Muscle Blood Flow Regulation in HFpEF

Mechanisms of Impaired Skeletal Muscle Blood Flow and Exercise Intolerance in Veterans With Heart Failure With Preserved Ejection Fraction: Efficacy of Knee Extensor Training

Heart failure with preserved ejection (HFpEF) disproportionately affects Veterans and is the number one reason for hospital discharge in the VA Health Care System. Exercise intolerance is a common complication experienced by patients with HFpEF, perpetuating physical inactivity and accelerating disease progression. This research proposal aims to elucidate mechanisms responsible for inadequate skeletal muscle blood flow and exercise intolerance in patients with HFpEF compared with healthy controls as well as following 8 weeks of exercise training in patients with HFpEF only.

Study Overview

• Status: Recruiting
• Conditions: HFpEF
• Intervention / Treatment: Other: Exercise training

Detailed Description

Heart failure (HF) with preserved ejection fraction (HFpEF) disproportionately afflicts Veterans and is the leading cause of hospitalization and mortality within the VA Health Care System. One chief symptom of HFpEF is severe exercise intolerance, an important predictor of quality of life, functional capacity, and mortality. In these patients, severe exercise intolerance is attributable to a disease-related loss of "peripheral vascular control," as evidenced by a marked attenuation in exercising skeletal muscle blood flow. Loss of peripheral vascular control is manifested as dysfunctions of the autonomic nervous system (ANS) and vasodilatory ability of the microvasculature, thereby restraining skeletal muscle blood flow and O2 delivery and limiting the capacity for sustained physical activity. This research proposal aims to elucidate peripheral vascular control mechanisms responsible for inadequate skeletal muscle blood flow and exercise intolerance in patients with HFpEF. In addition, there is some indication that aerobic exercise training may improve peripheral vascular function in HFpEF , though the mechanisms have yet to be elucidated. Thus, an additional aim of this research proposal is to evaluate peripheral vascular control mechanisms of skeletal muscle blood flow and exercise tolerance following 8 weeks of exercise training in patients with HFpEF. To test this, the initial phase will involve a cross-sectional comparison of patients with HFpEF (n=35) and age and sex-matched healthy controls (n=35), followed by an interventional phase where only patients with HFpEF will enter 8 weeks of exercise training. It is anticipated that knowledge gained will (a) improve the understanding of HFpEF pathophysiology and (b) determine the efficacy of a unique exercise training modality to restore functional capacity and exercise tolerance in patients with HFpEF.

• Study Type: Interventional
• Enrollment (Estimated): 35
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: David W Wray, PhD; Phone Number: 4162 (801) 582-1565; Email: David.Wray2@va.gov
• Study Contact Backup: Name: Kanokwan Bunsawat, PhD; Phone Number: 1951 (801) 582-1565; Email: Kanokwan.Bunsawat@va.gov

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States, 84148-0001
      • Recruiting
      • VA Salt Lake City Health Care System, Salt Lake City, UT
      • Principal Investigator: Kanokwan Bunsawat, PhD
      • Contact: David W Wray, PhD; Phone Number: 4162 (801) 582-1565; Email: David.Wray2@va.gov
      • Contact: Kanokwan Bunsawat, PhD; Phone Number: 1951 801-582-1565; Email: Kanokwan.Bunsawat@va.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Age 18 years or older and able to give written informed consent
• New York Heart Association (NYHA) functional class II or III
• Left Ventricular Ejection Fraction (LVEF) > 50%
• Plasma Brain Natriuretic Peptide (BNP) >200 pg/mL or NT-proBNP 400 pg/mL at enrollment

Exclusion Criteria:

• Prior EF of <50%.
• NYHA Class IV or HF that cannot be stabilized on optimized pharmacotherapy
• Acute coronary syndrome, infiltrative cardiomyopathy, or myocarditis
• Patients with HFpEF secondary to significant uncorrected primary valvular disease (except mitral regurgitation secondary to left ventricular dysfunction)
• Orthopedic limitations that would prohibit knee-extensor exercise
• Women currently taking hormone replacement therapy (HRT) will be excluded from the proposed studies due to the direct vascular effects of HRT
• Women who are pregnant or may become pregnant, but the typical age of female patients with HFpEF will be postmenopausal
• Current smokers

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Exercise training; Patients with HFpEF will participate in the 8 weeks of supervised, two-legged, knee extensor exercise training for 3 days per week. Each exercise session will involve a 5-min warm-up and a 5-min cool-down, and exercise intensity will range between 40%-90% of maximal work rate. Maximal work rate will be re-assessed every two weeks.	Other: Exercise training; Patients with HFpEF will undergo 8 weeks of exercise training.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Six-minute walk test	The six-minute walk test is used to measure distance covered during walking at a comfortable speed for six minutes	Change from baseline six-minute walk test distance at 8 weeks
Muscle blood flow	Muscle blood flow will be assessed non-invasively via Doppler ultrasound	Change from baseline skeletal muscle blood flow at 8 weeks

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Kanokwan Bunsawat, PhD, VA Salt Lake City Health Care System, Salt Lake City, UT

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2022
• Primary Completion (Estimated): July 31, 2027
• Study Completion (Estimated): February 29, 2028

Study Registration Dates

• First Submitted: October 21, 2021
• First Submitted That Met QC Criteria: November 8, 2021
• First Posted (Actual): November 10, 2021

Study Record Updates

• Last Update Posted (Actual): April 21, 2026
• Last Update Submitted That Met QC Criteria: April 20, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Exercise Tolerance; HFpEF; Muscle Blood Flow
• Additional Relevant MeSH Terms: Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena; Exercise
• Other Study ID Numbers: F3670-W

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