Molecular Mechanisms of Volume Overload-Aim 1(SCCOR in Cardiac Dysfunction and Disease) (P1A1)

The University of Alabama at Birmingham

Status and phase: Completed; Phase 3; Phase 2

Conditions: Mitral Regurgitation

Treatments: Drug: Placebo; Drug: metoprolol succinate (Toprol XL)

Study type: Interventional

Funder types: Other; Industry; NIH

Identifiers

NCT01052428

F040601008

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 38 patients

Sex: All

Ages: 19 to 70 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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38 participants in 2 patient groups, including a placebo group

Toprol XL

Active Comparator group

Description:

beta 1 receptor blockade; generic name metoprolol succinate

Treatment:

Drug: metoprolol succinate (Toprol XL)

Placebo

Placebo Comparator group

Description:

Pill that looks like Toprol XL but does not have the active ingredients

Treatment:

Drug: Placebo