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Molecular Mechanisms of Mitral Regurgitation—Aim 2 (P1A2)

This study has been completed.
Information provided by:
University of Alabama at Birmingham Identifier:
First received: January 15, 2010
Last updated: December 1, 2010
Last verified: December 2010
The investigators hypothesize that MR in humans is characterized by adrenergic overdrive, reactive nitrogen species, and an antifibrotic phenotype that relate to the severity of adverse LV remodeling prior to surgery and outcome after valve repair.

Mitral Regurgitation

Study Type: Observational
Study Design: Observational Model: Case-Only
Time Perspective: Prospective
Official Title: The Study to Define the Unique Molecular Mechanisms of Mitral Regurgitation in Order to Find New Targeted Therapy to Attenuate the Remodeling and Delay the Need for Surgery and Improve Surgical Outcomes.

Further study details as provided by University of Alabama at Birmingham:

Primary Outcome Measures:
  • Plasma levels of MT1MMP, MMP-1,-2 and -9, bradykinin type-2 receptor, AT1 and AT2 receptor, collagen type II and III and collagen breakdown products [ Time Frame: 12 months ]

Biospecimen Retention:   Samples With DNA
Plasma, myocyte tissue

Enrollment: 65
Study Start Date: June 2005
Study Completion Date: November 2010
Primary Completion Date: November 2010 (Final data collection date for primary outcome measure)
Mitral Regurgitation pre&post operation
Patients with severe Mitral Regurgitation without evidence of ischemia are tested prior to surgery and after valve repair.

Detailed Description:

In Western society, the most common causes of chronic nonischemic mitral regurgitation (MR) is myxomatous degeneration of the valve.Unlike pressure overload, where fibrosis reduction and renin-angiotensin system (RAS) blockade is beneficial, the dynamics of extracellular matrix homeostasis in volume overload produce minimal changes in collagen content. It is for this reason that RAS blockade is not beneficial in patients and in animal models with pure volume overload of MR. In particular, we have shown that ACE inhibition, which increases cardiac interstitial bradykinin—resulting in a reduction in collagen production and activation of matrix metalloproteinase (MMP)—is particularly harmful in volume overload. Further, we showed that MR in the dog is marked by an early and persistent decrease in LV interstitial collagen and MMP activation, as well as the expression of bradykinin. Thus, therapies targeted at matrix reduction may exacerbate the disease process by decreasing the collagen connections between cardiomyocytes.

Another important pathophysiologic mechanism in the adverse LV remodeling in MR is the adrenergic nervous system and inflammation. It is of interest that we and others have found increased adrenergic drive to be an important early mechanism in the volume overload of MR in dogs and MR in patients. This response can be attributed to the early recruitment of preload reserve in adaptation to the volume load. In fact, beta1-adrenergic receptor (AR) blockade improved LV remodeling, attenuated matrix degradation, and improved LV and cardiomyocyte function in the dog with MR. Increased adrenergic stimulation can also lead to the generation of reactive nitrogen species and TNF-alpha that, in turn, can activate MMPs, thereby perpetuating the cycle of matrix degradation and adverse LV remodeling.

The investigators hypothesize that MR in humans is characterized by adrenergic overdrive, reactive nitrogen species, and an antifibrotic phenotype that relate to the severity of adverse LV remodeling prior to surgery and outcome after valve repair.

Aim 1. To show that regional stress and strain of MR relates to indices of adrenergic efferent innervation and function of the LV myocardium. LV tissue will be analyzed for innervation density, catecholamine content and reuptake, and beta1- and beta2-AR density.

Aim 2. To define the extent and nature of reactive nitrogen species production in LV myocardium and determine whether peripheral plasma measurements correlate with myocardial origin. LV tissue and plasma will be analyzed for the extent of protein thiol oxidation and protein tyrosine nitration and myeloperoxidase and xanthine oxidase activities.

Aim 3. To show increased expression of antifibrotic factors in LV myocardium and that peripheral plasma measurements correlate with myocardial origin and whether these factors correlate with functional recovery by MRI. LV tissue will be analyzed for MT1MMP, MMP-1,-2 and -9, bradykinin type-2 receptor, AT1 and AT2 receptor, collagen type II and III and plasma will be analyzed for collagen breakdown products.

Currently, there is no recommended therapy for the pure volume overload of mitral regurgitation, these studies will define the unique molecular mechanisms that will lead to new targeted therapy to attenuate the remodeling and delay the need for surgery and improve surgical outcomes.


Ages Eligible for Study:   21 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Ptaients scheduled for Mitral valve repair from c ardiology clinic / Hospital

Inclusion Criteria:

  1. 21 years old or older.
  2. Severe MR by echo or catheterization without evidence of ischemia requiring surgery documented by cardiac catheterization and/or maximal stress test with myocardial perfusion imaging.

Exclusion Criteria:

  1. Significant obstructive coronary artery disease and/or myocardial ischemia on graded exercise test with myocardial perfusion.
  2. Previous myocardial infarction.
  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. Renal failure with creatinine > 2.5 mg/dl.
  7. Renal artery stenosis.
  8. Severe comorbidity such as liver disease, malignancy, collagen vascular disease, or chronic steroid requirement.
  9. Pregnancy (negative pregnancy test and effective contraceptive methods are required prior to enrollment of females of childbearing potential (not post-menopausal or surgically sterilized).

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.
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Please refer to this study by its identifier: NCT01052532

United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35294-2180
Sponsors and Collaborators
University of Alabama at Birmingham
Principal Investigator: Louis J Dell'Italia, M.D University of Alabama at Birmingham
  More Information

1. Dell'Italia LJ. Mitral Regurgitation. In Hurst The Heart. Eds. O'Rourke, Sclhant, Alexader, Fuster. 11th Edition, Chapter 57 pp 1169-1695, 2004.

Responsible Party: Louis J. Dell'Italia, MD, UAB Identifier: NCT01052532     History of Changes
Other Study ID Numbers: F0400105007
Study First Received: January 15, 2010
Last Updated: December 1, 2010

Keywords provided by University of Alabama at Birmingham:
Mitral Regurgitation
LV remodeling
Reactive nitrogen species
Cardiac MRI
Adrenergic overdrive

Additional relevant MeSH terms:
Mitral Valve Insufficiency
Heart Valve Diseases
Heart Diseases
Cardiovascular Diseases processed this record on May 25, 2017