Thesis: Multiscale Computational Modeling of Novel Treatments for Heart Failure with Reduced Ejection Fraction

Abstract: Heart failure is a major healthcare challenge, and most existing treatments mitigate its symptoms without addressing underlying mechanical dysfunction. Therefore, recent advancements aim to directly target the contractile machinery of the heart. In this work, we utilized a combination of multiscale modeling approaches spanning from the atom to whole heart to investigate the therapeutic potential of targeting proteins within the sarcomere to improve cardiac contractile function in heart failure with reduced ejection fraction. We specifically investigated 2-deoxy-ATP (dATP), a potential myosin-activating therapeutic. dATP improves cardiac function by increasing the rate of crossbridge cycling and calcium transient decay. However, the molecular mechanisms of these effects and how therapeutic responses to dATP are achieved, especially for small fractions of dATP, remain poorly understood. This is especially true in heart failure, where energy metabolism is impaired. We utilized a combination of molecular dynamics (MD), Brownian dynamics (BD), and Markov state modeling, to show that dATP increases the actomyosin association rate via stabilization of pre-powerstroke myosin. We also showed using MD and BD that dATP acts on the sarcoendoplasmic reticulum calcium-ATPase (SERCA) pump to accelerate calcium re-uptake into the sarcoplasmic reticulum during cardiac relaxation by increasing the rate of calcium association to SERCA. We then employed a spatially explicit model of the sarcomere to show that dATP increases the pool of myosin heads available for crossbridge cycling, increasing steady state force development at low dATP fractions due to mechanosensing and nearest-neighbor cooperativity. We extended our analysis to assess cardiomyocyte mechanics and excitation-contraction coupling, and found that the effects of dATP on SERCA, along with increased myosin recruitment, contributed to improved cell contraction and relaxation. These mechanisms extended to the ventricular level to improve contractility and metabolism, especially in heart failure, where our model of ventricular mechanics and circulation predicted that dATP increased ejection fraction and the energy efficiency of cardiac contraction. We finally extended our approach to demonstrate how our multiscale computational modeling approach can be utilized to provide insight into the link between genotype and phenotype in heart failure and to develop novel therapeutics.