Sex-specific human electromechanical multiscale in-silico models for virtual therapy evaluation

Abstract

Background and AimWomen are significantly under-represented in cardiovascular research and in the evaluation of treatment safety and efficacy, leading to poorer patient outcomes. Quantification and investigation of sex differences in human electromechanical function and underlying mechanisms is crucial. To address this, we present sex-specific human cellular and biventricular electromechanical models for mechanistic investigations into sex-differences in therapy evaluation through simulations. MethodsProtein genomic expression data from healthy human myocytes were used to calibrate sex-specific models of human cellular electrophysiology, subsequently integrated in biventricular electromechanical models with male and female anatomies. A validation, verification and uncertainty evaluation were implemented at the cellular and biventricular level, including validation using sex-specific datasets from randomised controlled trials for Dofetilide and Verapamil, with known sex-differences. Ionic mechanisms underlying sex-differences in drug response were mechanistically investigated. ResultsSex-specific electromechanical models recapitulate sex-differences from ionic currents to ECG biomarkers including QTc interval (Male: 312ms; Female: 339ms; 9% difference), T-wave amplitude (6-9% difference) and ST-steepness through electrophysiological changes alone. Sex-specific simulations demonstrate both ECG biomarkers and mechanical biomarkers (Female LVEF: 68%, Male LVEF: 50%) within healthy ranges in clinical data for male and female population in the UK Biobank (n= 806, 46% Male). ECGs sex-differences are primarily explained by ionic currents, whereas mechanical sex-differences are driven by anatomical differences, and secondarily through more robust calcium function in females. Under Dofetilide, simulations show exacerbated QT prolongation in women compared to men (54-78% increase in effect), and a T-wave amplitude decrease in males (up to 0.25 mV), consistent with clinical data. This is explained in simulations by lower repolarisation reserve in women (due to low potassium and high calcium currents) than men. Verapamil shows no effect on simulated QT in either sex, and divergent T-wave modulation (increased amplitude in females, decreased in males) consistent with clinical trial data. Simulations identify enhanced contractile reservoir in female compared to male, with lesser decreases to ejection fraction with calcium current block. ConclusionSimulations using novel, sex-specific cellular and biventricular electromechanical models reveal the primary role of ionic currents sex-differences in ECG and drug response, whereas mechanical sex-differences are also underpinned by anatomical differences. Main ContributionsO_LIDevelopment, calibration and validation of sex-specific human ventricular electromechanical, multiscale models. C_LIO_LIAn analysis of clinical randomised trial data in the context of sex-specific effects of multi-channel blockers on the ECG by dosage, where previous analysis focused on pharmacokinetics. C_LIO_LIConsideration of both sex-specific electrophysiology and anatomy explains sex-specific differences on the impact of drugs on ECG and mechanics. C_LIO_LISimulations demonstrate that the reduced repolarisation reserve in females increases the susceptibility to QTc prolongation via potassium channel block compared to males, and more robust calcium dynamics protect against t-wave amplitude reduction and the more severe contractility loss through L-type calcium inhibition observed in males. C_LI