Arrhythmogenic cardiomyopathy: Pathology, genetics, and concepts in pathogenesis

Edgar T. Hoorntje, Wouter P. te Rijdt, Cynthia A. James, Kalliopi Pilichou, Cristina Basso, Daniel P. Judge, Connie R. Bezzina, J. Peter van Tintelen*

*Corresponding author for this work

    Research output: Contribution to journalReview articlepeer-review

    89 Citations (Scopus)
    36 Downloads (Pure)

    Abstract

    Arrhythmogenic cardiomyopathy (ACM) is a rare, heritable heart disease characterized by fibro-fatty replacement of the myocardium and a high degree of electric instability. It was first thought to be a congenital disorder, but is now regarded as a dystrophic heart muscle disease that develops over time. There is no curative treatment and current treatment strategies focus on attenuating the symptoms, slowing disease progression, and preventing life-threatening arrhythmias and sudden cardiac death. Identification of mutations in genes encoding desmosomal proteins and in other genes has led to insights into the disease pathogenesis and greatly facilitated identification of family members at risk. The disease phenotype is, however, highly variable and characterized by incomplete penetrance. Although the reasons are still poorly understood, sex, endurance exercise and a gene-dosage effect seem to play a role in these phenomena. The discovery of the genes and mutations implicated in ACM has allowed animal and cellular models to be generated, enabling researchers to start unravelling it's underlying molecular mechanisms. Observations in humans and in animal models suggest that reduced cell-cell adhesion affects gap junction and ion channel remodelling at the intercalated disc, and along with impaired desmosomal function, these can lead to perturbations in signalling cascades like the Wnt/b-catenin and Hippo/YAP pathways. Perturbations of these pathways are also thought to lead to fibro-fatty replacement. A better understanding of the molecular processes may lead to new therapies that target specific pathways involved in ACM.

    Original languageEnglish
    Pages (from-to)1521-1531
    Number of pages11
    JournalCardiovascular Research
    Volume113
    Issue number12
    DOIs
    Publication statusPublished - 1-Oct-2017

    Keywords

    • Arrhythmogenic cardiomyopathy
    • Arrhythmogenic right ventricular cardiomyopathy
    • Pathology
    • Genetics
    • Pathogenesis
    • RIGHT-VENTRICULAR CARDIOMYOPATHY
    • DESMOSOMAL MUTATION CARRIERS
    • CARDIAC INTERCALATED DISC
    • DILATED CARDIOMYOPATHY
    • NUCLEAR PLAKOGLOBIN
    • SODIUM-CHANNEL
    • DYSPLASIA/CARDIOMYOPATHY
    • MICE
    • PLAKOPHILIN-2
    • DYSPLASIA

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