Molecular and Genetic Basis of Sudden Cardiac Death

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2013 Jan 3

PMID 23281413

Citations 39

Authors

Alfred L George Jr

Affiliations

Soon will be listed here.

Abstract

The abrupt cessation of effective cardiac function due to an aberrant heart rhythm can cause sudden and unexpected death at any age, a syndrome called sudden cardiac death (SCD). Annually, more than 300,000 cases of SCD occur in the United States alone, making this a major public health concern. Our current understanding of the mechanisms responsible for SCD has emerged from decades of basic science investigation into the normal electrophysiology of the heart, the molecular physiology of cardiac ion channels, fundamental cellular and tissue events associated with cardiac arrhythmias, and the molecular genetics of monogenic disorders of heart rhythm. This knowledge has helped shape the current diagnosis and treatment of inherited arrhythmia susceptibility syndromes associated with SCD and has provided a pathophysiological framework for understanding more complex conditions predisposing to this tragic event. This Review presents an overview of the molecular basis of SCD, with a focus on monogenic arrhythmia syndromes.

Citing Articles

The Multifunctional Role of KCNE2: From Cardiac Arrhythmia to Multisystem Disorders.

Song M, Zhuge Y, Tu Y, Liu J, Liu W Cells. 2024; 13(17.

PMID: 39272981 PMC: 11393857. DOI: 10.3390/cells13171409.

Putative causal relations among gut flora, serums metabolites and arrhythmia: a Mendelian randomization study.

Li K, Liu P, Liu M, Ye J, Zhu L BMC Cardiovasc Disord. 2024; 24(1):38.

PMID: 38212687 PMC: 10782588. DOI: 10.1186/s12872-023-03703-z.

Resistance to thyroid hormone induced tachycardia in RTHα syndrome.

Dore R, Watson L, Hollidge S, Krause C, Sentis S, Oelkrug R Nat Commun. 2023; 14(1):3312.

PMID: 37286550 PMC: 10247713. DOI: 10.1038/s41467-023-38960-1.

Microtubule plus-end tracking proteins: novel modulators of cardiac sodium channels and arrhythmogenesis.

Marchal G, Galjart N, Portero V, Remme C Cardiovasc Res. 2023; 119(7):1461-1479.

PMID: 37040608 PMC: 10318397. DOI: 10.1093/cvr/cvad052.

Strategies for Sudden Cardiac Death Prevention.

Coriano M, Tona F Biomedicines. 2022; 10(3).

PMID: 35327441 PMC: 8944952. DOI: 10.3390/biomedicines10030639.

References

January C, Moscucci A . Cellular mechanisms of early afterdepolarizations. Ann N Y Acad Sci. 1992; 644:23-32. DOI: 10.1111/j.1749-6632.1992.tb30999.x. View

Rook M, Bezzina Alshinawi C, Groenewegen W, van Gelder I, van Ginneken A, Jongsma H . Human SCN5A gene mutations alter cardiac sodium channel kinetics and are associated with the Brugada syndrome. Cardiovasc Res. 2000; 44(3):507-17. DOI: 10.1016/s0008-6363(99)00350-8. View

Martin C, Zhang Y, Grace A, Huang C . In vivo studies of Scn5a+/- mice modeling Brugada syndrome demonstrate both conduction and repolarization abnormalities. J Electrocardiol. 2010; 43(5):433-9. PMC: 3712183. DOI: 10.1016/j.jelectrocard.2010.05.015. View

Moss A, Zareba W, Schwarz K, Rosero S, McNitt S, Robinson J . Ranolazine shortens repolarization in patients with sustained inward sodium current due to type-3 long-QT syndrome. J Cardiovasc Electrophysiol. 2008; 19(12):1289-93. PMC: 2614458. DOI: 10.1111/j.1540-8167.2008.01246.x. View

Coronel R, Casini S, Koopmann T, Wilms-Schopman F, Verkerk A, de Groot J . Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: a combined electrophysiological, genetic, histopathologic, and computational study. Circulation. 2005; 112(18):2769-77. DOI: 10.1161/CIRCULATIONAHA.105.532614. View

Roden D . Long QT syndrome: reduced repolarization reserve and the genetic link. J Intern Med. 2005; 259(1):59-69. DOI: 10.1111/j.1365-2796.2005.01589.x. View

