Cardiac Remodeling Of Conduction, Repolarization and Excitation-Contraction Coupling: From Animal Model to Failing Human Heart
Date of Award
Doctor of Philosophy (PhD)
Chair and Committee
Heart failure is one of the leading causes of death worldwide, with rising impact with the increasing ageing population. This is in sharp contrast with the limited and non-ideal therapies available. Approximately 50% of deaths from heart failure are sudden and unexpected, and presumably the consequence of lethal ventricular arrhythmias. Despite significant reduction of mortality from sudden cardiac death achieved by ICDs and drugs such as beta-blockers, there remains a large room for improving the survivability of heart failure patients by advancing our understanding of arrhythmogenesis from molecular level to multi-cellular tissue level. Another important aspect of heart failure is abnormal excitation-contraction: EC) coupling and calcium handling, functional changes of which exert great impact on both arrhythmia vulnerability and pump failure. Advancing the understanding the remodeling of EC coupling and calcium handling might provide potential molecular and anatomical targets for clinical intervention. In this dissertation, I first developed two optical imaging systems: both hardware and software) for quantifying the conduction, repolarization and excitation-contraction coupling. The first one is the panoramic imaging system for mapping the entire ventricular epicardium of a rabbit heart. The second one is the dual imaging system for simultaneous measurement of action potential and calcium transient. Using the systems I developed, I conducted two rabbit studies to investigate the role electrical instability and structural heterogeneity in the induction and maintenance of arrhythmias. We first identified the importance of both dynamic instability and effective tissue size in the spontaneous termination of arrhythmia in the normal rabbit heart. We then identified novel mechanism of how healed myocardial infarction promotes the induction of ventricular arrhythmia. Finally, guided by the knowledge from the animal studies, I studied the failing human heart with the aim to advance our understanding of cardiac electrophysiology in human heart failure. We first demonstrated the transmural heterogeneity of EC coupling in nonfailing heart and identified potential mechanisms of electrical and mechanical dysfunction by quantifying the remodeling of EC coupling. We then studied the remodeling of conduction and repolarization with the aim to determine of the role of dispersion of repolarization and electrical instability in the induction of arrhythmia in human heart failure.
Lou, Qing, "Cardiac Remodeling Of Conduction, Repolarization and Excitation-Contraction Coupling: From Animal Model to Failing Human Heart" (2011). All Theses and Dissertations (ETDs). 610.
Permanent URL: http://dx.doi.org/10.7936/K71R6NH0