Sex Differences in Drug-Induced Arrhythmogenesis.

Mathias Peirlinck,Francisco Sahli Costabal,Ellen Kuhl

doi:10.3389/fphys.2021.708435

Abstract

The electrical activity in the heart varies significantly between men and women and results in a sex-specific response to drugs. Recent evidence suggests that women are more than twice as likely as men to develop drug-induced arrhythmia with potentially fatal consequences. Yet, the sex-specific differences in drug-induced arrhythmogenesis remain poorly understood. Here we integrate multiscale modeling and machine learning to gain mechanistic insight into the sex-specific origin of drug-induced cardiac arrhythmia at differing drug concentrations. To quantify critical drug concentrations in male and female hearts, we identify the most important ion channels that trigger male and female arrhythmogenesis, and create and train a sex-specific multi-fidelity arrhythmogenic risk classifier. Our study reveals that sex differences in ion channel activity, tissue conductivity, and heart dimensions trigger longer QT-intervals in women than in men. We quantify the critical drug concentration for dofetilide, a high risk drug, to be seven times lower for women than for men. Our results emphasize the importance of including sex as an independent biological variable in risk assessment during drug development. Acknowledging and understanding sex differences in drug safety evaluation is critical when developing novel therapeutic treatments on a personalized basis. The general trends of this study have significant implications on the development of safe and efficacious new drugs and the prescription of existing drugs in combination with other drugs.

Highlights

It is well-established that there are important discrepancies between male and female cardiac electrophysiology
Using the male and female multiscale cardiac electrophysiology models, we develop two sex-specific arrhythmogenic risk classifiers based on drug- and dose-specific ion channel blockage
To explore the male and female arrhythmogenic sensitivity to drug-induced ion channel blocking in a computationally tractable way, we focus on seven specific ion channel currents IKr, INa, INaL, ICaL, IKs, Ito, and IK1 identified to be important in both depolarization and repolarization of the cardiac action potential (Crumb et al, 2016; Fermini et al, 2016)

Summary

Introduction

It is well-established that there are important discrepancies between male and female cardiac electrophysiology. The gold standard for cardiac safety assessment focuses on the experimental measurement of the pharmacological block of the rapid delayed potassium rectifier current in single cell experiments (Redfern et al, 2003) and electrocardiographic analyses looking for QT prolongation in animal models or humans (Gintant et al, 2016) These biomarkers show good sensitivity but low specificity, potentially preventing useful drugs to reach the market (Sager, 2008). Over the past few years, these physics-based modeling approaches have been increasingly combined with machine learning approaches to further improve mechanistic arrhythmogenic risk classification (Lancaster and Sobie, 2016; Polak et al, 2018; Sahli Costabal et al, 2019a,c)

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