A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients.

The presence of multiple pathogenic variants in desmosomal genes (DSC2, DSG2, DSP, JUP, and PKP2) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) has been linked to a severe phenotype. However, the pathogenicity of variants is reclassified frequently, which may result in a changed clinical risk prediction. Here, we present the collection, reclassification, and clinical outcome correlation for the largest series of ARVC patients carrying multiple desmosomal pathogenic variants to date (n = 331). After reclassification, only 29% of patients remained carriers of two (likely) pathogenic variants. They reached the composite endpoint (ventricular arrhythmias, heart failure, and death) significantly earlier than patients with one or no remaining reclassified variant (hazard ratios of 1.9 and 1.8, respectively). Periodic reclassification of variants contributes to more accurate risk stratification and subsequent clinical management strategy. Graphical Abstract.

Cardiomyopathies in children: An overview.

Paediatric cardiomyopathies form a heterogeneous group of disorders characterized by structural and electrical abnormalities of the heart muscle, commonly due to a gene variant of the myocardial cell structure. Mostly inherited as a dominant or occasionally recessive trait, they might be part of a syndromic disorder of underlying metabolic or neuromuscular defects or combine early developing extracardiac abnormalities (i.e., Naxos disease). The annual incidence of 1 per 100,000 children appears higher during the first two years of life. Dilated and hypertrophic cardiomyopathy phenotypes share an incidence of 60% and 25%, respectively. Arrhythmogenic right ventricular cardiomyopathy (ARVC), restrictive cardiomyopathy, and left ventricular noncompaction are less commonly diagnosed. Adverse events such as severe heart failure, heart transplantation, or death usually appear early after the initial presentation. In ARVC patients, high-intensity aerobic exercise has been associated with worse clinical outcomes and increased penetrance in at-risk genotype-positive relatives. Acute myocarditis in children has an incidence of 1.4-2.1 cases/per 100,000 children per year, with a 6-14% mortality rate during the acute phase. A genetic defect is considered responsible for the progression to dilated cardiomyopathy phenotype. Similarly, a dilated or arrhythmogenic cardiomyopathy phenotype might emerge with an episode of acute myocarditis in childhood or adolescence. This review provides an overview of childhood cardiomyopathies focusing on clinical presentation, outcome, and pathology.

Importance of genotype for risk stratification in arrhythmogenic right ventricular cardiomyopathy using the 2019 ARVC risk calculator.

AIMS: To study the impact of genotype on the performance of the 2019 risk model for arrhythmogenic right ventricular cardiomyopathy (ARVC). METHODS AND RESULTS: The study cohort comprised 554 patients with a definite diagnosis of ARVC and no history of sustained ventricular arrhythmia (VA). During a median follow-up of 6.0 (3.1,12.5) years, 100 patients (18%) experienced the primary VA outcome (sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator intervention, aborted sudden cardiac arrest, or sudden cardiac death) corresponding to an annual event rate of 2.6% [95% confidence interval (CI) 1.9-3.3]. Risk estimates for VA using the 2019 ARVC risk model showed reasonable discriminative ability but with overestimation of risk. The ARVC risk model was compared in four gene groups: PKP2 (n = 118, 21%); desmoplakin (DSP) (n = 79, 14%); other desmosomal (n = 59, 11%); and gene elusive (n = 160, 29%). Discrimination and calibration were highest for PKP2 and lowest for the gene-elusive group. Univariable analyses revealed the variable performance of individual clinical risk markers in the different gene groups, e.g. right ventricular dimensions and systolic function are significant risk markers in PKP2 but not in DSP patients and the opposite is true for left ventricular systolic function. CONCLUSION: The 2019 ARVC risk model performs reasonably well in gene-positive ARVC (particularly for PKP2) but is more limited in gene-elusive patients. Genotype should be included in future risk models for ARVC.

Analysis of buccal mucosa as a prognostic tool in children with arrhythmogenic cardiomyopathy.

