Novel ion channel approaches to reentrant arrythymias

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DESCRIPTION (provided by applicant): The overall objective of our proposed research is to use our knowledge of the pathophysiology of reentry and of myocardial infarct-associated ventricular tachycardia to hypothesize innovative, mechanism-based approaches to therapy Our general hypothesis is that gene therapy using adult human mesenchymal stem cells (hMSCs) as platforms and/or using viral vectors can deliver overexpressed ion channel gene constructs to prevent/suppress this arrhythmia. Our proposed 5-year plan incorporates: (1) identification and testing the effect of overexpression of specific gene constructs in viral vectors and in hMSC platforms to modify specific ion channel expression in cell lines; (2) using mathematical modeling, cell systems, and animal models that previously have been validated by us and others to test the mechanism of action, efficacy and proarrhythmic potential of each gene and cell therapy approach we design. We specifically hypothesize that gene and cell therapies can be antiarrhythmic by speeding conduction and/or prolonging refractoriness (but not repolarization) and study these possibilities in the canine heart in situ. Our first two Aims (stated as hypotheses) employ novel approaches to speed conduction. 1: A non-cardiac Na channel that shifts inactivation to more depolarized potentials will enhance Na current density in normal myocytes firing at high rates and preserve Na current density in depolarized myocytes. This should increase action potential (AP) upstroke velocity and conduction velocity, such that antegrade activation is normalized to prevent reentrant arrhythmias and/or the "head" of the activating wave catches the "tail" to terminate reentrant arrhythmias. 2: Increasing diastolic K conductance should restore depolarized membrane potentials towards normal and enhance excitability for normal myocytes at high stimulation frequencies. The third strategy is to prolong the effective refractory period (ERP) with regard to AP duration (APD). 3: Here, we hypothesize that overexpression of a mutant hERG with slowed deactivation kinetics should improve rate responsiveness and prolong ERP compared to APD. This should speed conduction at high heart rates while blocking propagation of premature depolarizations, reducing the likelihood of reentry. The significance of our proposed research is seen in the identification of novel ion channel constructs, testing them via in silico modeling and then in cell experiments to understand and fine-tune mechanism of action; using innovative means to administer them in cell systems and finally in intact animals to treat a reentrant rhythm - ventricular tachycardia - that is a major cause of morbidity and mortality in the US today. The selectivity and specificity of these approaches far exceed those of drugs and of ablation and open promising new vistas for arrhythmia treatment and prevention. PUBLIC HEALTH RELEVANCE: Cardiac arrhythmias remain a major disabler and killer of US citizens and current drug and device therapies are inconsistently effective and often create further problems. We propose to use the techniques of gene and cell therapy to deliver novel genes to the heart that will target sites of arrhythmia generation with high selectivity and efficacy and offer a safer modality of treatment