Clinical Trial: Molecular Mechanisms of Mitral Regurgitation—Aim 2

Study Status: Completed
Recruit Status: Completed
Study Type: Observational

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 Surger

Brief Summary: 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.

Detailed Summary:

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 investi
Sponsor: University of Alabama at Birmingham

Current Primary Outcome: 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 ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

Original Secondary Outcome:

Information By: University of Alabama at Birmingham

Dates:
Date Received: January 15, 2010
Date Started: June 2005
Date Completion:
Last Updated: December 1, 2010
Last Verified: December 2010