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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.

AimsDesmoplakin (DSP) cardiomyopathy is an increasingly recognized form of arrhythmogenic cardiomyopathy. With a genotype-specific approach, we characterized the diagnosis, natural history, and risk for ventricular arrhythmia and heart failure in DSP cardiomyopathy.Methods and resultsWe followed 91 individuals [45 probands, 34% male, median age 27.5 years (interquartile interval 20.0–43.9)] with pathogenic or likely pathogenic DSP variants for a median of 4.3 years. Regarding the ventricular involvement, left predominance was most common (n = 22, 28%) followed by bi-ventricular in 12 (15%) and right predominance in 5 (6%). Myocardial injury (chest pain, elevated troponin, normal coronary angiogram) occurred in 20 (22%) individuals. Incidence rates of sustained ventricular arrhythmia and heart failure (ventricular dysfunction ± symptoms) were 5.9 [95% confidence interval (CI): 3.9–9.1] and 6.7 (95% CI: 4.5–9.8) per 100 person-years, respectively. In univariate regression, myocardial injury was associated with sustained ventricular arrhythmia [hazard ratio (HR) 2.53, 95% CI: 1.05–6.11] and heart failure (HR 7.53, 95% CI: 3.10–18.26). After adjustment, left ventricular ejection fraction ConclusionDSP cardiomyopathy affects both ventricles and carries high risk for ventricular arrhythmia and heart failure. Myocardial injury is associated with worse disease outcomes. Both diagnosis and risk stratification of DSP cardiomyopathy need refinement.

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.

Patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) classically initially present with ventricular arrhythmias or, less commonly, heart failure. Myocardial inflammation has been implicated in pathogenesis, but clinical myocarditis in ARVC is less described. We therefore studied clinical myocarditis as an initial ARVC presentation, and hypothesized that these patients have distinct clinical and genetic characteristics. Using the Johns Hopkins ARVC Registry, we identified 12 patients (all female, median age 20) referred between 2014 and 2019 diagnosed with myocarditis at presentation who were subsequently diagnosed with ARVC by Task Force Criteria. Majority presented with chest pain (n = 7, 58%) or ventricular arrhythmia (n = 3, 25%). All patients had troponin elevations and left ventricular (LV) function was reduced in 5 (42%). Magnetic resonance imaging demonstrated LV delayed gadolinium enhancement and/or pericardial enhancement in 10 (83%); only 3 (25%) patients had right ventricular abnormalities. Pathogenic genetic variants were identified in 11 (92%) patients: 10 desmoplakin (DSP) and 1 desmoglein-2 (DSG2). Thus, nearly 1/3 (10/32, 31%) of overall DSP ARVC patients were originally diagnosed with myocarditis. Patients were diagnosed with ARVC 1.8 years (IQR 2.7 years) after presentation and 8 (75%) patients did not meet Task Force Criteria without genetic testing. ARVC diagnosis led to an additional 5 (42%) patients referred for implantable cardiac defibrillator and 17 family member diagnoses. In conclusion, ARVC may initially present as myocarditis and these patients have distinct characteristics including female gender, LV involvement and DSP gene variants. Genetic testing is key to ARVC diagnosis and should be considered in select myocarditis patients.

Aims In arrhythmogenic right ventricular cardiomyopathy (ARVC) patients, exercise worsens disease course, so exercise restriction is recommended. However, recommendations for genotype-positive ARVC family members is incompletely resolved. We aimed to provide evidence for exercise recommendations for genotype-positive ARVC family members. Methods and results Arrhythmogenic right ventricular cardiomyopathy family members inheriting a pathogenic desmosomal variant were interviewed about exercise history from age 10. Exercise was characterized by duration, intensity, and dose (duration*intensity). Associations between exercise and (i) diagnosis by 2010 Task Force Criteria and (ii) development of sustained ventricular arrhythmias were examined. The study included 101 family members (age: 40.5 ± 19.3 years, male: 41%, Plakophilin-2 variant: 81%). Forty-four individuals (44%) met diagnostic criteria and 16 (16%) experienced sustained ventricular arrhythmia. Individuals who met diagnostic criteria had significantly higher average exercise duration and dose, but not peak intensity than those who did not. Only one individual who exercised below the American Heart Association recommended minimum (650 metabolic equivalent of task-hours/year) met diagnostic criteria or experienced sustained ventricular arrhythmia as opposed to 50% of individuals who exceeded it (adjusted odds ratio = 0.03, 95% confidence interval 0.003–0.26). The difference in exercise exposure between affected and unaffected individuals was more striking in females than in males. Females who had done high-dose exercise in adolescence had the worst survival free from diagnosis (P Conclusions In phenotype-negative ARVC family members with a pathogenic desmosomal variant, athletic activities should be limited, particularly exercise dose. Exercise may play a greater role in promoting disease in female family members.

