The Effect of Adiposity on Muscle and Microvascular Function in HFpEF

This project is an observational study in patients with heart failure with preserved ejection fraction (HFpEF) who are candidates for treatment with weight loss medication to manage obesity or diabetes as part of their standard clinical care. This study will include multiple experimental visits before and after treatment (minimum 7 percent weight loss, between 9-12 months) to understand how increased adiposity and inflammation effects skeletal muscle and cardiovascular health and function and to examine the effect of medically directed weight loss on skeletal muscle health and exercise tolerance. The objective of this study is to 1. Define the mechanisms by which adiposity impairs exercise hemodynamics, microvascular function, and oxygen transport/utilization in patients with HFpEF. 2. Determine if intensive medically directed weight loss can reduce microvascular inflammation and normalize exercise hemodynamics. 3. Quantify the effect of medically directed weight loss on skeletal muscle function and catabolism. Hypotheses 1. Perfusion of subcutaneous adipose tissue disrupts blood flow distribution and impairs muscle microvascular perfusion and exercise hemodynamics. 2. Extramyocellular muscular lipid deposition and microvascular endothelial inflammation is associated with reduced capillarity and impaired microvascular perfusions, while intramyocellular triglyceride content is associated with poor skeletal muscle oxidative capacity, 3. Intensive weight loss will improve exercise hemodynamics, microvascular perfusion, and reduce muscular inflammation, and resistance training will augment these effects.

Inclusion Criteria: Group 1: Patients with HFpEF * Diagnosis of heart failure or clear heart failure hospitalization * Stable ejection fraction \> 0.50 * Objective evidence of elevated left ventricular filling pressure by one of the following i) pulmonary capillary wedge pressure ≥25 mmHg during supine cardiopulmonary exercise testing or ii) a change in pulmonary capillary wedge pressure of \>15 mmHg during upright exercise * Must be candidates for pharmacological incretin-based directed intensive weight loss therapies as part of their SOC * BMI\>32kg/m2 * ≥45 years old * Incretin naïve for 6 months Group 2: Non-HFpEF controls * Adults who do not have heart failure with preserved ejection fraction * Age ≥ 18 years Exclusion Criteria: Group 1 * Prior history of reduced ejection fraction (\ 50kg/m2 * Other debilitating illness that would preclude participation * Any contra-indication to MRI * Any contra-indication to muscle biopsies. Group 2 * Age \< 18 years * BMI \> 50 kg/m2 * Atrial fibrillation with poorly controlled heart rate * PDE5 inhibitor use * Severe valvular disease * Severe COPD * CKD 4 or higher * Currently taking incretin-based drugs (SGL2, GLP1) * Any contra-indication to MRI * Any contra-indication to muscle biopsies.