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Canadian Journal of Cardiology

Pathogenesis of Arrhythmogenic Cardiomyopathy

Published:April 23, 2015DOI:https://doi.org/10.1016/j.cjca.2015.04.012

      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 remodelling. 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 might promote disease progression. It also appears that exercise increases disease penetrance and accelerates its development. More than 60% of probands harbour mutations in genes that encode desmosomal proteins, which has raised the possibility that defective cell-cell adhesion might play a role in disease pathogenesis. Recent advances have implicated changes in the canonical wingless-type mouse mammary tumour virus integration site (Wnt)/β-catenin and Hippo signalling pathways and defects in forwarding trafficking of ion channels and other proteins to the intercalated disk in cardiac myocytes. In this review we summarize the current understanding of the pathogenesis of ACM and highlight future research directions.

      Résumé

      La cardiomyopathie arythmogène (CMA) est une maladie myocardique primitive. Elle est caractérisée par de fréquentes arythmies ventriculaires et l’augmentation du risque de mort cardiaque subite se manifestant typiquement de manière précoce avant l’apparition d’un remodelage myocardique significatif. La dégénération myocardique, souvent limitée à la paroi libre du ventricule droit, avec le remplacement du tissu cicatriciel fibro-adipeux, se développe chez plusieurs patients. La MCA est une maladie familiale, mais la pénétrance peut être faible et l’expressivité de la maladie est très variable. L’inflammation favoriserait la progression de la maladie. Il semble également que l’exercice augmente la pénétrance de la maladie et accélère son développement. Plus de 60 % des proposants portent des mutations dans les gènes qui encodent les protéines desmosomales, ce qui soulève la possibilité que l’adhérence cellule-cellule défectueuse puisse jouer un rôle dans la pathogenèse de la maladie. De récentes avancées ont impliqué des changements dans les voies de signalisation Wnt/ β-caténine (voie canonique) et Hippo et des anomalies en transférant le trafic des canaux ioniques et les autres protéines au disque intercalé dans les myocytes cardiaques. Dans cette revue, nous résumons les connaissances actuelles sur la pathogenèse de la MCA et dégageons les orientations futures de la recherche.
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