Simulation and experimental evidence support the hypothesis that restitution of the cardiac action potential duration (APD) and conduction velocity (CV) are key dynamical factors determining whether spiral wave reentry remains stable as ventricular tachycardia (VT) or breaks up into multiple reentrant wavefronts as ventricular fibrillation (VF). A major objective of the SCOR renewal is to test the concept of targeting cardiac restitution as a primary antifibrillatory strategy, i.e. the Restitution Hypothesis. To assess its validity, it is essential to have a clear mechanistic understanding of cardiac restitution and how it is affected by antiarrhythmic drugs and other factors such as acute ischemia, specifically at rapid heart rates relevant to VT. In Project 3, cardiac restitution and its response to antiarrhythmic drugs and various ischemic components will be analyzed experimentally in isolated rabbit, porcine and canine ventricular myocytes (using patch clamp and fluorescent dye techniques), cultured monolayers of ventricular myocytes (using a newly-developed fast CCD camera-based optical mapping system), intact porcine and canine ventricular muscle and in situ hearts (using intracellular microelectrode recordings and optical mapping techniques), in situ human hearts (using monophasic action potential recordings during programmed ventricular stimulation). These experimental studies will be complemented by 2-D and 3-D computer simulations of cardiac tissue. The broad objective is to provide detailed mechanistic insights into the factors governing cardiac restitution. Specific objectives are: 1). To define a pacing protocol for measuring restitution properties which optimizes predictive value for VT stability/instability; 2). To characterize the role of the major ionic currents on APD and CV restitution (using dV/dtmax as a surrogate) in isolated myocytes at cycle lengths relevant to VT and VF; 3). To evaluate the effects of diffusive currents and wavefront curvature on cardiac restitution; 4). To characterize the influence of intracellular Ca dynamics on cardiac restitution properties and VT stability; 5). To evaluate the effects of various ischemic components on cardiac restitution properties in isolated ventricular myocytes and isolated intact tissue; 6). To characterize the effects of antiarrhythmic drugs on cardiac restitution properties at short cycle lengths relevant to VT/VF; 7). To characterize the effects of various antiarrhythmic drugs on restitution properties in humans at short cycle lengths relevant to VT/VF.
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