DES and PLN. The remaining 18 genes had limited or no evidence. RYR2 was refuted as an ARVC gene since clinical data and model systems exhibited a catecholaminergic polymorphic ventricular tachycardia phenotype. In ClinVar, only 5 pathogenic/likely pathogenic variants (1.1%) in limited evidence genes had been reported in ARVC cases in contrast to 450 desmosome gene variants (97.4%). Conclusions: Using the Clinical Genome Resource approach to gene-disease curation, only 8 genes (PKP2, DSP, DSG2, DSC2, JUP, TMEM43, PLN, and DES) had definitive or moderate evidence for ARVC, and these genes accounted for nearly all pathogenic/likely pathogenic ARVC variants in ClinVar. Therefore, only pathogenic/likely pathogenic variants in these 8 genes should yield a major criterion for ARVC diagnosis. Pathogenic/likely pathogenic variants identified in other genes in a patient should prompt further phenotyping as variants in many of these genes are associated with other cardiovascular conditions.

This international multidisciplinary document intends to provide clinicians with evidence‐based practical patient‐centered recommendations for evaluating patients and decedents with (aborted) sudden cardiac arrest and their families. The document includes a framework for the investigation of the family allowing steps to be taken, should an inherited condition be found, to minimize further events in affected relatives. Integral to the process is counseling of the patients and families, not only because of the emotionally charged subject, but because finding (or not finding) the cause of the arrest may influence management of family members. The formation of multidisciplinary teams is essential to provide a complete service to the patients and their families, and the varied expertise of the writing committee was formulated to reflect this need. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by Class of Recommendation and Level of Evidence. The recommendations were opened for public comment and reviewed by the relevant scientific and clinical document committees of the Asia Pacific Heart Rhythm Society (APHRS) and the Heart Rhythm Society (HRS); the document underwent external review and endorsement by the partner and collaborating societies. While the recommendations are for optimal care, it is recognized that not all resources will be available to all clinicians. Nevertheless, this document articulates the evaluation that the clinician should aspire to provide for patients with sudden cardiac arrest, decedents with sudden unexplained death, and their families.

Aims Arrhythmogenic right ventricular cardiomyopathy (ARVC) is diagnosed by a complex set of clinical tests as per 2010 Task Force Criteria (TFC). Avoiding misdiagnosis is crucial to prevent sudden cardiac death as well as unnecessary implantable cardioverter-defibrillator implantations. This study aims to validate the overall performance of the TFC in a real-world cohort of patients referred for ARVC evaluation. Methods and results We included patients consecutively referred to our centres for ARVC evaluation. Patients were diagnosed by consensus of three independent clinical experts. Using this as a reference standard, diagnostic performance was measured for each individual criterion as well as the overall TFC classification. Of 407 evaluated patients (age 38 ± 17 years, 51% male), the expert panel diagnosed 66 (16%) with ARVC. The clinically observed TFC was false negative in 7/66 (11%) patients and false positive in 10/69 (14%) patients. Idiopathic outflow tract ventricular tachycardia was the most common alternative diagnosis. While the TFC performed well overall (sensitivity and specificity 92%), signal-averaged electrocardiogram (SAECG, P = 0.43), and several family history criteria (P ≥ 0.17) failed to discriminate. Eliminating these criteria reduced false positives without increasing false negatives (net reclassification improvement 4.3%, P = 0.019). Furthermore, all ARVC patients met at least one electrocardiogram (ECG) or arrhythmia criterion (sensitivity 100%). Conclusion The TFC perform well but are complex and can lead to misdiagnosis. Simplification by eliminating SAECG and several family history criteria improves diagnostic accuracy. Arrhythmogenic right ventricular cardiomyopathy can be ruled out using ECG and arrhythmia criteria alone, hence these tests may serve as a first-line screening strategy among at-risk individuals.

We report a case of a woman with arrhythmogenic right ventricular cardiomyopathy (ARVC) who presented with severe right-sided heart failure and cardiac cirrhosis that mandated heart-liver transplantation. This case highlights an emerging sex-based difference in ARVC where female sex is associated with a higher risk of heart failure than in male patients with ARVC. (Level of Difficulty: Advanced.), Graphical abstract, We report a case of a woman with arrhythmogenic right ventricular cardiomyopathy (ARVC) who presented with severe right-sided heart failure…

IMPORTANCE: A high burden of premature ventricular contractions (PVCs) at disease diagnosis has been associated with an overall higher risk of ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy (ARVC). Data regarding dynamic modification of PVC burden at follow-up with Holter monitoring and its impact on arrhythmic risk in ARVC are scarce. OBJECTIVE: To describe changes in the PVC burden and to assess whether serial Holter monitoring is dynamically associated with sustained ventricular arrhythmias during follow-up in patients with ARVC. DESIGN, SETTINGS, AND PARTICIPANTS: In this cohort study, patients with a definite ARVC diagnosis, available Holter monitoring results at disease diagnosis, and at least 2 additional results of Holter monitoring during follow-up were enrolled from 6 ARVC registries in North America and Europe. Data were collected from June 1 to September 15, 2021. MAIN OUTCOMES AND MEASURES: The association between prespecified variables retrieved at each Holter monitoring follow-up (ie, overall PVC burden; presence of sudden PVC spikes, defined as absolute increase in PVC burden ≥5000 per 24 hours or a relative ≥75% increase, with an absolute increase of ≥1000 PVCs; presence of nonsustained ventricular tachycardia [NSVT]; and use of β-blockers and class III antiarrhythmic drugs) and sustained ventricular arrhythmias occurring within 12 months after that Holter examination was assessed using a mixed logistical model. RESULTS: In 169 enrolled patients with ARVC (mean [SD] age, 36.3 [15.0] years; 95 men [56.2%]), a total of 723 Holter examinations (median, 4 [IQR, 4-5] per patient) were performed during a median follow-up of 54 (IQR, 42-63) months and detected 75 PVC spikes and 67 sustained ventricular arrhythmias. The PVC burden decreased significantly from the first to the second Holter examination (mean, 2906 [95% CI, 1581-4231] PVCs per 24 hours; P

