Impact of Angiotensin Converting Enzyme Activity on Exercise Training Sensitivity

• ClinicalTrials.gov Identifier: NCT03949075
• Recruitment Status: Completed
• First Posted: May 14, 2019
• Last Update Posted: November 5, 2020
• Sponsor: University of Copenhagen
• Information provided by (Responsible Party): Nikolai Nordsborg, University of Copenhagen

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Exercise; Angiotensin-Converting Enzyme Inhibitors	Drug: Enalapril; Drug: Placebo	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 52 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Masking Description: The present study is double-blinded with regard to ACE genotype and study medication and the blinding is kept until completion of the trial
• Primary Purpose: Basic Science
• Official Title: Impact of Angiotensin Converting Enzyme Activity on Exercise Training Sensitivity
• Actual Study Start Date: May 15, 2019
• Actual Primary Completion Date: December 30, 2019
• Actual Study Completion Date: December 30, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Enalapril treatment	Drug: Enalapril; 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.
Placebo Comparator: Placebo treatment	Drug: Placebo; Participants will be assigned to daily administration of placebo (5-20 mg CaCO3) combined with an 8-week training period.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Other Outcome Measures:

1. ACE activity [ Time Frame: 10 minutes ]
   Obtained blood samples will be analyzed for ACE activity

Eligibility Criteria

• Ages Eligible for Study: 20 Years to 50 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Aged 20-50 years
• Healthy

Exclusion Criteria:

-

Contacts and Locations

Locations

Denmark

Department of Nutrition, Exercise and Sports

Copenhagen, Denmark, 2100

Sponsors and Collaborators

University of Copenhagen

Investigators

• Principal Investigator: Nikolai B Nordsborg, phD; University of Copenhagen

More Information

Publications:

Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990 Oct;86(4):1343-6.

Montgomery HE, Marshall R, Hemingway H, Myerson S, Clarkson P, Dollery C, Hayward M, Holliman DE, Jubb M, World M, Thomas EL, Brynes AE, Saeed N, Barnard M, Bell JD, Prasad K, Rayson M, Talmud PJ, Humphries SE. Human gene for physical performance. Nature. 1998 May 21;393(6682):221-2.

• Responsible Party: Nikolai Nordsborg, Associate Professor, University of Copenhagen
• ClinicalTrials.gov Identifier: NCT03949075
• Other Study ID Numbers: H-18016341
• First Posted: May 14, 2019
• Last Update Posted: November 5, 2020
• Last Verified: November 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided
• Plan Description: Fully anonymous data will be shared with other researchers.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Nikolai Nordsborg, University of Copenhagen:

Adaptation, Physiological; Genotype; Polymorphism, Genetic; Enalapril; Physiological Effects of Drugs

Additional relevant MeSH terms:

Hypersensitivity; Immune System Diseases; Enalapril; Angiotensin-Converting Enzyme Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents