Insights Into Genetics and Pathophysiology of Arrhythmogenic Cardiomyopathy

Abstract

Purpose of review: Arrhythmogenic cardiomyopathy (ACM) is a genetic disease characterized by life-threatening ventricular arrhythmias and sudden cardiac death (SCD) in apparently healthy young adults. Mutations in genes encoding for cellular junctions can be found in about half of the patients. However, disease onset and severity, risk of arrhythmias, and outcome are highly variable and drug-targeted treatment is currently unavailable.

Recent findings: This review focuses on advances in clinical risk stratification, genetic etiology, and pathophysiological concepts. The desmosome is the central part of the disease, but other intercalated disc and associated structural proteins not only broaden the genetic spectrum but also provide novel molecular and cellular insights into the pathogenesis of ACM. Signaling pathways and the role of inflammation will be discussed and targets for novel therapeutic approaches outlined. Genetic discoveries and experimental-driven preclinical research contributed significantly to the understanding of ACM towards mutation- and pathway-specific personalized medicine.

Keywords: Arrhythmogenic cardiomyopathy; Cardiovascular genetics; Desmosomes; Dilated cardiomyopathy; Junctions; Sudden cardiac death.

Fig. 1

A Explanted heart of an ACM patient with biventricular cardiomyopathy and fibrous-fatty remodeling (arrows). Of note, the myocardial tissue of the right ventricle is nearly completely replaced against fibro-fatty tissue (blue arrows). However, fibro-fatty replacement is also present in the left ventricular myocardial tissue (green arrows). LV, left ventricle; RV, right ventricle. B Hematoxylin and eosin staining of myocardial tissue from an ACM patient. Fat replacement is marked with blue arrows

Fig. 2

Genetic overlap of ACM with other cardiomyopathies and channelopathies. ACM, arrhythmogenic cardiomyopathy; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LVNC, left ventricular non-compaction cardiomyopathy; RCM, restrictive cardiomyopathy. Gene names according to HUGO Gene Nomenclature Committee, HGNC, https://www.genenames.org/. Sub-images of the DCM or HCM heart were licensed from shutterstock.com

Fig. 3

A Subcellular localization of proteins involved in ACM. Junctional multi-protein complexes involved in ACM, which are localized at the intercalated discs (B), at the costameres (C), sarcoplasmic reticulum (D), or the nuclear envelope (E). DSC2, desmocollin-2; DSG2, desmoglein-2; DSP, desmoplakin; PG, plakoglobin; PKP2, plakophilin-2