Stratifying response to omecamtiv mecarbil in HFrEF using multiscale cardiac digital twins
E Casoni, B Trenor, M Mora, F Carreras, M VazquezAbstract
Background
Omecamtiv mecarbil is a selective cardiac myosin activator that improves systolic function in heart failure with reduced ejection fraction (HFrEF) by prolonging systolic ejection without increasing intracellular calcium. However, its hemodynamic efficacy may depend on heart rate, as systolic prolongation can compromise diastolic filling at higher frequencies [1,2]. Clinical responses, however, appear to depend on both heart rate and baseline disease severity, suggesting that patient-specific ventricular mechanics may modulate therapeutic efficacy.
Purpose
To quantify the heart rate– and disease severity–dependent effects of Omecamtiv mecarbil across a spectrum of HFrEF phenotypes using a multiscale cardiac electromechanical digital twin framework.
Methods
A multiscale ventricular electromechanical model coupled to a closed-loop circulatory system was used to simulate HFrEF conditions [3]. The pharmacological action of Omecamtiv mecarbil was represented by modulating cross-bridge kinetics to prolong systolic force generation without altering calcium transient amplitude. Simulations were performed across a range of heart rates, while ventricular structural properties and loading conditions were held constant. Hemodynamic outputs, including stroke volume, cardiac output, ejection fraction and diastolic filling indices were quantified.
Results
Across virtual patients with more severe HFrEF (below 28%), Omecamtiv mecarbil produced greater relative improvements in systolic ejection duration, stroke volume and cardiac output at low-to-moderate heart rates (from 60 beats per minute to 90-100 beats per minute). In contrast, at higher heart rates (over 100 beats per minutes), the benefit on stroke volume diminished due to reduced diastolic filling time (around 30%), resulting in attenuated of absent gains in cardiac output across all severities levels. Ventricular ejection fraction remained relatively preserved across heart rate conditions (with an improvement of around 7% in the more severe HFrEF cases), reflecting improved systolic efficiency rather than increased contractility.
Conclusions
This digital twin study demonstrates that the hemodynamic efficacy of omecamtiv mecarbil in HFrEF is jointly determined by heart rate and baseline systolic impairment. Virtual patient simulations reveal that systolic enhancement is most effective in more severe HFrEF at controlled heart rates, whereas reduced diastolic filling limits benefit during tachycardia regardless of disease severity. These findings provide a mechanistic insight into clinical observations for patient stratification and highlight the importance of heart rate optimization when deploying myosin-targeted therapies in HFrEF.Cardiac output for different severitiesFor image description, please refer to the figure legend and surrounding text.