Background: The diagnosis of arrhythmogenic cardiomyopathy (ACM) is challenging especially in children at risk of adverse events. Analysis of cardiac myocyte junctional protein distribution may have diagnostic and prognostic implications, but its utility is limited by the need for a myocardial sample. We previously reported that buccal mucosa cells show junctional protein redistribution similar to that seen in cardiac myocytes of adult patients with ACM. Objectives: We aimed to determine when junctional protein distribution abnormalities first occur in children with ACM variants and whether they correlate with progression of clinically apparent disease. Methods: We analyzed buccal mucosa samples of children and adolescents with a family history of ACM (n = 13) and age-matched controls (n = 13). Samples were immunostained for plakoglobin, desmoplakin, plakophilin-1 and connexin43 and analyzed by confocal microscopy. All participants were swabbed at least twice with an average interval of 12-18 months between samplings. Results: Junctional protein re-localization in buccal mucosa cells did not correlate with the presence of ACM-causing variants but instead occurred with clinical onset of disease. No changes in protein distribution were seen unless and until there was clinical evidence of disease. In addition, progressive shifts in the distribution of key proteins correlated with worsening of the disease phenotype. Finally, we observed restoration of junctional signal for Cx43 in patient with a favorable response to anti-arrhythmic therapy. Conclusions: Due to ethical concerns about obtaining heart biopsies in children with no apparent disease, it has not been possible to analyze molecular changes in cardiac myocytes with the onset/progression of clinical disease. Using buccal smears as a surrogate for the myocardium may facilitate future studies of mechanisms and pathophysiological consequences of junctional protein redistribution in ACM. Buccal cells may also be a safe and inexpensive tool for risk stratification and potentially monitoring response to treatment in children bearing ACM variants.

Clinical and Molecular Aspects of Naxos Disease.

Naxos disease is a recessively inherited pattern of arrhythmogenic cardiomyopathy with palmoplantar keratoderma and woolly hair. The causative mutation identified in plakoglobin protein gene indicated a potential role of the desmosomal protein complex as culprit for cardiomyopathy. In the context of a family, the early evident cutaneous features may serve as a clinical screening tool to spot arrhythmogenic cardiomyopathy in subclinical stage. "Myocarditis-like episodes" may step up the disease evolution or mark a transition from concealed to symptomatic cardiomyopathy phase. Arrhythmogenic cardiomyopathy in Naxos disease shows increased penetrance and phenotypic expression but its arrhythmic risk is analogous to dominant forms.

Arrhythmogenic Right Ventricular Cardiomyopathy in Pediatric Patients: An Important but Underrecognized Clinical Entity.

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.

Definition and treatment of arrhythmogenic cardiomyopathy: an updated expert panel report.

It is 35 years since the first description of arrhythmogenic right ventricular cardiomyopathy (ARVC) and more than 20 years since the first reports establishing desmosomal gene mutations as a major cause of the disease. Early advances in the understanding of the clinical, pathological and genetic architecture of ARVC resulted in consensus diagnostic criteria, which proved to be sensitive but not entirely specific for the disease. In more recent years, clinical and genetic data from families and the recognition of a much broader spectrum of structural disorders affecting both ventricles and associated with a propensity to ventricular arrhythmia have raised many questions about pathogenesis, disease terminology and clinical management. In this paper, we present the conclusions of an expert round table that aimed to summarise the current state of the art in arrhythmogenic cardiomyopathies and to define future research priorities.

Common presentation of rare diseases: Arrhythmogenic right ventricular cardiomyopathy and its mimics.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is the most common phenotype described within the spectrum of arrhythmogenic cardiomyopathies. It usually presents in early adolescence with severe ventricular arrhythmias along with cardiac structural and functional alterations mainly of the right ventricular myocardium. Though the estimated prevalence of ARVC in the general population is only 1:5000, it represents one of the most common causes of juvenile sudden death. However, detection of early RV dysfunction in ARVC may be challenging requiring high clinical suspicion and an algorithmic approach. A thorough family history of juvenile sudden death, ventricular arrhythmias and ICD implants should always be sought. Diagnosis usually requires electrocardiographic interpretation as well as cardiac imaging. In this article, the key diagnostic steps in the assessment of ARVC and diagnostic red flags that aid its differential diagnosis are discussed.

Characterizing the Molecular Pathology of Arrhythmogenic Cardiomyopathy in Patient Buccal Mucosa Cells.

