Arrhythmogenic cardiomyopathy: An in-depth look at molecular mechanisms and clinical correlates

Arrhythmogenic cardiomyopathy (ACM) is a familial disease, with approximately 60% of patients displaying a pathogenic variant. The majority of genes linked to ACM code for components of the desmosome: plakophilin-2 ( PKP2 ), desmoglein-2 ( DSG2 ) and desmocollin-2 ( DSC2 ), plakoglobin ( JUP ) and desmoplakin ( DSP ). Genetic variants involving the desmosomes are known to cause dysfunction of cell-to-cell adhesions and intercellular gap junctions. In turn, this may result in failure to mechanically hold together the cardiomyocytes, fibrofatty myocardial replacement, cardiac conduction delay and ventricular arrhythmias. It is becoming clearer that pathogenic variants in desmosomal genes such as PKP2 are not only responsible for a mechanical dysfunction of the intercalated disc (ID), but are also the cause of various pro-arrhythmic mechanisms. In this review, we discuss in detail the different molecular interactions associated with desmosomal pathogenic variants, and their contribution to various ACM phenotypes. (c) 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license. ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Automated summary

ACM is a familial disease with the majority of genes linked to desmosomes, genetic variants may lead to dysfunction of cell-to-cell adhesions and intercellular gap junctions, causing cardiomyocyte separation, cardiac conduction delay, and arrhythmias.