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…

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by fibrofatty infiltration of predominantly the right ventricular (RV) myocardium. Affected patients typically present as young adults with hemodynamically stable ventricular tachycardia, although pediatric cases are increasingly recognized. These young subjects often have a more severe phenotype with a high risk of sudden cardiac death (SCD) and progression toward heart failure. Diagnosis of ARVC is made by combining multiple sources of information as prescribed by the consensus-based Task Force Criteria. The description of Naxos disease, a fully penetrant autosomal recessive disorder that is associated with ARVC and a cutaneous phenotype of palmoplantar keratoderma and wooly hair facilitated the identification of the genetic cause of ARVC. At present, approximately 60% of patients are found to carry a pathogenic variant in one of five genes associated with the cardiac desmosome. The incomplete penetrance and variable expressivity of these variants however implies an important role for environmental factors, of which participation in endurance exercise is a strong risk factor. Since there currently is no definite cure for ARVC, disease management is directed toward symptom reduction, delay of disease progression, and prevention of SCD. This clinically focused review describes the spectrum of ARVC among children and adolescents, the genetic architecture underlying this disease, the cardio-cutaneous syndromes that led to its identification, and current diagnostic and therapeutic strategies in pediatric ARVC subjects.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy, which is associated with life-threatening ventricular arrhythmias. Approximately 60% of patients carry a putative disease-causing genetic variant, but interpretation of genetic test results can be challenging. The aims of this study were to systematically reclassify genetic variants in patients with ARVC and to assess the impact on ARVC diagnosis. Methods: This study included patients from the Multicenter Zurich ARVC Registry who hosted a genetic variant deemed to be associated with the disease. Reclassification of pathogenicity was performed according to the modified 2015 American College of Medical Genetics criteria. ARVC diagnosis (categories: definite, borderline, possible) based on the 2010 Task Force Criteria was reclassified after genetic readjudication. Results: In 79 patients bearing 80 unique genetic variants, n=47 (58.8%) genetic variants were reclassified, and reclassification was judged to be clinically relevant in n=33 (41.3%). Variants in plakophilin-2 ( PKP2 ) were shown to reclassify less frequently as compared with other genes ( PKP2 , n=1, 8.3%; desmosomal non- PKP2 , n=20, 66.7%; nondesmosomal, n=26, 68.4%; P =0.001for overall comparison; PKP2 versus desmosomal non- PKP2, P =0.001; PKP2 versus nondesmosomal, P Conclusions: Given that approximately half of genetic variants were reclassified, with 10.1% of patients losing their definite disease status, accurate determination of variant pathogenicity is of utmost importance in the diagnosis of ARVC.

BackgroundThe FLNC gene has recently garnered attention as a likely cause of arrhythmogenic cardiomyopathy (ACM), which is considered an actionable genetic condition. However, the association with disease in an unselected clinical population is unknown. We hypothesized that individuals with loss-of-function variants in FLNC (FLNCLOF) would have increased odds for ACM-associated phenotypes versus variant-negative controls in the Geisinger MyCode cohort.MethodsWe identified rare, putative FLNCLOF among 171,948 individuals with exome sequencing linked to health records. Associations with ACM phenotypes from available diagnoses and cardiac evaluations were investigated.ResultsSixty individuals (0.03%; median age 58 years [47–70 IQR], 43% male) harbored 27 unique FLNCLOF. These individuals had significantly increased odds ratios (OR) for dilated cardiomyopathy (OR:4.9, [95% confidence interval: 2.6–7.6]; pFLNCLOF. Overall, at least 9% of FLNCLOF carriers demonstrated evidence of penetrant disease.ConclusionsFLNCLOF variants are associated with increased odds of ventricular arrhythmia and dysfunction in an unselected clinical population. These findings support genomic screening of FLNC for actionable secondary findings.

Background: Atrial arrhythmias are present in up to 20% of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Catheter ablation (CA) is an effective treatment for atrial arrhythmias in the general population. Data regarding CA for atrial arrhythmias in ARVC are scarce. Objective: To assess the safety and efficacy of CA for atrial arrhythmias in patients with ARVC. Methods: In this international collaborative effort, all patients with a definite diagnosis of ARVC undergoing CA for atrial fibrillation (AF), focal atrial tachycardia (AT), or cavotricuspid isthmus (CTI)-dependent atrial flutter (AFl) were extracted from twelve ARVC registries. Demographic, periprocedural, and long-term arrhythmic outcome data were collected. Results: Thirty-seven patients were enrolled in the study (age 50.2 ± 16.6 years, male 84%, CHA2DS2VASc 1 (1,2), HAS-BLED 0 (0–2)). The arrhythmia leading to CA was AF in 23 (62%), focal left AT in 5 (14%), and CTI-dependent AFl in 9 (24%). Acute procedural success was achieved in all procedures but one (n = 1 focal left AT, 97% acute success). The median follow-up period was 27 (13–67) months, and 96%, 74%, and 61% of patients undergoing AF ablation were free from any atrial arrhythmia recurrence after a single procedure at 6 months, 12 months, and last follow-up, respectively. After focal AT ablation, freedom from atrial arrhythmia recurrence was 80%, 80%, and 60% at 6 months, 12 months, and last follow-up, respectively. All patients undergoing CTI ablation were free from atrial arrhythmia recurrences at 6 months, with 89% single-procedural arrhythmic freedom at last follow-up. One major complication (2.7%, PV stenosis requiring PV stenting) occurred. Conclusions: CA is safe and effective in managing atrial arrhythmias in patients with ARVC, with success rates comparable to the general population.

