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Cardiovasc Res. 2017 Oct 1;113(12):1521-1531. doi: 10.1093/cvr/cvx150.

Arrhythmogenic cardiomyopathy: pathology, genetics, and concepts in pathogenesis.

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Department of Genetics, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
Netherlands Heart Institute, Moreelsepark 1, 3511 EP, Utrecht, The Netherlands.
Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, 1800 Orleans Street, Baltimore, MD, USA.
Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua 35121, Italy.
Department of Clinical and Experimental Cardiology, Heart Centre, Academic Medical Centre, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Department of Clinical Genetics, Academic Medical Centre Amsterdam, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.


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/β-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.


Arrhythmogenic cardiomyopathy; Arrhythmogenic right ventricular cardiomyopathy; Genetics; Pathogenesis; Pathology

[Indexed for MEDLINE]

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