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

心脏病中心脏机械-能量耦合的计算系统分析

• 批准号: 10376181
• 负责人: DANIEL A BEARD
• 金额: $ 44.24万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376181
• 关键词: 5' -Nucleotidase; ATP Hydrolysis; ATP Synthesis Pathway; Accounting; Adenine; Adenine Nucleotides; Affect; Anatomy; Animal Model; Biochemical; Biological Assay; Carbohydrates; Carbon; Cardiac; Cardiac Myocytes; Cardiovascular Physiology; Cell physiology; Chemicals; Chest; Chronic stress; Citric Acid Cycle; Computer Models; Congestive Heart Failure; Coupling; Data; Deamination; Degradation Pathway; EFRAC; Echocardiography; Energy Metabolism; Enzymes; Experimental Designs; Failure; Fatty acid glycerol esters; Financial compensation; Free Energy; Functional disorder; Heart; Heart Diseases; Heart Mitochondria; Heart failure; Hypertrophy; Impairment; Individual; Kinetics; Knock-out; Left Ventricular Remodeling; Light; Link; Measurement; Measures; Mechanics; Metabolic; Metabolic dysfunction; Metabolism; Mitochondria; Modeling; Molecular; Molecular Target; Myocardial; Myocardial Ischemia; Myocardium; Nucleotides; Organ; Oxidative Phosphorylation; Oxides; Pathologic; Pharmacology; Phenotype; Process; Protein Dephosphorylation; Pump; Purine Nucleotides; Purines; Rattus; Rodent; Rodent Model; Role; Study models; Systems Analysis; Testing; Transgenic Model; Transgenic Organisms; Work; animal data; base; constriction; experimental study; follow-up; heart function; human data; human model; improved; in vivo; inorganic phosphate; knock-down; metabolomics; mitochondrial dysfunction; models and simulation; multi-scale modeling; new therapeutic target; oxidation; predictive modeling; purine metabolism; repaired; small molecule inhibitor

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.

抽象的 心肌的能量状态在失败的心脏中被妥协的肥大损害， 具有化学能（以ATP水解电位的形式）可供心脏进行工作 与正常人相比减少。观测到的能量状态变化在机械上的后果 功能尚不清楚。在先前的研究中，我们开发了计算机模型，以解释 心肌中细胞质代谢物池的耗竭会影响心力衰竭的能量状态。和 代谢状态依赖的心肌力学计算机模型，可预测这些观察 能量状态的变化会影响体内的机械功能。使用这些模型来解释数据 人类和心脏代表性和心力衰竭的动物模型，我们预测代谢/能量 功能障碍直接导致心力衰竭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.）在心力衰竭的TAC大鼠模型中，代谢/能量功能障碍的主要原因是 线粒体能力降低氧化磷酸化和细胞质的病理耗竭 腺嘌呤核苷酸和其他关键代谢池。 （2.）减少了胞质ATP并增加无机磷酸盐（与能量受损有关 代谢）会损害心脏的机械功能。 （3.）通过阻止在长期压力和/或 周期性的缺血性心肌，我们可以增加/恢复核苷酸池并保护心脏免受 机械功能障碍和故障。 这三个特定目标是围绕测试和完善这三个假设而建立的。代谢和 来自实验的功能数据将根据多数 比例计算机模型将心脏能量和力学与全身心血管功能相结合。 假设将根据模型同时解释该模型的能力/无法进行测试和完善。 来自动物模型的代谢和机械数据。这种方法加快了假设的周期 测试（通过定量比较模型预测与实验观察结果），假设细化 （根据预测和数据之间的不匹配，重新设计和重新设计模型），并引入了模型 实验设计。第三个假设的成功检验有可能指向全新的班级 与嘌呤核苷酸去磷酸化，脱氨酸，降解，相关的药理学靶标 和运输。

项目成果

Quantification of Myocardial Creatine and Triglyceride Content in the Human Heart: Precision and Accuracy of in vivo Proton Magnetic Resonance Spectroscopy.

• DOI: 10.1002/jmri.27531
• 发表时间: 2021-08
• 期刊: Journal of magnetic resonance imaging : JMRI
• 作者: Bakermans AJ;Boekholdt SM;de Vries DK;Reckman YJ;Farag ES;de Heer P;Uthman L;Denis SW;Zuurbier CJ;Houtkooper RH;Koolbergen DR;Kluin J;Planken RN;Lamb HJ;Webb AG;Strijkers GJ;Beard DA;Jeneson JAL;Nederveen AJ
• 通讯作者: Nederveen AJ