Mitral regurgitation (MR) is a frequent complication of myocardial infarction (MI) and left ventricular (LV) dysfunction that doubles mortality, but the survival benefit of standard annular ring reduction therapy is intensely debated. LV remodeling often progresses after ring reduction, causing recurrent MR. We must therefore resolve in a controlled fashion whether MR contributes to remodeling;whether the benefit of repair is limited by being typically late;and why aggressive remodeling continues post-repair. In the initial grant period, we developed an apical MI model (no intrinsic MR) with standardized MR-type flow through an LV-to-LA shunt. In that sheep model, moderate MR flow typical of post-MI patients strongly increased LV remodeling at the whole-heart, cellular and molecular levels versus MI or MR alone, with a biphasic pattern of failed attempts at compensation (rise, then exhaustion of hypertrophic, anti-apoptotic signals). Early MR repair by shunt closure reversed remodeling, while early transgenic overexpression of sarcoplasmic reticulum Ca+2-ATPase (SERCA2a) improved it. Building on that, the current proposal addresses the central hypothesis that exacerbation of post-MI LV remodeling by MR can be reduced by appropriately timed molecular or mechanical interventions, with the following specific aims: 1) To test the hypothesis that the reversal of remodeling by MR repair decreases over time, in parallel with a reduced molecular """"""""momentum"""""""" for reverse remodeling, emphasizing the benefit of early repair. 2) To test the hypothesis that remodeling can be reduced by transgenically modulating the stress-sensitive calcium cycling pathway that is exhausted in the decompensated phase of MI+MR. In a clinically relevant spectrum of anterior and inferior MIs with MR, this molecular intervention will be tested for its ability to improve reversal of remodeling in response to delayed MR repair. This would correspond to improved postoperative function, extending the window for reverse remodeling beyond any """"""""point of no return"""""""" due to delayed repair. The resubmission is focused on the interaction between delayed repair and molecular interventions, supported by quantitative data from SERCA2a gene transfer studies. The research team combines expertise in surgical modeling (Dr. Gus Vlahakes), quantitative 3D cardiac imaging, and the molecular biology and transgenic modification of LV remodeling (Drs. Roger Hajjar and Ronen Beeri).
These aims focus on the current questions regarding the central impact of MR repair on LV function to increase our mechanistic understanding and identify potential therapeutic targets.

Public Health Relevance

Mitral regurgitation (MR) is a frequent complication of myocardial infarction (MI) and left ventricular (LV) dysfunction that doubles mortality, but the survival benefit of standard annular ring reduction therapy is intensely debated, and LV remodeling often progresses afterwards, with enlargement of the heart and weakened contraction. It is therefore critical to investigate this maladaptive response, how it relates to the timing of valve repair relative to molecular changes, and whether molecular interventions can """"""""buy time"""""""" for LV improvement following delayed repair. This proposal has assembled a research team with the key expertise and resources to address this public health problem by using gene transfer techniques to dissect why MR causes the heart muscle to become weak and to strengthen it. The work will focus on the central impact of MR repair on LV function as the key determinant of prognosis, and on increasing our mechanistic understanding to identify new therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL072265-07
Application #
8197425
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Schwartz, Lisa
Project Start
2002-03-15
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
7
Fiscal Year
2012
Total Cost
$409,849
Indirect Cost
$131,380
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Leinonen, Jussi V; Korkus-Emanuelov, Avishag; Wolf, Yochai et al. (2016) Macrophage precursor cells from the left atrial appendage of the heart spontaneously reprogram into a C-kit+/CD45- stem cell-like phenotype. Int J Cardiol 209:296-306
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; 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
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:
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
Levine, Robert A; Hagége, Albert A; Judge, Daniel P et al. (2015) Mitral valve disease--morphology and mechanisms. Nat Rev Cardiol 12:689-710
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
Durst, Ronen; Sauls, Kimberly; Peal, David S et al. (2015) Mutations in DCHS1 cause mitral valve prolapse. Nature 525:109-13
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:
Delling, Francesca N; Gona, Philimon; Larson, Martin G et al. (2014) Mild expression of mitral valve prolapse in the Framingham offspring: expanding the phenotypic spectrum. J Am Soc Echocardiogr 27:17-23

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