Molecular markers of early cardiometabolic health transitions in the CARDIA study

CARDIA 研究中早期心脏代谢健康转变的分子标记

• 批准号: 10581341
• 负责人: Venkatesh Locharla Murthy
• 金额: $ 11.73万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581341
• 关键词: Molecular; markers; early; cardiometabolic; health

Cardiometabolic diseases (CMD) are a major cause of morbidity and mortality, specifically among African Americans. CMD has origins in youth, and ongoing efforts focus CMD prevention to early adulthood, before clinically overt cardiovascular disease (CVD) or its risk factors develop. We have established that (1) subclini- cal CVD is present in children and young adults and forecasts long-term adverse outcomes; (2) adverse CMD trajectories appear in early adulthood and are associated with mid-life CVD; (3) relative to Caucasians, African Americans exhibit greater cardiac hypertrophy/dysfunction in response to early worsening in CMD risk; (4) tra- ditional metabolic risk factors do not identify African Americans or Caucasians in early adulthood with high life- time CMD risk. These results imply pathophysiologic distinctions in how African Americans respond to CMD and call for more specific markers of metabolic dysregulation early in adulthood for risk stratification. In this re- gard, metabolites and extracellular RNAs (ex-RNAs) are circulating, stable, functional biomolecules that inte- grate metabolic signals across tissues relevant to CMD (hepatic, adipose, muscle, cardiac). We recently ob- served circulating ex-RNAs associated with CMD phenotypes (insulin resistance, hepatic/visceral fat) in older Caucasians in the Framingham Heart Study (FHS). Strikingly, several of these ex-RNAs from FHS were asso- ciated with insulin resistance and adverse metabolite profiles (branched chain amino acids) in children, with in silico analysis suggesting a regulatory role for ex-RNAs in metabolism. Therefore, metabolites and ex-RNAs may sensitively identify global metabolic dysregulation early in CMD. Nevertheless, African Americans and young adults remain underrepresented in studies of metabolomics and ex-RNAs in CMD/CVD, representing a novel locus of investigation for biological insights and risk stratification. Here, we extend our preliminary find- ings in the Coronary Artery Risk Development in Youth (CARDIA) study (1) to identify molecular biomarkers in young adulthood across race that reflect cardiometabolic health transitions through life; (2) to understand how these biomolecules impact long-term clinical disease, leveraging long-term follow-up and CVD/CMD outcomes in CARDIA. In ~2,400 biracial CARDIA participants (45% African American; mean age 32), we hypothesize that circulating metabolites and ex-RNAs dysregulated in early adulthood will identify individuals with poor long-term CMD/CVD risk over >20 years. We will determine metabolite profiles in early adulthood that identify individuals in adverse lifetime CMD trajectories and how they impact long-term CMD risk (e.g., adiposity, met- abolic syndrome; SA1). We will investigate how early adverse metabolite profiles impact future CVD (cardiac hypertrophy, fitness, vascular calcification, clinical outcomes; SA2). Finally, following results in FHS, we will use systems biology to understand implications of ex-RNAs on global metabolic dysfunction (SA3). Completion of this project by our uniquely qualified multidisciplinary team will provide a shared public resource to the broad scientific community for investigation of CMD and CVD in a young, biracial population at high lifetime risk.

