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  • Review Article
  • Published:

Inherited calcium channelopathies in the pathophysiology of arrhythmias

Nature Reviews Cardiology volume 9, pages 561–575 (2012)Cite this article

Subjects

Abstract

Regulation of calcium flux in the heart is a key process that affects cardiac excitability and contractility. Degenerative diseases, such as coronary artery disease, have long been recognized to alter the physiology of intracellular calcium regulation, leading to contractile dysfunction or arrhythmias. Since the discovery of the first gene mutation associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) in 2001, a new area of interest in this field has emerged—the genetic abnormalities of key components of the calcium regulatory system. Such anomalies cause a variety of genetic diseases characterized by the development of life-threatening arrhythmias in young individuals. In this Review, we provide an overview of the structural organization and the function of calcium-handling proteins and describe the mechanisms by which mutations determine the clinical phenotype. Firstly, we discuss mutations in the genes encoding the ryanodine receptor 2 (RYR2) and calsequestrin 2 (CASQ2). These proteins are pivotal to the regulation of calcium release from the sarcoplasmic reticulum, and mutations can cause CPVT. Secondly, we review defects in genes encoding proteins that form the voltage-dependent L-type calcium channel, which regulates calcium entry into myocytes. Mutations in these genes cause various phenotypes, including Timothy syndrome, Brugada syndrome, and early repolarization syndrome. The identification of mutations associated with 'calcium-handling diseases' has led to an improved understanding of the role of calcium in cardiac physiology.

Key Points

  • Ca2+ transport in myocardial cells is a key process of cardiac excitability

  • A variety of clinical phenotypes can be caused by genetic mutations in genes controlling calcium handling

  • Mutations can affect both the 'intracellular' (sarcoplasmic reticulum calcium release) and the 'transmembrane' (Ca2+ influx through voltage-dependent L-type calcium channels) components of calcium handling

  • Inherited arrhythmias associated with Ca2+ dysfunction are often severe and life-threatening conditions

  • Risk stratification and therapy for patients with calcium channelopathies can save lives, but several knowledge gaps and uncertainties remain

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Figure 1: Calcium-induced calcium release.
Figure 2: Spontaneous diastolic Ca2+ release and triggered arrhythmias.
Figure 3: Structure and mutational clusters of RyR2.
Figure 4: Episode of bidirectional ventricular tachycardia during an exercise stress test in a patient with catecholaminergic polymorphic ventricular tachycardia.
Figure 5: The L-type Ca2+ channel is formed by the assembly of three subunits: α1c, β2, and α2δ.

Cosmocyte/Ben Smith.

Figure 6: Clinical manifestations of Timothy syndrome.

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Acknowledgements

Part of the data presented here has been produced thanks to the contribution of the following research grants: Telethon grants GGP04066, GGP06007, and GGP11141 (to S. G. Priori), Italian University Research and Technology RFMAU207641137D (to S. G. Priori), Fondation Leducq Award to the Alliance for Calmodulin Kinase Signaling in Heart Disease (08CVD01) (to S. G. Priori), Fondation Veronesi “Modelli cellulari e terapia sperimentale dei difetti cardiaci associati a patologie aritmogene ereditarie” (to S. G. Priori). CARIPLO pr.2008.2275 (to S. G. Priori), and British Heart Foundation Intermediate Clinical Research Fellowship FS10/63/28,374 (to L. Venetucci and S. G. Priori).

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  1. Molecular Cardiology, IRCCS Fondazione Salvatore Maugeri, Via Maugeri 10/10a, Pavia, 27100, Italy

    Luigi Venetucci, Marco Denegri, Carlo Napolitano & Silvia G. Priori

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  1. Luigi Venetucci
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All authors contributed to the discussion of content for this Review. In addition, L. Venetucci researched data for and wrote the article, M. Denegri and C. Napolitano reviewed/edited the manuscript before submission, and S. G. Priori wrote the article and reviewed/edited the manuscript before submission.

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Correspondence to Silvia G. Priori.

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Venetucci, L., Denegri, M., Napolitano, C. et al. Inherited calcium channelopathies in the pathophysiology of arrhythmias. Nat Rev Cardiol 9, 561–575 (2012). https://doi.org/10.1038/nrcardio.2012.93

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