Clinical Trial Details
— Status: Active, not recruiting
Administrative data
NCT number |
NCT03465072 |
Other study ID # |
STU 082017-038 |
Secondary ID |
|
Status |
Active, not recruiting |
Phase |
N/A
|
First received |
|
Last updated |
|
Start date |
February 1, 2018 |
Est. completion date |
March 1, 2025 |
Study information
Verified date |
April 2024 |
Source |
University of Texas Southwestern Medical Center |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial 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.
Description:
Protocol 1.1: To test hypothesis 1.1 the investigators will measure rapid onset vasodilation
in response to a single KE contraction as a marker of vascular responsiveness to muscle
contraction, as well as the dynamic onset, and steady state vasodilatory responses to
continuous KE exercise. The rapid onset vasodilatory (ROV) response to a brief (1-second)
single isometric knee extension contraction will be measured as described by our
collaborators50. Subjects will perform single contractions at 5, 10 or 20% of their maximal
voluntary contraction (MVC). Beat-by-beat local vascular responses (i.e. femoral blood flow;
FBF and vascular conductance; FVC) will be recorded continuously for 30-seconds with the
initial response (first un-interrupted cardiac cycle post-contraction), peak response
(maximal increase), latency (time to peak response) and area under the curve (total
vasodilator response across 30-seconds) analyzed to fully characterize ROV in HFpEF.
Additionally, the vascular and hemodynamic response to dynamic KE exercise (beat-by-beat
onset and steady state FBF and FVC) will be measured from the onset of exercise for six
minutes at submaximal work rates (10, 15 W, and 60% maximal work rate). These trials will be
performed individually and with 20 minutes of rest between conditions to ensure that patients
will be able to complete each of these trials. In addition to local vascular hemodynamics,
systemic hemodynamics (HR, MAP, CO, SV) will be monitored throughout to confirm that any
alterations in local blood flow are independent of central cardiovascular adjustments (See
Fig. 2, Day 2)
Hypothesis 1.2: Skeletal muscle V̇O2 kinetics will be slowed in HFpEF.
Protocol 1.2: Breath-by-breath pulmonary V̇O2 kinetics will be measured during cycle exercise
at a relatively light work rate of 20 W (~30% V̇O2 peak) to characterize V̇O2 kinetics where
there is no cardiac limitation, allowing for a submaximal assessment of "peripheral"
oxidative efficiency during large muscle mass exercise. During cycle exercise, V̇O2 kinetics
will be measured in conjunction near infrared spectroscopy as a marker of the coupling
between oxygen delivery and demand (see Fig. 2, Day 3).
Hypothesis 1.3: HFpEF patients will demonstrate elevated MSNA at rest, and exaggerated
metaboreflex sensitivity during exercise.
Protocol 1.3: Microneurography will be used to measure multi-unit muscle sympathetic nerve
discharge in subjects at rest, during dynamic knee extension exercise (30, 40% MVC), and
during 2 minutes and 15 seconds of post-exercise ischemia (PEI) achieved via inflation of a
blood pressure cuff to supra-systolic pressure. This approach allows for experimental
isolation of the metaboreflex contribution to changes in MSNA and hemodynamics by preventing
washout of metabolites produced by muscle contraction during exercise. Importantly, the
sympathetic response is independent of the confounding activation of the mechanoreflex or
central command as muscle contractions are no longer being performed. A cold pressor test
will be utilized to confirm specific sensitivity to the metaboreflex and not generalized
sensitivity to sympathoexcitatory stimuli. Multi-unit post-ganglionic MSNA will be recorded
from the peroneal nerve using standard microneurographic techniques and quantified as burst
frequency (bursts/min), burst incidence (burst/100 cardiac cycles) and total activity (burst
frequency x mean burst amplitude).
Experimental Series 2 - 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.
Approach: Hypothesis 2.1: Isolated KE exercise training will improve the vasodilatory
response to exercise, speed V̇O2 kinetics, and reduce MSNA at rest HFpEF.
Protocol 2.1: 1) Vascular response: ROV will be assessed as described in protocol 1. Subjects
will perform single contractions at 5, 10 or 20% of their pre- and post-testing maximal
voluntary contraction (MVC). The peripheral hemodynamic response to dynamic KE exercise
(beat-by-beat onset and steady state) will be measured continuously from the onset of
exercise for six minutes at the same absolute (10, and 15 W) and relative (60% of
post-intervention maximal work rate) exercise intensities. Local vascular (FBF, FVC) and
systemic (HR, MAP, CO, SV) hemodynamics will be monitored throughout these trials to confirm
that any alterations in local blood flow are independent of central cardiovascular
adaptations (See Fig 2, Day 2). 2) V̇O2 Kinetics: Breath-by-breath Pulmonary V̇O2 kinetics
will be measured during isolated single KE exercise and during upright cycle exercise.
Dynamic KE exercise will be performed for six minutes at the same absolute submaximal work
rates (10 and 15 W) as well as the same relative (60% post-intervention maximal work rate;
see Fig 2, Day 2) in conjunction with beat-by-beat blood flow measures. Additionally, V̇O2
kinetics will be assessed during mild intensity cycle exercise at 20 W and utilized as a
marker of intervention efficacy as discussed above (see Fig. 2, Day 3). 3) MSNA:
Microneurography will be used to measure multi-unit muscle sympathetic nerve discharge in
subjects at rest, during knee extension exercise, and PEI (See Fig 2, Day 3).
Hypothesis 2.2: Single KE exercise training will improve whole body exercise tolerance, peak
V̇O2, and functional capacity in HFpEF.
Protocol 2.2: In addition to submaximal V̇O2 kinetics: maximal KE work rate, peak V̇O2 during
cycle exercise, and performance in the 6-minute walk test will be re-evaluated after isolated
quadriceps exercise training in the same manner as prior to the intervention (see specific
exercise training protocol below).