MRI of epicardial adipose tissue composition: development of methods and application to heart failure with preserved ejection fraction

This proposal seeks to develop improved cardiac MRI (CMR) methods to quantify epicardial adipose tissue (EAT) composition and to demonstrate the advantages of EAT composition imaging (a) in advancing our understanding of the relationship between EAT and heart failure with preserved ejection fraction (HFpEF) and (b) for understanding mechanisms of and guiding medical therapy in HFpEF. EAT is the visceral adipose tissue situated immediately adjacent to the myocardium which is in direct contact and shares a microcirculation with both the myocardium itself and the coronary vessels. In healthy conditions EAT plays beneficial roles as a source of fuel for cardiomyocytes and by secreting anti-inflammatory adipokines. However, in obesity EAT accumulates, becomes proinflammatory, and promotes coronary vascular/microvascular inflammation, oxidative stress, and diffuse and perivascular fibrosis, contributing to atrial fibrillation, epicardial and microvascular coronary artery disease, and HFpEF. While imaging of EAT quantity has shown clinical value, basic studies implicate the EAT fatty acid composition (FAC) in the activation of proinflammatory signaling pathways. Consistent with the basic science, our preliminary data suggest that CMR of EAT FAC is a modifiable biomarker of proinflammatory EAT with greater clinical utility than imaging of EAT quantity. We recently developed the first method for quantifying EAT FAC in human subjects, utilizing a rate-6 accelerated radial 2D multi-echo gradient-echo breathhold acquisition with a local low rank reconstruction. In this project the first specific aim is to develop a rapid free-breathing 3D EAT FAC MRI method that reduces motion-related artifacts, increases coverage, and facilitates higher spatial resolution and improved FAC reproducibility. The second specific aim is to show that EAT FAC is more strongly associated than EAT volume with cardiometabolic HFpEF. In this context, individuals with known or suspected HFpEF will undergo CMR, echocardiography, and other testing to (a) diagnose cardiometabolic HFpEF; (b) characterize features associated with the severity of HFpEF; and (c) assess EAT volume and FAC. We will determine if EAT FAC is more strongly associated than EAT volume with HFpEF and with features associated with the severity of HFpEF. The third specific aim is to show, in the context of cardiometabolic HFpEF and pre-HFpEF, (a) that GLP-1 receptor agonism with semaglutide (SEMA) shifts the EAT FAC to a less proinflammatory profile and (b) that baseline EAT FAC is a stronger predictor than EAT volume of improved cardiovascular function due to SEMA. Cardiometabolic HFpEF and pre-HFpEF subjects will undergo echocardiography and CMR with EAT FAC at baseline and after 2 months to serve as a self-control. Subjects will then undergo repeat imaging 5 months after the initiation of SEMA. The change in FAC after treatment with SEMA will be compared to the change in FAC prior to SEMA. Data will be analyzed to show that SEMA changes EAT FAC, and that baseline EAT FAC is a stronger predictor than EAT volume of improvements in severity of HFpEF. Project Number: 1R01HL181257-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Frederick Epstein (+1 co-PI) | Institution: UNIVERSITY OF VIRGINIA, CHARLOTTESVILLE, VA | Award Amount: $802,611 | Activity Code: R01 | Study Section: Clinical Translational Imaging Science Study Section[CTIS] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL18125701