Impact of Heart Failure on Calcium Homeostasis and Mitochondrial Function in Human Skeletal Muscle (CALCICARD2)

Evaluation of Calcium Homeostasis and Mitochondrial Function in Skeletal Muscle in Subjects With Heart Failure

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.

Study Overview

• Status: Terminated
• Conditions: Heart Failure
• Intervention / Treatment: Procedure: Muscle biopsy; Procedure: Exercise training,

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 Type: Interventional
• Enrollment (Actual): 22
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Montpellier Cedex 5, France, 34295
    • physiologie clinique, hopital Arnaud de Villeneuve, 371 avenue du Doyen G;Giraud

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• - BMI < 30

Exclusion Criteria:

• Contra-indication to exercise testing performance and muscle biopsy

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Patients with heart failure (FEVG ≥ 50%)	Procedure: Muscle biopsy; Procedure: Exercise training,
Experimental: Patients with heart failure (FEVG ≤ 35%),	Procedure: Muscle biopsy; Procedure: Exercise training,
Other: Healthy Volunteers; Healthy Volunteers with no heart failure	Procedure: Muscle biopsy; Procedure: Exercise training,

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
calcium homeostasis	Cell analysis	8 days
mitochondrial function	Cell analysis	8 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
skeletal muscular function in two stages of heart failure	Cell analysis	8 days

Collaborators and Investigators

• Sponsor: University Hospital, Montpellier
• Collaborators: Institut National de la Santé Et de la Recherche Médicale, France; Ministry of Health, France; National Cancer Institute, France; Institut de Recherches Internationales Servier

Study record dates

Study Major Dates

• Study Start (Actual): September 18, 2013
• Primary Completion (Actual): June 21, 2016
• Study Completion (Actual): June 30, 2020

Study Registration Dates

• First Submitted: June 12, 2013
• First Submitted That Met QC Criteria: October 7, 2013
• First Posted (Estimate): October 8, 2013

Study Record Updates

• Last Update Posted (Actual): August 6, 2020
• Last Update Submitted That Met QC Criteria: August 5, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: Heart Failure , Skeletal muscle,Calcium,Ryanodine Receptor, Mitochondria, Exercise training, Muscle biopsy, Healthy volunteers
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: 9051