Genetic testing and genetic counseling (GC) are increasingly recommended in the cardiovascular setting, with multiple guidelines recommending GC for patients with or at risk for inherited cardiovascular conditions. There are scant data, however, describing patient outcomes to guide evidence-based care. No studies have quantified the influence of the strength of the genetic counselor:patient relationship on outcomes. Individuals referred for first time GC at the Johns Hopkins Arrhythmogenic Cardiomyopathy (ACM) center were surveyed prior to their visit and immediately after, before any genetic test results ordered at the session had been returned. Outcomes and measures were selected based on the Reciprocal Engagement Model of GC and include empowerment assessed by the Genetic Counseling Outcome Scale (GCOS), anxiety assessed by the Cardiac Anxiety Questionnaire (CAQ), and genetic counselor:patient therapeutic alliance assessed by the Working Alliance Inventory (WAI-SR). Response rate was 59% (120/203). 54 (45%) of patients had genetic testing ordered prior to their GC visit. There was a significant increase in GCOS score (mean 15.7 points) within 4 weeks post-GC session (p

Introduction Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited progressive cardiomyopathy characterized by frequent life-threatening arrhythmias. The diagnosis of ARVC is challenging and is on the basis of a set of major and minor criteria as described by the modified Task Force Criteria (TFC). We report our clinical experience in a series of patients who were misdiagnosed with ARVC and subsequently underwent removal of their implantable cardioverter defibrillator (ICD) after a re-evaluation at our center. Methods and results We studied 12 patients who were misdiagnosed with ARVC and had ICD implantation before our assessment. All patients had a repeat evaluation and were scored according to TFC before ICD removal. Cardiac magnetic resonance imaging (CMR) studies performed at outside institutions during the initial evaluation were reported abnormal and classified as meeting major TFC in ninety percent of patients. The most common abnormality reported was fatty infiltration of the right ventricular (RV) free wall and/or presence of focal intra-myocardial fat in six patients (50%). On re-evaluation, none of these findings fulfilled the TFC for the diagnosis. Conclusion This study demonstrated that high dependence on misinterpretation of CMR along with a misunderstanding of the TFC evaluation are the main reasons for the misdiagnosis of ARVC. Despite the updated criteria for almost a decade, this study reminds that the diagnosis of ARVC is complex and hence careful TFC evaluation and consideration of multiple cardiac test results should be the focused approach for clinicians when confronted with suspected ARVC patients.

Background The sympathetic nervous system plays an important role in arrhythmogenesis in arrhythmogenic right ventricular cardiomyopathy (ARVC). Sudden cardiac death commonly occurs during exertion, and β-blockers are associated with a reduction in arrhythmia burden. Bilateral cardiac sympathetic denervation (BCSD) has been shown to reduce implantable cardioverter-defibrillator (ICD) shocks in patients with structural heart disease and refractory ventricular tachycardia (VT); however, data in ARVC are sparse. Objective The purpose of this study was to evaluate the role of BCSD in patients with ARVC and refractory VT. Methods Consecutive patients with ARVC who underwent BCSD because of refractory VT were included. Number of ICD shocks, sustained VT episodes, VT storm, and antiarrhythmic therapy were assessed and compared before and after the intervention. VT-free survival rate, death, and heart transplantation were also evaluated. Results Eight patients with ARVC (mean age 32 ± 20 years; 3 men [38%]) underwent sympathectomy for recurrent VT. All patients failed catheter ablation, and 50% had a desmosomal mutation identified. Procedural complications included neuropathic pain, paravertebral venous plexus injury, and pneumothorax. Over a mean follow-up of 1.9 ± 0.9 years, 5 patients (63%) had no VT recurrence. BCSD significantly reduced the number of ICD shocks or sustained VT compared with 1-year pre-BCSD (mean 12.6 ± 18.2 and median 6.5 [interquartile range 4.5–10.5] pre-BCSD vs 0.9 ± 1.4 and 0 [interquartile range 0–1.5] post-BCSD; P = .011). Most of the patients (88%) were on β-blocker therapy alone at the end of follow-up. One patient underwent heart transplantation because of heart failure, and no deaths occurred. Conclusion BCSD may be an effective option for patients with ARVC and refractory ventricular arrhythmia who have failed conventional treatment modalities.

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 20.6% reduction of ICD placements with the same proportion of protected patients (P

Background: Each of the cardiomyopathies, classically categorized as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy, has a signature genetic theme. Hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning >10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted. Methods: An international panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The panel used the Clinical Genome Resource semiquantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories on the basis of the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated. Results: Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from 8 gene ontologies were classified as having definitive ( BAG3 , DES , FLNC , LMNA , MYH7 , PLN , RBM20 , SCN5A , TNNC1 , TNNT2 , TTN ) or strong ( DSP ) evidence. Seven genes (14%; ACTC1 , ACTN2 , JPH2 , NEXN , TNNI3 , TPM1 , VCL ) including 2 additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, 6 were similarly classified for hypertrophic cardiomyopathy and 3 for arrhythmogenic right ventricular cardiomyopathy. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of the 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence. Conclusions: In the curation of 51 genes, 19 had high evidence (12 definitive/strong, 7 moderate). It is notable that these 19 genes explain only a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high-evidence genes; however, genes lacking robust evidence are also commonly included. We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes.

Previous studies of radiofrequency catheter ablation (RFA) of ventricular tachycardia (VT) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), relying on limited numbers of procedures, have not reported VT-free survival in parallel for single and multiple procedures (ie, after the last procedure). Data regarding the impact of RFA on VT burden are scarce.The purpose of this study was to provide new insights on clinical outcomes based on a large series of VT ablation procedures from the current era in ARVC patients.We evaluated consecutive patients with definite ARVC who underwent RFA procedures between 2009 and 2019 at our center. We assessed VT-free survival, for single and multiple procedures, and changes in VT burden and antiarrhythmic drugs (AADs) after RFA.Among 116 patients, there were 166 RFA procedures, 106 (63.9%) of which involved epicardial ablation. Cumulative freedom from VT after a single procedure was 68.6% and 49.8% at 1 and 5 years, respectively. Cumulative VT-free survival after multiple procedures was 81.8% and 69.6% at 1 and 5 years, respectively. VT burden per RFA was reduced after vs before ablation (mean 0.7 vs 10.0 events/year; P.001). Furthermore, VT burden per patient was reduced after last ablation vs before first ablation (mean 0.5 vs 10.9 events/year; P.001). Use of AADs decreased after ablation (22.2% vs 51.9%; P.001).In ARVC patients, RFA provided good VT-free survival after a single procedure, with multiple procedures required for more sustained freedom from VT recurrence. Marked reduction in VT burden permitted discontinuation of AADs.

