Genetics of Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease that may result in arrhythmia, heart failure, and sudden death. The hallmark pathological findings are progressive myocyte loss and fibrofatty replacement, with a predilection for the right ventricle. However, variants of ARVC that preferentially affect the left ventricle are increasingly recognized. ARVC is distinguished from dilated cardiomyopathy by a propensity toward ventricular arrhythmia and sudden death in the absence of significant ventricular dysfunction. In the majority of families, ARVC shows autosomal dominant inheritance with incomplete penetrance. Recessive forms are also described, often in association with cutaneous disorders. Causative mutations have so far been identified in plakoglobin, desmoplakin, and plakophilin, all of which encode key components of the desmosome. Desmosomes are protein complexes that anchor intermediate filaments to the cytoplasmic membrane in adjoining cells, thereby forming a three-dimensional scaffolding that provides tissues with mechanical strength. Unraveling of the genetic etiology of ARVC has elicited a new model for pathogenesis. Impaired functioning of cell adhesion junctions during exposure to shear stress may lead to myocyte detachment and death, accompanied by inflammation and fibrofatty repair. At least three mechanisms contribute to the arrhythmic substrate: bouts of myocarditis, fibrous and adipose infiltrates that facilitate macroreentry, and gap junction remodeling secondary to altered mechanical coupling. The latter may underlie arrhythmogenicity in early disease. Although ARVC can be considered a disease of the desmosome, a variety of other genetic defects give rise to phenocopies, which may ultimately enhance our understanding of the broad phenotypic spectrum.