Clinical and Genetic Characterization of Families With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Provides Novel Insights Into Patterns of Disease Expression

Abstract

Background-According to clinical-pathological correlation studies, the natural history of arrhythmogenic right ventricular dysplasia/cardiomyopathy is purported to progress from localized to global right ventricular dysfunction, followed by left ventricular (LV) involvement and biventricular pump failure. The inevitable focus on sudden death victims and transplant recipients may, however, have created a skewed perspective of a genetic disease. We hypothesized that unbiased representation of the spectrum of disease expression in arrhythmogenic right ventricular dysplasia/cardiomyopathy would require in vivo assessment of families in a genetically heterogeneous population. Methods and Results-A cohort of 200 probands and relatives satisfying task force or modified diagnostic criteria for arrhythmogenic right ventricular dysplasia/cardiomyopathy underwent comprehensive clinical evaluation. Desmosomal mutations were identified in 39 individuals from 20 different families. Indices of structural severity correlated with advancing age and were increased in long-term endurance athletes. Fulfillment of modified criteria indicated phenotypically mild disease, whereas asymptomatic status did not. In Ͼ80%, ECG, rhythm monitoring, and/or gadolinium-enhanced cardiovascular magnetic resonance were suggestive of LV involvement, the extent of which often was marked among individuals with chain-termination mutations and/or desmoplakin disease. Three patterns of disease expression were identified: (1) classic, with isolated right ventricular disease or LV involvement in association with significant right ventricular impairment; (2) left dominant, with early and prominent LV manifestations and relatively mild right-sided disease; and (3) biventricular, characterized by parallel involvement of both ventricles. Conclusions-LV involvement in arrhythmogenic right ventricular dysplasia/cardiomyopathy may precede the onset of significant right ventricular dysfunction. Recognition of disease variants with early and/or predominant LV involvement supports adoption of the broader term arrhythmogenic cardiomyopathy.

Impact of Exercise Restriction on Arrhythmic Risk Among Patients With Arrhythmogenic Right Ventricular Cardiomyopathy

“…Finally, this study assesses only the association of exercise restriction with appropriate ICD therapy for VA. Experiencing VA is not necessarily a sign of structural disease progression in ARVC, although prior research suggests structural progression is also associated with exercise in ARVC patients 3, 24…”

Clinical utility gene card for: arrhythmogenic right ventricular cardiomyopathy (ARVC)

“…On average, the mutation detection rate for the most common ARVC-related genes are: PKP2 11-51%, DSG2 3-20%, DSC2 1-7%, JUP 0.5-16% and DSP 1-7%. 5,12,13,[17][18][19][20][21] …”

“…5,13,17,18 Index case in that family had not been tested: ARVC is believed to be familial in B30-50% of cases. 1,8,9,20 Therefore, when an index patient has been clinically diagnosed with ARVC, and no genetic test has been performed, the chance for a firstdegree relative to develop ARVC may reach up to 15-25%.…”

Mechanisms of Disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy

“…[44][45][46] The prevalence of DSG2 mutations in published reports varies from 7-26%. 44,45,47 Importantly, the populations analyzed in these studies also varied; some excluded individuals with recognized PKP2 or DSP mutations, 44,45 and one study included individuals with left ventricular or biventricular cardiomyopathy. 47 As such, these figures might not represent the true prevalence of DSG2 mutations in cohorts of individuals with ARVD/C.…”

“…44,45,47 Importantly, the populations analyzed in these studies also varied; some excluded individuals with recognized PKP2 or DSP mutations, 44,45 and one study included individuals with left ventricular or biventricular cardiomyopathy. 47 As such, these figures might not represent the true prevalence of DSG2 mutations in cohorts of individuals with ARVD/C. Individuals with DSG2 mutations-including two probands with compound heterozygous DSG2 mutations and consequently no normal desmoglein-2-seem to have isolated ARVD/ C without skin or hair abnormalities.…”