Assessment of drug-induced arrhythmic risk using limit cycle and autocorrelation analysis of human iPSC-cardiomyocyte contractility

Abstract

Cardiac safety assays incorporating label-free detection of human stem-cell derived cardiomyocyte contractility provide human relevance and medium throughput screening to assess compound-induced cardiotoxicity. In an effort to provide quantitative analysis of the large kinetic datasets resulting from these real-time studies, we applied bioinformatic approaches based on nonlinear dynamical system analysis, including limit cycle analysis and autocorrelation function, to systematically assess beat irregularity. The algorithms were integrated into a software program to seamlessly generate results for 96-well impedance-based data. Our approach was validated by analyzing dose- and time-dependent changes in beat patterns induced by known proarrhythmic compounds and screening a cardiotoxicity library to rank order compounds based on their proarrhythmic potential. We demonstrate a strong correlation for dose-dependent beat irregularity monitored by electrical impedance and quantified by autocorrelation analysis to traditional manual patch clamp potency values for hERG blockers. In addition, our platform identifies non-hERG blockers known to cause clinical arrhythmia. Our method provides a novel suite of medium-throughput quantitative tools for assessing compound effects on cardiac contractility and predicting compounds with potential proarrhythmia and may be applied to in vitro paradigms for pre-clinical cardiac safety evaluation.

An Industry Survey With Focus on Cardiovascular Safety Pharmacology Study Design and Data Interpretation

“…While this is likely attributed to both technological advances achieved with advanced engineering of hiPSC-CM as well as a plethora of published data using a multitude of drugs in recent years, there remains some concerns relative to the adult phenotype of the cells used in these emerging in vitro models. 5,21,22 It is important to compare and contrast findings derived from responses in this survey to previously conducted SPS survey as this informs whether change has occurred with regard to study design and practice over time during the conduct of SP studies. In a recent survey that investigated the developing CiPA initiative, 16 it was revealed that a majority (59%) of responders reported that their company had abandoned at least one pharmacophore (or potential "toxicophore") based on data obtained from assays characterizing drug-mediated blockade of I Kr .…”