Effect of ACE Genotype on Cardiovascular Rehabilitation

Cardiovascular Disease Clinical Trial

— ACE-REHAB  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02845063
• Other study ID #: W 549 ACE-REHAB
• Secondary ID: KEK-ZH-Nr. 2014-
• Status: Terminated
• Phase: Phase 2
• Start date: May 1, 2016
• Est. completion date: January 1, 2020

Study information

• Verified date: August 2023
• Source: Balgrist University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 60
• Est. completion date: January 1, 2020
• Est. primary completion date: January 1, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 20 Years to 65 Years

Eligibility

Patient group inclusion criteria:

• stable coronary heart patients/heart patients without ischemia

• Left ventricular ejection fraction > 50%

• Drug therapy with ACE inhibitors

• V?O2peak <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)

• V?O2peak <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])

Related Conditions & MeSH terms

• Cardiovascular Disease
• Cardiovascular Diseases

Intervention

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.
• 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.

Genetic:
• ACE genotyping
Subjects will be genotyped for the ACE-I/D gene polymorphism.

Locations

Country	Name	City	State
Switzerland	Balgrist University Hospital	Zurich
Switzerland	University Hospital Zurich	Zurich

Sponsors (2)

Lead Sponsor	Collaborator
Balgrist University Hospital	University of Zurich

Country where clinical trial is conducted

Switzerland, 

References & Publications (5)

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, 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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	Molecular muscle characteristics- ACE	• ACE activity [fmol min-1]	975 days: May 2016-January 2019
Primary	Cellular muscle characteristics - fiber type %	• Distribution of type I, IIA and IIX fibers [%]	975 days: May 2016-January 2019
Primary	Cellular muscle characteristics - fiber area %	• Area percentage of type I, IIA and IIX fibers [% area]	975 days: May 2016-January 2019
Primary	Cellular muscle characteristics - fiber type CSA	• Cross sectional area of type I, IIA and IIX fibers [micrometer2]	975 days: May 2016-January 2019
Primary	Cellular muscle characteristics - Capillary density	• Capillary density [capillaries micrometer-2]	975 days: May 2016-January 2019
Primary	Cellular muscle characteristics - Capillary-to-fiber ratio	• Capillary-to-fiber ratio	975 days: May 2016-January 2019
Primary	Functional muscle characteristics - Maximal Power	• Maximal power during ramp test on ergometer [Watt]	975 days: May 2016-January 2019
Primary	Functional muscle characteristics - Critical Power	• Critical power in ramp test on ergometer [Watt]	975 days: May 2016-January 2019
Primary	Functional muscle characteristics - Real Power	• Real Power as estimated on the soft robotic device [Watt]	975 days: May 2016-January 2019
Primary	Functional muscle characteristics - Reactive Power	• Reactive Power as estimated on the soft robotic device [Watt]	975 days: May 2016-January 2019
Primary	Functional muscle characteristics - Negative Power	• Negative Power as estimated on the soft robotic device [Watt]	975 days: May 2016-January 2019
Primary	Functional muscle characteristics - Maximal force	• Maximal force during the reactive power test on the soft robotic device [Newton]	975 days: May 2016-January 2019
Primary	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
Primary	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
Primary	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
Primary	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
Primary	Muscle metabolism - hemoglobin ramp	• Total hemoglobin during ramp test on ergometer [%]	975 days: May 2016-January 2019
Primary	Muscle metabolism - hemoglobin robot exercise	• Total hemoglobin during exercise on soft robot [%]	975 days: May 2016-January 2019
Primary	Muscle metabolism - lipid compounds	• Concentration of lipid compounds in m. vastus lateralis muscle during exercise on soft roboter	975 days: May 2016-January 2019
Primary	Muscle metabolism - metabolites	• Concentration of metabolites in m. vastus lateralis muscle during exercise on soft roboter	975 days: May 2016-January 2019
Primary	Muscle metabolism - serum glucose	• Concentration of glucose in serum during ramp test on ergometer [mmol l-1]	975 days: May 2016-January 2019
Primary	Muscle metabolism - serum lactate	• Concentration of lactate in serum during ramp test on ergometer [mmol l-1]	975 days: May 2016-January 2019
Primary	Cardiovascular function - Heart rate rest	• Heart rate at rest [beats per minute]	975 days: May 2016-January 2019
Primary	Cardiovascular function - Heart rate ramp	• Heart rate in ramp test on ergometer [beats per minute]	975 days: May 2016-January 2019
Primary	Cardiovascular function - cardiac output	• Cardiac output [L min-1]	975 days: May 2016-January 2019
Primary	Cardiovascular function - ejection fraction	• Ejection fraction	975 days: May 2016-January 2019
Primary	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
Primary	Cardiovascular function - ventilation	• Ventilation during ramp test on ergometer [L min-1]	975 days: May 2016-January 2019
Primary	Cardiovascular function - ventilation frequency	• Ventilation frequency ramp test on ergometer [min-1]	975 days: May 2016-January 2019
Primary	Cardiovascular function - respiration quotient	• Respiration quotient during ramp test on ergometer [ L O2 inspired / L CO2 expired]	975 days: May 2016-January 2019
Primary	Cardiovascular function - endurance	Time-to-exhaustion in constant load on ergometer [seconds]	975 days: May 2016-January 2019

External Links

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