The overall objective of this Program Project is to achieve a better understanding of the mechanisms of arrhythmias causing sudden cardiac death. Project 2 tackles the ionic and cellular mechanisms of early (EADs) and delayed (DADs) afterdepolarizations. EADs are classically attributed to reactivation of the L-type Ca current or to spontaneous SR Ca release (i.e. SR Ca release not directly gated by the L-type Ca current) in the setting of reduced repolarization reserve. DADs are attributed to spontaneous SR Ca release in the form of Ca waves stimulating Ca-sensitive inward currents such as Na-Ca exchange. Recently, we have presented evidence for a mechanism (chaos synchronization) by which EADs simultaneously create triggers and enhance tissue substrate vulnerability to promote lethal arrhythmias. A comparable theory does not yet exist for DADs. The goals of this project are: i) to explore the cellular basis of EADs that set the process of chaos synchronization in motion;ii) to test whether theoretically-predicted rotors mediated by the L-type Ca current (related to the biexcitability of cardiac tissue) can be detected experimentally in cardiac tissue as a mechanism of Torsades de pointes;iii) to explore the cellular basis of DADs, specifically how the microscopic behavior of Ca release units in the subcellular Ca cycling network integrates to generate Ca alternans, Ca waves and DADs at the whole cell level;iii) to explore the interactions between EADs and DADs that together generate triggers and modify tissue substrate by increasing tissue electrical dispersion predisposing to VF. To accomplish these goals, we will combine patch clamp (including a new dynamic clamp technique) and fluorescent dye studies at the cellular level with optical mapping studies at the tissue level. These studies will be performed in close collaboration with the mathematical modeling studies in Project 1, the tissue level studies in Project 3, and the therapeutic development in Project 4, and will utlize both Core A and B for support.
The proposed research will study the mechanisms of sudden cardiac death due to ventricular arrhythmias, which takes the lives of more than 300,000 U.S. citizens each year. The goal is to use this information to develop novel therapies to prevent this deadly manifestation of heart disease.
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