Voltage-sensing optical recording: A method of choice for high-throughput assessment of cardiotropic effects.

Introduction: Voltage and calcium-sensing optical recording (VSOR and CSOR, respectively) from human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have been validated for in vitro evaluation of cardiotropic effects of drugs. When compared to electrophysiological devices like microelectrode array, multi-well optical recordings present a lower sample rate that may limit their capacity to detect fast depolarization or propagation velocity alterations. Additionally, the respective sensitivities of VSOR and CSOR to different cardiac electrophysiological effects have not been compared in the same conditions.

Methods: FluoVolt and Cal520 dyes were used in 96 well format on hPSC-CMs to report sodium channel block by lidocaine and propagation slowing by the junctional uncoupler carbenoxolone at three recording frequencies (60, 120 and 200 Hz) as well as their sensitivity to early and late repolarization delay.

Results: Sodium channel block led to a dose-dependent decrease of the VSOR signal rising slope that was improved by an increased sampling frequency. In contrast, the CSOR signal rising slope was only decreased at the highest concentration with no influence from the sampling rate. A similar result was obtained with carbenoxolone. Early repolarization delay by Bay K8644 showed the same effects on VSOR and CSOR signal durations while repolarization slowing by dofetilide had a significantly stronger prolongating effect on the VSOR signal at the lowest concentration.

Discussion: VSOR showed a higher capacity to detect sodium channel block, propagation slowing and modest late repolarization delay than CSOR. Increasing the sampling rate improved the detection threshold of VSOR for excitability and conduction velocity alterations.