Background Premature ventricular contractions (PVCs) may be found in any stage of arrhythmogenic right ventricular cardiomyopathy (ARVC) and have been associated with the risk of sustained ventricular tachycardia (VT). Objective To investigate the role of PVC ablation in ARVC patients. Methods We studied consecutive ARVC patients who underwent PVC ablation due to symptomatic high PVC burden. Mean daily PVC burden and AAD use were assessed before and after the procedure. Complete long-term success was defined as > 80% reduction in PVC burden off of membrane-active AADs. Results Eight patients (37±15yo; 4 males) underwent PVC ablation. The mean daily PVC burden before ablation ranged from 5.4% to 24.8%. Seven (87.5%) patients underwent epicardial ablation. Complete acute elimination of PVCs was achieved in 4 (50%) patients (no complications). The mean daily PVC burden variation ranged from an 87% reduction to a 26% increase after the procedure. Over a median follow-up of 345 days (range: 182-3004 days), only one (12.5%) patient presented complete long-term success, and 6 (75%) patients either maintained or increased the need for Class I or Class III AADs. Two (25%) patients experienced sustained VT for the first time following the ablation procedure, requiring repeat ablation. No death or heart transplantation occurred. Conclusion PVC ablation was not associated with a consistent reduction of the PVC burden in ARVC patients with symptomatic, frequent PVCs. PVC ablation may be reserved for highly symptomatic patients who failed AADs. Additional investigation is required to improve the efficacy of PVC ablation in ARVC patients. This article is protected by copyright. All rights reserved.

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: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.

Introduction: With improved survival of sudden cardiac death in arrhythmogenic right ventricular cardiomyopathy (ARVC), progressive heart failure is increasingly recognized. Cardiopulmonary exercise testing (CPET) can play a role in prognostication. However, correlation of morphologic disease severity and exercise capacity is lacking. Hypothesis: Increased RV size and decreased RV function measured by two-dimensional echocardiography (2D echo) are associated with impaired exercise capacity parameters (peak oxygen consumption (pVO 2 ) and ventilator efficiency (VE/VCO 2 slope)). Methods: We retrospectively examined 21 patients who underwent 25 echocardiography and cardiopulmonary exercise testing (CPET) studies within 6 months of each other. A Spearman rank correlation was used to determine the relationship between RV dimensions and CPET parameters. Seven (28%) had submaximal effort defined as respiratory exchange ratio 2 . Results: Patients’ mean age was 44 ± 11 years and 28% were women. Despite more than half of patients (54%) being New York Heart Association Class I, mean pVO 2 was decreased at 19 ± 5 mL/kg per minute (63% ± 22% predicted for age and sex). There was a moderate negative correlation between pVO 2 and RV basal diameter ( r s = -0.46, p =0.05) and RV area in diastole ( r s = -0.55, p =0.02). There was no significant correlation between RV size or function with VE/VCO 2 slope. Conclusion: In this small study of ARVC patients, abnormalities on echo including increased RV basal diameter and RV diastolic area were associated with worse pVO 2 but not VE/VCO 2 slope. These findings suggest that RV structural abnormalities are related to reduced oxygen uptake on CPET, and larger studies are warranted to investigate the prognostic value and clinical course of ARVC patients with regards to the development of heart failure.

Introduction Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically inherited disease characterized by fibro-fatty infiltrations (FFI). FFI in ARVC patients usually originates in the ventricles, but recent imaging studies showed FFI at the atrial level as well. Effectiveness of catheter ablation (CA) for atrial arrhythmias (AA) in this subset of patients is currently unknown. Purpose Aim of our study is to describe acute and long-term effectiveness of CA for AA in ARVC patients. Methods Nine ARVC registries from Europe, US, and China were retrospectively searched for ARVC patients undergoing CA for AA (namely: atrial fibrillation (AF), atrial tachycardia (AT), and cavo-tricuspid dependent atrial flutter (CTI-FL)). Baseline, procedural, and long-term outcome data were collected. Results Thirty-five pts (86% male, median CHA2DS2-VASc 1 [1–2], HAS-BLED 1 [0–2], and EHRA scores 2 [2–3]) were enrolled, in which a total of 45 CA procedures for AA were performed (left atrial CA: n=19 AF, n=10 AT; right atrial CA: n=16 CTI). Mean age at AA CA was 48.2±14.8 y.o. At baseline, 63% of pts were on oral anticoagulants (OAC) (n=9 warfarin; n=13 NOAC). Catheter ablation was successful and sinus rhythm obtained at the end of the procedure in all patients, with 2 (6%) AF patients requiring electrical cardioversion. Over a median follow-up of 36 [14–74] months, 12 (27%) pts experienced arrhythmia recurrence (left atrial group: n=6 AF recurrences, n=3 AT recurrences; CTI-FL group: n=1 CTI-FL recurrence; n=1 new AF with previous CTI-dependent flutter ablation), with a 1-year follow-up resulting comparable to what has been reported in the literature for the general population. [Figure 1 and 2]. 61% pts were on OAC at last follow-up. Conclusion Age at the time of CA for AA is about 10 years younger in patients with ARVC as compared to the general population. CA for AA in ARVC pts is safe and effective; surprisingly, long-term CA outcomes for AF and left AT result comparable to those reported in the general population, whereas recurrence rates of CTI-dependent flutter seem to be higher. Funding Acknowledgement Type of funding source: None