Background Thorough investigation of sudden cardiac death (SCD) in those aged 1–40 years commonly reveals a heritable cause, yet access to postmortem genetic testing is variable. Objective The purpose of this study was to explore practices of postmortem genetic testing and attitudes of health care professionals worldwide. Methods A survey was administered among health care professionals recruited through professional associations, social media, and networks of researchers. Topics included practices around postmortem genetic testing, level of confidence in health care professionals’ ability, and attitudes toward postmortem genetic testing practices. Results There were 112 respondents, with 93% from North America, Europe, and Australia/New Zealand, and 7% from South America, Asia and Africa. Only 30% reported autopsy as mandatory, and overall practices were largely case by case and not standardized. North American respondents (87%) more often perceived practices as ineffective compared to those from Europe (58%) and Australia/New Zealand (48%; P = .002). Where a heritable cause is suspected, 69% considered postmortem genetic testing and 61% offered genetic counseling to surviving family members. Financial resources varied widely. Half of participants believed practices in their countries perpetuated health inequalities. Conclusion Postmortem genetic testing is not consistently available in the investigation of young SCD despite being a recommendation in international guidelines. Access to postmortem genetic testing, which is critical in ascertaining a cause of death in many cases, must be guided by well-resourced, multidisciplinary teams.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a progressive heart condition which causes fibro-fatty myocardial scarring, ventricular arrhythmias, and sudden cardiac death. Most cases of ARVC can be linked to pathogenic mutations in the cardiac desmosome, but the pathophysiology is not well understood, particularly in early phases when arrhythmias can develop prior to structural changes. Here, we created a novel human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model of ARVC from a patient with a c.2358delA variant in desmoglein-2 (DSG2). These DSG2-mutant (DSG2Mut) hiPSC-CMs were compared against two wildtype hiPSC-CM lines via immunostaining, RT-qPCR, Western blot, RNA-Seq, cytokine expression and optical mapping. Mutant cells expressed reduced DSG2 mRNA and had altered localization of desmoglein-2 protein alongside thinner, more disorganized myofibrils. No major changes in other desmosomal proteins were noted. There was increased pro-inflammatory cytokine expression that may be linked to canonical and non-canonical NFκB signaling. Action potentials in DSG2Mut CMs were shorter with increased upstroke heterogeneity, while time-to-peak calcium and calcium decay rate were reduced. These were accompanied by changes in ion channel and calcium handling gene expression. Lastly, suppressing DSG2 in control lines via siRNA allowed partial recapitulation of electrical anomalies noted in DSG2Mut cells. In conclusion, the aberrant cytoskeletal organization, cytokine expression, and electrophysiology found DSG2Mut hiPSC-CMs could underlie early mechanisms of disease manifestation in ARVC patients.

Myocyte death occurs in many inherited and acquired cardiomyopathies, including arrhythmogenic cardiomyopathy (ACM), a genetic heart disease plagued by the prevalence of sudden cardiac death. Individuals with ACM and harboring pathogenic desmosomal variants, such as desmoglein-2 (DSG2), often show myocyte necrosis with progression to exercise-associated heart failure. Here, we showed that homozygous Dsg2 mutant mice (Dsg2(mut/mut)), a model of ACM, die prematurely during swimming and display myocardial dysfunction and necrosis. We detected calcium (Ca(2+)) overload in Dsg2(mut/mut) hearts, which induced calpain-1 (CAPN1) activation, association of CAPN1 with mitochondria, and CAPN1-induced cleavage of mitochondrial-bound apoptosis-inducing factor (AIF). Cleaved AIF translocated to the myocyte nucleus triggering large-scale DNA fragmentation and cell death, an effect potentiated by mitochondrial-driven AIF oxidation. Posttranslational oxidation of AIF cysteine residues was due, in part, to a depleted mitochondrial thioredoxin-2 redox system. Hearts from exercised Dsg2(mut/mut) mice were depleted of calpastatin (CAST), an endogenous CAPN1 inhibitor, and overexpressing CAST in myocytes protected against Ca(2+) overload–induced necrosis. When cardiomyocytes differentiated from Dsg2(mut/mut) embryonic stem cells (ES-CMs) were challenged with β-adrenergic stimulation, CAPN1 inhibition attenuated CAPN1-induced AIF truncation. In addition, pretreatment of Dsg2(mut/mut) ES-CMs with an AIF-mimetic peptide, mirroring the cyclophilin-A (PPIA) binding site of AIF, blocked PPIA-mediated AIF-nuclear translocation, and reduced both apoptosis and necrosis. Thus, preventing CAPN1-induced AIF-truncation or barring binding of AIF to the nuclear chaperone, PPIA, may avert myocyte death and, ultimately, disease progression to heart failure in ACM and likely other forms of cardiomyopathies.

Supplemental Digital Content is available in the text., Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with ventricular arrhythmias (VA) and sudden cardiac death (SCD). A model was recently developed to predict incident sustained VA in patients with ARVC. However, since this outcome may overestimate the risk for SCD, we aimed to specifically predict life-threatening VA (LTVA) as a closer surrogate for SCD. Methods: We assembled a retrospective cohort of definite ARVC cases from 15 centers in North America and Europe. Association of 8 prespecified clinical predictors with LTVA (SCD, aborted SCD, sustained, or implantable cardioverter-defibrillator treated ventricular tachycardia >250 beats per minute) in follow-up was assessed by Cox regression with backward selection. Candidate variables included age, sex, prior sustained VA (≥30s, hemodynamically unstable, or implantable cardioverter-defibrillator treated ventricular tachycardia; or aborted SCD), syncope, 24-hour premature ventricular complexes count, the number of anterior and inferior leads with T-wave inversion, left and right ventricular ejection fraction. The resulting model was internally validated using bootstrapping. Results: A total of 864 patients with definite ARVC (40±16 years; 53% male) were included. Over 5.75 years (interquartile range, 2.77–10.58) of follow-up, 93 (10.8%) patients experienced LTVA including 15 with SCD/aborted SCD (1.7%). Of the 8 prespecified clinical predictors, only 4 (younger age, male sex, premature ventricular complex count, and number of leads with T-wave inversion) were associated with LTVA. Notably, prior sustained VA did not predict subsequent LTVA (P=0.850). A model including only these 4 predictors had an optimism-corrected C-index of 0.74 (95% CI, 0.69–0.80) and calibration slope of 0.95 (95% CI, 0.94–0.98) indicating minimal over-optimism. Conclusions: LTVA events in patients with ARVC can be predicted by a novel simple prediction model using only 4 clinical predictors. Prior sustained VA and the extent of functional heart disease are not associated with subsequent LTVA events.

Background: Filamin C truncating variants ( FLNCtv ) cause a form of arrhythmogenic cardiomyopathy: the mode of presentation, natural history, and risk stratification of FLNCtv remain incompletely explored. We aimed to develop a risk profile for refractory heart failure and life-threatening arrhythmias in a multicenter cohort of FLNCtv carriers. Methods: FLNCtv carriers were identified from 10 tertiary care centers for genetic cardiomyopathies. Clinical and outcome data were compiled. Composite outcomes were all-cause mortality/heart transplantation/left ventricle assist device (D/HT/LVAD), nonarrhythmic death/HT/LVAD, and sudden cardiac death/major ventricular arrhythmias. Previously established cohorts of 46 patients with LMNA and 60 with DSP -related arrhythmogenic cardiomyopathies were used for prognostic comparison. Results: Eighty-five patients carrying FLNCtv were included (42±15 years, 53% men, 45% probands). Phenotypes were heterogeneous at presentation: 49% dilated cardiomyopathy, 25% arrhythmogenic left dominant cardiomyopathy, 3% arrhythmogenic right ventricular cardiomyopathy. Left ventricular ejection fraction was FLNCtv carriers did not significantly differ from LMNA carriers and DSP carriers. In FLNCtv carriers, left ventricular ejection fraction was associated with the risk of D/HT/LVAD and nonarrhythmic death/HT/LVAD. Conclusions: Among patients referred to tertiary referral centers, FLNCtv arrhythmogenic cardiomyopathy is phenotypically heterogeneous and characterized by a high risk of life-threatening arrhythmias, which does not seem to be associated with the severity of left ventricular dysfunction.

Background:Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibrofatty replacement of the right and left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants in the nondesmosomal cadherin 2 (CDH2), a novel genetic substrate of ACM.Methods:A cohort of 500 unrelated patients with a definite diagnosis of ACM and no disease-causing variants in the main ACM genes was assembled. Genetic screening ofCDH2was performed through next-generation or Sanger sequencing. Whenever possible, cascade screening was initiated in the families ofCDH2-positive probands, and clinical evaluation was performed.Results:Genetic screening ofCDH2led to the identification of 7 rare variants: 5, identified in 6 probands, were classified as pathogenic or likely pathogenic. The previously established p.D407N pathogenic variant was detected in 2 additional probands. Probands and family members with pathogenic/likely pathogenic variants inCDH2were clinically evaluated, and along with previously published cases, altogether contributed to the identification of gene-specific features (13 cases from this cohort and 11 previously published, for a total of 9 probands and 15 family members). Ventricular arrhythmic events occurred in mostCDH2-positive subjects (20/24, 83%), while the occurrence of heart failure was rare (2/24, 8.3%). Among probands, sustained ventricular tachycardia and sudden cardiac death occurred in 5/9 (56%).Conclusions:In this worldwide cohort of previously genotype-negative ACM patients, the prevalence of probands withCDH2pathogenic/likely pathogenic variants was 1.2% (6/500). Our data show that this cohort ofCDH2-ACM patients has a high incidence of ventricular arrhythmias, while evolution toward heart failure is rare.

