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Molecular mechanisms of arrhythmogenic cardiomyopathy

Abstract

Arrhythmogenic cardiomyopathy is a genetic disorder characterized by the risk of life-threatening arrhythmias, myocardial dysfunction and fibrofatty replacement of myocardial tissue. Mutations in genes that encode components of desmosomes, the adhesive junctions that connect cardiomyocytes, are the predominant cause of arrhythmogenic cardiomyopathy and can be identified in about half of patients with the condition. However, the molecular mechanisms leading to myocardial destruction, remodelling and arrhythmic predisposition remain poorly understood. Through the development of animal, induced pluripotent stem cell and other models of disease, advances in our understanding of the pathogenic mechanisms of arrhythmogenic cardiomyopathy over the past decade have brought several signalling pathways into focus. These pathways include canonical and non-canonical WNT signalling, the Hippo–Yes-associated protein (YAP) pathway and transforming growth factor-β signalling. These studies have begun to identify potential therapeutic targets whose modulation has shown promise in preclinical models. In this Review, we summarize and discuss the reported molecular mechanisms underlying the pathogenesis of arrhythmogenic cardiomyopathy.

Key points

  • Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder characterized by the risk of life-threatening arrhythmias, myocardial dysfunction and fibrofatty replacement of myocardial tissue.

  • Disease-causing mutations, most commonly in genes encoding desmosomal proteins, can be identified in approximately half of patients with ACM.

  • The molecular links between desmosome mutations and the pathological hallmarks of ACM — cardiomyocyte loss, fibrosis, adipogenesis, inflammation and arrhythmogenesis — are under active investigation but remain poorly defined.

  • Probable pathogenic mechanisms include loss of mechanical integrity at cell–cell junctions, altered signalling pathways at intercalated discs, disruption of ion channels and gap junctions, and aberrant protein trafficking.

  • The development of refined disease models and studies of the molecular pathogenesis of ACM promise to yield novel therapeutic targets and disease treatments.

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Fig. 1: Cellular components implicated in ACM.
Fig. 2: Gross and histological features of ACM.
Fig. 3: Proposed molecular mechanisms contributing to the pathogenesis of ACM.

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Acknowledgements

M.A.T. is supported by the NIH (T32HL07572). D.J.A. is supported by the AHA (16CSA28750006). W.T.P. is supported by the NIH (UG3 HL141798) and the AHA (16CSA28750006) and by charitable donations from the Boston Children’s Heart Center. The Inherited Cardiac Arrhythmia Program (S.F.C., D.J.A. and W.T.P.) is generously supported by the Mannion and Roberts families.

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Nature Reviews Cardiology thanks M. Delmar, A. J. Marian and the other anonymous reviewer(s), for their contribution to the peer review of this work.

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K.M.A., M.A.T., S.F.C. and W.T.P. researched data for the article, and K.M.A., M.A.T. and W.T.P. discussed its content. K.M.A., M.A.T., S.F.C., D.J.A. and W.T.P. wrote the manuscript, and K.M.A., M.A.T., S.P.S., J.E.S., D.J.A. and W.T.P. reviewed and edited it before submission.

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Correspondence to William T. Pu.

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Austin, K.M., Trembley, M.A., Chandler, S.F. et al. Molecular mechanisms of arrhythmogenic cardiomyopathy. Nat Rev Cardiol 16, 519–537 (2019). https://doi.org/10.1038/s41569-019-0200-7

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