Arrhythmogenic Cardiomyopathy: Mechanisms, Genetics, and Their Clinical Implications

Abstract

Arrhythmogenic cardiomyopathy (ACM) represents a collection of cardiomyopathies with etiologies convergent upon highly arrhythmogenic clinical presentations not explained by ischemic, hypertensive, or valvular heart disease. This review describes the current state of knowledge regarding molecular mechanisms and genetic diagnosis in ACM. Clinical manifestations, specifically structural presentations, of ACM may span the right and left side of the heart. The umbrella definition of ACM encompasses disease mechanisms involving disruption of cell-cell adhesion, mechanotransduction, transcription, calcium handling, and post-transcriptional regulators. As such, the underlying genetics are themselves wide ranging but generally map to perturbations of proteins comprising the desmosome and regulating downstream cellular signaling. The recognition that many genetic forms of ACM share the feared outcomes of life-threatening ventricular arrhythmia and heart failure motivates the identification of causative genetic variants for family screening and in some cases precision therapy. In turn, contemporary clinical practice has shifted towards broadened genetic testing strategy and the discovery of complex gene-specific clinical ramifications. The molecular mechanisms of ACM are complex, and the genetic architecture is ever evolving. Given this, multidisciplinary patient care for the incorporation of genetics and family cardiovascular care is critical. Future work will refine the understanding of gene-specific outcomes in ACM and implications for tailored therapy.