BACKGROUND: Analysis of myocardium has revealed mechanistic insights into arrhythmogenic cardiomyopathy but cardiac samples are difficult to obtain from probands and especially from family members. To identify a potential surrogate tissue, we characterized buccal mucosa cells. METHODS AND RESULTS: Buccal cells from patients, mutation carriers, and controls were immunostained and analyzed in a blinded fashion. In additional studies, buccal cells were grown in vitro and incubated with SB216763. Immunoreactive signals for the desmosomal protein plakoglobin and the major cardiac gap junction protein Cx43 were markedly diminished in buccal mucosa cells from arrhythmogenic cardiomyopathy patients with known desmosomal mutations when compared with controls. Plakoglobin and Cx43 signals were also reduced in most family members who carried disease alleles but showed no evidence of heart disease. Signal for the desmosomal protein plakophilin-1 was reduced in buccal mucosa cells in patients with PKP2 mutations but not in those with mutations in other desmosomal genes. Signal for the desmosomal protein desmoplakin was reduced in buccal mucosa cells from patients with mutations in DSP, DSG2, or DSC2 but not in PKP2 or JUP. Abnormal protein distributions were reversed in cultured cells incubated with SB216763, a small molecule that rescues the disease phenotype in cardiac myocytes. CONCLUSIONS: Buccal mucosa cells from arrhythmogenic cardiomyopathy patients exhibit changes in the distribution of cell junction proteins similar to those seen in the heart. These cells may prove useful in future studies of disease mechanisms and drug screens for effective therapies in arrhythmogenic cardiomyopathy.

Arrhythmic risk assessment in genotyped families with arrhythmogenic right ventricular cardiomyopathy.

AIMS: Arrhythmogenic right-ventricular cardiomyopathy (ARVC) is a genetically determined disorder, mostly caused by mutations in genes encoding desmosomal proteins. We evaluated phenotype/genotype characteristics to predict the risk for the first major arrhythmic event in desmosomal-mutation-associated ARVC families. METHODS AND RESULTS: A cohort of 105 desmosomal-mutation carriers belonging to 39 consecutive ARVC families was evaluated. Serial clinical work-up consisting of history, physical examination, 12-lead/signal-averaged/24 h ambulatory ECG, and two-dimensional echocardiography was performed every 6-12 months. The predictive value of gender and genotype for the first major arrhythmic event was investigated within the cohort using time-to-event analysis. ECG/echocardiographic features were evaluated at the time of event and associated with the outcome using an age-matched nested case-control study within the cohort. Forty-three (41%) participants experienced the primary arrhythmic outcome at median age of 29 (21-46) years. The first event was sustained ventricular tachycardia in 31 and sudden cardiac death in 12. Definite diagnosis according to the 2010 Task Force criteria, showed 57% positive and 100% negative predictive value for the occurrence of arrhythmic outcome. Male gender (hazard ratio = 3.26, 95%CI, 1.63-6.51), predicted the first major arrhythmic event, independently of genotype, on multivariable analysis. Repolarization abnormalities and left-ventricular dysfunction independently associated with clinical disease profile at the time of event. CONCLUSION: Male gender, independently of genotype is an arrhythmic risk predictor in ARVC-associated desmosomal-mutation carriers. Repolarization abnormalities and left-ventricular dysfunction are important components of the first event-associated clinical disease profile.

Clinical Significance of Epsilon Waves in Arrhythmogenic Cardiomyopathy.

INTRODUCTION: Epsilon waves are hallmark features of arrhythmogenic cardiomyopathy (ACM) but information about their clinical significance is variable. We evaluated epsilon wave prevalence, characteristics, and their clinical significance in an ACM population. METHODS AND RESULTS: Eighty-six unselected patients fulfilling the 2010 Task Force criteria were enrolled. Seventy-six of them were carriers of desmosomal mutations. All subjects were serially evaluated with standard 12-lead ECG and 2-dimensional echocardiography. Epsilon waves were evaluated in all precordial and inferior leads. Novel parameters assessed included their duration and precordial/inferior lead extension. Twenty-five subjects (29%) had epsilon waves that were present in lead V3 and beyond in 9, and in the inferior leads in 7. Epsilon waves were associated with right ventricular outflow tract (RVOT) (P = 0.001) but not RV posterior wall (P = 0.21), RV apex (P = 0.30), or left ventricular (P = 0.94) wall motion abnormalities. Patients with epsilon waves had increased RVOT diameter (P < 0.0001). Extension of epsilon waves in lead V3 and beyond was associated with increased epsilon wave duration (P = 0.002) and RVOT diameter (P = 0.04). The duration of epsilon waves was positively correlated with RVOT diameter (r = 0.70, P = 0.0001). Epsilon waves were also associated with episodes of sustained ventricular tachycardia (P = 0.004) but not with heart failure (P = 0.41) or sudden cardiac death (P = 0.31). CONCLUSION: Detection of epsilon waves on 12-lead ECG reflects significant RVOT involvement, which was associated with episodes of sustained ventricular tachycardia but not sudden cardiac death.