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Characterization of Myocardial Interstitial Fibrosis and Cardiomyocyte Hypertrophy by Cardiac MRI in Heart Failure

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ClinicalTrials.gov Identifier: NCT03084679
Recruitment Status : Recruiting
First Posted : March 21, 2017
Last Update Posted : June 5, 2019
Sponsor:
Information provided by (Responsible Party):
Otavio Rizzi Coelho Filho, University of Campinas, Brazil

Brief Summary:
The investigators hypothesised that novel MRI metrics derived from myocardium post-gadolinium T1 mapping analysis will improve the current knowledge about the role interstitial fibrosis and cardiomyocyte hypertrophy in the development of left ventricular (LV) remodelling and clinical Heart Failure (HF). The investigators believe that these recently described variables will be associated with prognostically important indices in HF development.

Condition or disease Intervention/treatment Phase
Heart Failure Other: Aerobic exercise in treadmill Other: Local strengthening exercises Other: Stretching exercises Not Applicable

Detailed Description:
Cardiac hypertrophy is one of the earliest manifestations of myocardial disease, representing a modifiable, prognostic response to hemodynamic stimuli across physiologic (e.g., exercise) and pathologic states (e.g., hypertension, aortic stenosis). The extent of myocardial hypertrophy is determined by a combination of cardiomyocyte size and extracellular volume (ECV) expansion/interstitial fibrosis: while physiologic (exercise-induced) hypertrophy reflects mostly reversible cardiomyocyte hypertrophy, pathologic hypertrophy (e.g., in heart failure) is a combination of both interstitial fibrosis (potentially irreversible) and cardiomyocyte hypertrophy (reversible). Current methods to delineate the potential for LV reverse remodeling (e.g., natriuretic peptides and echocardiographic or clinical markers) detect primarily advanced disease, missing a critical opportunity to intervene and follow patients at an early disease phase where myocardial pathology may be reversible. Therefore, establishing novel, quantitative metrics of myocardial tissue phenotype that define a transition from hypertrophy to fibrosis, and then to irreversible LV remodeling/dysfunction may facilitate targeting therapies at a modifiable stage of disease in HF. The investigator's group has recently extended cardiac T1 mapping MRI techniques to quantify the intracellular lifetime of water (τic) serially as an index of cardiomyocyte diameter, validating this technique histologically in mouse models of pressure overload.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized trial in a 2:1 (intervention:control) proportion and in blocks of 6 participants.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Characterization of Myocardial Interstitial Fibrosis and Cardiomyocyte Hypertrophy by Cardiac MRI In Heart Failure: Implication on Early Remodeling and on the Transition to Heart Failure
Actual Study Start Date : November 1, 2017
Estimated Primary Completion Date : June 1, 2019
Estimated Study Completion Date : July 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arm Intervention/treatment
No Intervention: Conventional Clinical Care - HFpEF
Heart Failure patients with preserved ejection fraction (HFpEF) randomized to this arm will keep receiving their conventional clinical care, being instructed to continue and maintain their usual daily activities.
Supervised Exercise Training- HFpEF
Heart Failure patients with preserved ejection fraction (HFpEF) randomized to this arm will keep receiving their conventional clinical care and participate in a supervised, facility based training program consisting of stretching exercises and aerobic exercise in treadmill.
Other: Aerobic exercise in treadmill
30-40min of aerobic exercise in treadmill. The aerobic intensity will be established by heart rate levels that corresponded to anaerobic threshold up to 10% below the respiratory compensation point obtained in the cardiopulmonary exercise test. This intensity corresponded to 60-72% peak V̇o2. During the exercise sessions, when a training effect will be observed, as indicated by a decrease by 8 to 10% in heart rate, the treadmill velocity or inclination will be increased to return to the target heart rate levels.

Other: Local strengthening exercises
15 min of local strengthening exercises will be performed in major muscle groups (legs, arms and trunk muscles): three series of each exercise, 12-15 repetitions.

Other: Stretching exercises
5-min stretching exercises will be performed in major muscle groups (legs, arms and trunk muscles)

No Intervention: Conventional Clinical Care - HFrEF
Heart Failure patients with reduced ejection fraction (HFrEF) randomized to this arm will keep receiving their conventional clinical care, being instructed to continue and maintain their usual daily activities.
Supervised Exercise Training - HFrEF
Heart Failure patients with reduced ejection fraction (HFrEF) randomized to this arm will keep receiving their conventional clinical care and participate in a supervised, facility based training program consisting of stretching exercises and aerobic exercise in treadmill.
Other: Aerobic exercise in treadmill
30-40min of aerobic exercise in treadmill. The aerobic intensity will be established by heart rate levels that corresponded to anaerobic threshold up to 10% below the respiratory compensation point obtained in the cardiopulmonary exercise test. This intensity corresponded to 60-72% peak V̇o2. During the exercise sessions, when a training effect will be observed, as indicated by a decrease by 8 to 10% in heart rate, the treadmill velocity or inclination will be increased to return to the target heart rate levels.