心脏代谢性疾病(CMD)是发病率和死亡率的主要原因，特别是在非洲。 美国人。CMD起源于青年，持续的努力将CMD预防集中在成年早期，在此之前 临床显性心血管疾病(CVD)或其危险因素的发生。我们已经确定：(1)亚临床-- CAL心血管疾病存在于儿童和年轻人中，并预测长期的不良后果；(2)不利的CMD 轨迹出现在成年早期，与中年心血管疾病有关；(3)相对于高加索人，非洲人 美国人表现出更大的心肌肥厚/功能障碍，以应对CMD风险的早期恶化；(4)反式- 传统的新陈代谢风险因素不能确定成年早期的非裔美国人或高加索人生活质量高- 时间CMD风险。这些结果暗示了非裔美国人对CMD反应的病理生理学差异。 并呼吁在成年早期使用更具体的代谢失调标志物来进行风险分层。在这件事上- GARD、代谢物和胞外RNAs(ex-RNAs)是一种循环、稳定、具有功能的生物分子。 收集与CMD(肝脏、脂肪、肌肉、心脏)相关的组织的代谢信号。我们最近注意到- 与老年人CMD表型(胰岛素抵抗、肝脏/内脏脂肪)相关的循环前RNA 弗雷明翰心脏研究(FHS)中的高加索人。引人注目的是，这些来自FHS的前RNA中的几个也是如此- 与胰岛素抵抗和不良代谢产物(支链氨基酸)有关的儿童， 电子计算机分析表明，前RNA在新陈代谢中起着调节作用。因此，代谢物和前RNA 可在CMD早期敏感地识别全球代谢紊乱。尽管如此，非洲裔美国人和 年轻人在代谢组学和CMD/CVD的前RNA研究中的代表性仍然不足，这意味着 生物洞察和风险分层的新调查地点。在这里，我们扩大了我们的初步发现- INGS在青年冠状动脉危险发展(CARDIA)研究(1)中确定分子生物标记物 反映一生心脏代谢健康转变的不同种族的青年；(2)了解 这些生物分子影响长期临床疾病，影响长期随访和CVD/CMD结果 在卡迪亚。在大约2400名混血CARDIA参与者(45%是非洲裔美国人；平均年龄为32岁)中，我们假设 在成年早期，循环代谢产物和前RNA调节失调将识别出贫穷的个体 20年内CMD/CVD的长期风险。我们将测定成年早期的代谢物特征，以确定 处于不利的终生CMD轨迹中的个体及其如何影响长期CMD风险(例如，肥胖、满足- 代谢综合征；SA1)。我们将研究早期不良代谢物特征如何影响未来的心血管疾病(心脏 肥大，健康，血管钙化，临床结果；SA2)。最后，根据FHS的结果，我们将 使用系统生物学来理解前RNA对全球代谢功能障碍的影响(SA3)。完成 我们唯一合格的多学科团队将为广大公众提供共享的公共资源 科学界在高终生风险的年轻混血人群中研究CMD和CVD。

项目成果

Assessment of dyssynchrony by gated myocardial perfusion imaging does not improve patient management.

通过门控心肌灌注成像评估不同步并不能改善患者管理。

• DOI: 10.1007/s12350-017-1022-9
• 发表时间: 2018
• 期刊: Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology
• 作者: Lee,Ran;Shah,RaviV;Murthy,VenkateshL
• 通讯作者: Murthy,VenkateshL

Association of Multiorgan Computed Tomographic Phenomap With Adverse Cardiovascular Health Outcomes: The Framingham Heart Study.

多器官计算机断层扫描表型图与不良心血管健康结果的关联：弗雷明汉心脏研究。

• DOI: 10.1001/jamacardio.2017.3145
• 发表时间: 2017
• 期刊: JAMA cardiology
• 影响因子: 24
• 作者: Shah,RaviV;Yeri,AshishS;Murthy,VenkateshL;Massaro,JoeM;D'AgostinoSr,Ralph;Freedman,JaneE;Long,MichelleT;Fox,CarolineS;Das,Saumya;Benjamin,EmeliaJ;Vasan,RamachandranS;O'Donnell,ChristopherJ;Hoffmann,Udo
• 通讯作者: Hoffmann,Udo

The Impact of Age on the Likely Impact of Coronary Calcium Testing in the 2018 Cholesterol Guidelines.

2018 年胆固醇指南中年龄对冠状动脉钙检测可能产生的影响。

• DOI: 10.1007/s11606-019-05369-w
• 发表时间: 2020
• 期刊: Journal of general internal medicine
• 影响因子: 5.7
• 作者: Sussman,JeremyB;Murthy,VenkateshL
• 通讯作者: Murthy,VenkateshL

Arterial Stiffness and Cardiorespiratory Fitness Impairment in the Community.

• DOI: 10.1161/jaha.123.029619
• 发表时间: 2023-11-07
• 期刊: Journal of the American Heart Association
• 影响因子: 5.4

Safety of regadenoson positron emission tomography stress testing in orthotopic heart transplant patients.

原位心脏移植患者中热加腺松正电子发射断层扫描压力测试的安全性。

• DOI: 10.1007/s12350-018-01466-1
• 发表时间: 2020
• 期刊: Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology
• 作者: Lazarus,JohnJ;Saleh,Ashraf;Ghannam,Michael;Aaronson,Keith;Colvin,Monica;Pagani,Frank;Koelling,Todd;Corbett,JamesR;Weinberg,RichardL;Murthy,VenkateshL;Konerman,MatthewC
• 通讯作者: Konerman,MatthewC