Abnormal Vascular, Metabolic, and Neural Function During Exercise in Heart Failure With Preserved Ejection Fraction

NCT03465072 | Suspended

• 1 other identifier: STU 082017-038
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

Brief Summary

Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of the heart failure population in the United States. The primary chronic symptom in patients with HFpEF is severe exercise intolerance quantified as reduced peak oxygen uptake during whole body exercise (peak V̇O2). To date, studies have focused almost exclusively on central cardiac limitations of peak V̇O2 in HFpEF. However, in stark contrast to heart failure with reduced ejection fraction (HFrEF), drug therapies targeting central limitations have invariably failed to improve peak V̇O2, quality of life, or survival in HFpEF. Emerging evidence from our lab suggests reduced skeletal muscle oxidative capacity may contribute to exercise intolerance in HFpEF patients. However, the mechanisms responsible for peripheral metabolic inefficiency remain unclear. Reduced blood flow (oxygen delivery), and slowed oxygen uptake kinetics (O2 utilization) may both contribute to reduced peripheral oxidative capacity. Importantly, reduced oxidative capacity may result in increased production of metabolites known to activate muscle afferent nerves and stimulate reflex increases in muscle sympathetic (vasoconstrictor) nervous system activity (MSNA). However, to date there have been no studies specifically investigating the contribution of peripheral metabolic and neural impairments to reduced exercise capacity in HFpEF. The overall aim of this proposal will be 1) to identify impairments in peripheral vascular, metabolic, and sympathetic neural function and 2) to assess the ability of small muscle mass (knee extensor, KE) training, specifically targeting these peripheral skeletal muscle deficiencies, to improve aerobic capacity and exercise tolerance in HFpEF. GLOBAL HYPOTHESIS 1: HFpEF patients will demonstrate reduced skeletal muscle oxygen delivery, slowed oxygen uptake kinetics, and elevated resting and metaboreflex mediated MSNA. Hypothesis 1.1: The vasodilatory response to knee extensor exercise will be impaired in HFpEF patients. Specific Aim 1.1: To measure the immediate rapid onset vasodilatory response to muscle contraction, as well as the dynamic onset, and steady state vasodilatory responses to dynamic KE exercise. Hypothesis 1.2: Skeletal muscle oxygen uptake kinetics will be slowed in HFpEF. Specific Aim 1.2: To measure pulmonary oxygen uptake kinetics during isolated KE exercise in order to isolate peripheral impairments in metabolic function independent of any central impairment. Hypothesis 1.3: HFpEF patients will demonstrate elevated MSNA at rest, and exaggerated metaboreflex sensitivity during exercise. Specific Aim 1.3: To test this hypothesis the investigators will measure MSNA from the peroneal nerve at rest, and during post exercise ischemia to directly assess metaboreflex sensitivity in HFpEF. GLOBAL HYPOTHESIS 2: Isolating peripheral adaptations to exercise training using single KE exercise training will improve peripheral vascular, metabolic, and neural function and result in greater functional capacity in HFpEF. Hypothesis 2.1: Isolated KE exercise training will improve the vasodilatory response to exercise, speed oxygen uptake kinetics, and reduce MSNA at rest HFpEF. Specific Aim 2.1: The assessments of vascular, metabolic, and neural function proposed in hypothesis 1 will be repeated after completing 8 weeks of single KE exercise training. Hypothesis 2.2: Single KE exercise training will improve whole body exercise tolerance, peak V̇O2, and functional capacity in HFpEF. Specific Aim 2.2: To test this hypothesis the investigators will measure maximal single KE work rate, V̇O2 kinetics and peak V̇O2 during cycle exercise, as well as distance covered in the six minute walk test.

Conditions

Heart Failure With Normal Ejection Fraction

Outcome Measures

Primary Outcomes (2)

• Muscle sympathetic nervous system activity

  Sympathetic neural activity measured during exercise

  Change in muscle sympathetic nervous system activity after 8 weeks of exercise training

• VO2 onset kinetics

  Rise in oxygen uptake during exercise

  Change in VO2 onset kinetics after 8 weeks of exercise training

Secondary Outcomes (2)

• Reactive hyperemia

  Change in Reactive hyperemia after 8 weeks of exercise training

• Exercise hyperemia

  Change in exercise hyperemia after 8 weeks of exercise training

Study Arms (1)

Exercise training

EXPERIMENTAL

8 Weeks exercise training 3x per week 30-40 minutes per session

Other: Exercise training

Interventions

Exercise training OTHER

8 weeks, 3 times per week, 30-40 minutes

Exercise training

Eligibility Criteria

• Age: 65 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Older Adult (65+)

You may not qualify if:

• Patients will be \> 65 years old
• We will use a modification of the European Guidelines for the diagnosis of HFpEF to select the patient population.
• The key components of these guidelines include:
• signs and symptoms of heart failure;
• b) an ejection fraction \> 0.50; and
• c) objective evidence of diastolic dysfunction. To satisfy the first criteria, we will use the Framingham criteria (dyspnea, orthopnea, PND, edema); however we will require objective evidence of congestion including
• chest X-ray,
• elevated BNP,
• or elevated PCWP (pulmonary capillary wedge pressure) or
• LVEDP (left ventricular end-diastolic pressure) \> 16 mmHg; for the second, we will accept echo, nuclear or catheter documentation; and for
• we will require a depressed tissue Doppler mitral annular velocity \< 7.5 cm/s along with PCWP \> 16 mmHg if available.
• underlying valvular or congenital heart disease;
• restrictive or infiltrative cardiomyopathy;
• acute myocarditis;
• NYHA Class IV CHF, or CHF that cannot be stabilized on medical therapy;

Sponsors & Collaborators

• University of Texas Southwestern Medical Center: lead

Study Sites (1)

The Institute for Exercise and Environmental Medicine

Dallas, Texas, 75231, United States

Location

MeSH Terms

Interventions

Exercise

Intervention Hierarchy (Ancestors)

Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: February 20, 2018
• First Posted: March 14, 2018
• Study Start: February 1, 2018
• Primary Completion: March 1, 2026
• Study Completion: March 1, 2026
• Last Updated: April 1, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)