(Applicant?s Abstract) Immediate Goals: To examine the mechanism and therapy of ischemic mitral regurgitation (MR) with the goal of applying this information to clinical studies. Career Development Plan: To obtain experience and skills in experimental methodology and application to clinical studies. Research Project: Mitral valve function can be understood in terms of the force-balance concept in which tethering forces from the papillary muscles balance left ventricle closing forces. In ischemic MR, this force-balance may be altered in ways that impair the ability of the mitral leaflets to close effectively at the annular level. We plan a combined, parallel clinical and experimental approach to evaluate the mechanism, progression and therapy of ischemic MR, all relating to the central hypothesis that ischemic MR is caused by an abnormal relationship of the mitral valve to its supporting ventricular structures. These altered relationships involve both abnormal tethering forces due to displacement of the papillary muscles as well as reduced closing forces due to LV contractile dysfunction. Specific testable questions related to this hypothesis include: 1) the progression of mitral regurgitation in patients with acute myocardial infarction relates to abnormalities in the mitral valve-ventricular relationship; 2) These mechanisms also cause persistent MR despite coronary revascularization surgery, thereby impairing exercise capacity and raising pulmonary pressures; 3) both externally applied devices and afterload reduction provide effective means of reducing ischemic mitral regurgitation by normalizing these relationships between the valve and the ventricle.
The aims of the mentored award will be met by allowing the PI to translate her experimental expertise to direct clinical studies of progression and functional outcome of ischemic MR, and to make the transition from mechanism to therapy in models reflecting the clinical situation, with the ultimate goal of patient applications.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL004504-05
Application #
6931893
Study Section
Special Emphasis Panel (ZHL1-CSR-F (O1))
Program Officer
Scott, Jane
Project Start
2001-09-01
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2007-08-31
Support Year
5
Fiscal Year
2005
Total Cost
$129,949
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Chu, John W; Levine, Robert A; Chua, Sarah et al. (2008) Assessing mitral valve area and orifice geometry in calcific mitral stenosis: a new solution by real-time three-dimensional echocardiography. J Am Soc Echocardiogr 21:1006-9
Delling, Francesca N; Sanborn, Danita Y; Levine, Robert A et al. (2007) Frequency and mechanism of persistent systolic anterior motion and mitral regurgitation after septal ablation in obstructive hypertrophic cardiomyopathy. Am J Cardiol 100:1691-5
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Yosefy, Chaim; Levine, Robert A; Solis, Jorge et al. (2007) Proximal flow convergence region as assessed by real-time 3-dimensional echocardiography: challenging the hemispheric assumption. J Am Soc Echocardiogr 20:389-96
Ton-Nu, Thanh-Thao; Levine, Robert A; Handschumacher, Mark D et al. (2006) Geometric determinants of functional tricuspid regurgitation: insights from 3-dimensional echocardiography. Circulation 114:143-9
Hung, Judy; Papakostas, Lampros; Tahta, Stephen A et al. (2004) Mechanism of recurrent ischemic mitral regurgitation after annuloplasty: continued LV remodeling as a moving target. Circulation 110:II85-90
Levine, Robert A; Hung, Judy (2003) Ischemic mitral regurgitation, the dynamic lesion: clues to the cure. J Am Coll Cardiol 42:1929-32
Nesta, Francesca; Otsuji, Yutaka; Handschumacher, Mark D et al. (2003) Leaflet concavity: a rapid visual clue to the presence and mechanism of functional mitral regurgitation. J Am Soc Echocardiogr 16:1301-8
Hung, Judy; Guerrero, J Luis; Handschumacher, Mark D et al. (2002) Reverse ventricular remodeling reduces ischemic mitral regurgitation: echo-guided device application in the beating heart. Circulation 106:2594-600

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