Plasma Metabolomics and Myocardial Energetics in Heart Failure

心力衰竭的血浆代谢组学和心肌能量学

• 批准号: 9900043
• 负责人: David E Lanfear
• 金额: $ 76.33万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900043
• 关键词: Acetates; Address; Animal Model; Animals; Biological; Biological Markers; Blood; Brain natriuretic peptide; Canis familiaris; Cardiac; Cell Respiration; Clinical; Cohort Studies; Data; Development; Disease; Disease Progression; EFRAC; Energy Metabolism; Focus Groups; Genes; Genetic; Genomics; Genotype; Heart; Heart failure; Heritability; Hospitals; Human; Impairment; Individual; Infrastructure; Interdisciplinary Study; Intervention; Intervention Studies; Investigation; Laboratories; Lead; Link; Measures; Metabolic; Metabolic Pathway; Metabolism; Methods; Mitochondria; Modeling; Myocardial; Myocardial dysfunction; Myocardium; Natural History; Pathway interactions; Patients; Peripheral; Pharmacotherapy; Phenotype; Plasma; Positron-Emission Tomography; Public Health; Risk; Sampling; Series; Severity of illness; Source; Specific qualifier value; Structure; Subgroup; Technology; Testing; Validation; Variant; Work; clinical development; clinical phenotype; cohesion; cohort; disease heterogeneity; follow-up; genome-wide; improved outcome; in vivo; interest; metabolomics; novel; novel therapeutics; outcome forecast; personalized medicine; precision medicine; response; survival prediction; tool; treatment response; treatment strategy

ABSTRACT Heart failure (HF) remains an enormous public health problem despite advances in treatment. Disease progression and response to therapy in HF varies widely between individuals, but breakthrough technologies such as genomics and metabolomics are helping to unravel the disease heterogeneity that confounds patient management. Perturbed energy metabolism may be a key contributor to cardiac dysfunction and the development of clinical HF. Evidence from a variety of sources indicates that impaired structure and function of the energetic apparatus in the myocardium contributes to disease severity, progression, and may influence response to treatment. However, in order to advance these observations toward meaningful interventions for HF patients, several key steps are still needed: 1) confirming the importance of metabolic variation in human HF, 2) developing noninvasive markers of myocardial energetic status, and 3) identifying promising targets for intervention. Our proposed project is a series of interwoven translational investigations in humans and dogs with HF to define the association of plasma metabolite levels with disease severity, myocardial energetics, and disease progression. This project leverages substantial infrastructure already in place a large existing genetic cohort study, available plasma samples suitable for metabolomic profiling, comprehensive translational laboratory capabilities, and a cohesive multidisciplinary research group focused on HF. Together the planned studies will address the overarching hypothesis that the peripheral metabolomic signature can indicate disease progression/treatment responsiveness in HF patients and that this is driven by altered myocardial energy metabolism. If true, then these data will help advance personalized therapy and identify novel targets for HF intervention, leading to improved outcomes for HF patients.

摘要 尽管在治疗方面取得了进展，但心力衰竭(HF)仍然是一个巨大的公共卫生问题。疾病 心力衰竭的进展和治疗反应因个体而异，但突破性技术 例如基因组学和代谢组学正在帮助解开令患者困惑的疾病异质性 管理层。紊乱的能量代谢可能是导致心脏功能障碍的关键因素 临床心力衰竭的研究进展。来自各种来源的证据表明，结构和功能受损 心肌中能量装置的变化有助于疾病的严重程度和进展，并可能影响 对治疗的反应。然而，为了将这些观察结果推向有意义的干预措施， 对于心力衰竭患者，仍然需要几个关键步骤：1)确认人类代谢变异的重要性 HF，2)开发心肌能量状态的非侵入性标记物，以及3)确定有希望的靶点 干预。我们提出的项目是一系列相互交织的人类和狗的翻译研究 用心衰来确定血浆代谢物水平与疾病严重性、心肌能量学和 疾病的发展。该项目利用了已经到位的大量基础设施，现有的大型 队列研究，适用于代谢组学分析的可用血浆样本，全面翻译 实验室能力，以及一个专注于HF的具有凝聚力的多学科研究小组。共同规划的 研究将解决最重要的假设，即外周代谢特征可以指示疾病 心力衰竭患者的进展/治疗反应，这是由心肌能量改变驱动的 新陈代谢。如果是真的，那么这些数据将有助于推进个性化治疗，并确定心衰的新靶点 干预，使心力衰竭患者的预后得到改善。

项目成果

Barth syndrome cardiomyopathy: targeting the mitochondria with elamipretide.

• DOI: 10.1007/s10741-020-10031-3
• 发表时间: 2021-03
• 期刊: Heart failure reviews
• 影响因子: 4.6
• 作者: Sabbah HN

Effects of Angiotensin-Neprilysin Inhibition in Canines with Experimentally Induced Cardiorenal Syndrome.

• DOI: 10.1016/j.cardfail.2020.08.009
• 发表时间: 2020-11
• 期刊: Journal of cardiac failure
• 影响因子: 6
• 作者: Sabbah HN;Zhang K;Gupta RC;Xu J;Singh-Gupta V
• 通讯作者: Singh-Gupta V