Cardiac optogenetics: a decade of enlightenment

Optogenetic modulation of cardiac action potential properties may prevent arrhythmogenesis in short and long QT syndromes

“…Whereas, mechanistically, continuous ChR2 activation inhibited AP generation by clamping V m to a relatively depolarized potential, leading to inactivation of Na + channels, ACR2 activation clamps V m to a hyperpolarized potential, preventing the required depolarization for AP generation. These results may have important implications for better mechanistic understanding and for adding new optogenetic tools (use of ACR2) for optogenetic-based therapeutic strategies for tachyarrhythmias: for suppression of automaticity, generation of functional conduction blocks, and optogenetic defibrillation ( 12 , 40 ).…”

“…Optogenetics allows to control neuronal activity through the expression of light-sensitive microbial proteins (opsins), functioning as ion channels or pumps (6)(7)(8). More recently, similar concepts were applied to the heart (9)(10)(11)(12), leading to development of experimental optogenetic-based cardiac pacing (13,14), resynchronization (14,15), and defibrillation (16)(17)(18)(19)(20) approaches. While the focus of cardiac optogenetics has been on inducing or suppressing AP generation with depolarizing or hyperpolarizing light-sensitive proteins, similar concepts could potentially be used to modulate AP properties, as suggested by computational modeling (21), proof-of-concept experiments using optical dynamic clamp studies for drug testing in human cardiomyocytes (CMs) (22), and studies using neonatal rat CMs (23,24).…”

Integration of Engineered “Spark-Cell” Spheroids for Optical Pacing of Cardiac Tissue

“…Typical all-optical electrophysiology experiments (as in Figure 5) were done 12 h post spheroid deposition onto hiPSC-CMs grown in 96-well plates. For optical confirmation of pacing, we used two genetically-encoded calcium sensors (GECIs), R-GECO or jRGECO, expressed in the iPSC-CMs, or a near-infrared voltage-sensitive dye, BeRST1, both of which are spectrally compatible with the ChR2 actuator (Klimas et al, 2020;Entcheva and Kay, 2021). To further suppress potential crosstalk when using calcium recordings with R-GECO or jRGECO, we spatially patterned the light to confine the excitation near the spheroid and optically recorded from a nearby region, Figure 5B.…”

“…Optogenetic rhythm control has been deployed at the whole heart in a variety of studies (Arrenberg et al, 2010;Bruegmann et al, 2010Bruegmann et al, , 2016Zaglia et al, 2015;Crocini et al, 2016;Nyns et al, 2019). When combined with human induced pluripotent stem-cell-derived cardiomyocytes, human stem-cell-derived cardiomyocytes (hiPSC-CMs), in vitro, the contactless and scalable light-based optogenetic approaches hold promise to aid high-throughput (HT) capabilities for functional drug cardiotoxicity testing or other aspects of drug development (Lapp et al, 2017;Rehnelt et al, 2017;Zhang and Cohen, 2017;Entcheva and Kay, 2021). All-optical electrophysiology is poised to accelerate and streamline drug development (Hochbaum et al, 2014;Entcheva and Bub, 2016;Klimas et al, 2016Klimas et al, , 2020.…”

Advanced Optogenetic-Based Biosensing and Related Biomaterials

“…Not surprisingly, the last 15 years witnessed a ground-breaking impetus of optogenetic applications and tools (for applications in cardiac research see [ 23 ], one of the many recent reviews in the neuro and cardiac fields) progressing from basic research to (currently prospective) clinical therapeutic applications and industrial efforts to employ optogenetic strategy toward disease interventions [ 24 ]. In contrast, the biosensing applications of light-responsive cellular platforms are at an early developmental stage.…”