Clinical trial NCT02845063: Effect of ACE Genotype on Cardiovascular Rehabilitation
Official title: Effects of ACE Genotype on Muscular and Functional Adaptations Following a Cardiovascular Rehabilitation Program
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Cardiovascular Disease
Keywords: muscle plasticity
exercise
rehabilitation
perfusion
ACE
genotype
hypertension
molecular biology
Lead sponsor: Balgrist University Hospital
Sponsor class: OTHER
Collaborators: name: University of Zurich
First posted: 2016-07-27
Enrollment: 60
Sex: ALL
Minimum age (years): 20
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.

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.

Eligibility 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 \[Marfan syndrome, Ehlers-Danlos syndrome\])

Primary outcomes:
measure: ACE I/D genotype
timeFrame: 975 days: May 2016-January 2019
measure: Molecular muscle characteristics - mRNA
timeFrame: 975 days: May 2016-January 2019
measure: Molecular muscle characteristics- protein
timeFrame: 975 days: May 2016-January 2019
measure: Molecular muscle characteristics- phosphorylation
timeFrame: 975 days: May 2016-January 2019
measure: Molecular muscle characteristics- ACE
timeFrame: 975 days: May 2016-January 2019
measure: Cellular muscle characteristics - fiber type %
timeFrame: 975 days: May 2016-January 2019
measure: Cellular muscle characteristics - fiber area %
timeFrame: 975 days: May 2016-January 2019
measure: Cellular muscle characteristics - fiber type CSA
timeFrame: 975 days: May 2016-January 2019
measure: Cellular muscle characteristics - Capillary density
timeFrame: 975 days: May 2016-January 2019
measure: Cellular muscle characteristics - Capillary-to-fiber ratio
timeFrame: 975 days: May 2016-January 2019
measure: Functional muscle characteristics - Maximal Power
timeFrame: 975 days: May 2016-January 2019
measure: Functional muscle characteristics - Critical Power
timeFrame: 975 days: May 2016-January 2019
measure: Functional muscle characteristics - Real Power
timeFrame: 975 days: May 2016-January 2019
measure: Functional muscle characteristics - Reactive Power
timeFrame: 975 days: May 2016-January 2019
measure: Functional muscle characteristics - Negative Power
timeFrame: 975 days: May 2016-January 2019
measure: Functional muscle characteristics - Maximal force
timeFrame: 975 days: May 2016-January 2019
measure: Functional muscle characteristics - Maximal velocity
timeFrame: 975 days: May 2016-January 2019
measure: Functional muscle characteristics - Rate of force development
timeFrame: 975 days: May 2016-January 2019
measure: Muscle metabolism - muscle oxygenation ramp
timeFrame: 975 days: May 2016-January 2019
measure: Muscle metabolism - muscle oxygenation robot exercise
timeFrame: 975 days: May 2016-January 2019
measure: Muscle metabolism - hemoglobin ramp
timeFrame: 975 days: May 2016-January 2019
measure: Muscle metabolism - hemoglobin robot exercise
timeFrame: 975 days: May 2016-January 2019
measure: Muscle metabolism - lipid compounds
timeFrame: 975 days: May 2016-January 2019
measure: Muscle metabolism - metabolites
timeFrame: 975 days: May 2016-January 2019
measure: Muscle metabolism - serum glucose
timeFrame: 975 days: May 2016-January 2019
measure: Muscle metabolism - serum lactate
timeFrame: 975 days: May 2016-January 2019
measure: Cardiovascular function - Heart rate rest
timeFrame: 975 days: May 2016-January 2019
measure: Cardiovascular function - Heart rate ramp
timeFrame: 975 days: May 2016-January 2019
measure: Cardiovascular function - cardiac output
timeFrame: 975 days: May 2016-January 2019
measure: Cardiovascular function - ejection fraction
timeFrame: 975 days: May 2016-January 2019
measure: Cardiovascular function - Maximal oxygen uptake
timeFrame: 975 days: May 2016-January 2019
measure: Cardiovascular function - ventilation
timeFrame: 975 days: May 2016-January 2019
measure: Cardiovascular function - ventilation frequency
timeFrame: 975 days: May 2016-January 2019
measure: Cardiovascular function - respiration quotient
timeFrame: 975 days: May 2016-January 2019
measure: Cardiovascular function - endurance
timeFrame: 975 days: May 2016-January 2019
Secondary outcomes:
Other outcomes:
Locations:
city: Zurich
country: Switzerland
facility: Balgrist University Hospital
city: Zurich
country: Switzerland
facility: University Hospital Zurich
Study officials:
affiliation: Balgrist University Hospital, Move>med, Swiss Olympic Center, Zurich, Switzerland
name: Walter O Frey, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Cardiology, University Hospital Zurich, Zurich, Switzerland
name: Christian M Schmied, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: 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.
citation: 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.
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.
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.
citation: 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.