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Abstract

Cardiac action potential (AP) shape and propagation are regulated by several key dynamic factors such as ion channel
recovery and intracellular Ca2+ cycling. Experimental methods for manipulating AP electrical dynamics commonly use ion
channel inhibitors that lack spatial and temporal specificity. In this work, we propose an approach based on optogenetics to
manipulate cardiac electrical activity employing a light-modulated depolarizing current with intensities that are too low to
elicit APs (sub-threshold illumination), but are sufficient to fine-tune AP electrical dynamics. We investigated the effects of
sub-threshold illumination in isolated cardiomyocytes and whole hearts by using transgenic mice constitutively expressing
a light-gated ion channel (channelrhodopsin-2, ChR2). We find that ChR2-mediated depolarizing current prolongs APs and
reduces conduction velocity (CV) in a space-selective and reversible manner. Sub-threshold manipulation also affects the
dynamics of cardiac electrical activity, increasing the magnitude of cardiac alternans. We used an optical system that uses
real-time feedback control to generate re-entrant circuits with user-defined cycle lengths to explore the role of cardiac alternans in spontaneous termination of ventricular tachycardias (VTs). We demonstrate that VT stability significantly decreases during sub-threshold illumination primarily due to an increase in the amplitude of electrical oscillations, which implies that
cardiac alternans may be beneficial in the context of self-termination of VT.