Optogenetic manipulation of cardiac electrical dynamics using sub-threshold illumination: dissecting the role of cardiac alternans in terminating rapid rhythms


Cardiac action potential (AP) shape and propagation are regulated by several key dynamic factors such as ion channeltextlessbrtextgreaterrecovery and intracellular Ca2+ cycling. Experimental methods for manipulating AP electrical dynamics commonly use iontextlessbrtextgreaterchannel inhibitors that lack spatial and temporal specificity. In this work, we propose an approach based on optogenetics totextlessbrtextgreatermanipulate cardiac electrical activity employing a light-modulated depolarizing current with intensities that are too low totextlessbrtextgreaterelicit APs (sub-threshold illumination), but are sufficient to fine-tune AP electrical dynamics. We investigated the effects oftextlessbrtextgreatersub-threshold illumination in isolated cardiomyocytes and whole hearts by using transgenic mice constitutively expressingtextlessbrtextgreatera light-gated ion channel (channelrhodopsin-2, ChR2). We find that ChR2-mediated depolarizing current prolongs APs andtextlessbrtextgreaterreduces conduction velocity (CV) in a space-selective and reversible manner. Sub-threshold manipulation also affects thetextlessbrtextgreaterdynamics of cardiac electrical activity, increasing the magnitude of cardiac alternans. We used an optical system that usestextlessbrtextgreaterreal-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 thattextlessbrtextgreatercardiac alternans may be beneficial in the context of self-termination of VT.

Basic Research in Cardiology 117: 25