Bartko Philipp E, Dal-Bianco Jacob P, Guerrero J Luis, Beaudoin Jonathan, Szymanski Catherine, Kim Dae-Hee, Seybolt Margo M, Handschumacher Mark D, Sullivan Suzanne, Garcia Michael L, Titus James S, Wylie-Sears Jill, Irvin Whitney S, Messas Emmanuel, Hagège Albert A, Carpentier Alain, Aikawa Elena, Bischoff Joyce, Levine Robert A
Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Surgical Cardiovascular Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
J Am Coll Cardiol. 2017 Sep 5;70(10):1232-1244. doi: 10.1016/j.jacc.2017.07.734.
After myocardial infarction (MI), mitral valve (MV) tethering stimulates adaptive leaflet growth, but counterproductive leaflet thickening and fibrosis augment mitral regurgitation (MR), doubling heart failure and mortality. MV fibrosis post-MI is associated with excessive endothelial-to-mesenchymal transition (EMT), driven by transforming growth factor (TGF)-β overexpression. In vitro, losartan-mediated TGF-β inhibition reduces EMT of MV endothelial cells.
This study tested the hypothesis that profibrotic MV changes post-MI are therapeutically accessible, specifically by losartan-mediated TGF-β inhibition.
The study assessed 17 sheep, including 6 sham-operated control animals and 11 with apical MI and papillary muscle retraction short of producing MR; 6 of the 11 were treated with daily losartan, and 5 were untreated, with flexible epicardial mesh comparably limiting left ventricular (LV) remodeling. LV volumes, tethering, and MV area were quantified by using three-dimensional echocardiography at baseline and at 60 ± 6 days, and excised leaflets were analyzed by histopathology and flow cytometry.
Post-MI LV dilation and tethering were comparable in the losartan-treated and untreated LV constraint sheep. Telemetered sensors (n = 6) showed no significant losartan-induced changes in arterial pressure. Losartan strongly reduced leaflet thickness (0.9 ± 0.2 mm vs. 1.6 ± 0.2 mm; p < 0.05; 0.4 ± 0.1 mm sham animals), TGF-β, and downstream phosphorylated extracellular-signal-regulated kinase and EMT (27.2 ± 12.0% vs. 51.6 ± 11.7% α-smooth muscle actin-positive endothelial cells, p < 0.05; 7.2 ± 3.5% sham animals), cellular proliferation, collagen deposition, endothelial cell activation (vascular cell adhesion molecule-1 expression), neovascularization, and cells positive for cluster of differentiation (CD) 45, a hematopoietic marker associated with post-MI valve fibrosis. Leaflet area increased comparably (17%) in constrained and losartan-treated sheep.
Profibrotic changes of tethered MV leaflets post-MI can be modulated by losartan without eliminating adaptive growth. Understanding the cellular and molecular mechanisms could provide new opportunities to reduce ischemic MR.
心肌梗死（MI）后，二尖瓣（MV）的腱索牵拉刺激瓣叶适应性生长，但适得其反的瓣叶增厚和纤维化会加重二尖瓣反流（MR），使心力衰竭和死亡率加倍。MI后MV纤维化与过度的内皮-间充质转化（EMT）有关，由转化生长因子（TGF）-β过表达驱动。在体外，氯沙坦介导的TGF-β抑制可减少MV内皮细胞的EMT。
本研究检验了以下假设，即MI后促纤维化的MV改变在治疗上是可实现的，特别是通过氯沙坦介导的TGF-β抑制。
该研究评估了17只绵羊，包括6只假手术对照动物和11只发生心尖MI且乳头肌回缩但未产生MR的动物；11只中的6只每日接受氯沙坦治疗，5只未治疗，使用柔性心外膜网对左心室（LV）重塑进行类似限制。在基线和60±6天时，使用三维超声心动图对LV容积、腱索牵拉和MV面积进行定量，并通过组织病理学和流式细胞术分析切除的瓣叶。
在接受氯沙坦治疗和未治疗的LV受限绵羊中，MI后LV扩张和腱索牵拉情况相当。遥测传感器（n = 6）显示氯沙坦未引起动脉压的显著变化。氯沙坦显著降低了瓣叶厚度（0.9±0.2 mm对1.6±0.2 mm；p < 0.05；假手术动物为0.4±0.1 mm）、TGF-β以及下游磷酸化细胞外信号调节激酶和EMT（α平滑肌肌动蛋白阳性内皮细胞为27.2±12.0%对51.6±11.7%，p < 0.05；假手术动物为7.2±3.5%）、细胞增殖、胶原沉积、内皮细胞活化（血管细胞黏附分子-1表达）、新生血管形成以及分化簇（CD）45阳性细胞，CD45是一种与MI后瓣膜纤维化相关的造血标志物。在受限和接受氯沙坦治疗的绵羊中，瓣叶面积增加相当（17%）。
MI后受牵拉的MV瓣叶的促纤维化改变可通过氯沙坦调节，而不消除适应性生长。了解细胞和分子机制可为减少缺血性MR提供新机会。
