Discussion
ARVC is an inherited disorder, either autosomal dominant or rarely autosomal recessive, that is predominantly believed to affect the right ventricle, but a growing number of studies have noted involvement of both or either ventricle.4 It is characterized by fibro-fatty tissue substitution of healthy ventricular myocardium, predisposing these patients to ventricular tachycardia, heart failure, and sudden cardiac death. Its prevalence in the general population is estimated at 1 in 5000, but closer to 1 in 2000 in select European countries and constitutes up to 20% of sudden cardiac death cases in individuals under 30 years of age.5,6 In addition, phenotypic expression in males differs, in which males have a more malignant disease course and develop life threatening ventricular arrhythmias at an earlier age, possibly due to differences in sex hormones (testosterone) and increased level of physical activity, which may contribute to a greater degree of mechanical cardiac stress.7
Due to an expanding phenotypic spectrum of arrhythmogenic cardiomyopathy, from multi-gene variability in expression as well as incomplete penetrance, the diagnosis has been challenging requiring revisions to originally published criteria. The previously established Task Force criteria for diagnosis of arrhythmogenic cardiomyopathy first proposed in 1994, later revised in 2010, continues to evolve to include left-sided variants and CMR findings of late-gadolinium enhancement.8 The current criteria incorporate electrical features (12 lead ECG), structural features (seen on echocardiography and imaging), tissue characteristics (via biopsy) and genetic familial evaluation (Figure 1). While most of the Task Force criteria was originally developed from cohorts with predominantly right ventricular involvement, this potentially missed those with left ventricular dominant or biventricular disease. Pathological and imaging studies have reported the prevalence of LV involvement ranging between 17-87% of cases.9,10
While ARVC can involve multiple genes and proteins, its primary genetic defect involves proteins constituting desmosomes – cell adhesion structures – which over time disrupt normal functioning of intercellular junctions, as well as altering transcription to favor adipogenesis/fibrogenesis over normal myocyte differentiation and healthy cardiac development. Loss-of-function mutations in desmosomal proteins such as plakophilin, desmoplakin, or desmoglein have been most commonly described, but up to 13 other genes involved in ARVC have been identified to date. Furthermore, cardiac biopsies have suggested an immunological component of pathogenesis, noting the presence of inflammatory infiltrates with T lymphocytes associated with myocyte necrosis.11 As myocardial scarring develops, ventricular arrhythmias may develop through macro-reentry mechanisms but also due to gap-junction remodeling from the loss of desmosomal integrity and resulting in alteration of sodium current.