Molecular Mechanisms of Mitral Regurgitation-Aim 2 (P1A2)

December 1, 2010 updated by: University of Alabama at Birmingham

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.

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.

Study Overview

Status

Completed

Conditions

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.

Study Type

Observational

Enrollment (Actual)

65

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35294-2180
        • University of Alabama at Birmingham

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

Ptaients scheduled for Mitral valve repair from c ardiology clinic / Hospital

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Only
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Mitral Regurgitation pre&post operation
Patients with severe Mitral Regurgitation without evidence of ischemia are tested prior to surgery and after valve repair.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
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
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Alabama at Birmingham

Investigators

  • Principal Investigator: Louis J Dell'Italia, M.D, University of Alabama at Birmingham

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2005

Primary Completion (Actual)

November 1, 2010

Study Completion (Actual)

November 1, 2010

Study Registration Dates

First Submitted

January 15, 2010

First Submitted That Met QC Criteria

January 19, 2010

First Posted (Estimate)

January 20, 2010

Study Record Updates

Last Update Posted (Estimate)

December 2, 2010

Last Update Submitted That Met QC Criteria

December 1, 2010

Last Verified

December 1, 2010

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • F0400105007

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Mitral Regurgitation

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Azerbaijan

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe