Ventricular tachycardia from the healed myocardial infarction scar: validation of an animal model and utility of gene therapy

Abstract

Life-threatening ventricular arrhythmias generally occur in the setting of structural heart disease. Current clinical options for patients at risk for these rhythm disturbances are limited. We developed a porcine model of inducible ventricular tachycardia originating in the border region of a healed myocardial infarction scar. After validating the model, we assessed gene transfer techniques, focusing on local modification of border zone tissues. We found that gene transfer of the dominant negative KCNH2-G628S mutation to the anteroseptal infarct border caused localized prolongation of effective refractory period in the target region and eliminated all ventricular arrhythmia inducibility. In this work, we characterize the animal model and review the gene transfer results.

Figure 1. Ventricular tachycardia after myocardial infarction in the porcine model

A. Gross (left) and microscopic (right) pathology of the model. The picture on the left shows a slice through the middle of the left ventricle from a representative animal. Tissue was harvested 5 weeks after infarction and stained with 2,3,5-Triphenyl-2H-tetrazolium chloride (TTC) to contrast the white infarcted area from the red surviving tissue. The Hematoxylin- and eosin-stained microsection was taken from the septal border of a representative animal 5 weeks after MI. This section reveals surviving strands of myocardium surrounded by fibrotic scar in the anterior septum. B. ECG examples showing identical VT morphology and cycle length from one week to the next in a representative animal. C. Photograph of intracardiac 64-electrode basket placement (left) and basket electrograms (right). The photograph shows the basket with spline D in a mid-septal position, E in an anterior septal position, and F in a straight anterior position. The electrogram taken during VT shows progressive diastolic activation through the anterior septum suggesting that the VT originates in this region. D. Representative VT activation map. The view is anteroseptal. The area to the right of the solid line had bipolar voltage less than 1.5 mV on separate voltage mapping, and the area to the right of the dotted line had bipolar voltage less than 0.2 mV. Earliest activation is orange-red, and late activation is pink. The dashed line represents the likely VT circuit based on the activation data. The area marked with “*” had concealed entrainment with post-pacing interval of 0 ms when pacing into VT. (with permission from Sasano et al.14).

Figure 2. KCNH2-G628S gene transfer in the MI-VT model

A. X-gal staining to identify lacZ gene transfer. (left) Gross tissue shows intense blue staining indicative successful gene transfer and lacZ expression in the anterior septal target area. (right) Microscopic sections taken from the target region exhibit blue, lacZ positive myocytes. B. Graph showing VT inducibility before and 7 days after gene transfer with either KCNH2-G628S or controls lac Z or no virus. 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. The ECG tracing at the right shows a representative KCNH2-G628S animal with easily inducible VT before gene transfer and no arrhythmias when pacing down to refractoriness after gene transfer. C. Measurement of effective refractory period (ERP) from the indicated regions. Prolongation of APD90 and ERP is isolated to the septal border of the infarct scar. Non—non-infarcted basal lateral wall. MS—mid-anterior septal infarct border. DS—distal anterior septal infarct border. Lat—anterior lateral infarct border. * p < 0.05. (with permission from Sasano et al.14).