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(Circulation. 2009;119:19-27.)
© 2009 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Epicardial Border Zone Overexpression of Skeletal Muscle Sodium Channel SkM1 Normalizes Activation, Preserves Conduction, and Suppresses Ventricular Arrhythmia

An In Silico, In Vivo, In Vitro Study

David H. Lau, MD, PhD; Chris Clausen, PhD; Eugene A. Sosunov, PhD; Iryna N. Shlapakova, MD; Evgeny P. Anyukhovsky, PhD; Peter Danilo, Jr, PhD; Tove S. Rosen, MD; Caitlin Kelly, BA; Heather S. Duffy, PhD; Matthias J. Szabolcs, MD; Ming Chen, MS; Richard B. Robinson, PhD; Jia Lu, BS; Sinhu Kumari, PhD; Ira S. Cohen, MD, PhD; Michael R. Rosen, MD

From the Department of Pharmacology, Center for Molecular Therapeutics (D.H.L., E.A.S., I.N.S., E.P.A., P.D., T.S.R., C.K., H.S.D., M.C., R.B.R., M.R.R.), Department of Pediatrics (T.S.R., M.R.R.), and Department of Pathology (M.J.S.), College of Physicians and Surgeons, Columbia University, New York, NY; and Department of Physiology and Biophysics, Institute for Molecular Cardiology, Stony Brook University, Stony Brook, NY (C.C., J.L., S.K., I.S.C.).

Correspondence to Michael R. Rosen, MD, Gustavus A. Pfeiffer Professor of Pharmacology, Professor of Pediatrics, Director, Center for Molecular Therapeutics, Columbia University, 630 W 168 St, PH7West-321, New York, NY 10032. E-mail mrr1{at}columbia.edu

Received July 22, 2008; accepted October 6, 2008.

Background— In depolarized myocardial infarct epicardial border zones, the cardiac sodium channel (SCN5A) is largely inactivated, contributing to low action potential upstroke velocity (_max), slow conduction, and reentry. We hypothesized that a fast inward current such as the skeletal muscle sodium channel (SkM1) operating more effectively at depolarized membrane potentials might restore fast conduction in epicardial border zones and be antiarrhythmic.

Methods and Results— Computer simulations were done with a modified Hund-Rudy model. Canine myocardial infarcts were created by coronary ligation. Adenovirus expressing SkM1 and green fluorescent protein or green fluorescent protein alone (sham) was injected into epicardial border zones. After 5 to 7 days, dogs were studied with epicardial mapping, programmed premature stimulation in vivo, and cellular electrophysiology in vitro. Infarct size was determined, and tissues were immunostained for SkM1 and green fluorescent protein. In the computational model, modest SkM1 expression preserved fast conduction at potentials as positive as –60 mV; overexpression of SCN5A did not. In vivo epicardial border zone electrograms were broad and fragmented in shams (31.5±2.3 ms) and narrower in SkM1 (22.6±2.8 ms; P=0.03). Premature stimulation induced ventricular tachyarrhythmia/fibrillation >60 seconds in 6 of 8 shams versus 2 of 12 SkM1 (P=0.02). Microelectrode studies of epicardial border zones from SkM1 showed membrane potentials equal to that of shams and _max greater than that of shams as membrane potential depolarized (P<0.01). Infarct sizes were similar (sham, 30±2.8%; SkM1, 30±2.6%; P=0.86). SkM1 expression in injected epicardium was confirmed immunohistochemically.

Conclusions— SkM1 increases _max of depolarized myocardium and reduces the incidence of inducible sustained ventricular tachyarrhythmia/fibrillation in canine infarcts. Gene therapy to normalize activation by increasing _max at depolarized potentials may be a promising antiarrhythmic strategy.

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CLINICAL PERSPECTIVE

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