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited condition associated with ventricular arrhythmias and myocardial dysfunction; however, limited data exist on identifying patients at highest risk. The purpose of the study was to determine whether measures of right ventricular (RV) dysfunction on echocardiogram including RV strain were predictive of structural disease progression in ARVC. Methods and Results A retrospective analysis of serial echocardiograms from 40 patients fulfilling 2010 task force criteria for ARVC was performed to assess structural progression defined by an increase in proximal RV outflow tract dimensions (parasternal short or long axis) or decrease in RV fractional area change. Echocardiograms were analyzed for RV free‐wall peak longitudinal systolic strain using 2‐dimensional speckle tracking. Risk of structural progression and 5‐year change in RV outflow tract measurements were compared with baseline RV strain. Of the 40 ARVC patients, 61% had structural progression with an increase in the mean parasternal short‐axis RV outflow tract dimension from 36.2 to 38.5 mm ( P =0.022) and 68% by increase in parasternal long‐axis RV outflow tract dimension from 36.1 to 39.2 mm ( P =0.001). RV fractional area change remained stable over time. Baseline RV strain was significantly associated with the risk of structural progression and 5‐year rate of change. Patients with an RV strain more positive than −20% had a higher risk (odds ratio: 18.4; 95% CI, 2.7–125.8; P =0.003) of structural progression. Conclusions RV free wall strain is associated with the rate of structural progression in patients with ARVC. It may be a useful marker in determining which patients require closer follow‐up and treatment.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease associated with a high risk of sudden cardiac death. Among other factors, physical exercise has been clearly identified as a strong determinant of phenotypic expression of the disease, arrhythmia risk, and disease progression. Because of this, current guidelines advise that individuals with ARVC should not participate in competitive or frequent high-intensity endurance exercise. Exercise-induced electrical and morphological para-physiological remodelling (the so-called ‘athlete’s heart’) may mimic several of the classic features of ARVC. Therefore, the current International Task Force Criteria for disease diagnosis may not perform as well in athletes. Clear adjudication between the two conditions is often a real challenge, with false positives, that may lead to unnecessary treatments, and false negatives, which may leave patients unprotected, both of which are equally inacceptable. This review aims to summarize the molecular interactions caused by physical activity in inducing cardiac structural alterations, and the impact of sports on arrhythmia occurrence and other clinical consequences in patients with ARVC, and help the physicians in setting the two conditions apart.

Background Arrhythmogenic right ventricular cardiomyopathy/dysplasia ( ARVC /D) is characterized by high arrhythmic burden and progressive heart failure, which can prompt referral for heart transplantation. Cardiopulmonary exercise testing ( CPET ) has an established role in risk stratification for advanced heart failure therapies, but has not been described in ARVC /D. This study sought to determine the safety and prognostic utility of CPET in patients with ARVC /D. Methods and Results Using the Johns Hopkins ARVC /D Registry, we examined patients with ARVC /D undergoing CPET . Baseline characteristics and transplant‐free survival were compared on the basis of peak oxygen consumption (pVO2) (≤14 or >14 mL/kg per minute) and ventilatory efficiency (Ve/ VCO 2 slope ≤34 or >34). Thirty‐eight patients underwent 50 CPET s. There were no sustained arrhythmic events. Twenty‐nine patients achieved a maximal test. Patients with pVO2 ≤14 mL/kg per minute were more often men ( P =0.042) compared with patients with pVO2 >14 mL/kg per minute. Patients with Ve/ VCO 2 slope >34 tended to have more moderate/severe right ventricular dilation (7/9 [78%] versus 10/26 [38%]; P =0.060) and clinical heart failure (8/9 [89%] versus 13/26 [50%]; P =0.056) compared with patients with Ve/ VCO 2 slope ≤34. Patients who underwent heart transplantation were more likely to have clinical heart failure (10/10 [100%] versus 13/28 [46%]; P =0.003). Patients with Ve/ VCO 2 slope >34 had worse transplant‐free survival compared with patients with Ve/ VCO 2 slope ≤34 (n=35; hazard ratio, 6.57 [95% CI , 1.28–33.72]; log‐rank P =0.010), whereas transplant‐free survival was similar on the basis of pVO2 groups (n=29; hazard ratio, 3.38 [95% CI , 0.75–15.19]; log‐rank P =0.092). Conclusions CPET is safe to perform in patients with ARVC /D. Ve/ VCO 2 slope may be used for risk stratification and guide referral for heart transplantation in ARVC /D.

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 Implantable defibrillators (ICD) are an important therapy for arrhythmogenic right ventricular cardiomyopathy (ARVC) patients at high risk of sudden death. Given the high appropriate ICD therapy rate, some have argued that the mere act of implanting an ICD inflates the malignant arrhythmia rate in ARVC. OBJECTIVE To report the arrhythmic course of ARVC patients without ICDs at the fulfillment of the 2010 Task Force Criteria and explore predictors of malignant ventricular arrhythmias. METHODS We included 131 definite ARVC patients (age 32 ± 15 years, male 39%, proband 50%) either without ICDs (N = 47) or receiving an ICD at least 6 months after the fulfillment of the diagnostic criteria. The primary outcome was a composite of cardiac arrest (both resuscitated successfully and unsuccessfully) and sustained ventricular tachyarrhythmias (cycle length

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.

