REVERSAL OF POTASSIUM CHANNEL DEFICIENCY IN CELLS FROM FAILING HEARTSBY ADENOVIRAL GENE-TRANSFER - A PROTOTYPE FOR GENE-THERAPY FOR DISORDERS OF CARDIAC EXCITABILITY AND CONTRACTILITY

Heart failure is a common, often lethal disorder in which conventional pharmacologic strategies have achieved limited success. Failing heart s exhibit a delay of electrical repolarization which predisposes to fa tal arrhythmias. To explore the feasibility of gene therapy for this c ondition, we isolated myocytes from normal and failing dog hearts and quantified electrophysiologic and contractile parameters in primary cu lture. Action potentials were prolonged in failing cells as a result o f diminished potassium currents. Exposure to AdShK, an adenovirus that overexpresses potassium channels, reversed the action potential prolo ngation of failing cells. The precise phenotype varied as a function o f the density of expressed channels; modest increases in potassium cur rent sufficed to mimic the nondiseased state most faithfully, while mo re robust expression of the transgene excessively abbreviated excitati on and contraction. Our results demonstrate that viral gene transfer c an modify the electrical properties of adult mammalian heart cells in a manner appropriate to reverse a fundamental disorder of excitability . Realistic application of this form of therapy will need to include a sensitive mechanism for control of the level and distribution of tran sgene expression.