Molecular Mechanisms of Volume Overload-Aim 1(SCCOR in Cardiac Dysfunction and Disease)
Molecular Mechanisms of Volume Overload-Aim 1(SCCOR in Cardiac Dysfunction and Disease)
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.
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.
Inclusion Criteria:Patients who have Moderate MR documented by color flow doppler:

 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).

 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.

 Exclusion Criteria Related to MRI

 1. Severe claustrophobia.

 2. Presence of a pacemaker or non-removable hearing aid.

 3. Presence of metal clips in the body.