Impact of Angiotensin Converting Enzyme Activity on Exercise Training Sensitivity

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.

Study Overview

• Status: Completed
• Conditions: Exercise; Angiotensin-Converting Enzyme Inhibitors
• Intervention / Treatment: Drug: Enalapril; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Department of Nutrition, Exercise and Sports

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 50 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Aged 20-50 years
• Healthy

Exclusion Criteria:

-

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.
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.

What is the study measuring?

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
Mitochondrial biogenesis	Expression of complex I-V will be analyzed in order to evaluate if the applied training induced mitochondrial biogenesis.	60 minutes
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
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
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
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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
ACE activity	Obtained blood samples will be analyzed for ACE activity	10 minutes

Collaborators and Investigators

• Sponsor: University of Copenhagen
• Investigators: Principal Investigator: Nikolai B Nordsborg, PhD, University of Copenhagen

Publications and helpful links

General 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. doi: 10.1172/JCI114844.
• 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. doi: 10.1038/30374. No abstract available.
• Sjuretharson T, Bejder J, Breenfeldt Andersen A, Bonne TC, Kyhl K, Thomassen M, Prats J, Oddmarsdottir Gregersen N, Skoradal MB, Weihe P, Nordsborg NB, Mohr M. Robust arm and leg muscle adaptation to training despite ACE inhibition: a randomized placebo-controlled trial. Eur J Appl Physiol. 2022 Oct 22. doi: 10.1007/s00421-022-05072-5. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 15, 2019
• Primary Completion (ACTUAL): December 30, 2019
• Study Completion (ACTUAL): December 30, 2019

Study Registration Dates

• First Submitted: May 9, 2019
• First Submitted That Met QC Criteria: May 11, 2019
• First Posted (ACTUAL): May 14, 2019

Study Record Updates

• Last Update Posted (ACTUAL): November 5, 2020
• Last Update Submitted That Met QC Criteria: November 3, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Genotype; Physiological Effects of Drugs; Polymorphism, Genetic; Enalapril; Adaptation, Physiological
• Additional Relevant MeSH Terms: Immune System Diseases; Hypersensitivity; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Angiotensin-Converting Enzyme Inhibitors; Enalapril
• Other Study ID Numbers: H-18016341

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Fully anonymous data will be shared with other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No