Purpose The genetic architecture of Plakophilin 2 (PKP2) cardiomyopathy can inform our understanding of its variant pathogenicity and protein function. Methods We assess the gene-wide and regional association of truncating and missense variants in PKP2 with arrhythmogenic cardiomyopathy (ACM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) specifically. A discovery data set compares genetic testing requisitions to gnomAD. Validation is performed in a rigorously phenotyped definite ARVC cohort and non-ACM individuals in the Geisinger MyCode cohort. Results The etiologic fraction (EF) of ACM-related diagnoses from truncating variants in PKP2 is significant (0.85 [0.80,0.88], p < 2 x 10(-16)), increases for ARVC specifically (EF = 0.96 [0.94,0.97], p < 2 x 10(-16)), and is highest in definite ARVC versus non-ACM individuals (EF = 1.00 [1.00,1.00], p < 2 x 10(-16)). Regions of missense variation enriched for ACM probands include known functional domains and the C-terminus, which was not previously known to contain a functional domain. No regional enrichment was identified for truncating variants. Conclusion This multicohort evaluation of the genetic architecture of PKP2 demonstrates the specificity of PKP2 truncating variants for ARVC within the ACM disease spectrum. We identify the PKP2 C-terminus as a potential functional domain and find that truncating variants likely cause disease irrespective of transcript position.

BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease that affects predominantly the right ventricle and is part of the spectrum of arrythmogenic cardiomyopathies (ACMs). ARVC is a genetic condition; however, a pathogenic gene variant is found in only half of patients.ObjectiveFilamin C gene truncations (FLNCtv) have recently been identified in dilated cardiomyopathy with ventricular arrhythmia and sudden cardiac death, a phenotype partially overlapping with ARVC and part of the ACM spectrum. We hypothesised that FLNCtv could be a novel gene associated with ARVC.MethodsOne hundred fifty-six patients meeting 2010 ARVC Task Force Criteria and lacking variants in known ARVC genes were evaluated for FLNC variants. Available family members were tested for cosegregation.ResultsWe identified two unique FLNCtv variants in two families (c.6565 G>T, p.Glu2189Ter and c.8107delG, p.Asp2703ThrfsTer69), with phenotypes of dominant RV disease fulfilling ‘definite’ diagnosis of ARVC according to the 2010 Task Force Criteria. Variants in other cardiomyopathy genes were excluded in both kindreds, and segregation analysis revealed that p.Asp2703ThrfsTer69 was a de novo variant. In both families, the disease phenotype was characterised by prominent ventricular arrhythmias and sudden cardiac arrest.ConclusionThe identification of FLNCtv as a novel cause of ARVC in two unrelated families expands the spectrum of ARVC non-desmosome disease genes for this disorder. Our findings should prompt inclusion of FLNC genetic testing in ARVC to improve diagnostic yield and testing of at-risk relatives in ARVC.

Physiological stressors, such as exercise, can precipitate sudden cardiac death or heart failure progression in patients with arrhythmogenic cardiomyopathy (ACM). Yet, whether and to what extent a highly prevalent and more elusive environmental factor, such as psychosocial stress (PSS), can also increase ACM disease progression is unexplored. Here, we first quantified perceived stress levels in patients with ACM and found these levels correlated with the extent of arrhythmias and cardiac dysfunction. To determine whether the observed correlation is due to causation, we inflicted PSS-via the resident-intruder (RI) paradigm&mdash, upon Desmoglein-2 mutant mice, a vigorously used mammalian model of ACM. We found that ACM mice succumbed to abnormally high in-trial, PSS mortality. Conversely, no sudden deaths occurred in wildtype (WT) counterparts. Desmoglein-2 mice that survived RI challenge manifested markedly worse cardiac dysfunction and remodeling, namely apoptosis and fibrosis. Furthermore, WT and ACM mice displayed similar behavior at baseline, but Desmoglein-2 mice exhibited heightened anxiety following RI-induced PSS. This outcome correlated with the worsening of cardiac phenotypes. Our mouse model demonstrates that in ACM-like subjects, PSS is incisive enough to deteriorate cardiac structure and function per se, i.e., in the absence of any pre-existing anxious behavior. Hence, PSS may represent a previously underappreciated risk factor in ACM disease penetrance.

BACKGROUND: The clinical profile of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) patients with late presentation is unknown.OBJECTIVE: The purpose of this study was to characterize the genotype, cardiac phenotype, and long-term outcomes of ARVC/D patients with late presentation (age ≥50 years at diagnosis).METHODS: Five hundred two patients with an ARVC/D diagnosis from Johns Hopkins and Utrecht Registries were studied and long-term clinical outcomes ascertained.RESULTS: Late presentation was seen in 104 patients (21%; 38% PKP2 carriers); 3% were ≥65 years at diagnosis. Sustained ventricular tachycardia was the major (43%) mode of presentation in patients with late presentation, whereas cardiac syncope was infrequent (P CONCLUSION: One-fifth of all ARVC/D patients present after age 50 years, often with sustained ventricular tachycardia, and are less likely to have prior syncope, ECG changes, ventricular ectopy, or identifiable pathogenic mutation. In ARVC/D, late presentation does not confer a benign prognosis and is associated with high arrhythmic risk.

