Impact of Heart Failure on Calcium Homeostasis and Mitochondrial Function in Human Skeletal Muscle

Not Applicable

Terminated

• Conditions: Heart Failure
• Interventions: Procedure: Exercise training,; Procedure: Muscle biopsy

• Registration Number: NCT01956721
• Lead Sponsor: University Hospital, Montpellier

Brief Summary

The aim of this project is to investigate the impact of heart failure (HF) on calcium homeostasis, mitochondrial function and oxydative stress in human skeletal muscle. The role playing by circulating factors such as cytokines and catecholamines will also be evaluated. 24 HF patients wiil be enrolled in the study: 12 male volunteers with a fraction of ejection ≥ 50% and 12 male volunteers with a fraction of ejection ≤ 35%. They will be compared to 12 sedentary healthy male volunteers, matched on age and physical activity.

Detailed Description

Heart Failure ( HF) is associated with a skeletal muscle dysfunction, characterized by an increased fatigue that does not correlate with impaired myocardial function and physical inactivity that is commonly associated with HF. We identified in skeletal muscle of HF rats, a dysfunction of type 1 ryanodine receptors (RyR1) similar to that observed on the cardiac channel ( RyR2), due to an hyperphosphorylation of the RyR and a dissociation of the regulatory protein FKBP12. This dysfunction, in addition to mitochondrial impairment, contributes in this animal model to the reduced exercise capacity observed during HF. Our goal is to analyse the impact of HF on calcium homeostasis, mitochondrial function and oxydative stress in human skeletal muscle. This project, performed on muscle biopsies, will also allow us to correlate calcium homeostasis and mitochondrial function to circulating factors ( cytokines, catecholamines) susceptible to trigger this muscle dysfunction.This project addresses two straightforward questions about physiopathological mechanisms involved in skeletal muscle dysfunction during HF. To this aim we have built locally a network of laboratories and clinical services, used to work together, composed of two services of the University Hospital of Montpellier ( Dept. of Cardiology and Dept of Clinical Physiology), an inserm unit (U1046, team 2) all interfaced by an another Inserm facility: the Clinical Investigation center (CIC) of Montpellier. In this project we will focus on the dilated post-ischemic cardiomyopathy and compare two groups of patients under similar treatments studied at different stages of HF. The first patients with a fraction of ejection ≥ 50% will be compares with patients) with an ejection fraction ≤ 35% (12 males, 35-65 years old per HF). 12 voluntary healthy sedentary individuals carefully selected for similar level of activity as for patients will be matched to the HF groups. All individuals will undergo cardiovascular explorations (ECG and echocardiography, blood test) at the inclusion. They will perform an exercise testing to evaluate their exercise capacity. A muscle biopsy will be performed between 4 and 8 days after the exercise testing to assess the mitochondrial function and the Ca2+ homeostasis. This project will allow us to characterize the behavior of RyR in relation with mitochondrial function in human skeletal muscle during HF . The analysis of circulating factors will allow us to establish a relation of cause and effect between myocardial dysfunction and muscle dysfunction. This project could thus open important perspectives in therapeutic. Compounds analogues to JTV-519, acting in stabilizing RyR channels, could be prescribed as a potent medication for HF. This project could thus be determinant in the comprehension of the regulation of Ca2+ and energetic metabolism in human skeletal muscle which could be an appropriate model to evaluate the effects of new pharmacological agents.

Study Timeline

• Study First Submitted: 2013-06-12
• Study Start: 2013-09-18
• Study First Submitted QC: 2013-10-07
• Study First Posted: 2013-10-08
• Primary Completion: 2016-06-21
• Study Completion: 2020-06-30
• Status Verified: 2020-08
• Last Update Submitted: 2020-08-05
• Last Update Posted: 2020-08-06

Recruitment & Eligibility

• Status: TERMINATED
• Sex: Male
• Target Recruitment: 22

Inclusion Criteria

• • BMI < 30

Exclusion Criteria

• Contra-indication to exercise testing performance and muscle biopsy

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Patients with heart failure (FEVG ≤ 35%),	Exercise training,	Patients with heart failure (FEVG ≤ 35%),
Healthy Volunteers	Muscle biopsy	Healthy Volunteers with no heart failure
Patients with heart failure (FEVG ≥ 50%)	Exercise training,	Patients with heart failure (FEVG ≥ 50%)
Patients with heart failure (FEVG ≥ 50%)	Muscle biopsy	Patients with heart failure (FEVG ≥ 50%)
Patients with heart failure (FEVG ≤ 35%),	Muscle biopsy	Patients with heart failure (FEVG ≤ 35%),
Healthy Volunteers	Exercise training,	Healthy Volunteers with no heart failure

Primary Outcome Measures

Name	Time	Method
mitochondrial function	8 days	Cell analysis
calcium homeostasis	8 days	Cell analysis

Secondary Outcome Measures

Name	Time	Method
skeletal muscular function in two stages of heart failure	8 days	Cell analysis

Trial Locations

Locations (1)

physiologie clinique, hopital Arnaud de Villeneuve, 371 avenue du Doyen G;Giraud; 🇫🇷 Montpellier Cedex 5, France