Molecular ablation of ventricular tachycardia after myocardial infarction

Abstract

Ventricular tachycardia is a common and lethal complication after myocardial infarction. Here we show that focal transfer of a gene encoding a dominant-negative version of the KCNH2 potassium channel (KCNH2-G628S) to the infarct scar border eliminated all ventricular arrhythmias in a porcine model. No proarrhythmia or other negative effects were discernable. Our results demonstrate the potential viability of gene therapy for ablation of ventricular arrhythmias.

Figure 1

Ventricular tachycardia after myocardial infarction in a porcine 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. (d) X-gal staining to identify lacZ gene transfer. (left) Gross tissue shows intense blue staining indicative of lacZ expression in the target area at the anterior septal border zone. (right) Microscopic sections taken from the target region exhibit blue, lacZ positive myocytes.

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 the KCNH2-G628S infected animals. All control animals remained inducible. (b) RT-PCR results show increased ERG mRNA in mid and distal septum of G628S animals. Data is normalized to MCL-2v expression (copies of ERG per copy of MLC2v). Non—non-infarcted basal lateral wall. MS—mid-anterior septal infarct border. DS—distal anterior septal infarct border. Lat—anterior lateral infarct border. (c) Measurement of action potential duration to 90% repolarization (APD90) and effective refractory period (ERP) from the indicated regions. Prolongation of APD90 and ERP is isolated to the septal border of the infarct. (d) Patch clamp data of action potentials from uninfarcted anterior septal cells (Normal) compared to infarct-no virus (I-NV) or infarct-KCNH2-G628S (I-G628S) infected cells from the anterior septal infarct border zone. The left panel shows summary data from the indicated groups. The right panel shows representative tracings. * p < 0.05.