Gene therapy approaches to ventricular tachyarrhythmias

Abstract

Ventricular tachycardia arising from a healed myocardial infarction scar continues to be a significant cause of morbidity and mortality. Drug therapy has been inadequate to meet this challenge, and implantable devices are limited by expense and technical problems. We have proposed the use of gene therapy for cardiac arrhythmias. In this review, we present a model of postinfarct ventricular tachycardia, a method for gene delivery to this area, and results of KCNH2-G628S gene transfer to manipulate cellular refractory properties in the arrhythmia model.

Figure 1

Ventricular tachycardia in the porcine myocardial infarction model. A. ECG example showing identical VT morphology and cycle length from one week to the next in a representative animal. B. Intracardiac electrograms during sinus rhythm (SR) show low amplitude, fractionated signals in the anterior septal region (splines D and E). The ventricular tachycardia recording demonstrates slow, progressive activation of this region through diastole. C. Hematoxylin-Eosin stained microsection of the infarct border zone reveals surviving strands of myocardium surrounded by fibrotic scar in the anterior septum. (with permission from Sasano et al. Nat Med)

Figure 2

KCNH2-G628S gene transfer in the MI-VT model. A. Prior to gene transfer, VT was repeatedly inducible in all animals. After gene transfer, no arrhythmias could be induced in any KCNH2-G628S infected animal, but all control animals remained inducible. B. Example of triple extra stimuli in a representative G628S animal. The top tracing shows VT induced with triple extra stimuli immediately before gene transfer. The bottom two panels show triple extra stimuli one week after gene transfer. The middle panel shows the tightest possible coupling of S2-4 where all 3 extra stimuli capture the ventricles (which is tighter than the intervals that consistently produced VT before gene transfer). The bottom panel shows refractory stimulation. After progressive tightening of S2-4 coupling intervals, extra stimuli are now so tightly coupled that the ventricles are refractory to stimulation. (with permission from Sasano et al. Nat Med)