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L-type Ca2+ channels as therapeutic targets for Early afterdepolarization-related arrhythmias

Abstract

Early afterdepolarizations (EADs) are highly arrhythmogenic transient depolarizations occurring during phase 2 or 3 of the cardiac action potential (AP). Using the dynamic clamp technique, I combined mathematical modeling and electrophysiology in real-time to introduce a virtual L-type Ca2+ current (ICa,L) in dissociated rabbit ventricular myocytes. I sought to i) understand the etiology of EAD development and their dependence on ICa,L and ii) identify therapeutic strategies to suppress EADs by shaping a new L-type Ca2+ current. To investigate the therapeutic potential of ICa,L modifications in suppressing EADs, I first induced a robust EAD regime by exposing cardiomyocytes either to hypokalemia or oxidative stress. EADs were completely abolished by blocking the endogenous ICa,L with nifedipine, a specific Ca2+ channel blocker, but promptly restored under dynamic clamp by a virtual Ca2+ current modeled as modified by H2O2. Using this experimental paradigm, my results in Chapter 2 demonstrate that EADs are highly sensitive to minimal changes (1-5 mV) in the half activation/inactivation potentials (V1/2) of ICa,L, such that V1/2 modifications which reduce the window current voltage range were highly effective at suppressing EADs. In Chapter 3, I expand upon these findings and systematically explore the relevance of other biophysical parameters of ICa,L. The results highlight the importance of a third biophysical parameter, the non-inactivating component of ICa,L, in EAD suppression. As such, dynamic clamp experiments identified three steady-state biophysical properties of ICa,L as ideal therapeutic targets to suppress EADs and resulting cardiac arrhythmias while maintaining contractility. Chapter 4 builds upon these results by employing a biological approach to achieve the modifications to ICa,L biophysical properties by altering the subunit composition of L-type Ca2+ channels (LTCCs) in cardiac myocytes. The striking results demonstrate that the larger ICa,L window current produced by overexpressing the β2a subunit contributes to increased EAD susceptibility while the over expressing β3 subunit may have a protective effect regardless of the increase in overall current density. Based on these findings, I propose that knock-down of the pro-arrhythmic β2a subunit may represent a more appealing strategy to control the occurrence of EADs in cardiac myocytes. These results support the hypothesis that EAD occurrence can be controlled by fine-tuning the biophysical properties of the L-type Ca2+ current. Therefore, with the innovative combination of electrophysiology and mathematical modeling, this project brings forward a biological solution to suppress EAD under otherwise arrhythmogenic conditions and is of great cardiovascular relevance, as it is centered on finding a solution to a lethal cardiac arrhythmias by characterizing and manipulating the operation of cardiac ion channels.

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