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.
Nature Reviews Cardiology 06/2012; 9(10):561-75. · 8.83 Impact Factor