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(Circulation Research. 2008;102:364.)
© 2008 American Heart Association, Inc.

Cellular Biology

Divergent Biophysical Defects Caused by Mutant Sodium Channels in Dilated Cardiomyopathy With Arrhythmia

Thao P. Nguyen, Dao W. Wang, Thomas H. Rhodes, Alfred L. George, Jr

From the Department of Medicine (T.P.N.), The Johns Hopkins Medical Institutions, Baltimore, Md; and the Departments of Medicine (D.W.W., T.H.R., A.L.G.) and Pharmacology (A.L.G.), Vanderbilt University, Nashville, Tenn. T.P.N. is currently at the Division of Cardiology, UCLA Medical Center, Los Angeles, Calif.

Correspondence to Alfred L. George Jr, Division of Genetic Medicine, 529 Light Hall, Vanderbilt University, 2215 Garland Avenue, Nashville, TN 37232-0275. E-mail al.george{at}vanderbilt.edu

Mutations in SCN5A encoding the principal Na⁺ channel -subunit expressed in human heart (Na_V1.5) have recently been linked to an inherited form of dilated cardiomyopathy with atrial and ventricular arrhythmia. We compared the biophysical properties of 2 novel Na_V1.5 mutations associated with this syndrome (D2/S4 – R814W; D4/S3 – D1595H) with the wild-type (WT) channel using heterologous expression in cultured tsA201 cells and whole-cell patch-clamp recording. Expression levels were similar among WT and mutant channels, and neither mutation affected persistent sodium current. R814W channels exhibited prominent and novel defects in the kinetics and voltage dependence of activation characterized by slower rise times and a hyperpolarized conductance-voltage relationship resulting in an increased "window current." This mutant also displayed enhanced slow inactivation and greater use-dependent reduction in peak current at fast pulsing frequencies. By contrast, D1595H channels exhibited impaired fast inactivation characterized by slower entry into the inactivated state and a hyperpolarized steady-state inactivation curve. Our findings illustrate the divergent biophysical defects caused by 2 different SCN5A mutations associated with familial dilated cardiomyopathy. Retrospective review of the published clinical data suggested that cardiomyopathy was not common in the family with D1595H, but rather sinus bradycardia was the predominant clinical finding. However, for R814W, we speculate that an increased window current coupled with enhanced slow inactivation and rate-dependent loss of channel availability provided a unique substrate predisposing myocytes to disordered Na⁺ and Ca²⁺ homeostasis leading to myocardial dysfunction.

Key Words: arrhythmia • ion channels • cardiomyopathy • genetics

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				C. R. Bezzina and C. A. Remme Dilated Cardiomyopathy due to Sodium Channel Dysfunction: What Is the Connection? Circ Arrhythm Electrophysiol, June 1, 2008; 1(2): 80 - 82. [Full Text] [PDF]