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Aims We aimed to assess structural progression in arrhythmogenic cardiomyopathy (AC) patients and mutation-positive family members and its impact on arrhythmic outcome in a longitudinal cohort study. Methods and results Structural progression was defined as the development of new Task Force imaging criteria from inclusion to follow-up and progression rates as annual changes in imaging parameters. We included 144 AC patients and family members (48% female, 47% probands, 40 ± 16 years old). At genetic diagnosis and inclusion, 58% of family members had penetrant AC disease. During 7.0 [inter-quartile range (IQR) 4.5–9.4] years of follow-up, 47% of family members without AC at inclusion developed AC criteria, resulting in a yearly new AC penetrance of 8%. Probands and family members had a similar progression rate of right ventricular outflow tract diameter (0.5 mm/year vs. 0.6 mm/year, P = 0.28) by mixed model analysis of 598 echocardiographic examinations. Right ventricular fractional area change progression rate was even higher in family members (−0.6%/year vs. −0.8%/year, P

Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined disease associated with a significant risk of ventricular arrhythmias and sudden cardiac death (SCD)...

BACKGROUND: Epsilon waves and other depolarization abnormalities in the right precordial leads are thought to represent delayed activation of the right ventricular outflow tract in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). However, no study has directly correlated cardiac electrical activation with the surface ECG findings in ARVD/C. METHODS AND RESULTS: Thirty ARVD/C patients (mean age 32.7 ± 11.2 years, 16 men) underwent endocardial and epicardial electroanatomical activation mapping in sinus rhythm. Twelve-lead ECGs were classified into 5 patterns: (1) normal QRS (11 patients); (2) terminal activation delay (TAD) (3 patients); (3) incomplete right bundle branch block (IRBBB) (5 patients); (4) epsilon wave (5 patients); (5) complete right bundle branch block (CRBBB) (6 patients). Timing of local ventricular activation and extent of scar was then correlated with surface QRS. Earliest endocardial and epicardial RV activation occurred on the mid anteroseptal wall in all patients despite the CRBBB pattern on ECG. Total RV activation times increased from normal QRS to prolonged TAD, IRBBB, epsilon wave, and CRBBB, respectively (103.9 ± 5.6, 116.3 ± 6.5, 117.8 ± 2.7, 146.4 ± 16.3, and 154.3 ± 6.3, respectively, P < 0.05). The total epicardial scar area (cm(2) ) was similar among the different ECG patterns. Median endocardial scar burden was significantly higher in patients with epsilon waves even compared with patients with CRBBB (34.3 vs. 11.3 cm(2) , P < 0.01). Timing of epsilon wave corresponded to activation of the subtricuspid region in all patients. CONCLUSION: We found that epsilon waves are often associated with severe conduction delay and extensive endocardial scarring in addition to epicardial disease. The timing of epsilon waves on surface ECG correlated with electrical activation of the sub-tricuspid region.

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.

Background Despite growing use of the subcutaneous implantable cardioverter‐defibrillator (S‐ ICD ), its clinical role in arrhythmogenic right ventricular cardiomyopathy/dysplasia ( ARVC /D) patients remains undefined. We aim to elucidate the cardiac phenotype, implant characteristics, and long‐term efficacy regarding appropriate therapy and complications in ARVC /D patients with an S‐ ICD implant. Methods and Results A transatlantic cohort of ARVC /D patients who underwent S‐ ICD implantation was analyzed for clinical characteristics, S‐ ICD therapy, and long‐term outcome including device‐related complications. The cohort included 29 patients (52% male, 76% probands, 59% with ARVC /D‐associated mutation, 59% primary prevention [no prior sustained ventricular arrhythmias], and 45% first‐generation S‐ ICD devices). At implant, all inducible patients (27/29) had conversion of induced ventricular fibrillation. Two patients (7%) had superficial infections of the incision site that were treated conservatively. Over a median follow‐up of 3.16 years (interquartile range: 2.21–4.51 years), all episodes (6 patients, 4% per year) of sustained ventricular arrhythmias were appropriately detected and treated. Six patients (21%) experienced 39 inappropriate shocks, with 3 requiring device explantation. Oversensing of noncardiac signal (n=4; especially myopotentials) and cardiac signal (n=4) was the most frequent etiology. No lead or device dislodgement, infection, skin erosion, or explantation related to need for antitachycardia pacing was noted. Conclusions S‐ ICD can effectively treat both induced and spontaneous ventricular arrhythmias in patients with ARVC /D. The rate of inappropriate shocks, although considerable, is comparable to that in ARVC /D patients treated with transvenous ICD s. When they occurred, inappropriate shocks were primarily due to cardiac and, uniquely, noncardiac oversensing. We suggest potential strategies for minimizing inappropriate therapy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease characterized by fibrofatty replacement of the ventricular myocardium, a high risk of ventricular arrhythmias, and progressive ventricular dysfunction. The clinical course is highly variable, and optimal approaches to management remain undefined. ARVC is associated with pathogenic variants in genes encoding the cardiac desmosome. Genetic testing facilitates identification of at-risk family members, but penetrance of ARVC in pathogenic variant carriers is difficult to predict. Participation in endurance exercise is a known key risk factor. However, there remains significant uncertainty about which family member will develop disease and how best to approach longitudinal screening. Our clinically focused review describes how new insights gained from natural history studies, improved understanding of pathogenic mechanisms, and appreciation of genetic and environmental modifiers have set the stage for developing personalized approaches to managing both ARVC patients and their at-risk family members.

