Inherited calcium channelopathies in the pathophysiology of arrhythmias

• Published in: Nature reviews cardiology Vol. 9; no. 10; pp. 561 - 575
• Main Authors: Venetucci, Luigi, Denegri, Marco, Napolitano, Carlo, Priori, Silvia G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2012; Nature Publishing Group
• Subjects: 631/208/737; 631/378/1689/2115; 631/443/810; 692/699/75/29; Arrhythmia; Arrhythmias, Cardiac - genetics; Arrhythmias, Cardiac - pathology; Autistic Disorder; Brugada Syndrome - genetics; Brugada Syndrome - pathology; Calcium Channels; Calsequestrin - genetics; Cardiac Imaging; Cardiac Surgery; Cardiology; Causes of; Channelopathies; Channelopathies - genetics; Channelopathies - pathology; Genetic aspects; Health aspects; Heart Conduction System - abnormalities; Heart Conduction System - pathology; Heart Defects, Congenital - genetics; Heart Defects, Congenital - pathology; Humans; Long QT Syndrome - genetics; Long QT Syndrome - pathology; Medicine; Medicine & Public Health; Receptors, Adrenergic, beta - genetics; review-article; Risk Assessment; Ryanodine Receptor Calcium Release Channel - genetics; Syndactyly - genetics; Syndactyly - pathology
• ISSN: 1759-5002; 1759-5010
• DOI: 10.1038/nrcardio.2012.93

Abnormalities in the control of intracellular calcium are involved in several forms of inherited arrhythmias. The genetic mutations that cause these abnormalities have generated much research interest in the past decade. Here, Venetucci et al . provide an overview of the structural organization and the function of calcium-handling proteins and describe the mechanisms by which mutations determine the various clinical phenotypes of calcium channelopathies. 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 Ca 2+ 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' (Ca 2+ influx through voltage-dependent L-type calcium channels) components of calcium handling Inherited arrhythmias associated with Ca 2+ 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