Muscle Afferent Feedback Effects in Patients With Heart Failure

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

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.

Study Overview

• Status: Completed
• Conditions: Chronic Heart Failure
• Intervention / Treatment: Drug: Muscle Contraction with Metabolite Solution Administration

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 144
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States, 84148
      • Veterans Affairs Salt Lake City Heath Care System
    • Salt Lake City, Utah, United States, 84148
      • George E Wahlen Vetern Affairs Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Heart Failure Patients; 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; 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; Other Names: adenosine triphosphate, lactate, and protons with phosphate buffer
Other: Control Participants; 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; 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; Other Names: adenosine triphosphate, lactate, and protons with phosphate buffer

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University of Utah
• Investigators: Principal Investigator: Markus Amann, PhD, University of Utah

Study record dates

Study Major Dates

• Study Start: September 1, 2013
• Primary Completion (Actual): January 3, 2018
• Study Completion (Actual): January 3, 2018

Study Registration Dates

• First Submitted: July 29, 2013
• First Submitted That Met QC Criteria: August 6, 2013
• First Posted (Estimate): August 9, 2013

Study Record Updates

• Last Update Posted (Actual): January 8, 2018
• Last Update Submitted That Met QC Criteria: January 4, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Vasodilator Agents; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Purinergic Agents; Purinergic P1 Receptor Agonists; Purinergic Agonists; Adenosine
• Other Study ID Numbers: 62914