Background Prior studies have shown a close link between exercise and development of arrhythmogenic right ventricular cardiomyopathy. How much exercise restriction reduces ventricular arrhythmia (VA), how genotype modifies its benefit, and whether it reduces risk sufficiently to defer implantable cardioverter‐defibrillator ( ICD ) placement in arrhythmogenic right ventricular cardiomyopathy are unknown. Methods and Results We interviewed 129 arrhythmogenic right ventricular cardiomyopathy patients (age: 34.0±14.8 years; male: 60%) with ICD s (36% primary prevention) about exercise participation. Exercise change was defined as annual exercise duration and dose in the 3 years before clinical presentation minus that after presentation. The primary outcome was appropriate ICD therapy for VA. During the 5.1 years (interquartile range: 2.7–10.8 years) after presentation, 74% (95/129) patients reduced exercise dose and 85 (66%) patients experienced the primary outcome. In multivariate analyses, top tertile reduction in exercise duration and dose were both associated with less VA (duration: hazard ratio: 0.23 [95% confidence interval, 0.07–0.81]; dose: hazard ratio: 0.14 [95% confidence interval, 0.04–0.44]). Greater reduction in exercise dose conferred greater reduction in VA ( P =0.01 for trend). Patients without desmosomal mutations and those with primary‐prevention ICD s benefited more from exercise reduction ( P =0.16 and P =0.06 for interaction); however, 58% (18/31) of athletes who reduced exercise dose by >80% still experienced VA . Conclusions Exercise restriction should be recommended to all arrhythmogenic right ventricular cardiomyopathy patients with ICD s. Patients who are “gene‐elusive” and those with primary‐prevention devices may particularly benefit. Exercise reduction is unlikely to reduce arrhythmia sufficiently in high‐risk patients to alter decision‐making regarding ICD implantation.

Objectives The aims of this study were to determine the clinical characteristics and outcomes of pediatric-onset arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) and to compare these with those of adult-onset ARVD/C. Background Improved early detection and increased awareness of ARVD/C have led to a growing group of pediatric patients seeking management recommendations. Prior studies have mainly included adults with ARVD/C; however, clinical features and outcomes may differ in pediatric subjects. Methods Among 502 subjects fulfilling task force criteria for ARVD/C, we identified 75 (15%) with pediatric-onset disease (diagnosis at Results Pediatric patients presented at 15.3 ± 2.4 years of age. Most pediatric patients were male (55%) and ARVD/C-associated mutation carriers (80%). One-fourth of pediatric patients presented with sudden cardiac death (15%) or resuscitated sudden cardiac arrest (11%). Compared with adults, pediatric patients were disproportionately mutation carriers (p = 0.002) but not more often male (p = 0.696) or probands (p = 0.371). Pediatric patients were more likely to present with sudden cardiac death (p = 0.003), whereas adults more often presented with sustained ventricular tachycardia (p = 0.017). There were no other phenotypic differences between the groups. During 8.4 ± 7.5 years of follow-up, survival free from sustained ventricular tachycardia (p = 0.359), cardiac transplantation (p = 0.523), and death (p = 0.359) was similar between pediatric and adult patients. Conclusions Pediatric patients with ARVD/C are typically male mutation carriers presenting in adolescence. Pediatric patients disproportionately present with sudden cardiac death. However, once diagnosed, clinical characteristics and outcomes are similar between pediatric and adult patients.

BACKGROUND: Analysis of regional wall motion of the right ventricle (RV) is primarily qualitative with large interobserver variation in clinical practice. Thus, the purpose of this study was to use feature tracking to analyze regional wall motion abnormalities in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). METHODS: We enrolled 110 subjects (39 overt ARVC [mutation+/phenotype+] (35.5%), 40 preclinical ARVC [mutation+/phenotype-] (36.3%), and 31 control subjects (28.2%)). Cine steady state free precession cardiac MR was performed with temporal resolution ≤40 ms in the horizontal long axis (HLA), axial, and short axis directions. Regional strain was analyzed using feature tracking software and reproducibility was assessed by means of intraclass correlation coefficient. Dunnett's test was used in univariate analysis for comparisons to control subjects; cumulative odds logistic regression was used for minimally and fully adjusted multivariate models. RESULTS: Strain was significantly impaired in overt ARVC compared with control subjects both globally (P < 0.01) and regionally (all segments of HLA view, P < 0.01). In the HLA view, regional reproducibility was excellent within (intraclass correlation coefficient [ICC] = 0.81) and moderate between (ICC = 0.62) observers. Using a threshold of -31% subtricuspid strain in the HLA view, the sensitivity and specificity for overt ARVC were 75.0% and 78.2%, respectively. In multivariable analysis involving all three groups, subtricuspid strain less than -31% (beta = 1.38; P = 0.014) and RV end diastolic volume index (beta = 0.06; P = 0.001) were significant predictors of disease presence. CONCLUSION: RV strain can be reproducibly assessed with MR feature tracking, and regional strain is abnormal in overt ARVC compared with control subjects.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a genetically determined cardiomyopathy characterized by fibrofatty replacement of predominantly, right ventricular (RV) myocardium.1 Morphologic changes frequently occur at the inferior-subtricuspid and mid RV outflow (RVOT), and may involve the antero-apical region in severe cases (triangle of dysplasia).2 As disease progresses, global RV dilation and RV dysfunction may occur. RV structural changes may also lead to development of functional tricuspid regurgitation (TR), often in the absence of pressure overload from the pulmonary vasculature (e.g. pulmonary hypertension or left heart failure). Therefore, TR in the context of ARVD/C may represent a unique phenotype of patients with functional TR. Because RV volume overload from significant TR may in turn worsen RV function, surgical correction of TR could have therapeutic benefit. Both significant TR and RV dysfunction have been independently associated with worse prognosis in ARVD/C.3-4 In order to better understand the potential role of surgery in these patients, we reviewed our ARVD/C database to identify patients who underwent surgical correction of TR.