Aims Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is often associated with desmosomal mutations. Recent studies suggest an interaction between the desmosome and sodium channel protein Na(v)1.5. We aimed to determine the prevalence and biophysical properties of mutations in SCN5A (the gene encoding Na(v)1.5) in ARVD/C.Methods and results We performed whole-exome sequencing in six ARVD/C patients (33% male, 38.2 +/- 12.1 years) without a desmosomal mutation. We found a rare missense variant (p.Arg1898His; R1898H) in SCN5A in one patient. We generated induced pluripotent stem cell-derived cardiomyocytes (hIPSC-CMs) from the patient's peripheral blood mononuclear cells. The variant was then corrected (R1898R) using Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 technology, allowing us to study the impact of the R1898H substitution in the same cellular background. Whole-cell patch clamping revealed a 36% reduction in peak sodium current (P = 0.002); super-resolution fluorescence microscopy showed reduced abundance of Na(v)1.5 (P = 0.005) and N-Cadherin (P = 0.026) clusters at the intercalated disc. Subsequently, we sequenced SCN5A in an additional 281 ARVD/C patients (60% male, 34.8 +/- 13.7 years, 52% desmosomal mutation-carriers). Five (1.8%) subjects harboured a putatively pathogenic SCN5A variant (p.Tyr416Cys, p.Leu729del, p.Arg1623Ter, p.Ser1787Asn, and p.Val2016Met). SCN5A variants were associated with prolonged QRS duration (119 +/- 15 vs. 94 +/- 14 ms, P Conclusions Almost 2% of ARVD/C patients harbour rare SCN5A variants. For one of these variants, we demonstrated reduced sodium current, Na(v)1.5 and N-Cadherin clusters at junctional sites. This suggests that Na(v)1.5 is in a functional complex with adhesion molecules, and reveals potential non-canonical mechanisms by which Na(v)1.5 dysfunction causes cardiomyopathy.

International audience; Arrhythmogenic cardiomyopathy (ACM) is an arrhythmogenic disorder of the myocardium not secondary to ischemic, hypertensive, or valvular heart disease. ACM incorporates a broad spectrum of genetic, systemic, infectious, and inflammatory disorders. This designation includes, but is not limited to, arrhythmogenic right/left ventricular cardiomyopathy, cardiac amyloidosis, sarcoidosis, Chagas disease, and left ventricular noncompaction. The ACM phenotype overlaps with other cardiomyopathies, particularly dilated cardiomyopathy with arrhythmia presentation that may be associated with ventricular dilatation and/or impaired systolic function. This expert consensus statement provides the clinician with guidance on evaluation and management of ACM and includes clinically relevant information on genetics and disease mechanisms. PICO questions were utilized to evaluate contemporary evidence and provide clinical guidance related to exercise in arrhythmogenic right ventricular cardiomyopathy. Recommendations were developed and approved by an expert writing group, after a systematic literature search with evidence tables, and discussion of their own clinical experience, to present the current knowledge in the field. Each recommendation is presented using the Class of Recommendation and Level of Evidence system formulated by the American College of Cardiology and the American Heart Association and is accompanied by references and explanatory text to provide essential context. The ongoing recognition of the genetic basis of ACM provides the opportunity to examine the diverse triggers and potential common pathway for the development of disease and arrhythmia.

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Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with pathogenic/likely pathogenic (P/LP) variants in genes encoding the cardiac desmosomal proteins. Origin of these variants, including de novo mutation rate and extent of founder versus recurrent variants has implications for variant adjudication and clinical care, yet this has never been systematically investigated. Methods: We identified arrhythmogenic right ventricular cardiomyopathy probands who met 2010 Task Force Criteria and had undergone genotyping that included sequencing of the desmosomal genes ( PKP2 , DSP , DSG2 , DSC2 , and JUP ) from 3 arrhythmogenic right ventricular cardiomyopathy registries in America and Europe. We classified the desmosomal variants, defined the contribution of unique versus nonunique (ie, not family-specific) P/LP variants, and identified the frequency and characteristics of de novo variants. Next, we haplotyped nonunique variants to determine how often they likely represent a single mutation event in a common ancestor (implied by shared haplotypes) versus multiple mutation events at the same genetic location. Results: Of 501 arrhythmogenic right ventricular cardiomyopathy probands, 322 (64.3%) carried 327 desmosomal P/LP variants. Most variants (n=247, 75.6%, in 245 patients) were identified in more than one proband and, therefore, considered nonunique. For 212/327 variants (64.8%) genetic cascade screening was performed extensively enough to identify the parental origin of the P/LP variant. Only 3 variants were de novo, 2 of which were whole gene deletions. For 24 nonunique P/LP PKP2 variants, haplotyping was conducted in 183 available families. For all 24 variants, multiple seemingly unrelated families sharing identical haplotypes were identified, suggesting that these variants originate from common founders. Conclusions: Most desmosomal P/LP variants are inherited, nonunique, and originate from ancient founders. Two of 3 de novo variants were large deletions. These observations inform genetic testing, cascade screening, and variant adjudication.

Aims Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients. Methods and results Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 +/- 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44-9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 [95% confidence interval (CI) 0.73-0.81] and minimal over-optimism [calibration slope of 0.93 (95% CI 0.92-0.95)]. By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.3% reduction of ICD placements with the same proportion of protected patients (P < 0.001). Conclusion Using the Largest cohort of patients with ARVC and no prior VA, a prediction model using readily available clinical parameters was devised to estimate VA risk and guide decisions regarding primary prevention ICDs (www.arvcrisk.com). Funding Agencies|Canadian Heart Rhythm Society George Mines Traveling Fellowship; Montreal Heart Institute Foundation; Fondation LeducqLeducq Foundation [16 CVD 02]; Dutch Heart FoundationNetherlands Heart Foundation [2015T058, CVON2015-12 eDETECT, 2012-10 PREDICT]; Netherlands Organisation for Scientific ResearchNetherlands Organization for Scientific Research (NWO) [040.11.586]; Netherlands Heart Institute [06901]; Swiss National Science FoundationSwiss National Science Foundation (SNSF)European Commission [320030_160327]; UMC Utrecht 2017 Alexandre Suerman Stipend; UMC Utrecht Fellowship Clinical Research Talent; European Unions Horizon 2020 research and innovation program under the ERA-NET Co-fund action [680969]; Dr Francis P. Chiaramonte Private Foundation; Leyla Erkan Family Fund for ARVD Research; Dr Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins; Bogle Foundation; Healing Hearts Foundation; Campanella family; Patrick J. Harrison Family; Peter French Memorial Foundation; Wilmerding Endowments; Georg und Bertha Schwyzer-Winiker Foundation; Baugarten Foundation; Swiss Heart Foundation; Leonie-Wild Foundation; Marvin and Philippa Carsley Chair of Medicine; UCL Hospitals NIHR Biomedical Research Centre

