Pathogenesis of Arrhythmogenic Cardiomyopathy

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a primary myocardial disease. It is characterized by frequent ventricular arrhythmias and increased risk of sudden cardiac death typically arising as an early manifestation before the onset of significant myocardial remodeling. Myocardial degeneration, often confined to the right ventricular free wall, with replacement by fibrofatty scar tissue, develops in many patients. ACM is a familial disease but genetic penetrance can be low and disease expression is highly variable. Inflammation may promote disease progression. It also appears that exercise increases disease penetrance and accelerates its development. More than 60% of probands harbor mutations in genes encoding desmosomal proteins, which has raised the possibility that defective cell-cell adhesion may play a role in disease pathogenesis. Recent advances have implicated changes in the canonical Wnt/β-catenin and Hippo signaling pathways and defects in forwarding trafficking of ion channels and other proteins to the intercalated disk in cardiac myocytes. This review summarizes current understanding of the pathogenesis of ACM and highlights future research directions.

Electrical and Structural Substrate of Arrhythmogenic Right Ventricular Cardiomyopathy Determined Using Noninvasive Electrocardiographic Imaging and Late Gadolinium Magnetic Resonance Imaging

“…Arrhythmogenic right ventricular cardiomyopathy (ARVC) [abbreviations are defined in Supplemental Table S1] is an important hereditary cause of sudden cardiac death in young individuals with an estimated prevalence as high as 1:1000 1,2 . The ARVC phenotype is progressive, consisting of an early concealed phase, overt arrhythmias, and heart failure.…”

“…The ARVC phenotype is progressive, consisting of an early concealed phase, overt arrhythmias, and heart failure. However, penetrance is variable and the first manifestation of the disease may be sudden cardiac death 1,2 . Diagnosis and treatment of ARVC are challenging, with implications for family screening and risk stratification 3,4 .…”

Hereditary palmoplantar keratodermas. Part II: syndromic palmoplantar keratodermas – Diagnostic algorithm and principles of therapy

“…Syndromes characterized by the triad of PPK, woolly hair (WH) and arrhythmogenic cardiomyopathy (ACM), are due to mutations in JUP , DSP or rarely DSC2 genes (Table ). These genes encode major components of desmosomes and cardiac area composita (a mixed junction composed by both desmosomal and adherens junctional proteins), specifically plakoglobin (PG), desmoplakin (DSP) and desmocollin 2 (DSC2) (Table ; Fig.…”

“…Palmoplantar keratoderma with arrhythmogenic right ventricular cardiomyopathy and woolly hair due to JUP mutations (Naxos disease) Naxos disease is an autosomal recessive condition due to mutations in JUP, 60 encoding PG that links DSP in desmosomes and actin in adherens junctions to the intercellular cadherins desmoglein (DSG), DSC and N-cadherin 51,58 (Fig. 3).…”

Hippo vs. Crab: tissue‐specific functions of the mammalian Hippo pathway

“…In humans, arrhythmogenic cardiomyopathy is associated with impaired desmosome formation due to altered plakoglobin distribution. This change in plakoglobin distribution promotes cytoplasmic YAP1 retention and repression of WNT/b-catenin signaling, leading to fibroadipogenesis and increased myocyte death (Chen et al 2014b;Asimaki et al 2015).…”