This proposal describes multidisciplinary research aimed at the understanding of normal and abnormal electrical wave propagation in cardiac muscle. Our efforts are directed toward elucidating the underlying dynamics of wave propagation in the heart and the mechanisms of reentrant ventricular tachyarrhythmias, as well as the structure-function relations that determine acidification-induced gating of membrane channels formed by the major cardiac gap junction (Cx43) protein, and of a delayed rectifier potassium channel (IsK) that is associated with the human mink protein. The Program consists of five projects. Project 1 addresses the mechanisms of ventricular tachycardia (VT) and ventricular fibrillation (VF) in the non-ischemic isolated perfused heart. The hypothesis is that such arrhythmias are the result of 3-dimensional (3-D) electrical scroll waves activating the heart muscle at very high frequencies. Optical mapping, vectorcardiography, signal processing techniques and computer modeling will be used to test such a hypothesis and to determine whether sustained monomorphic VT is the result of a stationary scroll wave; whether polymorphic VT is the result of a nonstationary scroll wave; and whether VF is the result of a small number of nonstationary scroll waves. Project 2 focuses on the study of the 3-D organization of scroll wave s initiated in the opened coronary perfused ventricular wall. To reconstruct the 3-D structure of scroll waves spanning the myocardial wall we will use two video cameras to record electrical wave propagation simultaneously from the endocardial and epicardial surfaces of the ventricle. We will also take advantage of the translucent properties of the heart and use transillumination to record a 2-D project from the underlying 3-D activity. In Project 23 we will study 2-dimensional propagation in isolated sheets of cardiac muscle, and in computer simulations based on a new ionic model of the cardiac cell. We will study the roles played by global parameters such as wavefront curvature, and action potential duration in propagation in two-dimensional cardiac muscle. In Project 4 we will investigate molecular mechanism(s) that underlie the pH-dependent gating of the IsK. A combination of electrophysiological, optical and molecular biology techniques will be used to characterize the pH sensitivity of the exogenously expressed IsK; the role of the intracellular compartment in the pH sensitivity of the channel; and the functional expression and pH sensitivity of K channels associated with mutant forms of mink. In Project 5 we aim at characterizing in detail the regions of the Cx43 protein that are involved in acidification-induce closure of gap junctional channels. In this project, we will make use of a combination of electrophysiological, optical and molecular biology techniques to determine whether pH gating of Cx43 channels occurs through a process akin to the """"""""ball-and-chain"""""""" mechanism proposed for inactivation of Na channels. Thus, each particular project provides an equally important source of information related to intercellular coupling and/or excitation and propagation, and the proposed combination of molecular, biophysical, electrophysiological and numerical technologies is an ideal approach to this problem that involves many complex factors and interactions.
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