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Gene mutations in cardiac arrhythmias: a review of recent evidence in ion channelopathies
Authors Hsiao P, Tien H, Lo C, Juang JJ, Wang Y, Sung RJ
Received 1 November 2012
Accepted for publication 27 November 2012
Published 18 January 2013 Volume 2013:6 Pages 1—13
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Pi-Yin Hsiao,1 Hui-Chun Tien,2 Chu-Pin Lo,2 Jyh-Ming Jimmy Juang,3 Yi-Hsin Wang,2 Ruey J Sung4
1Institute of Life Sciences, National Central University, Taoyuan, Taiwan; 2Department of Financial and Computational Mathematics, Providence University, Taichung, Taiwan; 3Cardiovascular Center and Department of Cardiology, National Taiwan University, Taipei, Taiwan; 4Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA
Abstract: Over the past 15 years, molecular genetic studies have linked gene mutations to many inherited arrhythmogenic disorders, in particular, "ion channelopathies", in which mutations in genes encode functional units of ion channels and/or their transporter-associated proteins in patients without primary cardiac structural abnormalities. These disorders are exemplified by congenital long QT syndrome (LQTS), short QT syndrome, Brugada syndrome (BrS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). Functional and pathophysiological studies have led to better understanding of the clinical spectrum, ion channel structures and cellular electrophysiology involving dynamics of intracellular calcium cycling in many subtypes of these disorders and more importantly, development of potentially more effective pharmacological agents and even curative gene therapy. In this review, we have summarized (1) the significance of unveiling mutations in genes encoding transporter-associated proteins as the cause of congenital LQTS, (2) the technique of catheter ablation applied at the right ventricular outflow tract may be curative for severely symptomatic BrS, (3) mutations with channel function modulated by protein Kinase A-dependent phosphorylation can be the culprit of CPVT mimicry in Andersen-Tawil syndrome (LQT7), (4) ablation of the ion channel anchoring protein may prevent arrhythmogenesis in Timothy syndrome (LQT8), (5) altered intracellular Ca2+ cycling can be the basis of effective targeted pharmacotherapy in CPVT, and (6) the technology of induced pluripotent stem cells is a promising diagnostic and research tool as it has become a new paradigm for pathophysiological study of patient- and disease-specific cells aimed at screening new drugs and eventual clinical application of gene therapy. Lastly, we have discussed (7) genotype-phenotype correlation in relation to risk stratification of patients with congenital LQTS in clinical practice.
Keywords: Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, induced pluripotent stem cells, long QT syndrome, short QT syndrome.
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