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CLINICAL RESEARCH

Stretch-Sensitive KCNQ1 Mutation

A Link Between Genetic and Environmental Factors in the Pathogenesis of Atrial Fibrillation?

Robyn Otway, PhD^_*, Jamie I. Vandenberg, MB, BS, PhD^,, Guanglan Guo, PhD^_*, Anthony Varghese, PhD, M. Leticia Castro, BMedSc(Hons)^_*, Jian Liu, PhD^_*, JingTing Zhao, PhD, Jane A. Bursill, BTC, Ken R. Wyse, BSc, Haley Crotty, B Biomed Sc^_*, Olivia Baddeley, MSc^_*, Bruce Walker, MB, BS, PhD^||, Dennis Kuchar, MD, FACC^||, Charles Thorburn, MB, ChB^|| and Diane Fatkin, MD^_*,,||,_*

^_* Sr. Bernice Research Program in Inherited Heart Diseases
Mark Cowley Lidwill Program in Cardiac Electrophysiology and Biophysics, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia
Faculties of Medicine and Life Sciences, University of New South Wales, Kensington, New South Wales, Australia
Department of Computer Science, University of Wisconsin at River Falls, River Falls, Wisconsin
^|| Cardiology Department, St. Vincent's Hospital, Darlinghurst, New South Wales, Australia

Manuscript received July 14, 2006; revised manuscript received September 5, 2006, accepted September 27, 2006.

^_* Reprint requests and correspondence: Dr. Diane Fatkin, Victor Chang Cardiac Research Institute, Level 6, 384 Victoria Street, Darlinghurst NSW 2010, Australia. (Email: d.fatkin{at}victorchang.unsw.edu.au).

OBJECTIVES: This study sought to evaluate mutations in genes encoding the slow component of the cardiac delayed rectifier K⁺ current (I _Ks) channel in familial atrial fibrillation (AF).

BACKGROUND: Although AF can have a genetic etiology, links between inherited gene defects and acquired factors such as atrial stretch have not been explored.

METHODS: Mutation screening of the KCNQ1, KCNE1, KCNE2, and KCNE3 genes was performed in 50 families with AF. The effects of mutant protein on cardiac I _Ks activation were evaluated using electrophysiological studies and human atrial action potential modeling.

RESULTS: One missense KCNQ1 mutation, R14C, was identified in 1 family with a high prevalence of hypertension. Atrial fibrillation was present only in older individuals who had developed atrial dilation and who were genotype positive. Patch-clamp studies of wild-type or R14C KCNQ1 expressed with KCNE1 in CHO cells showed no statistically significant differences between wild-type and mutant channel kinetics at baseline, or after activation of adenylate cyclase with forskolin. After exposure to hypotonic solution to elicit cell swelling/stretch, mutant channels showed a marked increase in current, a leftward shift in the voltage dependence of activation, altered channel kinetics, and shortening of the modeled atrial action potential duration.

CONCLUSIONS: These data suggest that the R14C KCNQ1 mutation alone is insufficient to cause AF. Rather, we suggest a model in which a "second hit", such as an environmental factor like hypertension, which promotes atrial stretch and thereby unmasks an inherited defect in ion channel kinetics (the "first hit"), is required for AF to be manifested. Such a model would also account for the age-related increase in AF development.

Abbreviations and Acronyms   AF = atrial fibrillation   CHO = Chinese hamster ovary   DNA = deoxyribonucleic acid   I Ks = slow component of the delayed rectifier K+ current   PCR = polymerase chain reaction   WT = wild-type

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