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.