Objectives To characterise pregnancy course and outcomes in women with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C).Methods From a combined Johns Hopkins/Dutch ARVD/C registry, we identified 26 women affected with ARVD/C (by 2010 Task Force Criteria) during 39 singleton pregnancies > 13 weeks (1-4 per woman). Cardiac symptoms, treatment and episodes of sustained ventricular arrhythmias (VAs) and heart failure (HF) >= Class C were characterised. Obstetric outcomes were ascertained. Incidence of VA and HF were compared with rates in the non-pregnant state. Long-term disease course was compared with 117 childbearing-aged female patients with ARVD/C who had not experienced pregnancy with ARVD/C.Results Treatment during pregnancy (n=39) included beta blockers (n=16), antiarrhythmics (n=6), diuretics (n=3) and implantable cardioverter defibrillators (ICDs) (n=28). In five pregnancies (13%), a single VA occurred, including two ICD-terminated events. Arrhythmias occurred disproportionately in probands without VA history (p=0.045). HF, managed on an outpatient basis, developed in two pregnancies (5%) in women with pre-existing overt biventricular or isolated right ventricular disease. All infants were live-born without major obstetric complications. Caesarean sections (n=11, 28%) had obstetric indications, except one (HF). beta Blocker therapy was associated with lower birth weight (3.1 +/- 0.48 kg vs 3.7 +/- 0.57 kg; p=0.002). During follow-up children remained healthy (median 3.4 years), and mothers were without cardiac mortality or transplant. Neither VA nor HF incidence was significantly increased during pregnancy. ARVD/C course (mean 6.5 +/- 5.6 years) did not differ based on pregnancy history.Conclusions While most pregnancies in patients with ARVD/C were tolerated well, 13% were complicated by VA and 5% by HF.

PURPOSE: To compare epicardial fat in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) with that in healthy subjects. MATERIALS AND METHODS: In this retrospective study, cardiac CT scans in 44 patients with ARVD/C (mean age, 39 years ± 12; 23 men) were compared with those in 45 control group participants between January 2008 and July 2015. Volumes of intrathoracic adipose tissue, mediastinal adipose tissue (MAT), and total epicardial adipose tissue (EAT) were quantified. EAT was subdivided into three regions—right ventricular (RV) EAT, left ventricular (LV) EAT, and peri-atrial EAT (atrial EAT)—and normalized to MAT for all regions. Logistic regression and receiver operating characteristic analysis were performed to evaluate the association between epicardial fat with the diagnosis of ARVD/C. RESULTS: Total EAT volume was higher in patients with ARVD/C than in healthy control group participants (median, 98 mL vs 76 mL, respectively; P = .04). Regionally, LV and RV EAT volumes were higher in patients with ARVD/C than in control group participants, most notably when indexed to MAT (median LV EAT index: 0.49 vs 0.15, respectively; median RV EAT index: 0.91 vs 0.52; P ˂ .0005 for both). The optimal cutoff for diagnosis of ARVD/C was an LV EAT index of 0.24, with a sensitivity and specificity of 91% and 71%, respectively. Atrial EAT volume and total intrathoracic adipose tissue volume were not different between groups. RV diameter showed a positive correlation with total EAT index and LV EAT index (r = 0.21, P = .05 and r = 0.33, P = .002, respectively). CONCLUSION: Higher amounts of right ventricular and left ventricular epicardial fat are found in hearts with arrhythmogenic right ventricular dysplasia/cardiomyopathy, particularly adjacent to the left ventricle, which correlates with disease severity and helps differentiate patients from healthy subjects. © RSNA, 2018 Online supplemental material is available for this article.

OBJECTIVES: This study sought to compare electrocardiogram (ECG) variants in athletic and arrhythmogenic right ventricular cardiomyopathy (ARVC) cohorts matched for the confounders of age, sex, and ethnicity.BACKGROUND: Anterior T-wave inversion (TWIV1-V4) is a common electrocardiographic finding in both athletes and patients with ARVC, and is a frequent conundrum in the setting of pre-participation screening. J-point elevation (JPE) has been proposed as an accurate means of identifying athletes, whereas disease markers, including premature ventricular contractions (PVCs) and low-voltage signals, have been associated with ARVC.METHODS: This study examined 200 subjects with TWI V1-V4, including 100 healthy athletes and 100 ARVC patients matched 1:1 for age, sex, and ethnicity (age: 21 ± 5 years for athletes vs. 22 ± 5 years for ARVC patients; 47% male; 97% Caucasian). The presence of TWI, JPE, PVCs, and left ventricular hypertrophy (LVH) were assessed.RESULTS: JPE was observed in 27% of athletes versus 16% of ARVC patients (p = 0.09). Thus, JPE had poor specificity (27%) and accuracy (60%) in identifying healthy athletes. In contrast, ARVC patients demonstrated a greater prevalence of precordial TWI beyond lead V3 (34% vs. 8%; p < 0.001), inferior TWI (31% vs. 3%; p < 0.001), PVCs (18% vs. 0%; p < 0.001), and lower LVH scores (SV1 + RV5; 19 ± 1 mm vs. 30 ± 1 mm; p < 0.001). These combined factors provided more reliable differentiation between health and disease (specificity 82%, accuracy 81%).CONCLUSIONS: PVCs and low QRS voltages are more prevalent among ARVC patients than athletes, whereas JPE is a relatively poor discriminator of health and disease when the confounders of age, sex, and ethnicity are considered.

