Premature Fatigue in Veterans With Heart Failure: Neuronal Influences

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.

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.