Metabolic effects and mechanisms for heart failure in South Asians

项目摘要 该项目的目标是填补我们对心力衰竭早期阶段和心力衰竭的理解的空白， 射血分数保留（HFpEF）。超过一半的心力衰竭患者患有HFpEF， 老年人、糖尿病患者、肥胖者、高血压患者，其预后与那些 射血分数没有任何治疗可以改善HFpEF患者的结局，这突出了 迫切需要了解异质性表型和潜在的生物和生理 HFpEF的机制。我们已经建立了一个南亚人的前瞻性队列，称为调解人， 生活在美国的南亚人的动脉粥样硬化（MASALA）研究与多民族研究密切相关 （梅萨）进行有效的跨种族比较。我们发现南亚人 糖尿病和代谢异常的患病率明显较高，即使体重指数正常， 与四个梅萨种族/族裔群体相比。此外，南亚人有非常高的脂肪储存水平， 异位贮库（肝脏、肌肉和腹部内脏周围）。这个独特的群体， 表型可以用来理解心力衰竭中涉及的代谢效应和机制。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，并将在新的检查3中测量850名MASALA参与者的心力衰竭阶段。我们 将通过症状表征心力衰竭阶段，动态超声心动图、NTproBNP和HFpEF将 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 中老年南亚人，比较心力衰竭分期和HFpEF患病率， 亚洲人到四个梅萨种族/民族群体。我们将确定心力衰竭阶段和 南亚人和梅萨组之间的HFpEF患病率是由精神障碍的差异介导的， 异位脂肪和其他代谢因素; 2）确定是否内皮功能障碍，动脉僵硬， 冠状动脉微血管功能障碍驱动南亚人的HFpEF，如果它们介导了 心功能不全、肥胖和HFpEF; 3）确定心力衰竭的血液蛋白质组学特征 和HFpEF。我们将识别、验证和确认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。我们希望南亚人 HFpEF的患病率将很高，我们将更好地定义表型和潜在的 与代谢不健康但体重正常人群相关的HFpEF机制。

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.