Premature Fatigue in Veterans With Heart Failure: Neuronal Influences

Heart Failure Clinical Trial

Official title:

Premature Fatigue in Veterans With Heart Failure: Neuronal Influences

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02209610
• Other study ID #: E1572-P
• Status: Completed
• Phase: Early Phase 1
• Start date: July 1, 2015
• Est. completion date: January 15, 2017

Study information

• Verified date: June 2019
• Source: VA Office of Research and Development
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: January 15, 2017
• Est. primary completion date: January 15, 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 20 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Fatigue
• Heart Failure

Intervention

Device:
• Electrical and Magnetic Nerve Stimulators
Stimulation of motor nerve and central nervous system

Drug:
• Intrathecal Fentanyl
Mu-opioid receptor agonist

Locations

Country	Name	City	State
United States	VA Salt Lake City Health Care System, Salt Lake City, UT	Salt Lake City	Utah

Sponsors (2)

Lead Sponsor	Collaborator
VA Office of Research and Development	University of Utah

Country where clinical trial is conducted

United States, 

References & Publications (5)

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. Review. — View 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.000000000 — View 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):H14 — View 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. — View 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- — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	Muscle Afferent Affect	Corticospinal responsiveness will be quantified before and after exercise.	1 minute after exercise on study day