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

摘要 衰竭心脏的失代偿性肥厚损害了心肌的能量状态， 心脏做功所需的化学能(以ATP水解势的形式) 与正常情况相比有所减少。观测到的能量状态变化对力学性能的影响 功能是未知的。在之前的研究中，我们已经开发了计算机模型来解释 心肌中细胞质代谢物库的耗竭会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来自 在人类和动物的心脏失代偿和心力衰竭模型中，我们预测代谢/能量 功能障碍直接导致心力衰竭时的心肌收缩功能障碍。在这个项目中，我们将测试 与这一预测相关的假设如下： (1.)TAC大鼠心力衰竭模型中代谢/能量功能障碍的主要原因是 线粒体氧化磷酸化能力降低与细胞质病理性耗竭 腺嘌呤核苷酸和其他关键代谢池。 (2)胞浆ATP减少和无机磷增加(与能量受损有关 新陈代谢)损害心脏的机械功能。 (3)通过阻断在慢性应激和/或疾病中可能过度活跃的嘌呤降解途径 周期性缺血的心肌，我们可以增加/恢复核苷酸池，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着测试和提炼这三个假设而建立的。新陈代谢和 来自大鼠肥厚和衰竭模型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。 假说将根据模型同时解释 来自动物模型的代谢和机械数据。这种方法加速了假设的循环。 检验(通过模型预测与实验观测的定量比较)、假设改进 (根据预测和数据之间的不匹配重新设计和重新制定模型)，以及模型指导 实验设计。第三种假设的成功测试有可能指向全新的类别 与嘌呤核苷酸去磷酸化、脱氨基、降解有关的药理靶点， 和交通工具。

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.