A Coupled Electromechanical Myocyte Model to Assess the Effects of 2‐deoxy‐ATP on Contractile Function in the Heart

Abstract

IntroductionHeart failure (HF) remains a significant cause of morbidity, mortality, and medical costs. HF is characterized by reduced contractile function and inability of the heart to pump sufficient blood to meet the body’s demands. Existing treatments for HF do not permanently restore cardiac function and can lead to side effects such as impaired ventricular relaxation. 2‐deoxy‐ATP (dATP), a novel heart failure therapeutic, has been shown to increase contractile function while enhancing relaxation [1]. Previous studies have shown that dATP increases the rate of crossbridge cycling [2]. It has also been shown that dATP acts on the sarcoplasmic reticulum ATPase (SERCA), the pump responsible for removing calcium (Ca2+) from the cytosol, which could explain the enhanced relaxation kinetics seen experimentally [3]. However, the mechanism of dATP is still not fully understood. Further, it is not clear whether the increased rate of crossbridge cycling with dATP treatment could aggravate energy starvation in HF.MethodsTo assess the full mechanism of dATP at the cellular level, we utilized a myocyte model containing several ion channels, including SERCA [4]. We coupled this model to a mitochondria model to investigate whether dATP treatment aggravates energy starvation by tracking ATP, ADP, Pi, and oxygen concentrations over time [5]. We also coupled the myocyte model to a previously developed 5 state Markov model of crossbridge cycling, which captures regulation of contraction via Ca2+ binding to troponin [2]. The crossbridge cycling model was modified to capture the effects of sarcomere length on Ca2+ sensitivity. dATP treatment was simulated by adjusting the ATP and Ca2+ binding rates in the SERCA model and the rate of crossbridge cycling in the sarcomere model based on previous studies [2, 3].Results and ConclusionsWe found that the combined effects of dATP on both SERCA and the sarcomere within the coupled myocyte model could explain the increase in fractional shortening and time to 50% and 90% relaxation of the Ca2+ transient seen experimentally more accurately than either model alone. Additionally, we found no evidence that dATP aggravates energy starvation, affirming dATP as a promising therapeutic for HF.Support or Funding InformationNIH HLT32 TG