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Pathophysiology of arrhythmogenic cardiomyopathy

Abstract

Arrhythmogenic cardiomyopathy (AC) is a clinically and genetically heterogeneous disorder of heart muscle that is associated with ventricular arrhythmias and risk of sudden cardiac death, particularly in the young and athletes. Mutations in five genes that encode major components of the desmosomes, namely junction plakoglobin, desmoplakin, plakophilin-2, desmoglein-2, and desmocollin-2, have been identified in approximately half of affected probands. AC is, therefore, commonly considered a 'desmosomal' disease. No single test is sufficiently specific to establish a diagnosis of AC. The diagnostic criteria for AC were revised in 2010 to improve sensitivity, but maintain specificity. Quantitative parameters were introduced and identification of a pathogenic mutation in a first-degree relative has become a major diagnostic criterion. Caution in the interpretation of screening results is highly recommended because a 'pathogenic' mutation is difficult to define. Experimental data confirm that this genetically determined cardiomyopathy develops after birth because of progressive myocardial dystrophy, and is initiated by cardiomyocyte necrosis; cellular and animal models are necessary to gain insight into the cascade of underlying molecular events. Crosstalk from the desmosome to the nucleus, gap junctions, and ion channels is under investigation, to move from symptomatic to targeted therapy, with the ultimate aim to stop disease onset and progression.

Key Points

  • Arrhythmogenic cardiomyopathy (AC) is a familial heart-muscle disease that is usually inherited with an autosomal-dominant pattern; mutations in desmosomal-protein genes are found in approximately 50% of probands

  • The 1994 diagnostic criteria were updated in 2010 to increase their sensitivity, but maintain their specificity; differential diagnosis with AC 'phenocopies' is mandatory when dealing with sporadic forms of AC

  • Emerging tools offer the possibility to visualize the fibrofatty scar, as either low-voltage myocardial areas using electroanatomical mapping, or areas of delayed contrast-enhancement with cardiac MRI

  • Genotype–phenotype studies show that the clinicomorphological spectrum of AC is wider than originally thought, and includes variants with predominant or even isolated left ventricular involvement within a single family

  • Animal and cellular models indicate that both abnormal biomechanical properties and crosstalk from the desmosome to the nucleus, gap junctions, and ion channels are implicated in the pathobiology of AC

  • Electrical instability is the main clinical manifestation of AC; in addition to re-entry arrhythmias caused by fibrofatty replacement, current hypotheses implicate acute cell death, gap-junction remodeling, and ion-channel crosstalk

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Figure 1: The progression of the AC phenotype.
Figure 2: Hypothesized intracellular desmosome crosstalk.

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Acknowledgements

The authors are supported by Telethon, Rome; CARIPARO Foundation, Padova; and Veneto Region, Venice, Italy.

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C. Basso researched the data, and all the authors contributed substantially to discussion of the content of the article. C. Basso wrote the manuscript, and all the authors were involved in reviewing and editing it before submission.

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Correspondence to Cristina Basso.

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Basso, C., Bauce, B., Corrado, D. et al. Pathophysiology of arrhythmogenic cardiomyopathy. Nat Rev Cardiol 9, 223–233 (2012). https://doi.org/10.1038/nrcardio.2011.173

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