Premature Fatigue in Veterans With Heart Failure: Neuronal Influences

NCT02209610 | Completed Early Phase 1 Results DMC FDA Drug

• 1 other identifier: E1572-P
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

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.

Conditions

Heart Failure

Keywords

Heart Failure

Outcome Measures

Primary Outcomes (3)

• 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.

  1 minute after exercise on study day

• 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.

  During (20 second intervals) and 1 minute after exercise on study day

• Muscle Afferent Affect

  Corticospinal responsiveness will be quantified before and after exercise.

  1 minute after exercise on study day

Study Arms (2)

Patients With Heart Failure: Neuromuscular Abnormalities

OTHER

Patients with Heart Failure

Device: Electrical and Magnetic Nerve Stimulators; Drug: Intrathecal Fentanyl

Health Control Subjects and Neuromuscular Function

OTHER

Health Control Subjects

Device: Electrical and Magnetic Nerve Stimulators; Drug: Intrathecal Fentanyl

Interventions

Electrical and Magnetic Nerve Stimulators DEVICE

Stimulation of motor nerve and central nervous system

Health Control Subjects and Neuromuscular Function; Patients With Heart Failure: Neuromuscular Abnormalities

Intrathecal Fentanyl DRUG

Mu-opioid receptor agonist

Health Control Subjects and Neuromuscular Function; Patients With Heart Failure: Neuromuscular Abnormalities

Eligibility Criteria

• Age: 20 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• VA Office of Research and Development: lead
• University of Utah: collaborator

Study Sites (1)

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

Salt Lake City, Utah, 84148, United States

Location

Related Publications (5)

• 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.

  PMID: 26418560 RESULT

• 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.

  PMID: 26386110 RESULT

• 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.

  PMID: 27440242 RESULT

• 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.

  PMID: 25458423 RESULT

• 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.

  PMID: 27392715 RESULT

MeSH Terms

Conditions

Heart Failure

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Results Point of Contact

• Title: Dr Markus Amann
• Organization: VAORD

markus.amann@hsc.utah.edu

801-582-1565

Study Officials

• Markus Amann, PhD

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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 10, 2014
• First Posted: August 6, 2014
• Study Start: July 1, 2015
• Primary Completion: January 15, 2017
• Study Completion: January 15, 2017
• Last Updated: August 2, 2019
• Results First Posted: August 2, 2019

Record last verified: 2019-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)