Quantitative male-to-female translation of cardiac electrophysiological response to drugs.

Abstract

Despite evidence that women are at higher risk of drug-induced Torsade de Pointes and sudden cardiac death, female sex is vastly underrepresented in cardiovascular research studies and clinical trials, thus limiting our fundamental understanding of sex-specific arrhythmia mechanisms and our ability to predict arrhythmia propensity. Indeed, we have shown that adoption of male-biased metrics can lead to a systematic underestimation of torsadogenic risk in women. To facilitate evaluation of the impact of sex differences on cardiomyocyte function and arrhythmogenesis, we developed quantitative tools that predict the electrophysiological response to drug administration in female cardiomyocytes starting from data collected in males. Using our mathematical models of excitation-contraction coupling in male and female human ventricular myocytes, we generated populations of models by randomly varying baseline model parameters. We collected action potential (AP) and Ca2+ transient (CaT) properties in each model variants and used multivariable regression to construct a “male-to-female translator”, i.e., a set of regression coefficients mapping male features onto female electrophysiology. We validated our translator against independent simulated data sets describing the effects of a large group of drugs on the baseline male and female models. Our results show high accuracy of prediction of drug-induced effects on female AP and CaT, where the average discrepancy between predicted and actual biomarkers falls within 1-2%. Next, we will use "male-to-female" translated features as inputs into our previously developed female-specific classifier of drug-induced torsadogenic risk to test the suitability of our translator for cardiac safety assessment in women. Classifier performance obtained with simulated data as input features will be used as a benchmark. Completion of this work will facilitate the translatability of male-biased experimental observations to female physiology and advance the characterization of sex differences in cardiac electrophysiology and drug cardiotoxicity.