Stabilizer Cells: A Less-Is-More Gene Therapy Strategy To Prevent Cardiac Arrhythmias

Recent gene therapy experiments in mouse models of polymorphic catecholaminergic ventricular tachycardia (CPVT) demonstrated that arrhythmias could be prevented by transducing less than 50% of myocytes in mouse ventricles. The reasons why only a minority of transduced cells was needed for successful arrhythmia suppression are still incompletely understood. Because the heart is an electrical syncytium, a gene therapy strategy to prevent cardiac arrhythmias only requires transducing a minority of cardiac cells to stabilize them against arrhythmogenic triggers. This principle of “stabilizer” cells can be extended not only for delayed afterdepolarization (DAD)-mediated arrhythmias such as in CPVT, but also to early-afterdepolarization (EAD)-mediated arrhythmias. Systematic computational simulations of 1D, 2D and 3D tissue were performed with stabilizer cells engineered to be non-arrhythmogenic by virtually transducing either wild-type calmodulin for CPVT or Kir2.1 in general. We show that due to the source-sink relationships in cardiac tissue, only a minority (10-50% depending on the specific conditions) of randomly distributed stabilizer cells can suppress the ability of the tissue as a whole to generate triggered activity due to DADs or EADs. Tissue dimension, gap junction conductance, fibrosis, and spatial heterogeneity of the stabilizer cell distribution had relatively mild effects. Critically, the introduction of engineered stabilizer cells did not substantially increase the APD heterogeneity related to arrhythmia substrate. Our findings offer a mechanism explaining the successful experimental gene therapy results achieved in recent mouse models of CPVT, namely that transduction rates near 100% are not necessary, and suggest that transduction rates even as low as 10-50% may be effective for suppressing both DAD and EAD-mediated arrhythmias. Stabilizer cell gene therapy shows potential as an antiarrhythmic strategy without requiring gene expression in a majority of cardiac myocytes.