Effective contraction of the heart depends on ordered action potential (AP) propagation throughout the myocardium. Disturbances in AP propagation can produce cardiac arrhythmias, which under certain conditions can lead to cardiac arrest, and sudden cardiac death. Determination of the fundamental cellular and molecular mechanisms that contribute to disturbances in AP propagation is critical to developing a full understanding of the pathophysiology of sudden cardiac death, and rational development of novel therapeutic strategies.
Most structural heart diseases are associated with increased risk of developing lethal cardiac arrhythmias. Frequently reported in cardiac disease is remodeling of cardiomyocyte gap junctions (GJs), both in number and localization. GJs are responsible for the passage of electrical current between cardiomyocytes, and are a critical parameter in determining the speed of AP propagation throughout the myocardium, also known as conduction velocity (CV). Heterogeneous changes in CV can enhance the risk of reentrant arrhythmias, a common form of arrhythmia associated with disease. Characterizing the cellular and molecular bases for GJ remodeling in structural heart disease is likely to reveal novel insights into the mechanisms of reentrant arrhythmia formation.
This dissertation deals with mechanisms of GJ traffic, specifically as it may relate to the remodeling of connexin43 (Cx43)-based GJs associated with heart failure (HF). The first chapter introduces GJ structure and function, and outlines our current mechanistic understanding of GJ trafficking. The second chapter specifically deals with ultrastructural, cellular and biochemical aspects of GJ remodeling in a canine model of rapid pacing induced non-ischemic cardiomyopathy. In the third chapter, in vivo phosphorylation sites are identified within Cx43 in both normal and failing hearts. One novel phosphorylation site, Thr326, is further characterized and shown to regulate the turnover of GJs. The fourth chapter examines the functional significance of another phosphorylation site, Ser373, which is shown to regulate the targeting of Cx43 to GJs.
Overall, this dissertation identifies and functionally characterizes fundamental aspects of GJ function in normal and diseased hearts. From these studies will stem further work aimed at determining the contribution of these described phenomena in arrhythmogenesis associated with cardiac disease.
|Advisor:||Eyk, Jennifer Van|
|School:||The Johns Hopkins University|
|School Location:||United States -- Maryland|
|Source:||DAI-B 70/04, Dissertation Abstracts International|
|Keywords:||Action potential, Cardiac disease, Conduction velocity, Gap junction traffic|
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