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Premature Fatigue in Veterans With Heart Failure: Neuronal Influences

Primary Purpose

Heart Failure

Status
Completed
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Electrical and Magnetic Nerve Stimulators
Intrathecal Fentanyl
Sponsored by
VA Office of Research and Development
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Heart Failure focused on measuring Heart Failure

Eligibility Criteria

20 Years - 75 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • subjects with a history of stable cardiomyopathy (ischemic and non-ischemic, >1yr duration, ages 20-75 yr),
  • not pacemaker dependent (no biventricular pacers),
  • NYHA class II and III symptoms,
  • Left ventricular ejection fraction (LVEF)<35%,
  • no or minimal smoking history (<15 pk yrs) and on stable medications.

  • The investigators will also study subjects with preserved ejection fraction

    • heart failure with a preserved ejection fraction (HFpEF);
    • LVEF >50%,
    • >1yr duration,
    • ages 20-75 yr,
  • not pacemaker dependent,
  • NYHA class II and III symptoms,
  • no or minimal smoking history (<15 pk yrs) and on stable medications. The investigators will exclude morbidly obese patients (BMI >35), patients with uncontrolled hypertension (>160/100), anemia (Hgb<9) and severe renal insufficiency (individuals with creatinine clearance <30 by the Cockcroft-Gault formula).

Exclusion Criteria:

  • Patients with significant non-cardiac comorbidities, which if present could alter the study results, will be excluded.
  • Patients will be sedentary, defined here as no regular physical activity for at least the prior 6 months and current activity level will be documented by an activity questionnaire.
  • Candidates must have no orthopedic limitations that would prohibit them from performing exercise.

  • Due to the typical age of patients with heart failure, all women will be postmenopausal (either natural or surgical) defined as a cessation of menses for at least 2 years,

    • and in women without a uterus, follicle stimulating hormone (FSH) >40 IU/L.
  • Women currently taking hormone replacement therapy (HRT) will be excluded from the proposed studies due to the direct vascular effects of HRT.
  • Patients with a pacemaker and / or defibrillator will be excluded from the study due to the use of a magnetic/electric stimulators.

Sites / Locations

  • VA Salt Lake City Health Care System, Salt Lake City, UT

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Other

Arm Label

Patients With Heart Failure: Neuromuscular Abnormalities

Health Control Subjects and Neuromuscular Function

Arm Description

Patients with Heart Failure

Health Control Subjects

Outcomes

Primary Outcome Measures

Maximal Voluntary Quadriceps Force [% Change From Baseline]
Following dynamic single leg knee extension exercise for a given duration (4-8 min), the decline in maximal voluntary contraction force will be measured.
Quadriceps Twitch Force and Voluntary Activation (% Change From Baseline)
During a 2-min maximal voluntary quadriceps contraction, central and peripheral fatigue will develop progressively and significantly more in HF vs. CTRLs.
Muscle Afferent Affect
Corticospinal responsiveness will be quantified before and after exercise.

Secondary Outcome Measures

Full Information

First Posted
July 10, 2014
Last Updated
June 4, 2019
Sponsor
VA Office of Research and Development
Collaborators
University of Utah
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1. Study Identification

Unique Protocol Identification Number
NCT02209610
Brief Title
Premature Fatigue in Veterans With Heart Failure: Neuronal Influences
Official Title
Premature Fatigue in Veterans With Heart Failure: Neuronal Influences
Study Type
Interventional

2. Study Status

Record Verification Date
June 2019
Overall Recruitment Status
Completed
Study Start Date
July 1, 2015 (Actual)
Primary Completion Date
January 15, 2017 (Actual)
Study Completion Date
January 15, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
VA Office of Research and Development
Collaborators
University of Utah

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
A hallmark of patients with heart failure (HF) is premature fatigue which impairs their quality of life and depicts a major source of morbidity. Premature fatigue may be attributed to a) contraction-induced transient changes within muscles (i.e. peripheral fatigue) and/or b) failure of the central nervous system to 'drive' / activate locomotor muscles (i.e. central fatigue). Both determinants of fatigue can lead to a reduction in a muscle's force and power generating capacity and to a compromised ability to perform whole body activities (e.g. walking). Recent findings in health have documented that group III/IV afferent fibers from the working muscle play a critical role in the development of both components of fatigue. Specifically, group III/IV muscle afferents limit central motor drive (CMD) during exercise and thereby exaggerate the development of central fatigue. In contrast, muscle afferents optimize muscle O2 delivery through the precise regulation of circulation and ventilation during exercise and thereby attenuate the development of peripheral fatigue.
Detailed Description
Recent findings in HF suggest an altered effect of group III/IV muscle afferents in this population. Although normal afferent feedback is crucial for adequate O2 delivery during exercise, excessive neural feedback has substantial negative consequences. HF patients are characterized by augmented neural feedback arising from overactive muscle afferents. It has been hypothesized that this abnormality compromises locomotor muscle O2 delivery in these patients. Therefore, the abnormally elevated muscle afferent feedback in HF might exacerbate, compared to healthy age- and activity matched individuals (CTRLs), the development of both peripheral (via limiting O2 delivery) and central (via restricting CMD) fatigue during exercise. Recent advances in non-invasive stimulation techniques offer a genuine opportunity to identify the sites and synaptic mechanisms that mediate central and peripheral fatigue including alterations in the responsiveness of the corticospinal tract (i.e. a determinant of central fatigue). Taken together, the proposed studies aim to determine the impact of HF on the precise development of central and peripheral fatigue during both whole body and single muscle exercise and evaluate the extent to which group III/IV muscle afferents contribute to this development.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure
Keywords
Heart Failure

