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

Abstract

Background-In depolarized myocardial infarct epicardial border zones, the cardiac sodium channel (SCN5A) is largely inactivated, contributing to low action potential upstroke velocity (V 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 Ϫ60 mV; overexpression of SCN5A did not. In vivo epicardial border zone electrograms were broad and fragmented in shams (31.5Ϯ2.3 ms) and narrower in SkM1 (22.6Ϯ2.8 ms; Pϭ0.03). Premature stimulation induced ventricular tachyarrhythmia/fibrillation Ͼ60 seconds in 6 of 8 shams versus 2 of 12 SkM1 (Pϭ0.02). Microelectrode studies of epicardial border zones from SkM1 showed membrane potentials equal to that of shams and V max greater than that of shams as membrane potential depolarized (PϽ0.01). Infarct sizes were similar (sham, 30Ϯ2.8%; SkM1, 30Ϯ2.6%; Pϭ0.86). SkM1 expression in injected epicardium was confirmed immunohistochemically. Conclusions-SkM1 increases V max of depolarized myocardium and reduces the incidence of inducible sustained ventricular tachyarrhythmia/fibrillation in canine infarcts. Gene therapy to normalize activation by increasing V max at depolarized potentials may be a promising antiarrhythmic strategy. Key Words: arrhythmia Ⅲ gene therapy Ⅲ ion channels Ⅲ myocardial infarction Ⅲ tachyarrhythmias R eentry accounts for Ϸ85% of serious arrhythmias complicating ischemic heart disease. 1 Prevention and treatment are rooted in early 20th century research on reentry. [2][3][4] The goals are to create bidirectional conduction block (with drugs that block Na ϩ channels, surgery, or ablation), to prolong refractoriness so that reentry fails (with drugs that usually prolong repolarization), or both in combination. 5 These therapies have drawbacks ranging from incomplete success to toxicity, including proarrhythmia. Editorial p 6 Clinical Perspective p 27Less attention has been paid to another therapeutic approach suggested many years ago 2-5 : reentry should terminate if an activating waveform persists in conducting at normal velocity, even through depolarized tissues. Therefore, we hypothesized that "improving" the efficiency of propagation through depolarized regions by increasing the maximum Received July 22, 2008; accep...

Biologic Pacemaker - Role of Gene and Cell Therapy in Cardiac Arrhythmias

“…The effectiveness of this approach has been shown in a canine model in which the incidence of inducible polymorphic VT was 75% of controls and 17% of SkM1-administered dogs 5 days postinfarction. Moreover, SkM1 administration reduced electrogram fragmentation and increased Vmax of phase 0 (consistent with more rapid conduction), as had been predicted for SkM1 (Lau et al 2009).…”

“…Using mapping to identify sites for local radiofrequency ablation reduced the need for defibrillation in patients who had devices implanted for secondary prevention. Using mapping to identify the border zone of an infarct in a canine model ablation were replaced with intramyocardially-administered gene therapy in preliminary studies and without destroying tissue -achieved a reduction in VT/VF incidence (Reddy et al 2007, Lau et al 2009 14. Specific gene therapies for ischemic arrhythmias 14.1 Speeding conduction via connexins or Na channels The importance of connexins and hence gap junctions in arrhythmias has been shown in many studies.…”

“…At least 10 different Na channel genes encode alpha subunits in the mammalian genome; these have been cloned from brain, spinal cord, skeletal and cardiac muscle, uterus, and glia (Allessie et al 1977). Since slow conduction is an essential feature of reentrant cardiac arrhythmias, other mammalian Na channels that might have more favorable properties than the cardiac Na channel in circumstances that favor slow conduction were looked for (Lau et al 2009). One such circumstance is membrane depolarization, as in myocardial infarction in such circumstances the voltage dependence of steady state Na channel inactivation is of interest.…”

Cardiac gene therapy in large animals: bridge from bench to bedside

“…A ventricular tachycardia model was produced by applying programmed stimulation to the post myocardial infarction animals. 28,29 Ventricular tachycardia was reproducibly induced in the animals with remodeled hearts. Sick sinus syndrome and complete atrio-ventricular block was created by ablating either the sinus node 30 or the atrio-ventricular node.…”

“…In a post-myocardial infarction ventricular tachycardia pig model, gene delivery of KCNH2(HERG)-G628S, a dominant negative mutation of the I(Kr) potassium channel a-subunit, to the infarct border zone eliminated inducible ventricular tachycardia. 28 On the other hand, Lau et al 29 tried to modulate arrhythmogenic substrate by targeting the sodium channel. The skeletal muscle sodium channel gene was delivered to the infarct border zones.…”