The Effect of Adiposity on Muscle and Microvascular Function in HFpEF

Overview

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.

Detailed description

Objective one will also include a cross-sectional comparison between HFpEF patients before treatment and non-HFpEF controls matched for age and hypertension

Interventions

• Drug Weight loss SOC Treatment with second generation anti-diabetic medications
  To determine the best incretin-based drug for the treatment \[done as part of regular standard of care (SOC) treatment\], participants will go to UTSW weight wellness clinic and undergo a comprehensive history and physical exam to evaluate their overall health. This information is used to create an individualized approach to the participants weight loss regimen. As part of the regimen, participants will receive guidance on initiating lifestyle modifications including diet and exercise and may be

Primary outcome measures

• Peak muscle perfusion during exercise [Time frame: Pre intervention (Day 1)]
• Peak muscle perfusion during exercise [Time frame: Post intervention (Post Day 1)]
• Single cell RNA sequencing of skeletal muscle [Time frame: Pre intervention (Day 2)]
• Single cell RNA sequencing of skeletal muscle [Time frame: Post intervention (Day 2)]
• Muscle to fat ratio of leg [Time frame: Pre intervention (Day 3)]
• Peak change in microvascular perfusion from rest to exercise [Time frame: Pre intervention (Day 3)]
• Muscle to fat ratio of leg [Time frame: Post intervention (Day 3)]
• Peak change in microvascular perfusion from rest to exercise [Time frame: Post intervention (Day 3)]

Secondary outcome measures (12)

• Vascular function - endothelium dependent vasodilation [Time frame: Pre intervention (Day1)]
• Vascular function - endothelium dependent vasodilation [Time frame: Post intervention (Day 1)]
• Blood volume measurement [Time frame: Pre intervention (Day1)]
• Blood volume measurement [Time frame: Post intervention (Day 1)]
• 2min walk endurance test [Time frame: Pre intervention (Day 2)]
• Hand grip strength [Time frame: Pre intervention (Day 2)]
• 2min walk endurance test [Time frame: Post intervention (Day2)]
• Hand grip strength [Time frame: Post intervention (Day2)]
• Body composition [Time frame: Pre intervention (Day 0)]
• Body composition [Time frame: Post intervention (Day 1)]
• Apnea hypopnea index [Time frame: Pre intervention (Day 2)]
• Apnea hypopnea index [Time frame: Post intervention (Day 2)]

Eligibility criteria

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 (<50%)
• Infiltrative cardiomyopathy
• NYHA Class IV chronic heart failure
• Left bundle branch block
• Unstable coronary artery disease
• Uncontrolled arrhythmia
• CKD 4 or higher
• Currently taking incretin-based drugs (SGL2, GLP1)
• Severe valvular heart disease
• BMI > 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Case-control

Study locations

United States · 1 center

• University of Texas Southwestern Medical Center — Dallas

Identifiers

NCT: NCT06930495 · STU-2024-0279

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