Mitral RegurgitationP1A2NCT01052532
Molecular Mechanisms of Mitral Regurgitation-Aim 2
An observational study of Mitral Regurgitation, run by University of Alabama at Birmingham at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 21 years and older
- Conditions the study is for
- Mitral Regurgitation
- How many people
- 65 participants
- Where
- 1 siteUnited States
- Study dates
- Jun 2005to Nov 2010
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Ptaients scheduled for Mitral valve repair from c ardiology clinic / Hospital
Who may be able to join
- 21 years old or older.
- 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.
Who cannot join
- Significant obstructive coronary artery disease and/or myocardial ischemia on graded exercise test with myocardial perfusion.
- Previous myocardial infarction.
- Hypertrophic cardiomyopathy, congenital or pericardial disease.
- Aortic valve disease (> trace aortic regurgitation or mean gradient > 10 mmHg)
- Mitral stenosis (mean gradient > 5 mmHg, valve area < 1.5 cm2).
- Renal failure with creatinine > 2.5 mg/dl.
Show all 12Show fewer
- Renal artery stenosis.
- Severe comorbidity such as liver disease, malignancy, collagen vascular disease, or chronic steroid requirement.
- Pregnancy (negative pregnancy test and effective contraceptive methods are required prior to enrollment of females of childbearing potential (not post-menopausal or surgically sterilized).
- Severe claustrophobia.
- Presence of a pacemaker or non-removable hearing aid.
- Presence of metal clips in the body.
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Alabama at Birmingham
Birmingham, Alabama, 35294-2180
About this study
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.
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.
Read the 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.
- Conditions
- Mitral Regurgitation
- Keywords
- Mitral Regurgitation, LV remodeling, Reactive nitrogen species, Cardiac MRI, Adrenergic overdrive
- Medical subject headings
- Mitral Valve Insufficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| 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 being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Jan 2010 (estimated)
- Study startJun 2005
- Primary completionNov 2010
- Study completionNov 2010
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (23)Papers the sponsor has linked to this study.
- Other trials for Mitral RegurgitationStudies of the same condition, open and under way.
- More trials run by University of Alabama at BirminghamThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case only
- Time perspective
- Prospective
- Enrolment
- 65 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Alabama at Birmingham
- Sponsor type
- University, hospital or other
- Investigators
- Louis J Dell'Italia, M.D, Principal investigator, University of Alabama at Birmingham
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01052532
- Sponsor's protocol ID
- F0400105007
- Acronym
- P1A2
- Status last verified
- Dec 2010
- First submitted
- 15 Jan 2010
- Last updated
- 2 Dec 2010
- Results posted
- No
- Data monitoring committee
- No
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.
Olson LJ, Subramanian R, Ackermann DM, Orszulak TA, Edwards WD. Surgical pathology of the mitral valve: a study of 712 cases spanning 21 years. Mayo Clin Proc. 1987 Jan;62(1):22-34. doi: 10.1016/s0025-6196(12)61522-5.
PubMed 3796056Borer JS, Bonow RO. Contemporary approach to aortic and mitral regurgitation. Circulation. 2003 Nov 18;108(20):2432-8. doi: 10.1161/01.CIR.0000096400.00562.A3. No abstract available.
PubMed 14623790Wisenbaugh T, Essop R, Rothlisberger C, Sareli P. Effects of a single oral dose of captopril on left ventricular performance in severe mitral regurgitation. Am J Cardiol. 1992 Feb 1;69(4):348-53. doi: 10.1016/0002-9149(92)90232-n.
PubMed 1734647Rothlisberger C, Sareli P, Wisenbaugh T. Comparison of single dose nifedipine and captopril for chronic severe mitral regurgitation. Am J Cardiol. 1994 May 15;73(13):978-81. doi: 10.1016/0002-9149(94)90148-1. No abstract available.
PubMed 8184862Wisenbaugh T, Sinovich V, Dullabh A, Sareli P. Six month pilot study of captopril for mildly symptomatic, severe isolated mitral and isolated aortic regurgitation. J Heart Valve Dis. 1994 Mar;3(2):197-204.
