Improved translation of Nav1.5 channel inhibition to in vivo QRS interval prolongation via the hIPSC cardiomyocyte model

Introduction

Drug risk assessment to ventricular conduction typically involves measuring functional inhibition of the cardiac sodium channel (Na_v1.5) followed by nonclinical in vivo assessment of prolongation of the electrocardiographic QRS interval. The Na_v1.5 IC₅₀ concentration, however, underpredicts the threshold concentrations of in vivo QRS prolongation by 10–20-fold. We here develop and implement a novel human induced pluripotent stem cell derived cardiomyocyte (hIPSC-CM) field potential spike analysis paradigm that facilitates the use of this model for accurate forecasting of QRS prolongation concentration thresholds.

Methods and results

Using multi-electrode arrays we record the extracellular field potential spike of hIPSC-CM monolayers. Large variations in the field potential spike amplitudes across the array, however, confound translation of this parameter. To solve this shortcoming we derive a novel time parameter, T_A/Vmax, defined as the quotient of the amplitude (A) and the peak rate of change (V_max) of the of the cardiomyocyte field potential spike. T_A/Vmax normalizes effects on spike amplitude independent of Na_v1.5 inhibition, such as cell density, amplitude drift, and variable attachment of the monolayer to the field potential electrode. Small changes (< 5 %) in T_A/Vmax become statistically significant and directly comparable to threshold QRS interval changes in early in vivo screening models. Characterization of a set of 12 compounds including Class I antiarrhythmics and internal test compounds demonstrates that the T_A/Vmax EC5% more consistently and accurately predicts both clinical and non-clinical QRS prolongation than the Na_v1.5 IC₅₀; accuracy of threshold concentration forecasting improved 16-fold and the correlation coefficient, R, increased from 0.76 to 0.88.

Conclusion

Calculation of T_A/Vmax enables use of the hIPSC-CM field potential spike to predict in vivo QRS prolongation. Use of this in vitro model in early screening or mechanistic evaluation of risk to ventricular conduction should facilitate a broader cardiac in vitro electrophysiologic assessment strategy for new molecular entities.