Ohno S, Zankov D, Ding W, Itoh H, Makiyama T, Doi T . KCNE5 (KCNE1L) variants are novel modulators of Brugada syndrome and idiopathic ventricular fibrillation. Circ Arrhythm Electrophysiol. 2011; 4(3):352-61. DOI: 10.1161/CIRCEP.110.959619. View

Hosaka Y, Hanawa H, Washizuka T, Chinushi M, Yamashita F, Yoshida T . Function, subcellular localization and assembly of a novel mutation of KCNJ2 in Andersen's syndrome. J Mol Cell Cardiol. 2003; 35(4):409-15. DOI: 10.1016/s0022-2828(03)00046-4. View

Zaritsky J, Eckman D, Wellman G, Nelson M, Schwarz T . Targeted disruption of Kir2.1 and Kir2.2 genes reveals the essential role of the inwardly rectifying K(+) current in K(+)-mediated vasodilation. Circ Res. 2000; 87(2):160-6. DOI: 10.1161/01.res.87.2.160. View

10.

Brunner M, Peng X, Liu G, Ren X, Ziv O, Choi B . Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome. J Clin Invest. 2008; 118(6):2246-59. PMC: 2373420. DOI: 10.1172/JCI33578. View

11.

Chen Q, Kirsch G, Zhang D, Brugada R, Brugada J, Brugada P . Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature. 1998; 392(6673):293-6. DOI: 10.1038/32675. View

12.

Wang D, Yazawa K, Makita N, George Jr A, Bennett P . Pharmacological targeting of long QT mutant sodium channels. J Clin Invest. 1997; 99(7):1714-20. PMC: 507992. DOI: 10.1172/JCI119335. View

13.

Cheng J, Norstrand D, Medeiros-Domingo A, Valdivia C, Tan B, Ye B . Alpha1-syntrophin mutations identified in sudden infant death syndrome cause an increase in late cardiac sodium current. Circ Arrhythm Electrophysiol. 2009; 2(6):667-76. PMC: 2810855. DOI: 10.1161/CIRCEP.109.891440. View

14.

Poelzing S, Forleo C, Samodell M, Dudash L, Sorrentino S, Anaclerio M . SCN5A polymorphism restores trafficking of a Brugada syndrome mutation on a separate gene. Circulation. 2006; 114(5):368-76. DOI: 10.1161/CIRCULATIONAHA.105.601294. View

15.

Baroudi G, Pouliot V, Denjoy I, Guicheney P, Shrier A, Chahine M . Novel mechanism for Brugada syndrome: defective surface localization of an SCN5A mutant (R1432G). Circ Res. 2001; 88(12):E78-83. DOI: 10.1161/hh1201.093270. View

16.

Fernandez-Velasco M, Rueda A, Rizzi N, Benitah J, Colombi B, Napolitano C . Increased Ca2+ sensitivity of the ryanodine receptor mutant RyR2R4496C underlies catecholaminergic polymorphic ventricular tachycardia. Circ Res. 2008; 104(2):201-9, 12p following 209. PMC: 2796688. DOI: 10.1161/CIRCRESAHA.108.177493. View

17.

Casini S, Postma A . Decreased inward rectification of Kir2.1 channels is a novel mechanism underlying the short QT syndrome. Cardiovasc Res. 2012; 93(4):535-6. DOI: 10.1093/cvr/cvs084. View

18.

Sesti F, Abbott G, Wei J, Murray K, Saksena S, Schwartz P . A common polymorphism associated with antibiotic-induced cardiac arrhythmia. Proc Natl Acad Sci U S A. 2000; 97(19):10613-8. PMC: 27073. DOI: 10.1073/pnas.180223197. View

19.

Kannankeril P, Roden D, Darbar D . Drug-induced long QT syndrome. Pharmacol Rev. 2010; 62(4):760-81. PMC: 2993258. DOI: 10.1124/pr.110.003723. View

20.

Bendahhou S, Donaldson M, Plaster N, Tristani-Firouzi M, Fu Y, Ptacek L . Defective potassium channel Kir2.1 trafficking underlies Andersen-Tawil syndrome. J Biol Chem. 2003; 278(51):51779-85. DOI: 10.1074/jbc.M310278200. View