SCOR IN SUDDEN CARDIAC DEATH

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Ventricular tachycardia (VT) and fibrillation (VF), the most common causes of sudden death, remain an intractable health problem. The proposed SCOR represents a multidisciplinary effort to integrate clinical, whole organ, cellular and computer modelling studies to better understand the mechanisms promoting VF and other ventricular arrhythmias, the role of chaos in these arrhythmias, and the feasibility of applying pacing strategies based on chaos control theory to cardiac arrhythmias. The SCOR will be composed of 5 individual projects and 3 core units. Project 1 "Sympathetic responses in human ventricular tachycardia" is the major clinical component, and will assess the role of baroreceptor- mediated modulation of sympathetic nerve activity, measured by peroneal microneurography, as a determinant of hemodynamic stability during VT and a predisposing factor for degeneration of VT to VF. Chaos theory will be applied to study potentially destabilizing effects of sympathetic nerve activity on cardiac function. Project 2 "Reentrant wavefronts in ventricular fibrillation' will use high resolution activation mapping in the in vivo human and canine heart, and an in vitro canine ventricular epicardial slice preparation to delineate the electrophysiologic mechanisms by which VF is initiated and maintained, particularly with respect to the electrophysiological parameters which promote formation of multiple nonstationary circulating wavefronts. Project 3 'Chaos and cardiac arrhythmias' will correlate the experimental data from Project 2 with computer models of cardiac propagation in two dimensions, simulating the in vitro canine preparation, to determine whether spatio- temporal chaos plays a role in fibrillation and other ventricular arrhythmias, and, if so, whether chaos control strategies can be applied therapeutically. Project 4 'Mechanisms and consequences of intracellular Ca overload in heart' will probe the mechanisms underlying abnormalities in intracellular Ca regulation during impaired cardiac metabolism using patch clamp and fluorescent Ca indicator techniques is isolated ventricular myocytes, and will explore conditions under which Cai- overload in isolated myocytes may lead to chaotic arrhythmias mediated by afterdepolarizations. Project 5 'Metabolic regulation of cellular K balance' will focus on mechanisms of cellular K loss during early ischemia and hypoxia, a major arrhythmogenic factor contributing to ischemic VF, and will characterize properties of ATP-sensitive K channels and transmembrane lactate movement (and its relationship to K loss) in isolated myocytes. Computer Core A will facilitate implementation of computer simulations used in all of the projects, and Biomedical Instrumentation Core B will provide support for instrumentation development and maintenance. Administrative Core C will provide administrative support. The common goal of the projects and cores is to improve our understanding of the pathophysiology of VF, and provide the groundwork for new approaches to its prevention and treatment.