Beyond BMI: Role of Body Composition, Coronary Microvascular Dysfunction and HFpEF in Characterizing Cardiometabolic Disease Phenotypes - PROJECT SUMMARY/ABSTRACT: Obesity, coronary artery disease (CAD) and heart failure represent 3 of the most important threats to US public health, yet there is limited understanding of how these chronic multimorbid conditions manifest differently across heterogeneous populations, including women versus men. Ischemia with nonobstructive coronary arteries (INOCA) captures a chronic condition that has newly emerged as a major contributor to adverse cardiovascular disease (CVD) outcomes, especially in women. Current evidence suggests that a large proportion of these women have coronary microvascular dysfunction (CMD). CMD is associated with increased risk of adverse CVD outcomes, including death, myocardial infarction (MI), and heart failure with preserved ejection fraction (HFpEF), especially in patients with obesity and cardiometabolic risk factors. Yet conventional diagnostic and therapeutic strategies, tailored for identification and management of male-pattern obesity and CVD, miss a majority of these at-risk women with INOCA, who represent an understudied population with high unmet clinical need. To optimally address the heterogeneity of obesity in these patients, we propose to apply cutting-edge diagnostic technology to investigate the role of body composition, CMD and HFpEF in characterizing adverse cardiometabolic phenotypes in INOCA. The overall goal of this proposal is to leverage novel, sensitive multimodality imaging tools to identify mechanisms of cardiometabolic risk in INOCA and clarify targets for future intervention in this patient population. The PI is an Early Stage Investigator (ESI) cardiologist and expert in CMD ideally positioned, together with Co-I experts in cardiothoracic radiology, artificial intelligence methods for body composition, and clinical weight loss interventions, to build upon strong preliminary data and existing infrastructure from her NIH- funded research to advance this time-sensitive, high-impact work in a manner that is scientifically significant, clinically innovative, mechanistically plausible, and feasible for completion within the allotted time frame and budget. Our central hypothesis is that phenotypic characterization of INOCA patients beyond body mass index will yield important insights to understanding and treating this understudied cardiometabolic condition. We will investigate the following specific aims: (1) to comprehensively assess novel body composition metrics across lean and ectopic adipose tissue depots and identify their relationship to CMD in INOCA patients using multimodal imaging with PET/CT, (2) to identify cardiometabolic pheonotypes in INOCA patients associated with major CVD events, including death and hospitalization for MI and HFpEF, and (3) to evaluate the impact of serial clinical weight loss interventions (GLP-1 agonist and bariatric surgery) on body composition, coronary microvascular function, myocardial strain and cardiorespiratory fitness in patients with INOCA and severe obesity. By rigorously characterizing body composition, CMD and HFpEF risk in INOCA, the proposed aims will definitively clarify our understanding of this understudied condition overrepresented in women and tailor novel discovery to exert a sustained, powerful influence on obesity/cardiometabolic health research.
