Molecular Mechanisms of Volume Overload-Aim 1(SCCOR in Cardiac Dysfunction and Disease)
NCT ID: NCT01052428
Last Updated: 2012-11-22
Study Results
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Recruitment Status
COMPLETED
Clinical Phase
PHASE2/PHASE3
Total Enrollment
38 participants
Study Classification
INTERVENTIONAL
Study Start Date
2004-08-31
Study Completion Date
2010-07-31
Brief Summary
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The investigators hypothesize that beta-1 receptor blockade (ß1-RB) attenuates extracellular matrix (ECM) degradation and progressive adverse Left Ventricular (LV) remodeling and failure in the volume overload of mitral regurgitation (MR). Patients without coronary artery disease and moderate MR, as assessed by color/flow Doppler echocardiography, will be randomized to ß1-RB vs. placebo to address the following aims:
\*Aim 1: Establish whether ß1-RB attenuates adverse LV remodeling compared to placebo in patients with non-surgical, chronic MR. Using 3-dimensional magnetic resonance imaging (MRI) and tissue tagging, LV function and geometry will be assessed at baseline and every 6 months for up to 2 years.
Aim 2: Determine whether indices of inflammation correlate with degree of LV remodeling and whether ß1-RB decrease indices of inflammation and collagen turnover. At the time of MRI, blood samples for collagen breakdown products, matrix metalloproteinase (MMP) activity, and markers of excess production of reactive inflammatory species (RIS) will be obtained and related to changes in LV remodeling defined by serial 3-dimensional MRI and tissue tagging.
\*Aim 1: Establish whether ß1-RB attenuates adverse LV remodeling compared to placebo in patients with non-surgical, chronic MR. Using 3-dimensional magnetic resonance imaging (MRI) and tissue tagging, LV function and geometry will be assessed at baseline and every 6 months for up to 2 years.
Aim 2: Determine whether indices of inflammation correlate with degree of LV remodeling and whether ß1-RB decrease indices of inflammation and collagen turnover. At the time of MRI, blood samples for collagen breakdown products, matrix metalloproteinase (MMP) activity, and markers of excess production of reactive inflammatory species (RIS) will be obtained and related to changes in LV remodeling defined by serial 3-dimensional MRI and tissue tagging.
Detailed Description
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In Western society, the most common causes of chronic mitral regurgitation (MR) are ischemic heart disease and myxomatous degeneration of the valve, resulting in prolapse, ruptured chordae or partial flail leaflet. Current indications for surgery are only for patients with severe MR and either notable symptoms or overt Left Ventricular (LV) dysfunction (ejection fraction \< 60%, end-systolic diameter \> 40 mm). Therefore, despite the availability of surgery, most patients with MR of moderate severity are not immediate candidates for surgery, warranting analysis of potential beneficial effects of medical treatment. Chronic therapy with vasodilators reduces LV wall stress and thereby delays the need for valve replacement in aortic regurgitation; however, no such data are currently available in patients with chronic MR using standard vasodilators or agents that block the renin angiotensin system (RAS).
In a clinically-relevant dog model of MR, the investigators have shown increased LV ACE and chymase expression, increased LV angiotensin II but, as opposed to pressure overload, there was an absence of fibrosis with net extracellular matrix (ECM) degradation and activation of matrix metalloproteinases (MMPs). However, blockade of the RAS does not improve (and may actually exacerbate) LV remodeling in MR. Interestingly, the investigators and others have shown that ß1-receptor blockade (ß1-RB) is more effective than RAS blockade in attenuating progressive LV remodeling and ECM degradation in MR. Moreover, increased sympathetic drive and inflammation has been identified in patients with chronic MR. ß1-RB reduced plasma markers of inflammation in patients with heart failure and resulted in substantial reverse LV remodeling in patients with heart failure. Taken together, activation of the adrenergic nervous system early in the course of volume overload contributes to increased production of reactive inflammatory species (RIS) and that one mechanism underlying the salutary effects of ß1-blockade may relate to attenuation of myocardial formation of RIS with subsequent beneficial effects on MMP activation and ECM and LV remodeling and function.
In a clinically-relevant dog model of MR, the investigators have shown increased LV ACE and chymase expression, increased LV angiotensin II but, as opposed to pressure overload, there was an absence of fibrosis with net extracellular matrix (ECM) degradation and activation of matrix metalloproteinases (MMPs). However, blockade of the RAS does not improve (and may actually exacerbate) LV remodeling in MR. Interestingly, the investigators and others have shown that ß1-receptor blockade (ß1-RB) is more effective than RAS blockade in attenuating progressive LV remodeling and ECM degradation in MR. Moreover, increased sympathetic drive and inflammation has been identified in patients with chronic MR. ß1-RB reduced plasma markers of inflammation in patients with heart failure and resulted in substantial reverse LV remodeling in patients with heart failure. Taken together, activation of the adrenergic nervous system early in the course of volume overload contributes to increased production of reactive inflammatory species (RIS) and that one mechanism underlying the salutary effects of ß1-blockade may relate to attenuation of myocardial formation of RIS with subsequent beneficial effects on MMP activation and ECM and LV remodeling and function.
