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.

Geometry-dependent functional changes in iPSC-derived cardiomyocytes probed by functional imaging and RNA sequencing

“…In assaying functional maturity, tools of optical electrophysiology are particularly useful because the electrical and calcium dynamics reflect the aggregate activity of a large number of transporters, pumps, and ion channels [20]. Recently described systems enabled simultaneous voltage and calcium imaging in free-running or electrically paced hiPSC-CM [21], optogenetic pacing and either voltage or calcium imaging [22], or optogenetic pacing with simultaneous voltage and calcium imaging [23].…”

Non-invasive red-light optogenetic control ofDrosophilacardiac function

“…As a label-free technique, it could become a promising complement to previous Drosophila cardiac assessment methods that require staining, such as optical mapping, immunofluorescence, or histology. 5,36 The use of red excitation light for optogenetic cardiac control enables higher penetration depth and longitudinal cardiac arrhythmia studies. The combination of OCM and optogenetics establishes an all-optical, non-invasive manipulation and real-time imaging modality for cardiac optogenetics.…”

“…It has been increasingly studied as an alternative to electrical stimulation methods for cardiac control since 2010. [1][2][3][4][5] Arrenberg et al first developed transgenic Zebrafish models with a genetically-encoded, optically-controlled pacemaker expressing channelrhodopsin-2 (ChR2) or halorhodopsin (NpHR) in the heart. 6 Bruegmann et al used ChR2-expressing cardiac tissue for light-induced stimulation of heart muscle in vitro and in mice with open chest preparation.…”

Syncytium cell growth increases IK1 contribution in human iPS-cardiomyocytes

“…Albeit not ideal, e.g. in its present form, it cannot report directly contributions of a specific ion current as voltage clamp does, this approach can provide the most comprehensive view of functional responses of hiPS-CMs in a syncytium and can do so in a contactless high-throughput manner (Entcheva 2013, Entcheva andBub 2016). Further developments may make it possible to also obtain presently missing quantitative ion current information by implementing versions of an optical clamp (Quach, Krogh-Madsen et al 2018) in conjunction with computational tools.…”