Computational systems analysis of cardiac mechanical-energetic coupling in heart disease

摘要 在衰竭心脏的失代偿性肥大中，心肌的能量状态受到损害， 与化学能（以ATP水解电位的形式）可供心脏做功 与正常相比有所减少。观察到的能量状态变化对机械性能的影响 功能未知。在以前的研究中，我们开发了计算机模型，解释了 心肌细胞质代谢物库的消耗影响心力衰竭的能量状态; 代谢状态依赖的心肌力学计算机模型，预测这些观察到的 能量状态的变化影响体内的机械功能。使用这些模型来解释数据， 人类和动物模型的心脏代偿失调和心力衰竭，我们预测，代谢/能量 功能障碍直接导致心力衰竭中心肌的收缩功能障碍。在这个项目中，我们将测试 与该预测相关的以下假设： （1.）心脏衰竭的TAC大鼠模型中代谢/能量功能障碍的主要原因是 线粒体氧化磷酸化能力降低和细胞质病理性耗竭 腺嘌呤核苷酸和其他关键代谢池。 （2.）胞浆ATP减少和无机磷酸盐增加（与能量受损相关 代谢）损害心脏的机械功能。 （3.）通过阻断嘌呤降解途径，可能是过度活跃的慢性应激和/或 周期性缺血心肌，我们可以增加/恢复核苷酸库，保护心脏免受 机械功能障碍和故障。 这三个具体目标是围绕测试和完善这三个假设而建立的。代谢和 来自肥大和衰竭的大鼠模型的实验的功能数据将基于多个- 将心脏能量和力学与全身心血管功能相结合的比例计算机模型。 假设将根据模型同时解释 代谢和机械数据从动物模型。这种方法加快了假设的循环 测试（通过模型预测与实验观察的定量比较），假设细化 （根据预测和数据之间的不匹配重新设计和重新制定模型）， 实验设计第三个假设的成功验证有可能指向全新的类别 与嘌呤核苷酸去磷酸化，脱氨基，降解， 和交通。

Abstract The energetic status of the myocardium is compromised in decompensated hypertrophy in the failing heart, with the chemical energy (in the form of the ATP hydrolysis potential) available for the heart to do work diminished compared to normal. The consequences of the observed changes in energetic state on mechanical function are not known. In previous studies we have developed computer models that explain how the depletion of cytoplasmic metabolite pools in the myocardium affects energetic state in heart failure; and a metabolic state-dependent computer model for myocardial mechanics that predicts how these observed changes in energetic status affect mechanical function in vivo. Using these models to interpret data from humans and animal models of cardiac decompensation and heart failure, we predict that metabolic/energetic dysfunction directly causes contractile dysfunction of the myocardium in heart failure. In this project we will test the following hypotheses associated with that prediction: (1.) The primary causes of metabolic/energetic dysfunction in the TAC rat model of heart failure are reduction in mitochondrial capacity for oxidative phosphorylation and pathological depletion of cytoplasmic adenine nucleotides and other key metabolic pools. (2.) Diminished cytosolic ATP and increased inorganic phosphate (associated with impaired energy metabolism) impairs the mechanical function of the heart. (3.) By blocking purine degradation pathways that may be overactive in the chronically stressed and/or periodically ischemic myocardium, we can increase/restore the nucleotide pool and protect the heart against mechanical dysfunction and failure. The three specific aims are built around testing and refining these three hypotheses. Metabolic and functional data from experiments on rat models of hypertrophy and failure will be interpreted based on multi- scale computer models integrating cardiac energetic and mechanics with whole-body cardiovascular function. Hypotheses will be tested and refined based on the ability/inability of the models to simultaneously explain the metabolic and mechanical data from the animal models. This approach expedites the cycle of hypothesis testing (via quantitative comparison of model predictions to experimental observations), hypothesis refinement (redesign and reformulation of models in light of mismatches between predictions and data), and model-guided experimental design. Successful testing of the third hypothesis has the potential to point to whole new classes of pharmacological targets associated with purine nucleotide dephosphorylation, deamination, degradation, and transport.