Impact of obesity and diabetes on coronary microvascular defects in HFpEF

Project Summary Heart failure with preserved ejection fraction (HFpEF) is a complex and heterogeneous clinical syndrome accounting for over 50% of patients with heart failure. Major HFpEF risk factors include age, hypertension, diabetes, kidney disease and atherosclerosis. Prior studies have identified distinct phenogroups within the overall HFpEF population which are defined based on different predisposing co-morbidities. However, the links between these phenogroups and underlying pathophysiologic processes are poorly defined with limited tissue-based evidence. Recognizing that obesity and type-2 diabetes are pro-inflammatory, and that oxidative stress produces microvascular injury, I hypothesize that obesity and diabetes promote pathological structural and functional microvasculature remodeling that contribute to the development of HFpEF. I will test this hypothesis with a combination of observational and interventional studies using an animal model of HFpEF that is well-matched to the task. The ZSF1-obese rat is a genetic model of HFpEF with two leptin receptor mutations resulting in an obese, diabetic and hypertensive phenotype impacting multiple organ systems. Control ZSF-1 lean rats have a single leptin receptor mutation and develop hypertension without obesity or diabetes. I previously validated the accelerated development of HFpEF in ZSF1-obese vs. ZSF1- lean rats. In Aim 1, I will compare the temporal progression of microvascular structural and molecular changes in ZSF1-obese and lean rat myocardium using advanced morphological characterizations and spatial transcriptomic and proteomic techniques that resolve to cell type-specific expression patterns. In parallel, I will perform the same assays on banked myocardial specimens from a cohort of patients with features of HFpEF and relevant controls. In Aim 2, I will connect these tissue-based findings from the obese and lean rats with in vivo assessments of coronary microvascular function using micro single-photon emission computed tomography (µSPCT). In Aim 3, I will employ treatment with a GLP-1 receptor to test whether mitigation of obesity and diabetes can prevent and/or treat microvascular remodeling in the ZSF1- obese rat. Beyond the scientific merits of the proposed research, conducting these studies will broaden my understanding of cardiovascular pathophysiology and help develop my proficiency with several versatile and powerful techniques. My primary mentor, Dr. Ken Margulies, is a senior physician-scientist with expertise in myocardial pathophysiology and translational heart failure research using preclinical models and human myocardium. I have an advisory committee with expertise in each new topic area or technique (microvasculature, quantitative image analysis, spatial transcriptomics and proteomics, bioinformatics), and they are committed to my training. I have the full support of my institution where the environment favors dynamic and collaborative interactions among translational researchers and clinical experts. Together, the research, training, mentors and institutional environment assures my successful transition to independence.