Molecular Mechanisms of Volume Overload-Aim 1(SCCOR in Cardiac Dysfunction and Disease)

Study Overview
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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.

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.

Official Title
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Molecular Mechanisms of Volume Overload-Aim 1(SCCOR in Cardiac Dysfunction and Disease)

Conditions
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Mitral Regurgitation

Intervention / Treatment
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* Drug: metoprolol succinate (Toprol XL)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria:Patients who have Moderate MR documented by color flow doppler: LV ejection fraction > 55%; LV end-systolic dimension < 4.0 cm. Quantifiable by Doppler-Echo equal or more than moderate in severity. Organic disease of the mitral valve demonstrated by echocardiography (not normal valve as in functional or ischemic MR). Isolated MR (no valve disease other than mild tricuspid or pulmonic regurgitation by Doppler-Echocardiography that is often associated with mitral valve prolapse). Asymptomatic (or mildly symptomatic but not considered as candidates for immediate surgery by their attending physician). Exclusion Criteria: Significant obstructive coronary artery disease and/or myocardial ischemia on graded exercise test with myocardial perfusion. Previous myocardial infarction or percutaneous coronary intervention. Hypertrophic cardiomyopathy, congenital or pericardial disease. Aortic valve disease (> trace aortic regurgitation or mean gradient > 10 mmHg). Mitral stenosis (mean gradient >5 mmHg, valve area < 1.5 cm2). Intolerance or contraindication to Beta1-AR blockade. Renal failure with creatinine > 2.5 mg/dl. Hypertension requiring medical treatment or renal artery stenosis. Severe comorbidity: liver disease, malignancy, collagen vascular, steroid requirement. Pregnancy (negative pregnancy test and effective contraceptive methods are required prior to enrollment of females of childbearing potential). Uncontrolled (rate > 120/min) or recent (<4 weeks) atrial fibrillation. Routine, regular use of anti-inflammatory medications. Exclusion Criteria Related to MRI Severe claustrophobia. Presence of a pacemaker or non-removable hearing aid. Presence of metal clips in the body.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Toprol XL<br>beta 1 receptor blockade; generic name metoprolol succinate | Drug: metoprolol succinate (Toprol XL)<br>* Toprol XL 100 mg once a day for 2 years<br>|
| Placebo Comparator: Placebo<br>Pill that looks like Toprol XL but does not have the active ingredients | Drug: Placebo<br>* Placebo 100 mg once a day for 2 years<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Left Ventricular End Diastolic Volume Indexed to Body Surface Area | Left Ventricular End Diastolic Volume Indexed to Body Surface Area: As an indicator of heart size, the blood volume of the heart is related to the body size. The end diastolic volume is the blood volume of the heart at the end of filling, just before contraction. The relation of heart blood volume to body size is more accurate in determining pathology because larger people require a larger heart blood volume. The values that are too high or too low indicate a diseased myocardium. | 5 visits per Participant over 2 years (about every 6 months) | 
| Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume | Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume As an indicator of heart muscle mass and heart blood volume, the mass indexed to end diastolic volume determines whether there is an adequate amount of heart muscle to pump the heart blood volume obtained from a three-dimensional analysis. The values that are too high or too low indicate a diseased myocardium. | 5 visits per Participant over 2 years (about every 6 months) | 
| Left Ventricular End-Diastolic Radius to Wall Thickness | Left Ventricular End-Diastolic Radius to Wall Thickness As an indicator of heart muscle mass and heart volume chamber diameter, the end-diastolic radius indexed to end diastolic wall thickness determines whether there is an adequate amount of heart muscle to pump the heart blood volume obtained from a two-dimensional analysis. The values that are too high or too low indicate a diseased myocardium. | 5 visits per Participant over 2 years (about every 6 months) | 
| Left Ventricular End Systolic Volume Indexed to Body Surface Area | Left Ventricular End Systolic Volume Indexed to Body Surface Area As an indicator of heart size, the blood volume of the heart is related to the body size. The end systolic volume is the blood volume of the heart at the end of contraction and is an index of the pump function of the heart. This relation to body size is more accurate in determining pathology because larger people require a larger heart blood volume. The values that are too high or too low indicate a diseased myocardium. | 5 visits per Participant over 2 years (about every 6 months) | 
| Left Ventricular Ejection Fraction | Left Ventricular Ejection Fraction Is a calculation of heart pump function determined from the volume after complete filling minus the volume after complete contraction divided by the volume after complete filling. A value of 55% or greater is normal. | 5 visits per Participant over 2 years (about every 6 months) | 
| Systolic Longitudinal Strain | Systolic Longitudinal Strain. By identifying two points on the heart, the strain is the difference between the distance between these two points at the end of filling of the heart and the end of contraction divided by the length at the end of filling. Thus, the measure is like the ejection fraction, however the strain is more localized to a specified segment in the heart muscle. The higher values indicate a healthy heart. | 5 visits per Participant over 2 years (about every 6 months) | 
| Peak Early Filling Rate: Rate of Change Over Time | Peak Early Filling Rate The peak early filling rate of change is calculated from the slope of the volume during the early filling of the heart with respect to time. The higher values indicate a very healthy heart muscle and lower values are indicative of a very stiff muscle. | 5 visits per Participant over 2 years (about every 6 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic MR, Volume Overload, Beta-1 receptor blocker, LV remodelling, LV dimensions, LV systolic function, LV diastolic dysfunction, Cardiac MRI