Effect of ACE Genotype on Cardiovascular Rehabilitation (ACE-REHAB)

Effects of ACE Genotype on Muscular and Functional Adaptations Following a Cardiovascular Rehabilitation Program

The study aims to systematically investigate the interaction between training modality, ACE genotype and disease in heart patients whom complete a cardiovascular rehabilitation program. This is carried out with the goal to improve the benefit of cardiovascular rehabilitation for the patient by maximising adjustments in muscle structure and function with the intervention. A population of healthy individuals will be recruited who will carry out the same training program, in order to compare the training effects respective to the general population.

Study Overview

• Status: Terminated
• Conditions: Cardiovascular Disease
• Intervention / Treatment: Behavioral: concentric cardiovascular training; Genetic: ACE genotyping; Behavioral: eccentric cardiovascular training

Detailed Description

Pharmacological inhibition of angiotensin converting enzyme modifies exercise-induced pro-angiogenic and mitochondrial gene transcript expression. Exercise-induced muscle plasticity importantly interacts with the insertion/deletion genotype of ACE and the training modality and intensity. The aim of this study is to systematically investigate the interaction between training modality, ACE genotype and disease in heart patients whom complete a cardiovascular rehabilitation program.

There are two training modalities being used: The first modality involves cardiovascular training by an interval type of protocol that includes a high repetition number of shortening (i.e. concentric) type contractions on a softrobotic device. The second modality includes a high repetition number of lengthening (i.e. eccentric) type contractions on a softrobotic device. In both training modalities the same muscle groups are exercised over the same range of motion, with the same speed of movement, but with widely differing pedal force. Total absolute external mechanical work will be matched.

In order to assess the baseline values and the effect size of the muscle and training adjustments made, healthy male and female volunteers will be included who are matched with respect to age and sex to the patient population and undergo the same training program.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• Switzerland
  • Zurich, Switzerland, 8091
    • University Hospital Zurich
  • Zurich, Switzerland, 8008
    • Balgrist University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Patient group inclusion criteria:

• stable coronary heart patients/heart patients without ischemia
• Left ventricular ejection fraction > 50%
• Drug therapy with ACE inhibitors
• V̇O2peak <86% of the medical reference value Voluntary participation
• Written informed consent of the subject to participate in the study

exclusion criteria:

• relevant valvular heart disease
• arterial hypertension (blood pressure at rest> 140/90)
• arrhythmogenic cardiomyopathy
• ACE inhibitor intolerance
• contraindication for ethical reasons
• known or suspected non-compliance with the curriculum
• smoker
• drug or alcohol disease
• inability of the patient to follow the study procedures (e.g. because of language problems, mental illness, dementia)
• participation in another clinical trial within the last 30 days prior to confinement and during the study
• other, clinically significant comorbidities (cardiac arrhythmia, renal insufficiency, hepatic dysfunction, connective tissue disease [Marfan syndrome, Ehlers-Danlos syndrome])

Healthy subject group inclusion criteria:

• inconspicuous ECG under exercise (persons in whom the exercise ECG is abnormal will be referred for a cardiological evaluation recessed to the University Hospital Zurich)
• V̇O2peak <50 ml O2 min-1 kg-1
• Voluntary participation
• Written informed consent of the subject to participate in the study

exclusion criteria:

• relevant valvular heart disease
• arterial hypertension (blood pressure at rest> 140/90)
• arrhythmogenic cardiomyopathy
• ACE inhibitor intolerance
• contraindication for ethical reasons
• known or suspected non-compliance with the curriculum
• smoker
• drug or alcohol disease
• inability of the patient to follow the study procedures (e.g. because of language problems, mental illness, dementia)
• participation in another clinical trial within the last 30 days prior to confinement and during the study
• other, clinically significant comorbidities (cardiac arrhythmia, renal insufficiency, hepatic dysfunction, connective tissue disease [Marfan syndrome, Ehlers-Danlos syndrome])

