Tricuspid valve adaptation to right heart disease: A multiscale, histomechanical study in sheep

项目总结 大约有160万美国人患有右房室瓣膜渗漏，这是 称为三尖瓣(TV)反流(TR)。这一点值得注意，因为tr不仅是 发病率，但也是死亡率的独立预测指标。此外，对严重的tr的治疗选择是 次优，高达30%的患者在手术后五年内出现复发的tr。Tr在大多数情况下 被认为是次要于其他条件的病例，暗示其原因是瓣膜外在的。具体地说，它是 例如，我认为由肺动脉高压引起的右室重构会引起乳头肌 (PM)位移和环状扩张。PM位移随后对电视进行径向拉伸和固定 在电视环状扩张术中，通过弦绳系带拉紧小叶，而电视环状扩张术则对小叶进行周向拉紧。在一起，PM 移位和环状扩张阻碍了正确的粘合，导致电视反流。有趣的是，研究 心脏左侧的研究表明，二尖瓣(MV)组织生长和重塑是对 来自左心室(LV)疾病的病理机械(病理-机械)刺激，例如，由于瓣叶拉伤 在PM位移和环空扩张之后。尽管最初被认为是对一种 机械环境的变化，这种适应不良也会导致MV小叶增厚和变得僵硬， 进一步影响阀门功能。另一方面，人们对电视的研究严重不足。因此，它是 不知道电视机是否会对病理-机械刺激做出类似的重塑，以及是否重塑 导致阀门功能不正确。这一发现将使tr不完全是非瓣膜的，从而调用 质疑当前的治疗策略，并可能解释糟糕的结果。为了填补我们在这方面的空白 知识，拟议的项目旨在演示在活体电视重塑对叶应变的反应 绵羊疾病微观尺度模型(目标1)和组织尺度模型(目标2)。AIMS利用最先进的技术 形态计量分析、显微结构成像、机械测试和定量蛋白质技术 分析和都是基于一个公认的心动过速引起的心肌病绵羊模型。我们目前的情况 缺乏知识可能会阻碍更好的治疗tr的策略，否则可能会改善。 目前电视治疗的效果很差。因此，我的最终目标是启发药理学策略 改变导致电视重塑的潜在生物事件，优化组织对病理的反应- 机械刺激。这样的努力正在为氯沙坦进行药理测试的MV进行 MV反流的治疗。与研究战略一起，组织了奖学金培训计划，以提供 申请者在一流院校从事独立研究工作的职业发展 在著名心脏瓣膜组织专家的赞助下，德克萨斯大学奥斯汀分校的环境 生物力学。在完成培训计划后，申请者将做好进一步培训的理想准备 博士后培训，并最终在心血管疾病研究方面获得教职。

PROJECT SUMMARY Approximately 1.6 million Americans suffer from leakage of their right atrioventricular heart valve, which is referred to as tricuspid valve (TV) regurgitation (TR). This is noteworthy as TR is not only a significant source of morbidity but also an independent predictor of mortality. Furthermore, treatment options for severe TR are suboptimal, with as many as 30% of patients developing recurrent TR within five years of surgery. TR is in most cases considered secondary to other conditions, implying that its causes are valve-extrinsic. Specifically, it is thought that right ventricular remodeling due to pulmonary hypertension, for example, causes papillary muscle (PM) displacement and annular dilation. PM displacement subsequently radially strains and immobilizes the TV leaflets via chordal tethering, while TV annular dilation circumferentially strains the leaflets. Together, PM displacement and annular dilation prohibit proper coaptation, rendering the TV regurgitant. Interestingly, studies on the left side of the heart have shown that mitral valve (MV) tissue grows and remodels in response to pathological mechanical (patho-mechanical) stimuli from left ventricular (LV) disease, e.g., due to leaflet strains following PM displacement and annular dilation. Although at first believed to be a positive adaptation to a changing mechanical environment, this maladaptation also causes the MV leaflets to thicken and become stiffer, further compromising valve function. The TV, on the other hand, is severely understudied. Therefore, it is unknown whether the TV similarly remodels in response to patho-mechanical stimuli, and if remodeling contributes to improper valve function. This finding would render TR not entirely valve-extrinisic and thus call into question current treatment strategies as well as potentially explain poor outcomes. To fill this gap in our knowledge, the proposed project aims to demonstrate TV remodeling in vivo in response to leaflet strain in an ovine disease model at the micro-scale (Aim 1) and the tissue-scale (Aim 2). The aims utilize state-of-the-art techniques in morphometric analysis, microstructural imaging, mechanical testing, and quantitative protein analysis and are based on a well-established tachycardia-induced cardiomyopathy sheep model. Our current lack of knowledge is potentially withholding better treatment strategies for TR, which could otherwise improve the currently poor outcomes of TV therapy. Thus, my ultimate goal is to inspire pharmacological strategies to modify the underlying biological events that lead to TV remodeling and optimize the tissue’s response to patho- mechanical stimuli. Such efforts are underway for the MV where Losartan is tested as a pharmacological treatment of MV regurgitation. Along with the research strategy, the fellowship training plan is organized to offer the applicant professional development toward an independent research career in a top tier institutional environment at the University of Texas at Austin under the sponsorship of leading experts in heart valve tissue biomechanics. Upon completion of the training program, the applicant will be ideally-prepared for further postdoctoral training and eventually a faculty position in cardiovascular disease research.