Cardiac potassium channel dysfunction in sudden infant death syndrome

Troy E Rhodes; Robert L Abraham; Richard C Welch; Carlos G Vanoye; Lia Crotti; Marianne Arnestad; Roberto Insolia; Matteo Pedrazzini; Chiara Ferrandi; Ashild Vege; Torleiv Rognum; Dan M Roden; Peter J Schwartz; Alfred L George

doi:10.1016/j.yjmcc.2007.11.015

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Cardiac potassium channel dysfunction in sudden infant death syndrome

Journal article

Peer reviewed

Cardiac potassium channel dysfunction in sudden infant death syndrome

Troy E Rhodes, Robert L Abraham, Richard C Welch, Carlos G Vanoye, Lia Crotti, Marianne Arnestad, Roberto Insolia, Matteo Pedrazzini, Chiara Ferrandi, Ashild Vege, …

Journal of molecular and cellular cardiology, Vol.44(3), pp.571-581

03/2008

DOI: 10.1016/j.yjmcc.2007.11.015

PMCID: PMC2386856

PMID: 18222468

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Abstract

Life-threatening arrhythmias have been suspected as one cause of the sudden infant death syndrome (SIDS), and this hypothesis is supported by the observation that mutations in arrhythmia susceptibility genes occur in 5–10% of cases. However, the functional consequences of cardiac potassium channel gene mutations associated with SIDS and how these alleles might mechanistically predispose to sudden death are unknown. To address these questions, we studied four missense KCNH2 (encoding HERG) variants, one compound KCNH2 genotype, and a missense KCNQ1 mutation all previously identified in Norwegian SIDS cases. Three of the six variants exhibited functional impairments while three were biophysically similar to wild-type channels (KCNH2 variants V279M, R885C, and S1040G). When co-expressed with WT-HERG, R273Q and K897T/R954C generated currents resembling the rapid component of the cardiac delayed rectifier current (IKr) but with significantly diminished amplitude. Action potential modeling demonstrated that this level of functional impairment was sufficient to evoke increased action potential duration and pause-dependent early afterdepolarizations. By contrast, KCNQ1-I274V causes a gain-of-function in IKs characterized by increased current density, faster activation, and slower deactivation leading to accumulation of instantaneous current upon repeated stimulation. Action potential simulations using a Markov model of heterozygous I274V-IKs incorporated into the Luo–Rudy (LRd) ventricular cell model demonstrated marked rate-dependent shortening of action potential duration predicting a short QT phenotype. Our results indicate that certain potassium channel mutations associated with SIDS confer overt functional defects consistent with either LQTS or SQTS, and further emphasize the role of congenital arrhythmia susceptibility in this syndrome.

Long QT syndrome

Genetics

Short QT syndrome

Ion channels

Sudden death

Details

Title: Subtitle: Cardiac potassium channel dysfunction in sudden infant death syndrome
Creators: Troy E Rhodes - Department of Medicine, Vanderbilt University, Nashville, TN, USA
Robert L Abraham - Department of Medicine, Vanderbilt University, Nashville, TN, USA
Richard C Welch - Department of Medicine, Vanderbilt University, Nashville, TN, USA
Carlos G Vanoye - Department of Medicine, Vanderbilt University, Nashville, TN, USA
Lia Crotti - Molecular Cardiology Laboratory, IRCCS Policlinico S. Matteo, Pavia, Italy
Marianne Arnestad - Institute of Forensic Medicine, University of Oslo, Oslo, Norway
Roberto Insolia - Molecular Cardiology Laboratory, IRCCS Policlinico S. Matteo, Pavia, Italy
Matteo Pedrazzini - Molecular Cardiology Laboratory, IRCCS Policlinico S. Matteo, Pavia, Italy
Chiara Ferrandi - Molecular Cardiology Laboratory, IRCCS Policlinico S. Matteo, Pavia, Italy
Ashild Vege - Institute of Forensic Medicine, University of Oslo, Oslo, Norway
Torleiv Rognum - Institute of Forensic Medicine, University of Oslo, Oslo, Norway
Dan M Roden - Department of Medicine, Vanderbilt University, Nashville, TN, USA
Peter J Schwartz - Molecular Cardiology Laboratory, IRCCS Policlinico S. Matteo, Pavia, Italy
Alfred L George - Department of Medicine, Vanderbilt University, Nashville, TN, USA
Resource Type: Journal article
Publication Details: Journal of molecular and cellular cardiology, Vol.44(3), pp.571-581
DOI: 10.1016/j.yjmcc.2007.11.015
PMID: 18222468
PMCID: PMC2386856
NLM abbreviation: J Mol Cell Cardiol
ISSN: 0022-2828
eISSN: 1095-8584
Publisher: Elsevier Ltd
Language: English
Date published: 03/2008
Academic Unit: Cardiovascular Medicine; Internal Medicine
Record Identifier: 9984094380402771

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