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

项目摘要 大约160万美国人患有右房室心脏瓣膜渗漏， 称为三尖瓣（TV）反流（TR）。这是值得注意的，因为TR不仅是 发病率也是死亡率的独立预测因子。此外，严重TR的治疗选择是 次优，多达30%的患者在手术后5年内复发TR。在大多数情况下， 被认为继发于其他疾病的病例，这意味着其原因是瓣膜外在的。具体来说就是 我认为，例如，由于肺动脉高压引起的右心室重构， (PM)移位和瓣环扩张。PM位移随后径向应变并固定TV 瓣叶通过腱索栓系，而TV瓣环扩张周向拉紧瓣叶。在一起，PM 移位和瓣环扩张阻碍了正确的接合，使得TV不稳定。有趣的是， 心脏左侧的二尖瓣（MV）组织生长和重塑， 来自左心室（LV）疾病的病理性机械（病理机械）刺激，例如，由于瓣叶应变 PM位移和瓣环扩张后。虽然起初认为这是一种积极的适应， 改变机械环境，这种适应不良也会导致MV瓣叶膨胀并变得更硬， 进一步损害阀功能。另一方面，电视的研究严重不足。因此有 不清楚TV是否会响应于病理机械刺激而进行类似的重构， 导致阀门功能不正常。这一发现将使TR不完全是瓣膜外的，因此需要 质疑目前的治疗策略，并可能解释不良结果。为了填补这个空白， 知识，拟议的项目旨在证明体内TV重塑，以应对瓣叶应变， 绵羊疾病模型在微观尺度（目标1）和组织尺度（目标2）。目标是利用最先进的 形态分析、显微结构成像、机械测试和定量蛋白质 分析，并基于完善的心动过速诱导的心肌病绵羊模型。我们目前 缺乏知识可能会阻碍更好的TR治疗策略，否则可能会改善 目前电视治疗效果不佳因此，我的最终目标是激发药理学策略， 改变导致TV重塑的潜在生物学事件，并优化组织对病理的反应， 机械刺激这些努力正在进行中的MV，其中氯沙坦是作为一种药理学 二尖瓣返流的治疗。沿着研究战略，组织研究员培训计划， 申请人的专业发展，走向一个独立的研究生涯在顶级机构 在心脏瓣膜组织领域领先专家的赞助下， 生物力学完成培训计划后，申请人将为进一步的培训做好理想的准备。 博士后培训，并最终在心血管疾病研究的教师职位。

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.