Metabolic effects and mechanisms for heart failure in South Asians

南亚人心力衰竭的代谢效应和机制

基本信息

批准号：
10049526
负责人：
ALKA M. KANAYA
金额：
$ 124.12万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-07 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10049526
关键词：
Abdomen Adenosine Adult Affect Age Americas Asians Atherosclerosis Biological Blood Body Weight Body mass index Cardiac Cardiovascular system Cell surface Central obesity Coronary Development Diabetes Mellitus EFRAC Echocardiography Endothelium Enzyme-Linked Immunosorbent Assay Epidemiology Ethnic group Exercise Failure Fatty acid glycerol esters Female Glucose Intolerance Goals Heart Abnormalities Heart failure Hepatic High Prevalence Hypertension Immunologics Individual Inflammation Insulin Resistance Knowledge Light Link Liver Mass Spectrum Analysis Measures Mechanics Mediating Mediator of activation protein Metabolic Metabolic dysfunction Methods Microvascular Dysfunction Molecular Morbidity - disease rate Multi-Ethnic Study of Atherosclerosis Muscle Non obese Obesity Participant Pathogenesis Pathway interactions Patients Peripheral Blood Mononuclear Cell Phenotype Physiological Plasma Population Population Heterogeneity Prediabetes syndrome Prevalence Process Prognosis Prospective cohort Proteins Proteomics Protocols documentation Race Risk Factors Role Sampling South Asian Stress Stress Echocardiography Structure Subgroup Symptoms Testing Treatment Failure Viscera Visceral fat Weight aged aptamer arterial stiffness base cardiovascular disorder risk cohort diabetic endothelial dysfunction ethnic difference experimental study high risk improved outcome lens mortality novel novel therapeutics preservation prevent proteomic signature sex single-cell RNA sequencing tool

项目摘要

PROJECT SUMMARY The goal of this project is to fill gaps in our understanding of early heart failure stages and of heart failure with preserved ejection fraction (HFpEF). Over half of all heart failure patients have HFpEF, and are more likely to be older, diabetic, obese, hypertensive and have a prognosis that is equally poor as those with reduced ejection fraction. No treatment has been shown to improve outcomes in patients with HFpEF, highlighting an urgent need to understand the heterogeneous phenotypes and underlying biologic and physiologic mechanisms for HFpEF. We have established a prospective cohort of South Asians called the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study that is closely tied to the Multi-Ethnic Study of Atherosclerosis (MESA) for efficient cross-ethnic comparisons. We have found that South Asians have significantly higher prevalence of diabetes and metabolic abnormalities, even with normal body mass index, compared to the four MESA race/ethnic groups. Additionally, South Asians have very high levels of fat stored in ectopic depots (in the liver, muscle and around the abdominal viscera). This unique cohort with its distinct phenotype can be leveraged to understand the metabolic effects and mechanisms involved in heart failure. In this proposed study, we will use the thorough baseline and repeated metabolic characterization of MASALA study participants and will measure heart failure stages among 850 MASALA participants in a new Exam 3. We will characterize heart failure stages by symptoms, dynamic echocardiography, NTproBNP, and HFpEF will be confirmed by exercise stress echocardiography. We propose to 1) determine the epidemiology of heart failure among middle to older aged South Asians and compare heart failure stages and HFpEF prevalence in South Asians to the four MESA race/ethnic groups. We will determine whether differences in heart failure stages and HFpEF prevalence between South Asians and MESA groups are mediated by differences in dysglycemia, ectopic fat and other metabolic factors; 2) determine whether endothelial dysfunction, arterial stiffness, and coronary microvascular dysfunction drive HFpEF in South Asians, and if they mediate the association between dysglycemia, adiposity, and HFpEF; and 3) determine the blood-based proteomic signatures of heart failure and HFpEF among South Asians. We will identify, verify, and validate the proteomics profile of heart failure and HFpEF, and determine the immunologic signatures characterizing HFpEF. We expect that South Asians will have a high prevalence of HFpEF, and that we will better define the phenotype and underlying mechanisms for HFpEF relevant for metabolically unhealthy but normal weight populations.

项目概要该项目的目标是填补我们对早期心力衰竭阶段和心力衰竭的理解空白保留射血分数（HFpEF）。超过一半的心力衰竭患者患有 HFpEF，并且更有可能年龄较大、患有糖尿病、肥胖、高血压，且预后与低血压患者一样差射血分数。目前尚无任何治疗方法能够改善 HFpEF 患者的预后，这凸显了迫切需要了解异质表型和潜在的生物学和生理学 HFpEF 的机制。我们建立了一个南亚人前瞻性群体，称为“调解者” 居住在美国的南亚人动脉粥样硬化 (MASALA) 研究与多种族研究密切相关动脉粥样硬化 (MESA) 进行有效的跨种族比较。我们发现南亚人即使体重指数正常，糖尿病和代谢异常的患病率也显着升高，与四个 MESA 种族/族裔群体相比。此外，南亚人的脂肪储存量非常高在异位库（在肝脏、肌肉和腹部内脏周围）。这个独特的群体有着独特的表型可用于了解心力衰竭的代谢效应和机制。在在这项拟议的研究中，我们将使用 MASALA 的全面基线和重复代谢特征研究参与者，并将在新的考试 3 中测量 850 名 MASALA 参与者的心力衰竭阶段。我们将通过症状、动态超声心动图、NTproBNP 和 HFpEF 来表征心力衰竭阶段经运动负荷超声心动图证实。我们建议 1) 确定心力衰竭的流行病学在南亚中老年人中进行研究，并比较南亚的心力衰竭阶段和 HFpEF 患病率亚洲人分为四个 MESA 种族/族裔群体。我们将确定心力衰竭阶段和时间是否存在差异南亚人和 MESA 群体之间的 HFpEF 患病率是由血糖异常差异介导的，异位脂肪和其他代谢因素； 2) 确定内皮功能障碍、动脉僵硬度是否存在冠状动脉微血管功能障碍导致南亚人的 HFpEF，以及它们是否介导两者之间的关联血糖异常、肥胖和 HFpEF； 3) 确定心力衰竭的血液蛋白质组特征南亚人中的 HFpEF。我们将识别、验证和验证心力衰竭的蛋白质组学特征和 HFpEF，并确定表征 HFpEF 的免疫学特征。我们预计南亚人 HFpEF 的患病率很高，我们将更好地定义表型和潜在的 HFpEF 的机制与代谢不健康但体重正常的人群相关。