This study 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 the 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. The investigators 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. The investigators 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 3 months to serve as a self-control. Subjects will then undergo repeat imaging 6 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.

Inclusion Criteria:

• Age ≥ 18 years - 90 years;
• LVEF ≥ 50%;
• ≥ 2 risk factors for HFpEF or symptoms that could be related to HFpEF (e.g., dyspnea, orthopnea, paroxysmal nocturnal dyspnea, lower extremity edema, pulmonary edema, etc);
• Not currently being treated with GLP-1RA therapy.

Exclusion Criteria:

• • Previously or currently reduced EF (<50%), including heart transplant; (2) Obstructive un-revascularized coronary disease by coronary CT or invasive coronary angiography;

  • MI/PCI/CABG within the past 6 months;
  • Untreated severe stenotic or regurgitant valvular disease;
  • Infiltrative cardiomyopathy (Fabry/HCM/sarcoid/amyloid, etc);
  • Myocarditis;
  • Claustrophobia/inability to tolerate MRI;
  • Implants that are a contraindication for MRI or may negatively impact image quality (e.g. pacemakers and ICDs);
  • Active systemic inflammatory disorder;
  • Atrial fibrillation with rapid ventricular response at time of study; and
  • Hemodynamic instability
  • Pregnancy
  • Prisoners
  • Inability to provide informed consent

Exclusion Criteria for Optional Cardiac Stress Imaging Procedure

• allergy to gadolinium-based contrast agents
• Acute kidney injury
• Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m²
• Hepatorenal syndrome
• History of liver transplant
• High-grade atrioventricular (AV) block
• Active asthma exacerbation
• Known allergy to vasodilator agents
• Recent seizure