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: concentric cardiovascular rehabilitation; Heart patients under ACE inhibitor intake will be enrolled in the intervention 'concentric cardiovascular training' and evaluated by the intervention 'ACE genotyping'	Behavioral: concentric cardiovascular training; Subjects will carry out 8 weeks of cardiovascular training by an interval type of protocol that includes a high repetition number of concentric type contractions on a softrobotic device.; Genetic: ACE genotyping; Subjects will be genotyped for the ACE-I/D gene polymorphism.
Experimental: eccentric cardiovascular rehabilitation; Heart patients under ACE inhibitor intake will be enrolled in the intervention 'eccentric cardiovascular training' and evaluated by the intervention 'ACE genotyping'	Genetic: ACE genotyping; Subjects will be genotyped for the ACE-I/D gene polymorphism.; Behavioral: eccentric cardiovascular training; Subjects will carry out 8 weeks of cardiovascular training by an interval type of protocol that includes a high repetition number of eccentric type contractions on a softrobotic device.
Active Comparator: concentric cardiovascular training; Healthy subjects will be enrolled in the intervention 'concentric cardiovascular training' and evaluated by the intervention 'ACE genotyping'	Behavioral: concentric cardiovascular training; Subjects will carry out 8 weeks of cardiovascular training by an interval type of protocol that includes a high repetition number of concentric type contractions on a softrobotic device.; Genetic: ACE genotyping; Subjects will be genotyped for the ACE-I/D gene polymorphism.
Active Comparator: eccentric cardiovascular training; Healthy subjects will be enrolled in the intervention 'eccentric cardiovascular training' and evaluated by the intervention 'ACE genotyping'	Genetic: ACE genotyping; Subjects will be genotyped for the ACE-I/D gene polymorphism.; Behavioral: eccentric cardiovascular training; Subjects will carry out 8 weeks of cardiovascular training by an interval type of protocol that includes a high repetition number of eccentric type contractions on a softrobotic device.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ACE I/D genotype	Genotype of the assessed insertion/deletion gene polymorphism of angiotensin converting enzyme ACE, i.e. ACE-II, ACE-ID or ACE-DD.	975 days: May 2016-January 2019
Molecular muscle characteristics - mRNA	• mRNA expression of VEGF, HIF-1a, HIF-1b, tenascin-C, Angpt1, Angpt1R, neuropilin, midkine, restin, COX4-1, COX4I-2, CPTI, LPL, LIPE, FATP, CD36 [relative expression per 28S rRNA]	975 days: May 2016-January 2019
Molecular muscle characteristics- protein	• Protein content of FAK, FRNK, p70S6K, mTOR, JNK, NDUFA9, SDH, UQCRC1, COX4I1, COX4I2, ATP5A1, VEGF, HIF-1a, CD31, MHC-1, MHC-2A, MHC-2X, MyoD, myogenin, CaMKII [pixel counts per actin]	975 days: May 2016-January 2019
Molecular muscle characteristics- phosphorylation	• Phosphorylation of proteins phospho-Y397- FAK, phospho-T421/S424-P70S6K, phospho -T183/Y185-JNK, phospho-S2448-mTOR [pixel counts per actin]	975 days: May 2016-January 2019
Molecular muscle characteristics- ACE	• ACE activity [fmol min-1]	975 days: May 2016-January 2019
Cellular muscle characteristics - fiber type %	• Distribution of type I, IIA and IIX fibers [%]	975 days: May 2016-January 2019
Cellular muscle characteristics - fiber area %	• Area percentage of type I, IIA and IIX fibers [% area]	975 days: May 2016-January 2019
Cellular muscle characteristics - fiber type CSA	• Cross sectional area of type I, IIA and IIX fibers [micrometer2]	975 days: May 2016-January 2019
Cellular muscle characteristics - Capillary density	• Capillary density [capillaries micrometer-2]	975 days: May 2016-January 2019
Cellular muscle characteristics - Capillary-to-fiber ratio	• Capillary-to-fiber ratio	975 days: May 2016-January 2019
Functional muscle characteristics - Maximal Power	• Maximal power during ramp test on ergometer [Watt]	975 days: May 2016-January 2019
Functional muscle characteristics - Critical Power	• Critical power in ramp test on ergometer [Watt]	975 days: May 2016-January 2019
Functional muscle characteristics - Real Power	• Real Power as estimated on the soft robotic device [Watt]	975 days: May 2016-January 2019
Functional muscle characteristics - Reactive Power	• Reactive Power as estimated on the soft robotic device [Watt]	975 days: May 2016-January 2019
Functional muscle characteristics - Negative Power	• Negative Power as estimated on the soft robotic device [Watt]	975 days: May 2016-January 2019
Functional muscle characteristics - Maximal force	• Maximal force during the reactive power test on the soft robotic device [Newton]	975 days: May 2016-January 2019
Functional muscle characteristics - Maximal velocity	• Maximal velocity during the reactive power test on the soft robotic device [m sec-1]	975 days: May 2016-January 2019
Functional muscle characteristics - Rate of force development	• Rate of force development as estimated during the Real Power test on the soft robotic device [meter sec-2]	975 days: May 2016-January 2019
Muscle metabolism - muscle oxygenation ramp	• Muscle oxygenation (m. vastus lateralis, m. gastrocnemius, m. gluteus maximus) during ramp test on ergometer [%]	975 days: May 2016-January 2019
Muscle metabolism - muscle oxygenation robot exercise	• Muscle oxygenation (m. vastus lateralis, m. gastrocnemius, m. gluteus maximus) during exercise on soft robot [%]	975 days: May 2016-January 2019
Muscle metabolism - hemoglobin ramp	• Total hemoglobin during ramp test on ergometer [%]	975 days: May 2016-January 2019
Muscle metabolism - hemoglobin robot exercise	• Total hemoglobin during exercise on soft robot [%]	975 days: May 2016-January 2019
Muscle metabolism - lipid compounds	• Concentration of lipid compounds in m. vastus lateralis muscle during exercise on soft roboter	975 days: May 2016-January 2019
Muscle metabolism - metabolites	• Concentration of metabolites in m. vastus lateralis muscle during exercise on soft roboter	975 days: May 2016-January 2019
Muscle metabolism - serum glucose	• Concentration of glucose in serum during ramp test on ergometer [mmol l-1]	975 days: May 2016-January 2019
Muscle metabolism - serum lactate	• Concentration of lactate in serum during ramp test on ergometer [mmol l-1]	975 days: May 2016-January 2019
Cardiovascular function - Heart rate rest	• Heart rate at rest [beats per minute]	975 days: May 2016-January 2019
Cardiovascular function - Heart rate ramp	• Heart rate in ramp test on ergometer [beats per minute]	975 days: May 2016-January 2019
Cardiovascular function - cardiac output	• Cardiac output [L min-1]	975 days: May 2016-January 2019
Cardiovascular function - ejection fraction	• Ejection fraction	975 days: May 2016-January 2019
Cardiovascular function - Maximal oxygen uptake	• Maximal oxygen uptake (VO2max) during ramp test on ergometer [ml O2 min-1 kg-1]	975 days: May 2016-January 2019
Cardiovascular function - ventilation	• Ventilation during ramp test on ergometer [L min-1]	975 days: May 2016-January 2019
Cardiovascular function - ventilation frequency	• Ventilation frequency ramp test on ergometer [min-1]	975 days: May 2016-January 2019
Cardiovascular function - respiration quotient	• Respiration quotient during ramp test on ergometer [ L O2 inspired / L CO2 expired]	975 days: May 2016-January 2019
Cardiovascular function - endurance	Time-to-exhaustion in constant load on ergometer [seconds]	975 days: May 2016-January 2019

