Molecular Mechanisms of Mitral Regurgitation—Aim 2 (P1A2)

This study has been completed.
Sponsor:
Information provided by:
University of Alabama at Birmingham
ClinicalTrials.gov Identifier:
NCT01052532
First received: January 15, 2010
Last updated: December 1, 2010
Last verified: December 2010
  Purpose

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.


Condition
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 ] [ Designated as safety issue: Yes ]

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)
Groups/Cohorts
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.

  Eligibility

Ages Eligible for Study:   21 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population

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

Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01052532

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

Publications:
1. Dell'Italia LJ. Mitral Regurgitation. In Hurst The Heart. Eds. O'Rourke, Sclhant, Alexader, Fuster. 11th Edition, Chapter 57 pp 1169-1695, 2004.
3. Borer JS, Bonow RO. Contemporary approach to aortic and mitral regurgitation. Circulation 108:2432-2438, 2003.
5. Rothisberger C, Sareli P, Wisenbaugh T: Comparison of single dose nifedipine and captopril for chronic severe mitral regurgitation. Am J Cardiol 73:978-981, 1994.
6. Wisenbaugh T, Sinovich V, Dullbh A, Sareli P: Six month pilot study of captopril for mildly symptomatic, severe isolated mitral and isolated aortic regurgitation. J Heart Valve Dis 3:197-204, 1994.
7. Marcotte F, Honos G, Walling A, et al: Effect of angiotensin converting enzyme inhibitor therapy in mitral regurgitation with normal left ventricular function. Can J Cardiol 13:479-485, 1997.
8. Host U, Kelbaek H, Hildebrandt P, Skagen K, Aldershvile J: Effect of Ramipril on mitral regurgitation secondary to mitral valve prolapse. Am J Cardiol 80:655-658, 1997.
9. Tischler M, Rowan M, LeWinter M: Effect of Enalapril on left ventricular mass and volumes in asymptomatic chronic, severe mitral regurgitation secondary to mitral valve prolapse. Am J Cardiol 82:242-245, 1998.
10. Dujardin KS, Enriquez-Sarano M, Bailey KR, Seward JB, Tajik AJ: Effect of losartan on degree of mitral regurgitation quantified by echocardiography. Am J Cardiol 87:570-576, 2001.
12. Stewart JA, Wei C-C, Brower GL, Rynders PE, Hankes GH, Dillon AR, Lucchesi P, Janicki JS, Dell'Italia LJ. Cardiac Mast Cell and Chymase Mediated Matrix Metalloproteinase Activity and Left Ventricular Remodeling in Mitral Regurgitation in the Dog. J Mol Cell Cardiol 35:311-319, 2003.
14. Dell'Italia LJ, Meng QC, Balcells E, Straeter-Knowlen I, Hankes GH, Dillon R, Cartee RE, Orr R, Bishop SP, Oparil S, Elton TS. Volume-overload cardiac hypertrophy is unaffected by ACE inhibitor treatment in dogs. Am J Physiol 273:H961-H970, 1997.
15. Perry, GJ, Wei CC, Su X, Bishop SP, Hankes GH, Dillon GH, Mukherjee R, Spinale FG Dell'Italia LJ. Angiotensin II receptor blockade does not improve left ventricular function and remodeling in subacute mitral regurgitation in the dog. J Am Coll Cardiol 39:1374-1379, 2002.
16. Nagatsu M, Zile MR, Tsutsui H et al. Native beta-adrenergic support for left ventricular dysfunction in experimental mitral regurgitation normalizes indexes of pump and contractile function. Circulation 1994;89:818-26.
17. Tallaj J, Wei CC, Hankes GH, Holland M, Rynders P, Dillon AR, Ardell JL, Armour JA, Lucchesi PA, Dell'Italia LJ. beta1-adrenergic receptor blockade attenuates angiotensin II-mediated catecholamine release into the cardiac interstitium in mitral regurgitation. Circulation 108:225-230, 2003.
18. Hankes GH, Ardell JL, Tallaj J, Wei C-C, Aban I, Holland M, Rynders P, Dillon SR, Cardenale R, Hoover DA, Armour JA, Husain A, Dell'Italia LJ. Beta 1-adrenoreceptor blockade mitigates norepinephrine release into the cardiac interstitium in mitral regurgitation in the dog. Am J Physiol. 2006:291:H151- .
19. Tsutsui H, Spinale FG, Nagatsu M, Schmid PG, Ishihara K, DeFreyte G, Cooper IV G, Carabello BA: Effects of chronic beta-adrenergic blockade on the left ventricular and cardiocyte abnormalities of chronic canine mitral regurgitation. J Clin Invest 93:2639-2648, 1994.
20. Mehta RH, Supiano MA, Oral H et al. Compared with control subjects, the systemic sympathetic nervous system is activated in patients with mitral regurgitation. Am Heart J 2003;145:1078-85.
21. Mehta RH, Supiano MA, Oral H et al. Relation of systemic sympathetic nervous system activation to echocardiographic left ventricular size and performance and its implications in patients with mitral regurgitation. Am J Cardiol 2000;(86):1193-7.
23. Siwik DA and Colucci WS. Regulation of matrix metalloproteinases by cytokines and reactive oxygen/nitrogen species in the myocardium. Heart Failure Rev 9: 43-51, 2004.

Responsible Party: Louis J. Dell'Italia, MD, UAB
ClinicalTrials.gov Identifier: NCT01052532     History of Changes
Other Study ID Numbers: F0400105007
Study First Received: January 15, 2010
Last Updated: December 1, 2010
Health Authority: United States: Institutional Review Board

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
Cardiovascular Diseases
Heart Diseases
Heart Valve Diseases

ClinicalTrials.gov processed this record on October 20, 2014