Muscle Afferent Feedback Effects in Patients With Heart Failure

A substantial part in limiting exercise and/or physical activity in humans results from the
development of peripheral and central fatigue during physical activity. Peripheral fatigue
comprises biochemical changes within the metabolic milieu of the working muscle leading to an
attenuated response to neural excitation, while central fatigue comprises a failure of the
central nervous system to drive motoneurons.

Patients with HF have overactive group III/IV muscle afferents and an exaggerated development
of central fatigue during physical activity that is not explained by their reduced physical
conditioning or cardiac insufficiency caused by their failing heart. The exact mechanisms
accounting for the exaggerated central fatigue in HF remains elusive, however, the
development of central fatigue during exercise has recently been linked to signaling by group
III/IV muscle afferents. This makes the heightened neural feedback in HF a likely candidate
for these patients' increased susceptibility to central fatigue.

Lower pH, increased lactate and increased adenosine triphosphate has been shown to activate
group III/IV afferents in a physiological manner and thus induce, in a rested and unfatigued
muscle, the intramuscular milieu associated with moderate to heavy exercise. The objective of
this study is to quantitate and compare the sensitivity of group III/IV afferents and
associated effects on central fatigue in HF patients and healthy controls when skeletal
muscle is subject to controlled lower pH, increased lactate and increased adenosine
triphosphate.

Heart Failure Inclusion Criteria:

- Subjects with a history of stable cardiomyopathy (ischemic and non-ischemic, greater
than 1 year duration, ages 20-79 years)

- New York Heart Association class I through IV symptoms

- Left ventricular ejection fraction less than 35 percent (heart failure patients with
reduced left ventricular ejection fraction) or greater than 50 percent (heart failure
patients with preserved left ventricular ejection fraction)

- Sedentary, no regular physical activity for at least 6 months prior

- Post-menopausal for at least 2 years and follicle stimulating hormone greater than 40

Heart Failure Exclusion Criteria:

- Patients with atrial fibrillation or heart failure believed to be secondary to atrial
fibrillation

- Morbidly obese patients with a body mass index greater than 35

- Patients with uncontrolled hypertension, greater than 160/100

- Anemia with a hemoglobin less than 9

- Severe renal insufficiency (creatinine clearance less than 30 by the Cockcroft-Gault
formula)

- Patients with significant non-cardiac comorbidities

- Orthopedic limitations that would prohibit them from performing the elbow-flexor
exercise

- Current smoker or smoking history of 15 packs or more per year

- Women currently taking hormone replacement therapy

Healthy Control Inclusion Criteria:

- Ages 20-75 years

- Sedentary, no regular physical activity for at least 6 months prior

- Post-menopausal for at least 2 years and follicle stimulating hormone greater than 40

Healthy Control Exclusion Criteria:

- History of cardiovascular related abnormalities or pulmonary abnormalities

- Morbidly obese patients with a body mass index greater than 35

- Patients with uncontrolled hypertension, greater than 160/100

- Anemia with a hemoglobin less than 9

- Orthopedic limitations that would prohibit them from performing the elbow-flexor
exercise

- Current smoker or smoking history of 15 packs or more per year

- Women currently taking hormone replacement therapy