Collaborators and Investigators

• Sponsor: Balgrist University Hospital
• Collaborators: University of Zurich
• Investigators: Principal Investigator: Walter O Frey, MD, Balgrist University Hospital, Move>med, Swiss Olympic Center, Zurich, Switzerland; Principal Investigator: Christian M Schmied, MD, Cardiology, University Hospital Zurich, Zurich, Switzerland

Publications and helpful links

General Publications

• van Ginkel S, Ruoss S, Valdivieso P, Degens H, Waldron S, de Haan A, Fluck M. ACE inhibition modifies exercise-induced pro-angiogenic and mitochondrial gene transcript expression. Scand J Med Sci Sports. 2016 Oct;26(10):1180-7. doi: 10.1111/sms.12572. Epub 2015 Sep 26.
• van Ginkel S, Amami M, Dela F, Niederseer D, Narici MV, Niebauer J, Scheiber P, Muller E, Fluck M. Adjustments of muscle capillarity but not mitochondrial protein with skiing in the elderly. Scand J Med Sci Sports. 2015 Aug;25(4):e360-7. doi: 10.1111/sms.12324. Epub 2014 Sep 28.
• Mathes S, van Ginkel SL, Vaughan D, Valdivieso P, Flück M, Gene-pharmacologial effects on exercise-induced muscle gene expression in healthy men. Anat Physiol 2015, S5.
• van Ginkel S, de Haan A, Woerdeman J, Vanhees L, Serne E, de Koning J, Fluck M. Exercise intensity modulates capillary perfusion in correspondence with ACE I/D modulated serum angiotensin II levels. Appl Transl Genom. 2015 Mar 27;4:33-7. doi: 10.1016/j.atg.2015.03.002. eCollection 2015 Mar.
• Vaughan D, Huber-Abel FA, Graber F, Hoppeler H, Fluck M. The angiotensin converting enzyme insertion/deletion polymorphism alters the response of muscle energy supply lines to exercise. Eur J Appl Physiol. 2013 Jul;113(7):1719-29. doi: 10.1007/s00421-012-2583-6. Epub 2013 Feb 9.
• Fitze DP, Franchi M, Popp WL, Ruoss S, Catuogno S, Camenisch K, Lehmann D, Schmied CM, Niederseer D, Frey WO, Fluck M. Concentric and Eccentric Pedaling-Type Interval Exercise on a Soft Robot for Stable Coronary Artery Disease Patients: Toward a Personalized Protocol. JMIR Res Protoc. 2019 Mar 27;8(3):e10970. doi: 10.2196/10970.

Helpful Links

• Mathes et al, 2015
• van Ginkel et al, 2015

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2016
• Primary Completion (Actual): January 1, 2019
• Study Completion (Actual): January 1, 2020

Study Registration Dates

• First Submitted: November 27, 2015
• First Submitted That Met QC Criteria: July 22, 2016
• First Posted (Estimated): July 27, 2016

Study Record Updates

• Last Update Posted (Actual): August 16, 2023
• Last Update Submitted That Met QC Criteria: August 14, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: exercise; rehabilitation; hypertension; genotype; perfusion; molecular biology; ACE; muscle plasticity
• Additional Relevant MeSH Terms: Cardiovascular Diseases
• Other Study ID Numbers: W 549 ACE-REHAB; KEK-ZH-Nr. 2014-0319 (Other Identifier: Ethics Committee of the Canton Zurich, Switzerland)