Action potential prolongation in heart failure may contribute to the generation of arrhythmia in heart failure. The action potential could be prolonged either by decreasing outward currents or by increasing inward currents during the plateau phase. Nearly all studies of electrical remodeling underlying this prolongation have emphasized decreased outward current by down-regulation of potassium channels. Recent studies, including our own preliminary results, show an increase in late inward sodium current in animals models of heart failure, and we show in this application for the first time that it is also significantly increased in human heart failure. We propose to study this sodium current in ventricular cells from normal and failing hearts from a canine tachycardia pacing model of heart failure, and for normal and failing human hearts. Using whole cell and single channel voltage clamp techniques we will determine the amplitude and kinetics of this current under conditions important for physiological and pathophysiological interpretation including Ca and Na dependence, temperature dependence, regional and transmural distribution and heterogeneity, and antiarrhythmic drug block. We will also study the effect of sodium channel block on action potential duration for cells from epi, endo, and mid-myocardium. The potential mechanisms for the increase in late current in heart failure will be studied. These include alpha subunit isoform switching or beta subunit down-regulation, altered regulation by cell signaling pathways (alpha and beta adrenergic, endothelin and angiotensin), and other mechanisms such as altered free fatty acids, cytoskeleton, and nitric oxide regulation. These studies will produce the first detailed data on late sodium currents in humans and its regulation, and at the same time investigate the mechanism and the significance for this current in the electrical remodeling underlying arrhythmogenesis in heart failure.