PubMed 8012639Marcotte F, Honos GN, Walling AD, Beauvais D, Blais MJ, Daoust C, Lisbona A, McCans JL. Effect of angiotensin-converting enzyme inhibitor therapy in mitral regurgitation with normal left ventricular function. Can J Cardiol. 1997 May;13(5):479-85.
PubMed 9179087Host U, Kelbaek H, Hildebrandt P, Skagen K, Aldershvile J. Effect of ramipril on mitral regurgitation secondary to mitral valve prolapse. Am J Cardiol. 1997 Sep 1;80(5):655-8. doi: 10.1016/s0002-9149(97)00445-1.
PubMed 9295005Tischler MD, Rowan M, LeWinter MM. Effect of enalapril therapy on left ventricular mass and volumes in asymptomatic chronic, severe mitral regurgitation secondary to mitral valve prolapse. Am J Cardiol. 1998 Jul 15;82(2):242-5. doi: 10.1016/s0002-9149(98)00325-7.
PubMed 9678300Dujardin KS, Enriquez-Sarano M, Bailey KR, Seward JB, Tajik AJ. Effect of losartan on degree of mitral regurgitation quantified by echocardiography. Am J Cardiol. 2001 Mar 1;87(5):570-6. doi: 10.1016/s0002-9149(00)01433-8.
PubMed 11230841Gaasch WH, Aurigemma GP. Inhibition of the renin-angiotensin system and the left ventricular adaptation to mitral regurgitation. J Am Coll Cardiol. 2002 Apr 17;39(8):1380-3. doi: 10.1016/s0735-1097(02)01766-7. No abstract available.
PubMed 11955859Stewart JA Jr, Wei CC, Brower GL, Rynders PE, Hankes GH, Dillon AR, Lucchesi PA, 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. 2003 Mar;35(3):311-9. doi: 10.1016/s0022-2828(03)00013-0.
PubMed 12676546Nemoto S, Hamawaki M, De Freitas G, Carabello BA. Differential effects of the angiotensin-converting enzyme inhibitor lisinopril versus the beta-adrenergic receptor blocker atenolol on hemodynamics and left ventricular contractile function in experimental mitral regurgitation. J Am Coll Cardiol. 2002 Jul 3;40(1):149-54. doi: 10.1016/s0735-1097(02)01926-5.
PubMed 12103269Dell'italia LJ, Balcells E, Meng QC, Su X, Schultz D, Bishop SP, Machida N, Straeter-Knowlen IM, Hankes GH, Dillon R, Cartee RE, Oparil S. Volume-overload cardiac hypertrophy is unaffected by ACE inhibitor treatment in dogs. Am J Physiol. 1997 Aug;273(2 Pt 2):H961-70. doi: 10.1152/ajpheart.1997.273.2.H961.
PubMed 9277516Perry GJ, Wei CC, Hankes GH, Dillon SR, Rynders P, 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. 2002 Apr 17;39(8):1374-9. doi: 10.1016/s0735-1097(02)01763-1.
PubMed 11955858
Study at a glance
From the registry record, last updated by the sponsor on 2 Dec 2010. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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.
- ClinicalTrials.gov ID
- NCT01052532
- Acronym / sponsor ID
- P1A2 / F0400105007
- Conditions
- Mitral Regurgitation
- Keywords
- Mitral Regurgitation, LV remodeling, Reactive nitrogen species, Cardiac MRI, Adrenergic overdrive
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 65 participants (actual)
- Lead sponsor
- University of Alabama at BirminghamUniversity, hospital or other
- Study start
- Jun 2005
- Primary completion
- Nov 2010 (actual)
- Study completion
- Nov 2010 (actual)
- First posted
- 20 Jan 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 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 design
- Observational model
- Case only
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Mitral Regurgitation pre&post operation | – | –Patients with severe Mitral Regurgitation without evidence of ischemia are tested prior to surgery and after valve repair. |
Who may qualify
- Ages
- 21 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Ptaients scheduled for Mitral valve repair from c ardiology clinic / Hospital
Key inclusion criteria (2 listed)
- 21 years old or older.
- 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.
Key exclusion criteria (12 listed)
- Significant obstructive coronary artery disease and/or myocardial ischemia on graded exercise test with myocardial perfusion.
- Previous myocardial infarction.
