Optimizing Rate Correction of Field Potential Duration, a Biomarker for QT Risk Assessment, in Human Ipsc-Cardiomyocytes

Abstract

The combination of human induced pluripotent stem cell-differentiated cardiomyocytes (hiPSC-CMs) with multi-electrode array (MEA) technology allows for a medium throughput assessment of cardiovascular risk at preclinical stages of drug discovery well in advance of candidate selection. Field potential duration (FPD) is a surrogate marker for QT duration and, like QT duration, is beat rate-dependent. Correction for changes in rate is required to properly interpret direct effects on FPD or QT. The FPD is defined as the time interval between initiation of the fast (Na+ spike) voltage deflection due to INa and subsidence of the slow, positive deflection due to repolarizing IK currents, and is a biomarker for QT duration. Our data demonstrate that FPD is highly correlated with the beat period in a largely non-linear fashion. Additionally, non-paced hiPSC-CMs are susceptible to dramatic drug-induced beat period changes. Consequently, interpretation of the effects of drugs on these parameters requires a beating rate correction. However, commonly used human ECG-derived QT correction formulae (e.g. Fredericia's, Bazett's) prove inadequate outside a narrow range of FPD-beat period linearity. Their use may incorrectly classify QT/FPD modifying compounds. We therefore developed and qualified a set of algorithms for FPD:beat period correction based on the response of hiPSC-CMs to the If inhibitor ZD7288 and the beta adrenergic agonist isoproterenol. The resulting FPD:beat period relationship had a limited linear range and an extended non-linear range. These algorithms were compared to other common correction methods. We found that individual correction provided a statistically significantly improvement over classical correction formulae (on parameters of linearity & slope) in the non-linear range. This correction algorithm has been incorporated into our MEA assay for QT risk assessment.