Other: Local strengthening exercises
15 min of local strengthening exercises will be performed in major muscle groups (legs, arms and trunk muscles): three series of each exercise, 12-15 repetitions.

Other: Stretching exercises
5-min stretching exercises will be performed in major muscle groups (legs, arms and trunk muscles)




Primary Outcome Measures :
  1. Myocardial remodeling assessed by CMR in rehabilitation vs usual care. [ Time Frame: 4 months ]
    Investigate whether rehabilitation compared to usual care is associated with significant favorable myocardial remodeling assessed by CMR determination of ECV.


Secondary Outcome Measures :
  1. Change in left ventricular ejection fraction [ Time Frame: 4 months ]
    Left Ventricular ejection fraction (%) will be determined by cardiac magnetic resonance using a previously described cine steady-state free precession imaging. All patients will be imaged with ECG gating and breath holding in a supine position. Patients will be imaged at baseline and after 4 months of the intervention.

  2. Change in right ventricular ejection fraction [ Time Frame: 4 months ]
    Right Ventricular ejection fraction (%) will be determined by cardiac magnetic resonance using a previously described cine steady-state free precession imaging. All patients will be imaged with ECG gating and breath holding in a supine position. Patients will be imaged at baseline and after 4 months of the intervention.

  3. Change in left ventricular mass (absolute/index) [ Time Frame: 4 months ]
    Left ventricular mass absolute (g) and index (g/m2) will be determined by cardiac magnetic resonance using a previously described cine steady-state free precession imaging. All patients will be imaged with ECG gating and breath holding in a supine position. Patients will be imaged at baseline and after 4 months of the intervention.

  4. Change in left ventricular diastolic volume (absolute/index) [ Time Frame: 4 months ]
    Left ventricular diastolic volume absolute (ml) and index (ml/m2) will be determined by cardiac magnetic resonance using a previously described cine steady-state free precession imaging. All patients will be imaged with ECG gating and breath holding in a supine position. Patients will be imaged at baseline and after 4 months of the intervention.

  5. Change in right ventricular diastolic volume (absolute/index) [ Time Frame: 4 months ]
    Right ventricular diastolic volume absolute (ml) and index (ml/m2) will be determined by cardiac magnetic resonance using a previously described cine steady-state free precession imaging. All patients will be imaged with ECG gating and breath holding in a supine position. Patients will be imaged at baseline and after 4 months of the intervention.

  6. Change in left ventricular systolic volume (absolute/index) [ Time Frame: 4 months ]
    Left ventricular systolic volume absolute (ml) and index (ml/m2) will be determined by cardiac magnetic resonance using a previously described cine steady-state free precession imaging. All patients will be imaged with ECG gating and breath holding in a supine position. Patients will be imaged at baseline and after 4 months of the intervention.

  7. Change in right ventricular systolic volume (absolute/index) [ Time Frame: 4 months ]
    Right ventricular systolic volume absolute (ml) and index (ml/m2) will be determined by cardiac magnetic resonance using a previously described cine steady-state free precession imaging. All patients will be imaged with ECG gating and breath holding in a supine position. Patients will be imaged at baseline and after 4 months of the intervention.

  8. Change in left ventricular stroke volume (absolute/index) [ Time Frame: 4 months ]
    Left ventricular stroke volume absolute (ml) and index (ml/m2) will be determined by cardiac magnetic resonance using a previously described cine steady-state free precession imaging. All patients will be imaged with ECG gating and breath holding in a supine position. Patients will be imaged at baseline and after 4 months of the intervention.

  9. Change in right ventricular stroke volume (absolute/index) [ Time Frame: 4 months ]
    Right ventricular stroke volume (absolute (ml) and index (ml/m2) will be determined by cardiac magnetic resonance using a previously described cine steady-state free precession imaging. All patients will be imaged with ECG gating and breath holding in a supine position. Patients will be imaged at baseline and after 4 months of the intervention.

  10. Change in late gadolinium enhancement [ Time Frame: 4 months ]
    Late gadolinium enhancement (LGE) will be determined by cardiac magnetic resonance using a previously describe inversion recovery sequence after 10-15 minutes of a cumulative dose of 0,2 mmol/kg of gadolinium diethylenetriamine pentaacetic acid. All patients will be imaged with ECG gating and breath holding in a supine position. Patients will be imaged at baseline and after 4 months of the intervention.

