Clinical trial NCT02209610: Premature Fatigue in Veterans With Heart Failure: Neuronal Influences
Official title: Premature Fatigue in Veterans With Heart Failure: Neuronal Influences
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Heart Failure
Keywords: Heart Failure
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
Collaborators: name: University of Utah
First posted: 2014-08-06
Enrollment: 32
Sex: ALL
Minimum age (years): 20
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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.

Primary outcomes:
measure: Maximal Voluntary Quadriceps Force [% Change From Baseline]
timeFrame: 1 minute after exercise on study day
measure: Quadriceps Twitch Force and Voluntary Activation (% Change From Baseline)
timeFrame: During (20 second intervals) and 1 minute after exercise on study day
measure: Muscle Afferent Affect
timeFrame: 1 minute after exercise on study day
Secondary outcomes:
Other outcomes:
Locations:
city: Salt Lake City
country: United States
facility: VA Salt Lake City Health Care System, Salt Lake City, UT
state: Utah
Study officials:
affiliation: VA Salt Lake City Health Care System, Salt Lake City, UT
name: Markus Amann, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.