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

Heart Failure Clinical Trial

— Calcicard  

Official title:

Evaluation of Calcium Homeostasis and Mitochondrial Function in Skeletal Muscle in Subjects With Heart Failure, Before and After Exercise Training

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01014611
• Other study ID #: C08-23
• Secondary ID: 2008-A00936-49
• Status: Terminated
• Phase: N/A
• First received: November 16, 2009
• Last updated: September 26, 2012
• Start date: April 2010
• Est. completion date: November 2011

Study information

• Verified date: September 2012
• Source: Institut National de la Santé Et de la Recherche Médicale, France
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Observational

Clinical Trial Summary

The aim of this project is to investigate the impact of heart failure (HF) on calcium homeostasis, mitochondrial function and oxidative stress in human skeletal muscle, before and after exercise training. The role playing by circulating factors such as cytokines and catecholamines will also be evaluated.

24 HF patients will be enrolled in the study: 12 class II NYHA HF volunteers with a fraction of ejection between 40% and 30 %, and 12 class III NYHA HF volunteers with a fraction of ejection lower than 30 %. They will be compared to 24 sedentary healthy volunteers, matched on age and physical activity.

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 oxidative stress in human skeletal muscle. This project, performed on muscle biopsies, will also allow us to correlate calcium homeostasis and mitochondrial function (before and after exercise training) 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 (U637, 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 defined by the NYHA. The first patients (class II of NYHA) with a fraction of ejection between 40% and 30 % will be compared with patients (class III) with an ejection fraction lower than 30% (12 males, 35-65 years old per HF). 24 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 4 days after the exercise testing to assess the mitochondrial function and the Ca2+ homeostasis. After a rest period of 5 days, HF patients will perform a resistance-training program (3 times per week for 10 weeks). A 2nd cardiovascular explorations, exercise testing and muscle biopsy will then be performed to evaluate the beneficial effect of training. Mitochondrial function will be measured by oxygraphy and ATP production. Ca2+ homeostasis will be evaluated by confocal microscopy by recording spontaneous Ca2+ release events (i.e. RyR activity). Mitochondrial and RyR biochemical analysis will complete these functional studies as well as circulating factors (cytokines, catecholamine) and their associated receptors.

This project will allow us to characterize the behaviour of RyR in relation with mitochondrial function in human skeletal muscle during HF and identify beneficial effects of exercise training routinely proposed to HF patients. 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 3
• Est. completion date: November 2011
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 35 Years to 65 Years

Eligibility

Inclusion Criteria:

• BMI < 30

Exclusion Criteria:

• Contra-indication to exercise testing performance and muscle biopsy

Study Design

Observational Model: Cohort, Time Perspective: Prospective

Related Conditions & MeSH terms

• Heart Failure

Locations

Country	Name	City	State
France	Centre Hospitalier Régional Universitaire	Montpellier

Sponsors (4)

Lead Sponsor	Collaborator
Institut National de la Santé Et de la Recherche Médicale, France	Institut de Recherches Internationales Servier, Ministry of Health, France, National Cancer Institute, France

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To evaluate the skeletal muscular function (calcium homeostasis, mitochondrial function and oxidative stress) in two stages of heart failure patients compared to healthy volunteers		Baseline measurement	No
Secondary	To analyse the link between the hypothetical skeletal muscular function in two stages of heart failure and circulating factors such as cytokines and catecholamines		Baseline measurement	No
Secondary	To investigate the effect of exercise training on skeletal muscular hypothetical dysfunction in two stages of heart failure patients		10 weeks	No