  11. Change in LV mass/volume ratio [ Time Frame: 4 months ]
    LV mass/volume ratio (g/mL) will be determined by cardiac magnetic resonance using a previously described cine steady-state free precession imaging. All patients will be imaged with ECG gating and breath holding in a supine position. Patients will be imaged at baseline and after 4 months of the intervention.

  12. Change in functional capacity [ Time Frame: 4 months ]
    VO2max will be evaluated by cardiopulmonary test. Patients will performed the cardiopulmonary test at baseline and after 4 months of the intervention.

  13. Change in quality of life [ Time Frame: 4 months ]

    Quality of life will be evaluated by numerical score of Minnesota Questionnaire.

    Patients will performed the Minnesota Questionnaire at baseline and after 4 months of the intervention.


  14. Change in N-Terminal pro-B-type Natriuretic Peptide (NT-proBNP) [ Time Frame: 4 months ]
    Change in NT-proBNP with the intervention.

  15. Change in diastolic dysfunction assessed by transthoracic echocardiogram [ Time Frame: 4 months ]
    Change in parameters of diastolic dysfunction assessed before and after the intervention.

  16. Change in cardiac sympathetic function [ Time Frame: 4 months ]
    Change in cardiac sympathetic function assessed by cardiac uptake of metaiodobenzylguanidine (MIBG) labeled with I-123. Patients will performed the MIBG study at baseline and after 4 months of the intervention.

  17. Change in intracellular lifetime of water (τic - a marker of cardiomyocyte hypertrophy) [ Time Frame: 4 months ]
    τic will be determined by cardiac magnetic resonance T1 measurements acquired before and after administration of gadolinium diethylenetriamine pentaacetic acid (0,2mmol/kg), at 2 different time points (baseline and 4-moths after the intervention)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age> 18 years
  • Functional limitation (New York Heart Association Class II or worse)
  • No contraindication to exercise (American College of Cardiology / American Heart Association criteria)
  • Eligibility to take MRI (absence of metallic devices, and glomerular filtration rate > 40ml / min / 1.73m2, etc.)
  • Prior diagnosis of Heart Failure (by the Framingham criterion)
  • Therapy with diuretic and euvolemia state (evaluated by cardiologist and cardiopulmonary exercise testing)
  • Transthoracic echocardiogram

Exclusion Criteria:

  • Severe ischemia in any stress test
  • Hypertrophic cardiomyopathy or any infiltrative heart disease
  • Chronic obstructive pulmonary disease , pulmonary hypertension (Pulmonary artery pressure> 60mmHg)
  • Severe left or right valve disease.
  • Pacemaker or implantable cardioverter defibrillator
  • Myocardial infarction or revascularization in 3 months
  • Anemia (hemoglobin <10 grams / dl) until 1 month before cardiopulmonary exercise testing

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): NCT03084679


Contacts
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Contact: OTAVIO R COELHO-FILHO, MD, MPH, PhD 996038484 ext +5519 tavicocoelho@gmail.com
Contact: FERNANDO B CARDOSO, MD 999203131 ext +5519 fermedesportiva@yahoo.com.br

Locations
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Brazil
University of Campinas Recruiting
Campinas, São Paulo, Brazil
Contact: Otavio R Coelho Filho, MD, PhD    +5519996038484    tavicocoelho@gmail.com   
Contact: Fernando B Cardoso, MD    +5519999203131    fermedesportiva@yahoo.com.br   
Sponsors and Collaborators
University of Campinas, Brazil
Investigators
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Principal Investigator: OTAVIO R COELHO-FILHO, MD, MPH, PhD University of Campinas, Brazil

Publications:
Coelho-Filho OR, Mitchell RN, Moreno H, Kwong RY and Jerosch-Herold M. MRI based non-invasive detection of cardiomyocyte hypertrophy and cell-volume changes. J Cardiovasc Magn Reson. 2012;14:O10.

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Responsible Party: Otavio Rizzi Coelho Filho, Assistant Professor, University of Campinas, Brazil
ClinicalTrials.gov Identifier: NCT03084679     History of Changes
Other Study ID Numbers: HF-CMR-53967215800005404
FAPESP 2015/15402-2 ( Other Grant/Funding Number: São Paulo Research Foundation )
First Posted: March 21, 2017    Key Record Dates
Last Update Posted: June 5, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: No plan to Share individual participant data.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Otavio Rizzi Coelho Filho, University of Campinas, Brazil:
Heart Failure
Hypertrophy
Fibrosis
Magnetic Resonance
Additional relevant MeSH terms:
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Heart Failure
Fibrosis
Hypertrophy
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Pathological Conditions, Anatomical