AIMS: Likely pathogenic/pathogenic variants in genes encoding desmosomal proteins play an important role in the pathophysiology of arrhythmogenic right ventricular cardiomyopathy (ARVC). However, for a substantial proportion of ARVC patients, the genetic substrate remains unknown. We hypothesized that plectin, a cytolinker protein encoded by the PLEC gene, could play a role in ARVC because it has been proposed to link the desmosomal protein desmoplakin to the cytoskeleton and therefore has a potential function in the desmosomal structure.METHODS: We screened PLEC in 359 ARVC patients and compared the frequency of rare coding PLEC variants (minor allele frequency [MAF] RESULTS: Forty ARVC patients carried one or more rare PLEC variants (11%, 40/359). However, rare variants also seem to occur frequently in the control population (18%, 4754/26197 individuals). Nor did we find a difference in the prevalence of rare PLEC variants in ARVC patients with or without a desmosomal likely pathogenic/pathogenic variant (14% versus 8%, respectively). However, immunofluorescence analysis did show decreased plectin junctional localization in myocardial tissue from 5 ARVC patients with PLEC variants.CONCLUSIONS: Although PLEC has been hypothesized as a promising candidate gene for ARVC, our current study did not show an enrichment of rare PLEC variants in ARVC patients compared to controls and therefore does not support a major role for PLEC in this disorder. Although rare PLEC variants were associated with abnormal localization in cardiac tissue, the confluence of data does not support a role for plectin abnormalities in ARVC development.

AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by ventricular arrhythmias and sudden death. Currently 60% of patients meeting Task Force Criteria (TFC) have an identifiable mutation in one of the desmosomal genes. As much overlap is described between other cardiomyopathies and ARVC, we examined the prevalence of rare, possibly pathogenic sarcomere variants in the ARVC population.METHODS: One hundred and thirty-seven (137) individuals meeting 2010 TFC for a diagnosis of ARVC, negative for pathogenic desmosomal variants, TMEM43, SCN5A, and PLN were screened for variants in the sarcomere genes (ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNC1, TNNI3, TNNT2, and TPM1) through either clinical or research genetic testing.RESULTS: Six probands (6/137, 4%) were found to carry rare variants in the sarcomere genes. These variants have low prevalence in controls, are predicted damaging by Polyphen-2, and some of the variants are known pathogenic hypertrophic cardiomyopathy mutations. Sarcomere variant carriers had a phenotype that did not differ significantly from desmosomal mutation carriers. As most of these probands were the only affected individuals in their families, however, segregation data are noninformative.CONCLUSION: These data show variants in the sarcomere can be identified in individuals with an ARVC phenotype. Although rare and predicted damaging, proven functional and segregational evidence that these variants can cause ARVC is lacking. Therefore, caution is warranted in interpreting these variants when identified on large next-generation sequencing panels for cardiomyopathies.

Background Arrhythmogenic right ventricular dysplasia/cardiomyopathy is characterized by ventricular arrhythmias and sudden cardiac death. Once the diagnosis is established, risk stratification to determine whether implantable cardioverter‐defibrillator ( ICD ) placement is warranted is critical. Methods and Results The cohort included 312 patients (163 men, age at presentation 33.6±13.9 years) with definite arrhythmogenic right ventricular dysplasia/cardiomyopathy who received an ICD . Over 8.8±7.33 years, 186 participants (60%) had appropriate ICD therapy and 58 (19%) had an intervention for ventricular fibrillation/flutter. Ventricular tachycardia at presentation (hazard ratio [ HR ]: 1.86; 95% confidence interval [ CI ], 1.38–2.49; P P P =0.001), inverted T waves in ≥3 precordial leads (HR: 1.66; 95% CI, 1.09–2.52; P =0.018), and premature ventricular contraction count ≥1000/24 hours (HR: 2.30; 95% CI, 1.32–4.00; P =0.003) were predictors of any appropriate ICD therapy. Inducibility at electrophysiology study (HR: 2.28; 95% CI, 1.10–4.70; P =0.025) remained as the only predictor after multivariable analysis. The predictors for ventricular fibrillation/flutter were premature ventricular contraction ≥1000/24 hours (HR: 4.39; 95% CI, 1.32–14.61; P =0.016), syncope (HR: 1.85; 95% CI, 1.10–3.11; P =0.021), aged ≤30 years at presentation (HR: 1.76; 95% CI, 1.04–3.00; P P =0.046). Younger age at presentation (HR: 3.14; 95% CI, 1.32–7.48; P =0.010) and high premature ventricular contraction burden (HR: 4.43; 95% CI, 1.35–14.57; P ICD interventions. Overall mortality was low at 2%, and 4% underwent heart transplantation. Conclusion These findings represent an important step in identifying predictors of ICD therapy for potentially fatal ventricular fibrillation/flutter and should be considered when developing a risk stratification model for arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Background Endurance exercise is associated with adverse outcomes in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Exercise recommendations for family members remain undetermined. Objective The purposes of this study were to determine if (1) endurance exercise (Bethesda class C) and exercise intensity (metabolic equivalent hours per year [MET-Hr/year]) increase the likelihood of fulfilling 2010 Task Force Criteria and ventricular arrhythmias/implantable cardioverter-defibrillator shock (ventricular tachycardia/ventricular fibrillation [VT/VF]), and (2) exercise restriction to the American Heart Association (AHA)-recommended minimum for healthy adults is associated with favorable outcomes of at-risk family members. Methods Twenty-eight family members of 10 probands inheriting a PKP2 mutation were interviewed about exercise from age 10. Exercise threshold to maintain overall health was based on the 2007 AHA guidelines of a minimum 390 to 650 MET-Hr/year. Results After adjustment for age, sex, and family membership, both participation in endurance athletics (odds ratio [OR] 7.4, P = .03) and higher-intensity exercise (OR = 4.2, P = .004) were associated with diagnosis (n = 13). Endurance athletes were also significantly more likely to develop VT/VF (n = 6, P = .02). Family members who restricted exercise at or below the upper bound of the AHA goal (≤650 MET-Hr/year) were significantly less likely to be diagnosed (OR = 0.07, P = .002) and had no VT/VF. At diagnosis and first VT/VF, family members had accumulated 2.8-fold ( P = .002) and 3.5-fold ( P = .03), respectively, greater MET-Hr exercise than the AHA-recommended minimum. Those who developed VT/VF had performed particularly high-intensity exercise in adolescence compared to unaffected family members (age 10–14: P = .04; age 14–19: P = .02). Conclusion The results of this study suggest restricting unaffected desmosomal mutation carriers from endurance and high-intensity athletics but potentially not from AHA-recommended minimum levels of exercise for healthy adults.

