Heart failure is a multifactorial disease, having both electrical and contractile components. Downregulation of key potassium channels and concomitant prolongation and instability of repolarization, predispose the heart to arrhythmias. Meanwhile, downregulation of the sarcoplasmic reticulurn Ca2+ ATPase and concomitant calcium handling abnormalities contribute to depressed myocardial contractility. The electrical abnormalities and the contractile abnormalities are not mutually exclusive. Alterations in the control of membrane voltage will modulate the triggered release of Ca2+ from the sarcoplasmic reticulurn and, conversely, alterations in the intracellular calcium transient will influence membrane potential. It is the interplay between the electrical and contractile abnormalities of heart failure which compounds the complexity of abnormalities and confounds the design of successful treatments. Novel antiarrhythmic gene therapy based upon manipulation of a select K channel gene alone to decrease susceptibility to arrhythmias may lead to depressed contractility, which is already depressed in heart failure. Conversely, genetic manipulation of a SR Ca2+ ATPase protein alone, to amplify contractility, may create a proarrhythmic substrate in a failing heart which is already predisposed to fatal arrhythmic events. Thus, monogenic strategies, based upon selective overexpression of a single gene, may not suffice to correct heart failure abnormalities because of the interplay between excitation and contraction in cardiac muscle. This proposal seeks to offset abnormalities of tachycardia, pacing- induced heart failure in rabbits using combination gene therapy: overexpression of a select K channel gene and a SR Ca2+ ATPase gene in tandem. As a prelude we will test the hypotheses that gene therapy targeted to correct the electrical abnormalities alone or the calcium handling abnormalities alone will result in adverse conditions. The proposal focuses on potassium channels and SR Ca2+ ATPase's that are highly relevant to repolarization and contractility in the human heart failure. In vivo adenoviral mediated gene transfer, cellular and cardiac electrophysiology, and quantitative modeling will be used to investigate repolarization and calcium handling with the goal of correcting the electrical and contractile abnormalities in heart failure.
