Premature Fatigue in Veterans With Heart Failure: Neuronal Influences

June 4, 2019 updated by: VA Office of Research and Development
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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

32

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Utah
      • Salt Lake City, Utah, United States, 84148
        • VA Salt Lake City Health Care System, Salt Lake City, UT

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

20 years to 75 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: BASIC_SCIENCE
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: SINGLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
OTHER: Patients With Heart Failure: Neuromuscular Abnormalities
Patients with Heart Failure
Device: Electrical and Magnetic Nerve Stimulators
Stimulation of motor nerve and central nervous system
Drug: Intrathecal Fentanyl
Mu-opioid receptor agonist
OTHER: Health Control Subjects and Neuromuscular Function
Health Control Subjects
Device: Electrical and Magnetic Nerve Stimulators
Stimulation of motor nerve and central nervous system
Drug: Intrathecal Fentanyl
Mu-opioid receptor agonist

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maximal Voluntary Quadriceps Force [% Change From Baseline]
Time Frame: 1 minute after exercise on study day
Following dynamic single leg knee extension exercise for a given duration (4-8 min), the decline in maximal voluntary contraction force will be measured.
1 minute after exercise on study day
Quadriceps Twitch Force and Voluntary Activation (% Change From Baseline)
Time Frame: During (20 second intervals) and 1 minute after exercise on study day
During a 2-min maximal voluntary quadriceps contraction, central and peripheral fatigue will develop progressively and significantly more in HF vs. CTRLs.
During (20 second intervals) and 1 minute after exercise on study day
Muscle Afferent Affect
Time Frame: 1 minute after exercise on study day
Corticospinal responsiveness will be quantified before and after exercise.
1 minute after exercise on study day

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

VA Office of Research and Development

Collaborators

University of Utah

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

July 1, 2015

Primary Completion (ACTUAL)

January 15, 2017

Study Completion (ACTUAL)

January 15, 2017

Study Registration Dates

First Submitted

July 10, 2014

First Submitted That Met QC Criteria

August 4, 2014

First Posted (ESTIMATE)

August 6, 2014

Study Record Updates

Last Update Posted (ACTUAL)

August 2, 2019

Last Update Submitted That Met QC Criteria

June 4, 2019

Last Verified

June 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • E1572-P

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

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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