Heart failure remains a significant cause of morbidity, mortality, and medical costs. 2-deoxy-ATP (dATP), a novel heart failure therapeutic, has been shown to improve contractile function without impairing relaxation. Previous studies in our group have shown that elevated dATP increases the rate of crossbridge binding cycling and the rate of calcium transient decay. However, the precise molecular mechanisms of these effects and how therapeutic responses are achieved when dATP is only a small fraction of the total ATP pool are unknown. We used multiscale computational modeling to integrate a filament-scale model of acto-myosin interactions, whole myocyte model, organ scale model of biventricular mechanoenergetics, and whole body circulatory model to predict the effects of dATP on ventricular mechanics in normal and heart failure conditions. We discovered synergistic interactions between calcium dynamics and force development that leads to improvements in myocyte contractility and lusitropy. Simulations also predicted that increased transition out of the super-relaxed state of myosin with elevated dATP can explain the large increases in force observed at low percentages of dATP. We further showed that this effect likely depends on both nearest neighbor cooperativity and thick filament mechanosensing. We predicted improvements in ventricular function consistent with experimental data in both healthy and failing conditions, with no additional impairment of metabolic state. Ventricular function was improved to a greater degree in failure than in healthy conditions, due at least in part to improved energy efficiency with elevated dATP.

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