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

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

Interventions

OTHER

Exercise training

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

Sponsors & Collaborators

• University of Texas Southwestern Medical Center

  lead OTHER

Study Design

Allocation

NA

Purpose

BASIC_SCIENCE

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

65 Years

Max Age

85 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2018-02-01

Primary Completion

2026-03-01

Completion

2026-03-01

Countries

• United States

Study Locations