Evaluation of laser optoporation-induced action-potential-like measurements on iPSC-cardiomyocytes and the assessment of drug-induced effects on APD and contractility

Abstract

Physiological relevance and accuracy in cardiac safety pharmacology studies is of the utmost importance, as supported by the recent changes in ICH guidelines and the CiPA committee's efforts. Although most of the studies focused on hERG-affecting molecules and the arrhythmic risk related to Action Potential elongation, iPSC-derived cardiomyocytes have the potential to be a more thorough assay with more physiological relevance. In this study, we demonstrate how laser optoporation technology opens transient nanopores within the cell's membrane and allows for Action Potential (AP) recordings from cardiac cells and compare the results to traditional MEA-based Field Potential Measurements. In particular, we show how the response to a potassium channel blocker (dofetilide) is comparable when looking at the APD90(>30 % increase) but that the APD30 is shortened (>10 % decrease) which we would not be able to measure with traditional MEA. The response to an Ica blocker (Nifedipine) reveals how the drug affects the depolarization currents, which can not be measured with traditional MEA. In addition, Beta-adrenergic (isoproterenol) receptor response demonstrated how the AP-amplitude remains unchanged while the contractility is increased (>30 %). We also show how the technology is non-invasive and label-free, allowing for reliable and stable measurements over 3 weeks, and how the results are comparable to previous validated data. With these results, we suggest further exploration of this technique in its use in safety pharmacology to predict cardiotoxic effects, potentially serving as an upgrade on previous technology which was limited to Field Potential Duration elongation effects.