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.