Molecular Mechanisms of Volume Overload-Aim 1(SCCOR in Cardiac Dysfunction and Disease)
Condition: Mitral Regurgitation
MeSH terms: Mitral Valve Insufficiency
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      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: 
      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.
    

Intervention name(s): metoprolol succinate (Toprol XL); Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Toprol XL 100 mg once a day for 2 years; Placebo 100 mg once a day for 2 years
Intervention MeSH terms: Metoprolol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Chronic MR; Volume Overload; Beta-1 receptor blocker; LV remodelling, LV dimensions; LV systolic function; LV diastolic dysfunction; Cardiac MRI