7. Study Design

Primary Purpose
Basic Science
Study Phase
Early Phase 1
Interventional Study Model
Parallel Assignment
Masking
Participant
Allocation
Randomized
Enrollment
32 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Patients With Heart Failure: Neuromuscular Abnormalities
Arm Type
Other
Arm Description
Patients with Heart Failure
Arm Title
Health Control Subjects and Neuromuscular Function
Arm Type
Other
Arm Description
Health Control Subjects
Intervention Type
Device
Intervention Name(s)
Electrical and Magnetic Nerve Stimulators
Intervention Description
Stimulation of motor nerve and central nervous system
Intervention Type
Drug
Intervention Name(s)
Intrathecal Fentanyl
Intervention Description
Mu-opioid receptor agonist
Primary Outcome Measure Information:
Title
Maximal Voluntary Quadriceps Force [% Change From Baseline]
Description
Following dynamic single leg knee extension exercise for a given duration (4-8 min), the decline in maximal voluntary contraction force will be measured.
Time Frame
1 minute after exercise on study day
Title
Quadriceps Twitch Force and Voluntary Activation (% Change From Baseline)
Description
During a 2-min maximal voluntary quadriceps contraction, central and peripheral fatigue will develop progressively and significantly more in HF vs. CTRLs.
Time Frame
During (20 second intervals) and 1 minute after exercise on study day
Title
Muscle Afferent Affect
Description
Corticospinal responsiveness will be quantified before and after exercise.
Time Frame
1 minute after exercise on study day

10. Eligibility

Sex
All
Minimum Age & Unit of Time
20 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: subjects with a history of stable cardiomyopathy (ischemic and non-ischemic, >1yr duration, ages 20-75 yr), not pacemaker dependent (no biventricular pacers), NYHA class II and III symptoms, Left ventricular ejection fraction (LVEF)<35%, no or minimal smoking history (<15 pk yrs) and on stable medications. The investigators will also study subjects with preserved ejection fraction heart failure with a preserved ejection fraction (HFpEF); LVEF >50%, >1yr duration, ages 20-75 yr, not pacemaker dependent, NYHA class II and III symptoms, no or minimal smoking history (<15 pk yrs) and on stable medications. The investigators will exclude morbidly obese patients (BMI >35), patients with uncontrolled hypertension (>160/100), anemia (Hgb<9) and severe renal insufficiency (individuals with creatinine clearance <30 by the Cockcroft-Gault formula). Exclusion Criteria: Patients with significant non-cardiac comorbidities, which if present could alter the study results, will be excluded. Patients will be sedentary, defined here as no regular physical activity for at least the prior 6 months and current activity level will be documented by an activity questionnaire. Candidates must have no orthopedic limitations that would prohibit them from performing exercise. Due to the typical age of patients with heart failure, all women will be postmenopausal (either natural or surgical) defined as a cessation of menses for at least 2 years, and in women without a uterus, follicle stimulating hormone (FSH) >40 IU/L. Women currently taking hormone replacement therapy (HRT) will be excluded from the proposed studies due to the direct vascular effects of HRT. Patients with a pacemaker and / or defibrillator will be excluded from the study due to the use of a magnetic/electric stimulators.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Markus Amann, PhD
Organizational Affiliation
VA Salt Lake City Health Care System, Salt Lake City, UT
Official's Role
Principal Investigator
Facility Information:
Facility Name
VA Salt Lake City Health Care System, Salt Lake City, UT
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84148
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
26418560
Citation
Ives SJ, Amann M, Venturelli M, Witman MA, Groot HJ, Wray DW, Morgan DE, Stehlik J, Richardson RS. The Mechanoreflex and Hemodynamic Response to Passive Leg Movement in Heart Failure. Med Sci Sports Exerc. 2016 Mar;48(3):368-76. doi: 10.1249/MSS.0000000000000782.
Results Reference
result
PubMed Identifier
26386110
Citation
Sidhu SK, Weavil JC, Venturelli M, Rossman MJ, Gmelch BS, Bledsoe AD, Richardson RS, Amann M. Aging alters muscle reflex control of autonomic cardiovascular responses to rhythmic contractions in humans. Am J Physiol Heart Circ Physiol. 2015 Nov;309(9):H1479-89. doi: 10.1152/ajpheart.00433.2015. Epub 2015 Sep 18.
Results Reference
result
PubMed Identifier
27440242
Citation
Weavil JC, Sidhu SK, Mangum TS, Richardson RS, Amann M. Fatigue diminishes motoneuronal excitability during cycling exercise. J Neurophysiol. 2016 Oct 1;116(4):1743-1751. doi: 10.1152/jn.00300.2016. Epub 2016 Jul 20.
Results Reference
result
PubMed Identifier
25458423
Citation
Amann M, Sidhu SK, Weavil JC, Mangum TS, Venturelli M. Autonomic responses to exercise: group III/IV muscle afferents and fatigue. Auton Neurosci. 2015 Mar;188:19-23. doi: 10.1016/j.autneu.2014.10.018. Epub 2014 Oct 23.
Results Reference
result
PubMed Identifier
27392715
Citation
Wray DW, Amann M, Richardson RS. Peripheral vascular function, oxygen delivery and utilization: the impact of oxidative stress in aging and heart failure with reduced ejection fraction. Heart Fail Rev. 2017 Mar;22(2):149-166. doi: 10.1007/s10741-016-9573-4.
Results Reference
result

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Premature Fatigue in Veterans With Heart Failure: Neuronal Influences

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