Molecular Mechanisms of Mitral Regurgitation-Aim 2
Molecular Mechanisms of Mitral Regurgitation-Aim 2
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.
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.
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.