Muscle Afferent Feedback Effects in Patients With Heart Failure

Study Overview
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Brief Summary
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The purpose of the study is to find out more about the mechanism by which neural feedback from the working muscle affects the development of central fatigue during exercise. Subjects with chronic heart failure (HF) and healthy subject counterparts will be tested to determine the mechanisms accounting for the premature fatigue characterizing HF patients during physical activity.

Detailed Description
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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.

Official Title
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Muscle Afferent Feedback Effects in Patients With Heart Failure: The Development of Central Fatigue

Conditions
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Chronic Heart Failure

Intervention / Treatment
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* Drug: Muscle Contraction with Metabolite Solution Administration


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Heart Failure Patients<br>Patients with heart failure will undergo intervention of muscle contraction with metabolite solution administration. Maximal voluntary muscle contraction exercise with varying metabolite solution administration of adenosine triphosphate, lactate, and protons with phosphate buffer. | Drug: Muscle Contraction with Metabolite Solution Administration<br>* Participants will perform maximal elbow flexor or knee extensor contractions before and after administration of metabolite solutions of pH 7.2, pH 7.0 and pH 6.6<br>* Other names: adenosine triphosphate, lactate, and protons with phosphate buffer;|
| Other: Control Participants<br>Healthy control participants will undergo intervention of muscle contraction with metabolite solution administration. Maximal voluntary muscle contraction exercise with varying metabolite solution administration of adenosine triphosphate, lactate, and protons with phosphate buffer. | Drug: Muscle Contraction with Metabolite Solution Administration<br>* Participants will perform maximal elbow flexor or knee extensor contractions before and after administration of metabolite solutions of pH 7.2, pH 7.0 and pH 6.6<br>* Other names: adenosine triphosphate, lactate, and protons with phosphate buffer;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Elbow Flexor Maximal Voluntary Contraction in newton-meters |  | 2 minutes |