Structural and Functional Determinants of Cardiac Impulse Propagation and Arrhythmias.

Abstract

Each year, sudden cardiac death (SCD) attributed to ventricular fibrillation (VF) kills approximately 200,000 people in the United States. However, the mechanisms responsible for VF, and therefore VF-related SCD, are incompletely understood. My PhD studies focused on two major topics directly related to the mechanisms of reentry in VF. My general approach was based on the use of neonatal cardiac cell monolayers, gene transfer, immunolocalization, patch clamping and optical mapping techniques. First, I examined how a delayed rectifier potassium channel gene (hERG) involved in cardiac repolarization affects reentry frequency in a ventricular myocyte monolayer model of reentry. The results provided strong evidence for a role of hERG in controlling the frequency and stability of reentry. The mechanisms underlying the acceleration in reentry frequency were shown to be action potential duration (APD) shortening and a transient hyperpolarization after each action potential. APD shortening reduced reentry wavelength which prevented wave front-wave tail interactions and increased reentry stability. The transient hyperpolarization enhanced sodium channel availability and excitability of tissue ahead of the propagating electrical wave front. Together they set the stage for fast and stable reentry that maintains VF. Second, I examined the principle of whether rescuing normal electrical impulse propagation in damaged or fibrotic myocardium using cell therapy would be an effective approach to alter reentry behavior. Electrically excitable cardiac fibroblasts were generated using viral constructs encoding Kir2.1, NaV1.5 and Cx43 proteins. Excitable fibroblasts were able to form monolayers and conduct electrical waves at high velocity. When used to replace normal fibroblasts in heterocellular monolayers, they significantly increased conduction velocity to values similar to those of pure myocytes monolayers. Moreover, during reentry, propagation was faster and more organized, with a significantly lower number of wavebreaks. Altogether, the work accomplished in my dissertation should lead to a better understanding of VF and to the development of novel therapeutic approaches for the prevention of SCD.