Abstract Body: Hypothesis:
The human induced pluripotent stem cell derived cardiomyocyte (hIPSC-CM) model can improve in vitro assessment of risk to ventricular conduction by new molecular entities.
Aims:
Drug risk assessment to ventricular conduction typically involves measuring functional inhibition of the cardiac sodium channel (Nav1.5) followed by nonclinical in vivo assessment of prolongation of the electrocardiographic QRS interval. The Nav1.5 IC₅₀ concentration, however, underpredicts the threshold concentration of in vivo QRS prolongation by 10 – 20-fold. We here develop and test a novel hIPSC-CM field potential spike analysis paradigm that facilitates the use of this model to greatly improve the accuracy of threshold forecasting of in vivo QRS prolongation.
Methods and Results:
Using multi-electrode arrays we recorded 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 derived 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 Nav1.5 inhibition, such as cell density, amplitude drift, and variable attachment of the monolayer to the field potential electrode. Very small changes (< 5%) in T_A/Vmax become statistically significant and directly comparable to threshold QRS interval changes in the Guinea pig in vivo screening model. Characterization of a set of 12 compounds including Class I antiarrhythmics and internal test compounds in both the hIPSC-CM and Guinea pig models demonstrates that the T_A/Vmax EC5% more consistently and accurately predicts both clinical and non-clinical QRS prolongation than the Nav1.5 IC₅₀. Accuracy of threshold concentration forecasting improved 16-fold and the correlation coefficient, R, increased from 0.76 to 0.88 over the in vitro Nav1.5 IC₅₀.
Conclusions:
The derived hIPSC-CM spike time parameter T_A/Vmax can accurately predict the pharmacology of in vivo QRS prolongation. Use of the hIPSC-CM model in drug screening can contribute to a broader in vitro cardiac electrophysiologic risk assessment for new molecular entities. This approach provides an improved translational assessment of Nav1.5 block to ventricular conduction slowing which has traditionally relied on testing in nonclinical species.