Conditions
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Mitral Regurgitation
Keywords
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Chronic MR
Volume Overload
Beta-1 receptor blocker
LV remodelling, LV dimensions
LV systolic function
LV diastolic dysfunction
Cardiac MRI
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
PARALLEL
Primary Study Purpose
TREATMENT
Blinding Strategy
TRIPLE
Participants
Caregivers
Investigators
Study Groups
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Toprol XL
beta 1 receptor blockade; generic name metoprolol succinate
Group Type
ACTIVE_COMPARATOR
metoprolol succinate (Toprol XL)
Intervention Type
DRUG
Toprol XL 100 mg once a day for 2 years
Placebo
Pill that looks like Toprol XL but does not have the active ingredients
Group Type
PLACEBO_COMPARATOR
Placebo
Intervention Type
DRUG
Placebo 100 mg once a day for 2 years
Interventions
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metoprolol succinate (Toprol XL)
Toprol XL 100 mg once a day for 2 years
Intervention Type
DRUG
Placebo
Placebo 100 mg once a day for 2 years
Intervention Type
DRUG
Eligibility Criteria
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Inclusion Criteria
1. LV ejection fraction \> 55%; LV end-systolic dimension \< 4.0 cm.
2. Quantifiable by Doppler-Echo equal or more than moderate in severity.
3. Organic disease of the mitral valve demonstrated by echocardiography (not normal valve as in functional or ischemic MR).
4. Isolated MR (no valve disease other than mild tricuspid or pulmonic regurgitation by Doppler-Echocardiography that is often associated with mitral valve prolapse).
5. Asymptomatic (or mildly symptomatic but not considered as candidates for immediate surgery by their attending physician).
2. Quantifiable by Doppler-Echo equal or more than moderate in severity.
3. Organic disease of the mitral valve demonstrated by echocardiography (not normal valve as in functional or ischemic MR).
4. Isolated MR (no valve disease other than mild tricuspid or pulmonic regurgitation by Doppler-Echocardiography that is often associated with mitral valve prolapse).
5. Asymptomatic (or mildly symptomatic but not considered as candidates for immediate surgery by their attending physician).
Exclusion Criteria
1. Significant obstructive coronary artery disease and/or myocardial ischemia on graded exercise test with myocardial perfusion.
2. Previous myocardial infarction or percutaneous coronary intervention.
3. Hypertrophic cardiomyopathy, congenital or pericardial disease.
4. Aortic valve disease (\> trace aortic regurgitation or mean gradient \> 10 mmHg).
5. Mitral stenosis (mean gradient \>5 mmHg, valve area \< 1.5 cm2).
6. Intolerance or contraindication to Beta1-AR blockade.
7. Renal failure with creatinine \> 2.5 mg/dl.
8. Hypertension requiring medical treatment or renal artery stenosis.
9. Severe comorbidity: liver disease, malignancy, collagen vascular, steroid requirement.
10. Pregnancy (negative pregnancy test and effective contraceptive methods are required prior to enrollment of females of childbearing potential).
11. Uncontrolled (rate \> 120/min) or recent (\<4 weeks) atrial fibrillation.
12. Routine, regular use of anti-inflammatory medications.
1. Severe claustrophobia.
2. Presence of a pacemaker or non-removable hearing aid.
3. Presence of metal clips in the body.
2. Previous myocardial infarction or percutaneous coronary intervention.
3. Hypertrophic cardiomyopathy, congenital or pericardial disease.
4. Aortic valve disease (\> trace aortic regurgitation or mean gradient \> 10 mmHg).
5. Mitral stenosis (mean gradient \>5 mmHg, valve area \< 1.5 cm2).
6. Intolerance or contraindication to Beta1-AR blockade.
7. Renal failure with creatinine \> 2.5 mg/dl.
8. Hypertension requiring medical treatment or renal artery stenosis.
9. Severe comorbidity: liver disease, malignancy, collagen vascular, steroid requirement.
10. Pregnancy (negative pregnancy test and effective contraceptive methods are required prior to enrollment of females of childbearing potential).
11. Uncontrolled (rate \> 120/min) or recent (\<4 weeks) atrial fibrillation.
12. Routine, regular use of anti-inflammatory medications.
1. Severe claustrophobia.
2. Presence of a pacemaker or non-removable hearing aid.
3. Presence of metal clips in the body.
Minimum Eligible Age
19 Years
Maximum Eligible Age
70 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
Yes
Sponsors
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National Heart, Lung, and Blood Institute (NHLBI)
NIH
Sponsor Role
collaborator
AstraZeneca
INDUSTRY
Sponsor Role
collaborator
University of Alabama at Birmingham
OTHER
Sponsor Role
lead
Responsible Party
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Dr. Louis J. Dell'Italia
Professor
Responsibility Role
PRINCIPAL_INVESTIGATOR
Principal Investigators
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Louis . J. Dell'Italia, M.D
Role: PRINCIPAL_INVESTIGATOR
University of Alabama at Birmingham
Locations
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University of Alabama at Birmingham
Birmingham, Alabama, United States
Site Status
Countries
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United States
References
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1. Dell'Italia LJ. Mitral Regurgitation. In Hurst The Heart. Eds. O'Rourke, Sclhant, Alexader, Fuster. 11th Edition, Chapter 57 pp 1169-1695, 2004.
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BACKGROUND
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BACKGROUND
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Reference Type
DERIVED
Other Identifiers
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F040601008
Identifier Type: -
Identifier Source: org_study_id