Cardiovascular Research Advance Access originally published online on October 31, 2008
Cardiovascular Research 2009 81(3):528-535; doi:10.1093/cvr/cvn290
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Expression of skeletal but not cardiac Na+ channel isoform preserves normal conduction in a depolarized cardiac syncytium
1 Department of Pharmacology, College of Physicians and Surgeons, Columbia University, 630 West 168 Street, Room PH7West-318, New York, NY 10032, USA
2 Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY, USA
3 The Center for Molecular Therapeutics, College of Physicians and Surgeons, Columbia University, New York, NY, USA
4 Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY, USA
5 Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA
6 Institute for Molecular Cardiology, Stony Brook University, Stony Brook, NY, USA
* Corresponding author. Tel: +1 212 305 8371; fax: +1 212 305 8780. E-mail address: rbr1{at}columbia.edu
Aims: Reentrant arrhythmias often develop in the setting of myocardial infarction and ensuing slow propagation. Increased Na+ channel expression could prevent or disrupt reentrant circuits by speeding conduction if channel availability is not limited by membrane depolarization within the diseased myocardium. We therefore asked if, in the setting of membrane depolarization, action potential (AP) upstroke and normal conduction can be better preserved by the expression of a Na+ channel isoform with altered biophysical properties compared to the native cardiac Na+ channel isoform, namely having a positively shifted, voltage-dependent inactivation.
Methods and results: The skeletal Na+ channel isoform (SkM1) and the cardiac Na+ channel isoform (Nav1.5) were expressed in newborn rat ventricular myocyte cultures with a point mutation introduced in Nav1.5 to increase tetrodotoxin (TTX) sensitivity so native and expressed currents could be distinguished. External K+ was increased from 5.4 to 10 mmol/L to induce membrane depolarization. APs, Na+ currents, and conduction velocity (CV) were measured. In control cultures, elevated K+ significantly reduced AP upstroke (
75%) and CV (25%). Expression of Nav1.5 did not protect AP upstroke from K+ depolarization. In contrast, in SkM1 expressing cultures, high K+ reduced AP upstroke <50% and conduction was not significantly reduced. In a simulated anatomical reentry setting (using a void), the angular velocity (AV) of induced reentry was faster and the excitable gap shorter in SkM1 cultures compared to control for both normal and high K+.
Conclusion: Expression of SkM1 but not Nav1.5 preserves AP upstroke and CV in a K+-depolarized syncytium. The higher AV and shorter excitable gap observed during reentry excitation around a void in SkM1 cultures would be expected to facilitate reentry self-termination. SkM1 Na+ channel expression represents a novel gene therapy for the treatment of reentrant arrhythmias.
KEYWORDS Na+ channel; Gene therapy; Arrhythmia; Conduction; Mapping
Time for primary review: 25 days