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

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ClinicalTrials.gov Identifier: NCT02845063
Recruitment Status : Recruiting
First Posted : July 27, 2016
Last Update Posted : August 9, 2016
Sponsor:
Collaborator:
University of Zurich
Information provided by (Responsible Party):
Balgrist University Hospital

Brief 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.

Condition or disease Intervention/treatment Phase
Cardiovascular Disease Behavioral: concentric cardiovascular training Behavioral: eccentric cardiovascular training Genetic: ACE genotyping Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Effects of ACE Genotype on Muscular and Functional Adaptations Following a Cardiovascular Rehabilitation Program
Study Start Date : May 2016
Estimated Primary Completion Date : January 2019
Estimated Study Completion Date : January 2020

Resource links provided by the National Library of Medicine


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'
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.

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

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'
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.

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




Primary Outcome Measures :
  1. ACE I/D genotype [ Time Frame: 975 days: May 2016-January 2019 ]
    Genotype of the assessed insertion/deletion gene polymorphism of angiotensin converting enzyme ACE, i.e. ACE-II, ACE-ID or ACE-DD.

  2. Molecular muscle characteristics - mRNA [ Time Frame: 975 days: May 2016-January 2019 ]
    • 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]

  3. Molecular muscle characteristics- protein [ Time Frame: 975 days: May 2016-January 2019 ]
    • 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]

  4. Molecular muscle characteristics- phosphorylation [ Time Frame: 975 days: May 2016-January 2019 ]
    • Phosphorylation of proteins phospho-Y397- FAK, phospho-T421/S424-P70S6K, phospho -T183/Y185-JNK, phospho-S2448-mTOR [pixel counts per actin]

  5. Molecular muscle characteristics- ACE [ Time Frame: 975 days: May 2016-January 2019 ]
    • ACE activity [fmol min-1]

  6. Cellular muscle characteristics - fiber type % [ Time Frame: 975 days: May 2016-January 2019 ]
    • Distribution of type I, IIA and IIX fibers [%]

  7. Cellular muscle characteristics - fiber area % [ Time Frame: 975 days: May 2016-January 2019 ]
    • Area percentage of type I, IIA and IIX fibers [% area]

  8. Cellular muscle characteristics - fiber type CSA [ Time Frame: 975 days: May 2016-January 2019 ]
    • Cross sectional area of type I, IIA and IIX fibers [micrometer2]

  9. Cellular muscle characteristics - Capillary density [ Time Frame: 975 days: May 2016-January 2019 ]
    • Capillary density [capillaries micrometer-2]

  10. Cellular muscle characteristics - Capillary-to-fiber ratio [ Time Frame: 975 days: May 2016-January 2019 ]
    • Capillary-to-fiber ratio

  11. Functional muscle characteristics - Maximal Power [ Time Frame: 975 days: May 2016-January 2019 ]
    • Maximal power during ramp test on ergometer [Watt]

  12. Functional muscle characteristics - Critical Power [ Time Frame: 975 days: May 2016-January 2019 ]
    • Critical power in ramp test on ergometer [Watt]

  13. Functional muscle characteristics - Real Power [ Time Frame: 975 days: May 2016-January 2019 ]
    • Real Power as estimated on the soft robotic device [Watt]

  14. Functional muscle characteristics - Reactive Power [ Time Frame: 975 days: May 2016-January 2019 ]
    • Reactive Power as estimated on the soft robotic device [Watt]

  15. Functional muscle characteristics - Negative Power [ Time Frame: 975 days: May 2016-January 2019 ]
    • Negative Power as estimated on the soft robotic device [Watt]

  16. Functional muscle characteristics - Maximal force [ Time Frame: 975 days: May 2016-January 2019 ]
    • Maximal force during the reactive power test on the soft robotic device [Newton]

  17. Functional muscle characteristics - Maximal velocity [ Time Frame: 975 days: May 2016-January 2019 ]
    • Maximal velocity during the reactive power test on the soft robotic device [m sec-1]

  18. Functional muscle characteristics - Rate of force development [ Time Frame: 975 days: May 2016-January 2019 ]
    • Rate of force development as estimated during the Real Power test on the soft robotic device [meter sec-2]

  19. Muscle metabolism - muscle oxygenation ramp [ Time Frame: 975 days: May 2016-January 2019 ]
    • Muscle oxygenation (m. vastus lateralis, m. gastrocnemius, m. gluteus maximus) during ramp test on ergometer [%]

