All-optical control of cardiac excitation: combined high-resolution optogenetic actuation and optical mapping

Abstract

Cardiac tissue is an excitable system that can support complex spatiotemporal dynamics, including instabilities (arrhythmias) with lethal consequences. While over the last two decades optical mapping of excitation (voltage and calcium dynamics) has facilitated the detailed characterization of such arrhythmia events, until recently, no precise tools existed to actively interrogate cardiac dynamics in space and time. In this work, we discuss the combined use of new methods for space- and time-resolved optogenetic actuation and simultaneous fast, high resolution optical imaging of cardiac excitation waves. First, the mechanisms, limitations and unique features of optically induced responses in cardiomyocytes are outlined. These include the ability to bidirectionally control the membrane potential using depolarizing and hyperpolarizing opsins; the ability to induce prolonged sustained voltage changes; and the ability to control refractoriness and the shape of the cardiac action potential. At the syncytial tissue level, we discuss optogenetically enabled experimentation on cell-cell coupling, alteration of conduction properties and termination of propagating waves by light. Specific attention is given to space- and time-resolved application of optical stimulation using dynamic light patterns to perturb ongoing activation and to probe electrophysiological properties at desired tissue locations. The combined use of optical methods to perturb and to observe the system can offer new tools for precise feedback control of cardiac electrical activity, not available previously with pharmacological and electrical stimulation. These new experimental tools for all-optical electrophysiology allow for a level of precise manipulation and quantification of cardiac dynamics comparable in robustness to the computational setting, and can provide new insights into pacemaking, arrhythmogenesis and suppression or cardioversion.

Figure 1

Control of emergent cardiac tissue‐level function by all‐optical technology

Figure 2. Optical control of spiral wave chirality in cardiac monolayer

A, snapshots from an ongoing counter‐clockwise spiral wave (frames 2000–2160), an optically applied computer‐generated clockwise spiral wave (frames 2240–2480) and the persisting spiral wave post‐chirality reversal (frames 2560–2720). B, temporal traces of activity from the indicated red and blue pixels showing four light‐controlled chirality reversals (computer‐generated spirals were faster and imposed at random phase for less than two rotations, as seen in the four higher‐intensity transients; black arrows indicate the time period presented in panel A; red and blue arrows indicate the switch of order of excitation at the chosen locations due to chirality reversal. C, activation maps for the initial spiral wave and the four resultant spirals after each of the chirality reversals by light. Note the slight difference in spiral wave tip location and in rotation frequency for clockwise vs. counter‐clockwise spirals. Reproduced with permission from Burton et al. (2015).