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.

Study Overview

• Status: Enrolling by invitation
• Conditions: Heart Failure With Preserved Ejection Fraction (HFPEF)
• Intervention / Treatment: Drug: Weight loss SOC Treatment with second generation anti-diabetic medications

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

• Study Type: Observational
• Enrollment (Estimated): 95

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

Group 1: Patients with HFpEF

- UTSW HFpEF clinic: lead by Dr. Ambarish Pandey

Group 2: non-HFpEF controls

• subjects in the UTSW volunteer research registry who meet inclusion/exclusion criteria
• community outreach (emailers, word of mouth, referrals)

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
HFpEF and Obesity Group; Patients with HFpEF (heart failure with preserved ejection fraction) and diabetes will undergo standard of care treatment using the most appropriate second-generation anti-diabetic drug that induces clinically significant weight loss after completing baseline (pre) testing.	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 referred to a clinical psychologist for evaluation and management of factors like stress, anxiety and depression, and exercise which may influence their health behaviors and body weight.
Control Group (Non-HFpEF and Obesity); Controls matched for age and hypertension

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak muscle perfusion during exercise	Peak muscle perfusion (Aβ) during exercise will be assessed by Contrast enhanced ultrasound (CEU)	Pre intervention (Day 1)
Peak muscle perfusion during exercise	Peak muscle perfusion (Aβ) during exercise will be assessed by Contrast enhanced ultrasound (CEU)	Post intervention (Post Day 1)
Single cell RNA sequencing of skeletal muscle	Skeletal muscle biopsies will be taken from the vastus lateralis using the modified Bergstrom technique and immediately prepared for single cell RNA sequencing. Samples will be digested, filtered, washed and resuspended in freezing media and checked for concentration and viability before single cell RNA sequencing is performed	Pre intervention (Day 2)
Single cell RNA sequencing of skeletal muscle	Skeletal muscle biopsies will be taken from the vastus lateralis using the modified Bergstrom technique and immediately prepared for single cell RNA sequencing. Samples will be digested, filtered, washed and resuspended in freezing media and checked for concentration and viability before single cell RNA sequencing is performed	Post intervention (Day 2)
Muscle to fat ratio of leg	MRI of the leg will be performed to acquire clear visualization of fasciae separating different muscle groups and thus allowing for quantification of intermuscular fat (muscle:fat ratio)	Pre intervention (Day 3)
Peak change in microvascular perfusion from rest to exercise	MRI of the leg will be performed utilizing the PIVOT sequence which will measure global and regional perfusion of blood to the muscles in the lower leg at rest and during exercise. the peak change will be reported as the change from baseline to peak exercise	Pre intervention (Day 3)
Muscle to fat ratio of leg	MRI of the leg will be performed utilizing the PIVOT sequence which will measure the change in perfusion of blood to the muscles in the lower leg from rest to during exercise	Post intervention (Day 3)
Peak change in microvascular perfusion from rest to exercise	MRI of the leg will be performed utilizing the PIVOT sequence which will measure global and regional perfusion of blood to the muscles in the lower leg at rest and during exercise. the peak change will be reported as the change from baseline to peak exercise	Post intervention (Day 3)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vascular function - endothelium dependent vasodilation	A small ultrasound probe will be placed over the brachial artery and a small blood pressure cuff will be positioned on the lower arm, just below the elbow. Images of the vessel will be continuously recorded for 1 min (baseline) before the cuff is inflated to a high pressure (220mmHg) for 5minutes and immediately after the cuff is deflated for 3 minutes. The change in brachial artery diameter following deflation of cuff from baseline will represent a marker of vascular function	Pre intervention (Day1)
Vascular function - endothelium dependent vasodilation	A small ultrasound probe will be placed over the brachial artery and a small blood pressure cuff will be positioned on the lower arm, just below the elbow. Images of the vessel will be continuously recorded for 1 min (baseline) before the cuff is inflated to a high pressure (220mmHg) for 5minutes and immediately after the cuff is deflated for 3 minutes. The change in brachial artery diameter following deflation of cuff from baseline will represent a marker of vascular function	Post intervention (Day 1)
Blood volume measurement	The carbon monoxide rebreathe technique will be performed to measure blood volume	Pre intervention (Day1)
Blood volume measurement	The carbon monoxide rebreathe technique will be performed to measure blood volume	Post intervention (Day 1)
2min walk endurance test	Participants will be asked to walk on a flat surface back and forth between 2 cones for 2minutes. the total distance covered (in meters) during the 2-minutes will be recorded as a marker of endurance	Pre intervention (Day 2)
Hand grip strength	Participants will squeeze a handheld dynamometer as hard as they can to measure handgrip strength (in kg). This will be performed on both hands	Pre intervention (Day 2)
2min walk endurance test	Participants will be asked to walk on a flat surface back and forth between 2 cones for 2minutes. the total distance covered (in meters) during the 2-minutes will be recorded as a marker of endurance	Post intervention (Day2)
Hand grip strength	Participants will squeeze a handheld dynamometer as hard as they can to measure handgrip strength (in kg). This will be performed on both hands	Post intervention (Day2)
Body composition	measured using dual xray absorptiometry (DEXA) to get lean mass, muscle mass, body fat percentage	Pre intervention (Day 0)
Body composition	measured using dual xray absorptiometry (DEXA) to get lean mass, muscle mass, body fat percentage	Post intervention (Day 1)
Apnea hypopnea index	Participants will be given an at home sleep apnea test that is incorporated into a wrist-based wearable that enables non-invasive tracking of sleep apnea burden. Sleep apnea will be determined from the apnea hypopnea index measured by the device. Apnea hypopnea index will be calculated as the average number of apneas or hypopneas that occurs per hour of sleep	Pre intervention (Day 2)
Apnea hypopnea index	Participants will be given an at home sleep apnea test that is incorporated into a wrist-based wearable that enables non-invasive tracking of sleep apnea burden. Sleep apnea will be determined from the apnea hypopnea index measured by the device. Apnea hypopnea index will be calculated as the average number of apneas or hypopneas that occurs per hour of sleep	Post intervention (Day 2)

Collaborators and Investigators

• Sponsor: University of Texas Southwestern Medical Center
• Investigators: Principal Investigator: Christopher M Hearon Jr, PhD, University of Texas Southwestern Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): December 10, 2024
• Primary Completion (Estimated): March 1, 2028
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: March 31, 2025
• First Submitted That Met QC Criteria: April 8, 2025
• First Posted (Actual): April 16, 2025

Study Record Updates

• Last Update Posted (Actual): March 27, 2026
• Last Update Submitted That Met QC Criteria: March 23, 2026
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Weight loss; inflammation; adiposity; skeletal muscle; HFpEF; RNA sequencing
• Additional Relevant MeSH Terms: Pathologic Processes; Nutrition Disorders; Overnutrition; Body Weight; Body Weight Changes; Overweight; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Obesity; Weight Loss; Inflammation; Physiological Effects of Drugs; Hypoglycemic Agents
• Other Study ID Numbers: STU-2024-0279

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No