  20. Muscle metabolism - muscle oxygenation robot exercise [ Time Frame: 975 days: May 2016-January 2019 ]
    • Muscle oxygenation (m. vastus lateralis, m. gastrocnemius, m. gluteus maximus) during exercise on soft robot [%]

  21. Muscle metabolism - hemoglobin ramp [ Time Frame: 975 days: May 2016-January 2019 ]
    • Total hemoglobin during ramp test on ergometer [%]

  22. Muscle metabolism - hemoglobin robot exercise [ Time Frame: 975 days: May 2016-January 2019 ]
    • Total hemoglobin during exercise on soft robot [%]

  23. Muscle metabolism - lipid compounds [ Time Frame: 975 days: May 2016-January 2019 ]
    • Concentration of lipid compounds in m. vastus lateralis muscle during exercise on soft roboter

  24. Muscle metabolism - metabolites [ Time Frame: 975 days: May 2016-January 2019 ]
    • Concentration of metabolites in m. vastus lateralis muscle during exercise on soft roboter

  25. Muscle metabolism - serum glucose [ Time Frame: 975 days: May 2016-January 2019 ]
    • Concentration of glucose in serum during ramp test on ergometer [mmol l-1]

  26. Muscle metabolism - serum lactate [ Time Frame: 975 days: May 2016-January 2019 ]
    • Concentration of lactate in serum during ramp test on ergometer [mmol l-1]

  27. Cardiovascular function - Heart rate rest [ Time Frame: 975 days: May 2016-January 2019 ]
    • Heart rate at rest [beats per minute]

  28. Cardiovascular function - Heart rate ramp [ Time Frame: 975 days: May 2016-January 2019 ]
    • Heart rate in ramp test on ergometer [beats per minute]

  29. Cardiovascular function - cardiac output [ Time Frame: 975 days: May 2016-January 2019 ]
    • Cardiac output [L min-1]

  30. Cardiovascular function - ejection fraction [ Time Frame: 975 days: May 2016-January 2019 ]
    • Ejection fraction

  31. Cardiovascular function - Maximal oxygen uptake [ Time Frame: 975 days: May 2016-January 2019 ]
    • Maximal oxygen uptake (VO2max) during ramp test on ergometer [ml O2 min-1 kg-1]

  32. Cardiovascular function - ventilation [ Time Frame: 975 days: May 2016-January 2019 ]
    • Ventilation during ramp test on ergometer [L min-1]

  33. Cardiovascular function - ventilation frequency [ Time Frame: 975 days: May 2016-January 2019 ]
    • Ventilation frequency ramp test on ergometer [min-1]

  34. Cardiovascular function - respiration quotient [ Time Frame: 975 days: May 2016-January 2019 ]
    • Respiration quotient during ramp test on ergometer [ L O2 inspired / L CO2 expired]

  35. Cardiovascular function - endurance [ Time Frame: 975 days: May 2016-January 2019 ]
    Time-to-exhaustion in constant load on ergometer [seconds]



Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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])

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02845063


Contacts
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Contact: Martin Flück, PhD +41 44 386 3791 mflueck@research.balgrist.ch
Contact: Marco Toigo, PhD +41 44 386 3791 mtoigo@research.balgrist.ch

Locations
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Switzerland
Balgrist University Hospital Recruiting
Zurich, Switzerland, 8008
Contact: Martin Flück, PhD    +41445107350    mflueck@research.balgrist.ch   
Contact: Marco Toigo, PhD    +41445107351    mtoigo@research.balgrist.ch   
University Hospital Zurich Not yet recruiting
Zurich, Switzerland, 8091
Contact: Christian M Schmied, MD    +41 44 255 3478    Christian.Schmied@usz.ch   
Contact: David Niederseer, MD    +41 44 255 1111    david.niederseer@usz.ch   
Sponsors and Collaborators
Balgrist University Hospital
University of Zurich
Investigators
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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

Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Balgrist University Hospital
ClinicalTrials.gov Identifier: NCT02845063     History of Changes
Other Study ID Numbers: W 549 ACE-REHAB
KEK-ZH-Nr. 2014-0319 ( Other Identifier: Ethics Committee of the Canton Zurich, Switzerland )
First Posted: July 27, 2016    Key Record Dates
Last Update Posted: August 9, 2016
Last Verified: May 2016

Keywords provided by Balgrist University Hospital:
muscle plasticity
exercise
rehabilitation
perfusion
ACE
genotype
hypertension
molecular biology

Additional relevant MeSH terms:
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Cardiovascular Diseases