Tricuspid Valve Maladaptation: Its Stimuli, its Effect on Valve Function, and itsResponse to Therapy

抽象的。三尖瓣反流严重影响了160多万美国人。在大多数患者中， 三尖瓣返流被认为是“功能性的”或由瓣膜外在因素引起。阀门本身就被认为是 完好无损，因此被视为无辜的旁观者。因此，大多数治疗策略都集中在这些瓣膜上- 外部因素，忽略阀门本身。最近，我们发现三尖瓣返流可能不是这样。 毕竟是有功能的。在两个不同的功能性三尖瓣反流绵羊模型中，我们证明了 三尖瓣叶纤维重塑，即适应不良。这些小叶在面积上生长，并变得更厚 变得更僵硬。通过计算研究，我们进一步表明，适应不良会降低小叶顺应性。 以及它们成功粘合的能力，从而阻碍瓣膜功能。这些发现至关重要，因为 三尖瓣适应不良可能是疾病进展和患者预后的预测因子。他们还可以解释说 当前治疗策略的有限成功。也就是说，他们可能解释了为什么三尖瓣修复长期失败- 在多达30%的患者中出现了足月现象。最后，三尖瓣适应不良也可能是一个药理靶点。 为未来的治疗做准备。而另一些研究表明，人类三尖瓣瓣叶可能通过以下方式在疾病中重塑 增加它们的面积，还没有显示出它们也变厚变硬。因此，三尖瓣适应不良 没有在患者中得到充分证实，这是我们的新发现和改进之间的知识鸿沟 三尖瓣反流的诊断和治疗策略。这项管理的首要目标是 补充就是为了填补这一知识空白。具体地说，我们的目标是证明人类三尖瓣也 由于加厚和僵硬而不适应。为此，我们将采用体外方法，使用捐赠的身体 红心。我们还将探索次要目标，并确定这些瓣膜属性是否为年龄和/或 对性别的依赖。因此，我们的具体目标是：1)证明人类三尖瓣在疾病中不适应 通过增厚和硬化；以及2)测试人类三尖瓣厚度和硬度是否随年龄增长-以及 性爱成瘾。这项工作的预期结果将是双重的。第一，在工作结束后，我们将 知道人类的三尖瓣是否也不适应。这对于翻译我们的研究是至关重要的 绵羊(通过母公司R01提供资金)给患者。因此，本补编和 家长基金将提供对心脏瓣膜疾病的基本病理生理学的洞察。此外，我们 从而可能建立三尖瓣适应不良作为患者的新的治疗靶点。第二，我们将拥有 测试三尖瓣厚度和硬度是否与性别和年龄有关。这是非常重要的 我们对基本瓣膜生理学/病理生理学的了解，也可能有助于区别对待 治疗策略取决于患者的性别和年龄。总体而言，我们的努力将为一种致命的疾病和 显然是在《卡罗尔法案》的帮助下利用了我们的父母拨款。

ABSTRACT. Tricuspid valve regurgitation severely impacts more than 1.6 million Americans. In most patients, tricuspid regurgitation is considered “functional” or due to valve-extrinsic factors. The valve itself is considered intact and thus viewed as an innocent bystander. Therefore, most treatment strategies focus on these valve- extrinsic factors and ignore the valve itself. Recently, we have shown that tricuspid regurgitation may not be so functional after all. In two separate sheep models of functional tricuspid regurgitation, we showed that the tricuspid valve leaflets fibrotically remodel, i.e., maladapt. Those leaflets grow in area and become both thicker and stiffer. Through computational studies, we further showed that maladaptation reduces leaflet compliance and their ability to successfully coapt, thus impeding valve function. These findings are of critical importance as tricuspid maladaptation may be a predictor for disease progression and patient outcomes. They may also explain the limited success of current treatment strategies. That is, they may explain why tricuspid valve repairs fail long- term in as many as 30% of patients. Finally, tricuspid maladaptation may also serve as a pharmacological target for future therapies. While others have shown that human tricuspid valve leaflets may remodel in disease by increasing their area, it has yet to be shown that they also thicken and stiffen. Thus, tricuspid maladaptation has not been fully confirmed in patients, a knowledge gap that stands between our novel discovery and improved diagnostic and therapeutic strategies for tricuspid regurgitation. The primary objective of this Administrative Supplement is to fill this knowledge gap. Specifically, we aim to demonstrate that human tricuspid valves also maladapt by thickening and stiffening. To this end, we will take an in-vitro approach using donated cadaver hearts. We will also explore a secondary objective and determine whether those valve properties are age and/or sex dependent. Thus, our specific aims are: 1) Demonstrate that human tricuspid valves maladapt in disease via thickening and stiffening; and 2) Test whether human tricuspid valve thickness and stiffness are age- and sex-dependent. The expected outcome of this work will be two-fold. First, at the conclusion of our work, we will know whether human tricuspid valves also maladapt. This is critically important to translating our research on sheep (as funded through the parent R01) to patients. Thereby, the combined work of this supplement and the parent grant will provide insight into the fundamental pathophysiology of heart valve disease. Additionally, we may thereby establish tricuspid maladaptation as a novel therapeutic target in patients. Second, we will have tested whether tricuspid valve thickness and stiffness are sex- and age-dependent. This is highly important to our understanding of basic valvular physiology/pathophysiology and will also likely inform differential treatment strategies dependent on patient sex and age. Overall, our effort will shed new light on a deadly disease and clearly leverages our parent grant with the help of the CAROL Act.