Background: Ventricular arrhythmias are a feared complication of arrhythmogenic right ventricular dysplasia/cardiomyopathy. In 2015, an International Task Force Consensus Statement proposed a risk stratification algorithm for implantable cardioverter-defibrillator placement in arrhythmogenic right ventricular dysplasia/cardiomyopathy. Methods and Results: To evaluate performance of the algorithm, 365 arrhythmogenic right ventricular dysplasia/cardiomyopathy patients were classified as having a Class I, IIa, IIb, or III indication per the algorithm at baseline. Survival free from sustained ventricular arrhythmia (VT/VF) in follow-up was the primary outcome. Incidence of ventricular fibrillation/flutter cycle length 10%/year Class I; 15.5 [confidence interval 11.1–21.6] versus 1% to 10%/year Class IIa). In addition, the algorithm did not differentiate survival free from ventricular fibrillation/flutter between Class I and IIa patients ( P =0.97) or for VT/VF in Class I and IIa primary prevention patients ( P =0.22). Adding Holter results ( Conclusions: While the algorithm differentiates arrhythmic risk well overall, it did not distinguish ventricular fibrillation/flutter risks of patients with Class I and IIa implantable cardioverter-defibrillator indications. Limited differentiation was seen for primary prevention cases. As these are vital uncertainties in clinical decision-making, refinements to the algorithm are suggested prior to implementation.

Background Exercise is associated with age‐related penetrance and arrhythmic risk in carriers of arrhythmogenic right ventricular dysplasia/cardiomyopathy ( ARVD /C)‐associated desmosomal mutations; however, its role in patients without desmosomal mutations (gene‐elusive) is uncertain. This study investigates whether exercise is (1) associated with onset of gene‐elusive ARVD /C and (2) has a differential impact in desmosomal and gene‐elusive patients. Methods and Results Eighty‐two ARVD /C patients (39 desmosomal, all probands) were interviewed about regular physical activity from age 10. Participation in endurance athletics, duration (hours/year), and intensity ( MET ‐Hours/year) of exercise prior to clinical presentation were compared between patients with desmosomal and gene‐elusive ARVD /C. All gene‐elusive patients were endurance athletes. Gene‐elusive patients were more likely to be endurance athletes ( P MET ‐Hrs/year) exercise prior to presentation ( P P =0.027). Family history was less prevalent among gene‐elusive patients (9% versus 40% desmosomal, P ARVD /C patients ( P =0.004). Gene‐elusive patients who had done the most intense (top quartile MET ‐Hrs/year) exercise prior to presentation had a younger age of presentation ( P =0.025), greater likelihood of meeting ARVD /C structural Task Force Criteria (100% versus 43%, P =0.02), and shorter survival free from a ventricular arrhythmia in follow‐up ( P =0.002). Conclusions Gene‐elusive, non‐familial ARVD /C is associated with very high intensity exercise suggesting exercise has a disproportionate role in the pathogenesis of these cases. As exercise negatively modifies cardiac structure and promotes arrhythmias, exercise restriction is warranted.

Prior reports have identified associations between SCN10A and cardiac disorders, such as atrial fibrillation and Brugada syndrome. We evaluated SCN10A in 151 probands with ARVD/C. In this cohort, 10 putatively pathogenic SCN10A variants were identified, including a novel frameshift insertion. Despite a known role for the encoded protein in peripheral nerve function, the proband with the frameshift variant had no discernible neurological abnormalities. Arrhythmic phenotypes were not different between those with a rare variant in SCN10A and those without. The prevalence of rare variants in SCN10A was similar among ARVD/C probands with and without a desmosome mutation and similar among healthy Caucasian controls. These results indicate the absence of a primary role for SCN10A mutations in ARVD/C.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterized by fibrofatty replacement of the ventricular myocardium, right ventricular (RV) dysfunction, and ventricular arrhythmias. The Johns Hopkins ARVD Program Registry, which was established in