Impact of Angiotensin Converting Enzyme Activity on Exercise Training Sensitivity

Study Overview
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Brief Summary
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The phenotype based on the insertion/deletion (I/D) polymorphism of the human angiotensin converting enzyme (ACE) gene has been associated with individual training response. Briefly, intervention studies have demonstrated an 11-fold greater training-induced improvement in muscular endurance for ACE I/I homozygotes compared to ACE D/D homozygotes. Importantly, the ACE I/D polymorphism causes large inter-individual differences in serum ACE activity. Because the ACE D/D genotype is characterized by high plasma ACE activity and potentially blunted endurance exercise training response, it appears likely that ACE inhibitors (ACEi) have the potential to improve the outcome of exercise training for ACE D/D homozygotes. Thus, in the present study the investigators apply a randomized double-blind placebo-controlled longitudinal design to investigate whether pharmacological inhibition of ACE activity can amplify the exercise training response in healthy humans carrying either the ACE D/D or ACE I/I genotype. The study hypothesis is that inhibition of ACE activity in healthy humans with the ACE D/D genotype will amplify the health beneficial effects of exercise training while this is not the case in ACE I/I homozygotes.

Official Title
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Impact of Angiotensin Converting Enzyme Activity on Exercise Training Sensitivity

Conditions
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Exercise, Angiotensin-Converting Enzyme Inhibitors

Intervention / Treatment
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* Drug: Enalapril
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 20-50 years Healthy Exclusion Criteria: -

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 50 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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enalapril treatment<br> | Drug: Enalapril<br>* Participants will be assigned to daily administration of ACE inhibitors (Initially 5 mg Corodil® 'Enalapril' daily followed by up to 20 mg daily dependent on the blood pressure response) combined with an 8-week training period.<br>|
| Placebo Comparator: Placebo treatment<br> | Drug: Placebo<br>* Participants will be assigned to daily administration of placebo (5-20 mg CaCO3) combined with an 8-week training period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal systemic oxygen uptake | Training-induced changes in maximal systemic oxygen uptake (L/min) is evaluated with an incremental maximal cycle protocol on a cycle ergometer | 20 minutes | 
| Skeletal muscle endurance | Training-induced changes in muscle endurance evaluated as changes in duration (sec) of a repetitive elbow-flexion exercise | 5 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood volume | Training-induced changes in total blood volume (mL) is measured using the Carbon-monoxide rebreathing method. | 20 minutes | 
| Endurance performance | Training-induced changes in endurance performance is determined by a 2000 meter time trial on an indoor rowing ergometer | 15 minutes | 
| Skeletal muscle oxidative capacity | Training-induced changes in muscle oxidative capacity is evaluated as maximal citrate synthase and 3- hydroxy-acetylCoa-dehydrogenase activity (µmol/g/min) | 60 minutes | 
| Mitochondrial biogenesis | Expression of complex I-V will be analyzed in order to evaluate if the applied training induced mitochondrial biogenesis. | 60 minutes | 
| Mean arterial pressure (MAP) | Training-induced changes in resting MAP (mmHg) will be estimated using this formula: MAP = diastolic pressure + 1/3 (systolic pressure - diastolic pressure) | 10 minutes | 
| Steady-state systemic oxygen uptake | Training-induced changes in steady-state systemic oxygen uptake (mL/min) is determined by indirect calorimetry during a submaximal cycle protocol on a cycle ergometer | 10 minutes | 
| Muscle strength | Training-induced changes in muscle strength (kg) is measured using a handgrip dynamometer | 1 minute | 
| Fat mass | Training-induced changes in fat mass (kg) is determined by dual-energy x-ray absorptiometry (DXA)-scan | 20 minutes | 
| Fat free mass | Training-induced changes in fat free mass (kg) is determined by DXA-scan | 20 minutes | 
| Body fat percentage | Training-induced changes in body fat percentage (%) is determined by DXA-scan | 20 minutes | 
| Left ventricular (LV) mass | Training-induced changes in LV mass (g) is determined by cardiac magnetic resonance imaging (cMRI) | 45 minutes | 
| LV end-diastolic volume | Training-induced changes in LV end-diastolic volume (mL) is determined by cMRI | 45 minutes | 
| LV mean wall thickness | Training-induced changes in LV mean wall thickness (cm) is determined by cMRI | 45 minutes | 
| LV stroke volume | Training-induced changes in LV stroke volume (mL) is determined by cMRI | 45 minutes | 
| LV ejection fraction | LV stroke volume (mL) and LV end-diastolic volume (mL) will be used to measure training-induced changes in LV ejection fraction (%) | 45 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adaptation, Physiological, Genotype, Polymorphism, Genetic, Enalapril, Physiological Effects of Drugs