Improving Mitral Compensation in Ischemic Regurgitation

改善缺血性反流的二尖瓣代偿

• 批准号: 8656760
• 负责人: Elena Aikawa
• 金额: $ 81.43万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8656760
• 关键词: Address; Adhesions; Affect; Animal Model; Apical; Apical Myocardial Infarction; Area; Biomechanics; Blood; Cells; Cellular biology; Characteristics; Clinical; Clinical Research; Collagen; Complication; Cutaneous; Deposition; Developmental Process; Differentiation and Growth; Disease; Distal; Endothelial Cells; Endothelium; Event; Extracellular Matrix; Fibrosis; Financial compensation; Functional Imaging; Growth; Heart; Heart failure; Histopathology; In Vitro; Inferior Myocardial Infarction; Infiltration; Kidney; Left; Left Ventricular Remodeling; Losartan; Lung; Mechanics; Mediating; Mesenchymal; Mitral Valve; Mitral Valve Insufficiency; Modeling; Molecular; Myocardial Infarction; Myocardial Ischemia; Myofibroblast; Organ; PTPRC gene; Pathway interactions; Patients; Process; Research Personnel; Sclerosis; Sheep; Signal Transduction; Smooth Muscle Actin Staining Method; Staging; Stretching; Study models; Surface; Testing; Therapeutic; Thick; Time; Traction; Transforming Growth Factors; Translating; Vascular Cell Adhesion Molecule-1; Ventricular; Wound Healing; base; cytokine; flexibility; improved; in vitro testing; in vivo; inhibitor/antagonist; interstitial cell; mortality; neovascularization; papillary muscle; peripheral blood; physiologic model; prevent; repaired; seal

DESCRIPTION (provided by applicant): 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.

描述(由申请人提供)：缺血性二尖瓣返流(IMR)是心肌梗死(MI)后一种常见的并发症，可使死亡率增加一倍，并增加心力衰竭。IMR一直难以有效修复，这是由于左室(LV)重塑束缚了二尖瓣(MV)叶并限制了它们的关闭-瓣膜和LV大小不匹配。晚期瓣膜也僵硬和纤维化，进一步限制了有效的关闭。标准的治疗方法假定瓣膜大小是固定的，但瓣膜具有激活细胞的潜力，而灵活扩大拴系的MV可以减少IMR。机械拉伸、缺血环境和MR湍流都会影响瓣膜适应性。因此，我们开发了一个大型动物模型，利用3D ECHO无创地跟踪MV区域，并与细胞和分子研究相关联，独立地改变这些因素。在该模型中，在两个月内，由乳头肌牵引诱导的机械拴系增加了MV的面积和厚度，并重新激活了内皮-间充质转化(EMT)，这是一个发育过程。在机械拴系基础上增加心尖远端MI(有限心尖LV重塑)2个月可显著增加EMT，促纤维化转化生长因子(TGF)-β的表达、内皮细胞活化(VCAM-1)、胶原沉积和CD45+细胞的浸润。血液传播的伤口愈合CD45+细胞通过分化为产生胶原的肌成纤维细胞而导致其他器官的硬化。因此，我们将检验这一中心假设，即IMR环境中早期代偿性MV生长机制稍后变得失代偿，导致僵硬增加MR。目的1在MI+栓系模型和临床类型的下壁MI模型中，在2、6和10个月时，纤维化和僵硬与转化生长因子-β的表达、内皮激活和CD45+细胞浸润相关。目的分离MV CD45+细胞，检测其是否具有成纤维细胞、循环肌成纤维细胞前体的特性；检测MV和外周血CD45+细胞在MI释放的细胞因子刺激下与MV内皮细胞的黏附、分化为肌成纤维细胞，并可能影响天然MV细胞发生类似的促纤维化改变。目的3是基于初步的研究，即转化生长因子-β抑制剂氯沙坦在两个月后减少系留+心肌梗死模型中的EMT、CD45+细胞、内皮激活和中膜增厚；相反，当机械约束的左心室重构相对减少时，这些发现仍然存在。氯沙坦在体外也能抑制转化生长因子-β介导的EMT。我们将测试氯沙坦是否与LV约束不同，在栓系+MI模型中将长期促纤维化事件从2个月减少到6个月和10个月，并研究最近显示具有治疗意义的下游转化生长因子-β信号。这一建议结合了研究人员在生理建模和成像、MV组织病理学、内皮细胞生物学和生物力学方面的互补优势。它解决了一种常见疾病中未满足的临床需求，旨在增加我们对MV适应的理解。它开始测试潜在的治疗方法，如果得到证实，可以迅速转化为减少患者的IMR。