Metabolic Signatures Underlying Cardiac Function for Heart Failure in Multi-Ethnic Populations

摘要 心力衰竭(HF)影响着600多万美国成年人，估计患病率和护理费用为 预计将大幅增加。心衰的特征是心脏代谢功能障碍，包括受损 支链氨基酸(BCAA)分解代谢，减少脂肪酸氧化，抑制尿素循环功能。 随着高通量代谢组学的出现，数十种循环代谢特征已经被 被确定为协助心力衰竭的临床治疗。心肌能量代谢紊乱可在 高危个体在发生心力衰竭之前，并可能导致心脏结构和心脏结构的改变 作为HF基础的功能。然而，代谢功能障碍在心脏结构和功能改变中的作用 功能及其与心力衰竭发展的关系尚未得到很好的研究，特别是在非洲和 拉美裔美国人是美国最大的两个少数群体，他们表现出不成比例的心力衰竭风险。我们的 先前的工作和初步结果支持血清代谢物，反映系统代谢和 心肌能量学及其遗传决定因素与心功能不全和心力衰竭风险有关 在不同的种族中既有一致的时尚，也有不同的时尚。这项研究的目标是确定血清 代谢特征及其导致心功能不全和心力衰竭风险的基因决定因素 在欧洲裔美国人(EA)、非裔美国人(AA)和西班牙裔美国人(HAS)中。这项拟议的研究 将利用社区动脉粥样硬化风险(ARIC)研究和西班牙裔研究的丰富基础设施 社区健康研究/拉丁裔研究(HCHS/SOL)，两个具有独特资源的预期队列 包括代谢组谱、基因组数据、心脏结构/功能的测量和心衰的随访。 我们的目标是：(1)确定与亚临床心功能不全相关的代谢特征及其 与心功能不全进展和心力衰竭风险的关系；以及(2)确定 与亚临床心功能不全相关的代谢物及其与心功能不全的关系 进展和心力衰竭风险。我们将应用综合方法来确定潜在的遗传和代谢原因。 在心力衰竭病因学中实施的标记物，并考虑种族/民族和 性。我们的团队处于独特的地位，考虑到我们在代谢组谱、基因组学、心脏 结构/功能、HF裁决、生物统计学和生物信息学。这项研究的结果将使 在理解心力衰竭病理生理学方面不断取得的科学进展，对 预防和潜在的治疗方法。

ABSTRACT Heart failure (HF) affects more than 6 million American adults, and the estimated prevalence and cost of care is expected to increase markedly. HF is characterized by cardiac metabolic dysfunction, including impaired branched-chain amino acid (BCAA) catabolism, decreased fatty acid oxidation and depressed urea cycle function. With the advent of high-throughput metabolomics, scores of circulating metabolic signatures have been identified to assist clinical management of HF. Perturbations in myocardial energy metabolism are detectable in at-risk individuals prior to the development of HF, and may contribute to alterations in cardiac structure and function that underlie HF. However, the role of metabolic dysfunction in the changes of cardiac structure and function and its relationship to the development of HF has not been well studied, specifically among African and Hispanic Americans, the two largest minority groups in the U.S. who exhibit a disproportionate risk of HF. Our previous work and preliminary results support that serum metabolites, reflecting systemic metabolism and myocardial energetics, and their genetic determinants are associated with cardiac dysfunction and HF risk, in both consistent and divergent fashion across different ethnic groups. The goal of this study is to identify serum metabolic signatures along with their genetic determinants that contribute to cardiac dysfunction and HF risk in European Americans (EAs), African Americans (AAs) and Hispanic Americans (HAs). This proposed study will leverage the rich infrastructure of the Atherosclerosis Risk in Communities (ARIC) study and the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), two prospective cohorts with unique resources encompassing metabolome profiles, genomic data, measures of cardiac structure/function, and HF follow-up. Our aims are: (1) to identify metabolic signatures associated with subclinical cardiac dysfunction and their association with progression of cardiac dysfunction and HF risk; and (2) to identify genetic determinants of metabolites related to subclinical cardiac dysfunction, and their association with cardiac dysfunction, its progression and HF risk. We will apply integrative approaches to identify potential causal genetic and metabolic markers implemented in HF etiology, and consider the potential for effect modification by race/ethnicity and sex. Our team is uniquely positioned, given our expertise in metabolome profiling, genomics, cardiac structure/function, HF adjudication, biostatistics and bioinformatics. The results of this research will enable continued scientific progress toward an understanding of HF pathophysiology, with direct implications for prevention and potential therapies.