- Hypertrophic cardiomyopathy, congenital or pericardial disease.
- Aortic valve disease (> trace aortic regurgitation or mean gradient > 10 mmHg)
- Mitral stenosis (mean gradient > 5 mmHg, valve area < 1.5 cm2).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Dec 2010.
- Background1. Dell'Italia LJ. Mitral Regurgitation. In Hurst The Heart. Eds. O'Rourke, Sclhant, Alexader, Fuster. 11th Edition, Chapter 57 pp 1169-1695, 2004.
- Background: PubMed 3796056Olson LJ, Subramanian R, Ackermann DM, Orszulak TA, Edwards WD. Surgical pathology of the mitral valve: a study of 712 cases spanning 21 years. Mayo Clin Proc. 1987 Jan;62(1):22-34. doi: 10.1016/s0025-6196(12)61522-5.
- Background: PubMed 14623790Borer JS, Bonow RO. Contemporary approach to aortic and mitral regurgitation. Circulation. 2003 Nov 18;108(20):2432-8. doi: 10.1161/01.CIR.0000096400.00562.A3. No abstract available.
- Background: PubMed 1734647Wisenbaugh T, Essop R, Rothlisberger C, Sareli P. Effects of a single oral dose of captopril on left ventricular performance in severe mitral regurgitation. Am J Cardiol. 1992 Feb 1;69(4):348-53. doi: 10.1016/0002-9149(92)90232-n.
- Background: PubMed 8184862Rothlisberger C, Sareli P, Wisenbaugh T. Comparison of single dose nifedipine and captopril for chronic severe mitral regurgitation. Am J Cardiol. 1994 May 15;73(13):978-81. doi: 10.1016/0002-9149(94)90148-1. No abstract available.
- Background: PubMed 8012639Wisenbaugh T, Sinovich V, Dullabh A, Sareli P. Six month pilot study of captopril for mildly symptomatic, severe isolated mitral and isolated aortic regurgitation. J Heart Valve Dis. 1994 Mar;3(2):197-204.
- Background: PubMed 9179087Marcotte F, Honos GN, Walling AD, Beauvais D, Blais MJ, Daoust C, Lisbona A, McCans JL. Effect of angiotensin-converting enzyme inhibitor therapy in mitral regurgitation with normal left ventricular function. Can J Cardiol. 1997 May;13(5):479-85.
- Background: PubMed 9295005Host U, Kelbaek H, Hildebrandt P, Skagen K, Aldershvile J. Effect of ramipril on mitral regurgitation secondary to mitral valve prolapse. Am J Cardiol. 1997 Sep 1;80(5):655-8. doi: 10.1016/s0002-9149(97)00445-1.
- Background: PubMed 9678300Tischler MD, Rowan M, LeWinter MM. Effect of enalapril therapy on left ventricular mass and volumes in asymptomatic chronic, severe mitral regurgitation secondary to mitral valve prolapse. Am J Cardiol. 1998 Jul 15;82(2):242-5. doi: 10.1016/s0002-9149(98)00325-7.
- Background: PubMed 11230841Dujardin KS, Enriquez-Sarano M, Bailey KR, Seward JB, Tajik AJ. Effect of losartan on degree of mitral regurgitation quantified by echocardiography. Am J Cardiol. 2001 Mar 1;87(5):570-6. doi: 10.1016/s0002-9149(00)01433-8.
- Background: PubMed 11955859Gaasch WH, Aurigemma GP. Inhibition of the renin-angiotensin system and the left ventricular adaptation to mitral regurgitation. J Am Coll Cardiol. 2002 Apr 17;39(8):1380-3. doi: 10.1016/s0735-1097(02)01766-7. No abstract available.
- Background: PubMed 12676546Stewart JA Jr, Wei CC, Brower GL, Rynders PE, Hankes GH, Dillon AR, Lucchesi PA, 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. 2003 Mar;35(3):311-9. doi: 10.1016/s0022-2828(03)00013-0.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Louis J Dell'Italia, M.D principal investigator
University of Alabama at Birmingham
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Mitral Regurgitation, run by University of Alabama at Birmingham at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Dec 2010. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01052532, which also lists 23 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Dec 2010.