Immediate Goals: To examine the mechanism of ischemic mitral regurgitation (MR) with the goal of designing and implementing more effective therapy to reduce adverse impact on patients. Career Development Goals: To provide sufficient time for mentoring and research activities. 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 ventricular valve 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. This proposal uses 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 an externally applied device and afterload reduction provide effective means of reducing ischemic mitral regurgitation by normalizing these relationships between the valve and the ventricle; cutting a minimum number of critically positioned strut chordae also has the potential to relieve tethering, and opens the way to potential minimally invasive percutaneous approaches.
The aims of the mentored award will be met by allowing the PI to translate his 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
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24HL067434-05
Application #
6888162
Study Section
Special Emphasis Panel (ZHL1-CSR-F (F1))
Program Officer
Scott, Jane
Project Start
2001-07-10
Project End
2007-02-28
Budget Start
2005-06-01
Budget End
2007-02-28
Support Year
5
Fiscal Year
2005
Total Cost
$137,638
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Bartko, Philipp E; Dal-Bianco, Jacob P; Guerrero, J Luis et al. (2017) Effect of Losartan on Mitral Valve Changes After Myocardial Infarction. J Am Coll Cardiol 70:1232-1244
Beaudoin, Jonathan; Dal-Bianco, Jacob P; Aikawa, Elena et al. (2017) Mitral Leaflet Changes Following Myocardial Infarction: Clinical Evidence for Maladaptive Valvular Remodeling. Circ Cardiovasc Imaging 10:
Dal-Bianco, Jacob P; Bartko, Philipp E; Beaudoin, Jonathan et al. (2016) 3D Ultrasound: seeing is understanding-from imaging to pathophysiology to developing therapies in secondary MR. Eur Heart J Cardiovasc Imaging 17:510-1
Dal-Bianco, Jacob P; Aikawa, Elena; Bischoff, Joyce et al. (2016) Myocardial Infarction Alters Adaptation of the Tethered Mitral Valve. J Am Coll Cardiol 67:275-87
Dal-Bianco, Jacob P; Levine, Robert A (2015) The mitral valve is an actively adapting tissue: new imaging evidence. Eur Heart J Cardiovasc Imaging 16:286-7
Hagège, Albert A; Carpentier, Alain; Levine, Robert A (2015) Dynamic changes of the mitral valve annulus: new look at mitral valve diseases. Circ Cardiovasc Imaging 8:
Afilalo, Jonathan; Grapsa, Julia; Nihoyannopoulos, Petros et al. (2015) Leaflet area as a determinant of tricuspid regurgitation severity in patients with pulmonary hypertension. Circ Cardiovasc Imaging 8:
Levine, Robert A; Hagége, Albert A; Judge, Daniel P et al. (2015) Mitral valve disease--morphology and mechanisms. Nat Rev Cardiol 12:689-710
Zeng, Xin; Zou, Lin; Levine, Robert A et al. (2015) Efficacy of polymer injection for ischemic mitral regurgitation: persistent reduction of mitral regurgitation and attenuation of left ventricular remodeling. JACC Cardiovasc Interv 8:355-363
Dina, Christian; Bouatia-Naji, Nabila; Tucker, Nathan et al. (2015) Genetic association analyses highlight biological pathways underlying mitral valve prolapse. Nat Genet 47:1206-11

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