Variable success rates have been reported after epicardial radiofrequency catheter ablation (RFA) in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). The details of the electroanatomic substrate are limited to a few studies, and the characteristics of the recurrent ventricular tachycardia (VT) in ARVD/C remain largely unknown.The purpose of this study was to report procedural strategy, safety, and efficacy of epicardial RFA at a tertiary single center with a focus on the characteristics of the substrate and recurrent VT.We included 30 ARVD/C patients (mean age 33.1 ± 11.1 years, 53% male) who underwent endocardial/epicardial mapping and epicardial catheter ablation of VT at the Johns Hopkins Hospital. Implantable cardioverter-defibrillator interrogations were evaluated for VT recurrence.The majority of critical VT circuits (69%) were on the epicardial surface, mostly in the subtricuspid region. Eight patients (27%) experienced VT recurrence after epicardial RFA, and the VT-free survival was 83%, 76%, and 70% at 6,12, and 24, months respectively. A significant reduction of VT burden was observed (P.001), even among those with VT recurrence. No complications occurred except for acute pericarditis in 1 patient. The majority of VT recurrences occurred during the first year after RFA, during exercise, had fast cycle lengths, and required implantable cardioverter-defibrillator shock for termination.The vast majority of critical VT circuits were epicardial, mostly in the subtricuspid region. Epicardial RFA of VT appears to be both safe and effective in achieving arrhythmia control in ARVD/C. The features of the recurrent VT suggest a possible catecholamine-mediated mechanism with an origin in a region not targeted for ablation.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a rare inherited heart muscle disease characterized by ventricular tachyarrhythmia, predominant right ventricular dysfunction, and sudden cardiac death. Its pathophysiology involves close interaction between genetic mutations and exposure to physical activity. Mutations in genes encoding desmosomal protein are the most common genetic basis. Genetic testing plays important roles in diagnosis and screening of family members. Syncope, palpitation, and lightheadedness are the most common symptoms. The 2010 Task Force Criteria is the standard for diagnosis today. Implantation of a defibrillator in high-risk patients is the only therapy that provides adequate protection against sudden death. Selection of patients who are best candidates for defibrillator implantation is challenging. Exercise restriction is critical in affected individuals and at-risk family members. Antiarrhythmic drugs and ventricular tachycardia ablation are valuable but palliative components of the management. This review focuses on the current diagnostic and therapeutic strategies in ARVD/C and outlines the future area of development in this field.

While many studies evaluate predictors of ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy (ARVC), a systematic review consolidating this evidence is currently lacking. Therefore, we searched MEDLINE and Embase for studies analyzing predictors of ventricular arrhythmias (sustained ventricular tachycardia/fibrillation (VT/VF), appropriate implantable cardioverter-defibrillator therapy, or sudden cardiac death) in patients with definite ARVC, patients with borderline ARVC, and ARVC-associated mutation carriers. In the case of multiple publications on the same cohort, the study with the largest population was included. This yielded 45 studies with a median cohort size of 70 patients (interquartile range 60 patients) and a median follow-up of 5.0 years (interquartile range 3.3 - 6.7 years). The average proportion of arrhythmic events observed was 10.6%/y in patients with definite ARVC, 10.0%/y in patients with borderline ARVC, and 3.7%/y with mutation carriers. Predictors of ventricular arrhythmias were population dependent: consistently predictive risk factors in patients with definite ARVC were male sex, syncope, T-wave inversion in lead >V3, right ventricular dysfunction, and prior (non)sustained VT/VF; in patients with borderline ARVC, 2 additional predictors—inducibility during electrophysiology study and strenuous exercise—were identified; and with mutation carriers, all aforementioned predictors as well as ventricular ectopy, multiple ARVC-related pathogenic mutations, left ventricular dysfunction, and palpitations/presyncope determined arrhythmic risk. Most evidence originated from small observational cohort studies, with a moderate quality of evidence. In conclusion, the average risk of ventricular arrhythmia ranged from 3.7 to 10.6%/y depending on the population with ARVC. Male sex, syncope, T-wave inversion in lead >V3, right ventricular dysfunction, and prior (non)sustained VT/VF consistently predict ventricular arrhythmias in all populations with ARVC.

Background Regional right ventricular (RV) dysfunction is the hallmark of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C), but is currently only qualitatively evaluated in the clinical setting. Feature Tracking Cardiovascular Magnetic Resonance (FT-CMR) is a novel quantitative method that uses cine CMR to calculate strain values. However, most prior FT-CMR studies in ARVD/C have focused on global RV strain using different software methods, complicating implementation of FT-CMR in clinical practice. We aimed to assess the clinical value of global and regional strain using FT-CMR in ARVD/C and to determine differences between commercially available FT-CMR software packages. Methods We analyzed cine CMR images of 110 subjects (39 overt ARVD/C [mutation+/phenotype+], 40 preclinical ARVD/C [mutation+/phenotype-] and 31 control) for global and regional (subtricuspid, anterior, apical) RV strain in the horizontal longitudinal axis using four FT-CMR software methods (Multimodality Tissue Tracking, TomTec, Medis and Circle Cardiovascular Imaging). Intersoftware agreement was assessed using Bland Altman plots. Results For global strain, all methods showed reduced strain in overt ARVD/C patients compared to control subjects (p 0.275). For regional strain, overt ARVD/C patients showed reduced strain compared to control subjects in all segments which reached statistical significance in the subtricuspid region for all software methods (p