Ischemic mitral regurgitation (IMR) is a common complication that doubles mortality and increases heart failure after myocardial infarction (MI). Effective repair has been elusive for IMR, which is caused by left ventricular (LV) remodeling that tethers the mitral valve (MV) leaflets and restricts their closure - a mismatch between valve and LV size. Late-stage valves are also stiff and fibrotic, further limiting effective closure. Standard therapies assume valve size is fixed, but valves have the potential for cellular activation, and flexible enlargement of the tethered MV could reduce IMR. Valve adaptation can be affected by mechanical stretch, the ischemic milieu, and MR turbulence. We therefore developed a large-animal model to vary these factors independently using 3D echo to follow MV area noninvasively, correlated with cellular and molecular studies. In that model, mechanical tethering induced by papillary muscle traction short of producing MR increases MV area and thickness over two months with reactivated endothelial-mesenchymal transformation (EMT), a developmental process. Adding a distal apical MI (limited apical LV remodeling) to mechanical tethering over two months markedly increases EMT, with expression of pro-fibrotic transforming growth factor (TGF)-?, endothelial activation (VCAM-1), collagen deposition, and infiltration of CD45+ cells. Blood-borne wound- healing CD45+ cells create sclerosis of other organs by differentiating into collagen-producing myofibroblasts. We will therefore test the central hypothesis that early compensatory MV growth mechanisms in the IMR setting later become decompensatory, leading to stiffness that increases MR.
Aim 1 will correlate fibrosis and stiffness with TGF-? expression, endothelial activation and CD45+ cell infiltration at 2, 6 and 10 months in models of MI+tethering and the clinical-type scenario, inferior MI.
Aim 2 will isolate the MV CD45+ cells and test whether they have the characteristics of fibrocytes, circulating myofibroblast precursors;MV and peripheral blood CD45+ cells will be tested for adhesion to MV endothelial cells stimulated by MI-released cytokines, differentiation into myofibroblasts, and possibly influencing native MV cells to undergo similar pro-fibrotic change.
Aim 3 is based on preliminary studies that Losartan, a TGF-? inhibitor, reduces EMT, CD45+ cells, endothelial activation and MV thickening at two months in the tethering+MI model;in contrast, those findings persist when LV remodeling is comparably reduced by mechanical LV constraint. Losartan also inhibits TGF- ?-mediated EMT in vitro. We will test whether Losartan, unlike LV constraint, reduces long-term pro-fibrotic events from 2 to 6 and 10 months in the tethering+MI model, and study downstream TGF-? signaling, recently shown to have therapeutic implications. This proposal combines investigators with complementary strengths in physiologic modeling and imaging, MV histopathology, endothelial cell biology and biomechanics. It addresses unmet clinical needs in a common disease, aiming to increase our understanding of MV adaptation. It begins to test potential therapies that, if corroborated, could be rapidly translated to reduce IMR in patients.

Public Health Relevance

Mitral regurgitation (MR) is a frequent, difficult to repair complication of myocardial infarction (MI) that doubles heart failure and mortality;it is caused b tethering (stretch) of the mitral valve by damaged and bulging heart walls that prevents valve closure, and is compounded by late valve stiffening. Until recently, mitral valve size has been viewed as fixed in this setting, but valve growth in adaptation to tethering could reduce this regurgitation if valve flexibility can be maintained. In this project, an interdisciplinary team wil use a new model to fill this unmet clinical need in a common disease by increasing our understanding of how adaptive valve processes can become maladaptive, and will begin to test new therapies to reduce this complication that, if corroborated, can be rapidly translated to benefit patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Desvigne-Nickens, Patrice
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Massachusetts General Hospital
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Rogers, Maximillian A; Aikawa, Elena (2014) Modifying vascular calcification in diabetes mellitus: contribution of O-GlcNAcylation. Circ Res 114:1074-6
Wylie-Sears, Jill; Levine, Robert A; Bischoff, Joyce (2014) Losartan inhibits endothelial-to-mesenchymal transformation in mitral valve endothelial cells by blocking transforming growth factor-?-induced phosphorylation of ERK. Biochem Biophys Res Commun 446:870-5
Goettsch, Claudia; Iwata, Hiroshi; Aikawa, Elena (2014) Parathyroid hormone: critical bridge between bone metabolism and cardiovascular disease. Arterioscler Thromb Vasc Biol 34:1333-5
Duval, D; Lardeux, A; Le Tourneau, T et al. (2014) Valvular dystrophy associated filamin A mutations reveal a new role of its first repeats in small-GTPase regulation. Biochim Biophys Acta 1843:234-44
Ghatak, Shibnath; Misra, Suniti; Norris, Russell A et al. (2014) Periostin induces intracellular cross-talk between kinases and hyaluronan in atrioventricular valvulogenesis. J Biol Chem 289:8545-61
Hutcheson, Joshua D; Maldonado, Natalia; Aikawa, Elena (2014) Small entities with large impact: microcalcifications and atherosclerotic plaque vulnerability. Curr Opin Lipidol 25:327-32
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
Schmidt, Ehud J; Fung, Maggie M; Ciris, Pelin Aksit et al. (2014) Navigated DENSE strain imaging for post-radiofrequency ablation lesion assessment in the swine left atria. Europace 16:133-41
Itou, Takahiro; Maldonado, Natalia; Yamada, Iwao et al. (2014) Cystathionine ýý-lyase accelerates osteoclast differentiation: identification of a novel regulator of osteoclastogenesis by proteomic analysis. Arterioscler Thromb Vasc Biol 34:626-34
Yabusaki, Katsumi; Faits, Tyler; McMullen, Eri et al. (2014) A novel quantitative approach for eliminating sample-to-sample variation using a hue saturation value analysis program. PLoS One 9:e89627

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