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

抽象的。160万美国人患有功能性三尖瓣反流(FTR)；即三尖瓣 瓣膜外在因素引起的瓣膜渗漏，如肺动脉高压所致的右室 改建。在这些患者中，只有大约8000到10000人接受了手术治疗。这种不适当的待遇 FTR患者已被宣布为“公共健康危机”。尽管治疗不足的原因是多方面的， 一种是无可争辩的是，现有的治疗方案在高风险的同时，结果并不理想；因此， 倾向于保守治疗的风险-收益量表。例如，FTR在多达10%-30%的患者中复发 通过黄金标准的外科技术三尖瓣成形术进行治疗。此外，再发的死亡率-- 运营率过高(&gt；30%)。显然，需要更好的治疗方法来治疗FTR和 停止对大量患者进行不充分的治疗。我们的协作团队最近在两个独立的 绵羊在FTR中建立三尖瓣叶生长和纤维重塑的模型。三尖瓣的发现 瓣膜(MAL)适应现在提高了利用瓣膜的天然生长能力的可能性，从而 对抗疾病，并在治疗上针对小叶纤维化。然而，在能够使用我们的新功能之前 对改进FTR治疗和克服当今大规模治疗不足的三尖瓣的认识 必须更好地了解瓣膜适应不良：到目前为止，我们还不知道它的刺激因素，它的机制 对瓣膜功能的有害影响，或如何使用治疗来抑制纤维化。这样做的目的是 目前的建议是克服这些知识上的差距。为此，我们将测试我们的中心假设 疾病诱导的叶应变刺激叶适应不良，进而阻碍瓣膜粘合和 小叶适应不良可通过对抗疾病诱导的刺激而停止。我们 我们将在三个方面追求目标：1)确定三尖瓣适应不良的刺激因素；2)描述 适应不良阻碍瓣膜功能的机制，3)检测预防性干预是否 停止适应不良。为了实现这些目标，我们将把创新的慢性绵羊模型与体外培养相结合 使用高速3D成像和广泛的机械、成分和 生物组织表型。我们的团队在研究三尖瓣功能方面有着长期的合作记录 并得到一位在体外瓣膜实验方面拥有30年经验的资深同事的支持。 在这项工作结束后，我们预计已经确定了三尖瓣适应不良的刺激因素， 了解它阻碍瓣膜功能的机制，并已证明它可以被阻止 通过外科手术治疗。因此，我们将阐明最近发现的一种致病机制 三尖瓣并建议将其作为一个新的治疗靶点。因此，我们的工作将为实现 更好地理解和处理FTR这一公共卫生危机。虽然我们的工作是以外科手术为重点， 同样重要的是经导管修复策略，它放大了我们工作的意义和影响。

ABSTRACT. 1.6 million Americans suffer from functional tricuspid valve regurgitation (FTR); that is, tricuspid valve leakage due to valve-extrinsic factors such as pulmonary hypertension-induced right ventricular remodeling. Of those patients, only approximately 8-10 thousand are surgically treated. This undertreatment of patients with FTR has been declared “a public health crisis”. While the reasons for undertreatment are multi-fold, one is unarguably that available treatment options have suboptimal outcomes while being high-risk; thus, tilting the risk-benefit scale toward conservative treatment. For example, FTR recurs in as many as 10-30% of patients treated via the gold-standard surgical technique tricuspid valve annuloplasty. Additionally, mortality rates of re- operation are exorbitantly high (>30%). Clearly, better therapeutic approaches are needed to treat FTR and to stop undertreatment of a large patient population. Our collaborative team has recently shown in two separate sheep models that the tricuspid valve leaflets grow and fibrotically remodel in FTR. The discovery of tricuspid valve (mal)adaptation now raises the possibility to both harness the valve’s native ability to grow, and thereby counteract disease, and to therapeutically target leaflet fibrosis. However, before being able to use our new knowledge toward improving treatment of FTR and toward overcoming today’s massive undertreatment, tricuspid valve maladaptation must be better understood: To date, we don’t know its stimuli, the mechanisms of its detrimental effects on valve function, or how therapy may be used to suppress fibrosis. The objective of this current proposal is to overcome these gaps in knowledge. To this end, we will test our central hypothesis that disease-induced leaflet strains stimulate leaflet maladaptation which, in turn, hinders valve coaptation and contributes to FTR, and that leaflet maladaptation may be halted by counteracting disease-induced stimuli. We will pursue our objective in three aims: 1) Identify the stimuli of tricuspid valve maladaptation, 2) Delineate the mechanisms through which maladaptation impedes valve function, 3) Test whether prophylactic intervention halts maladaptation. To accomplish these aims, we will combine innovative, chronic sheep models with in-vitro flow loop valve characterization using high-speed 3D imaging, and extensive mechanical, compositional, and biological tissue phenotyping. Our team has a long collaborative track record of studying tricuspid valve function and disease, and is supported by a senior colleague with 30 years of experience in in-vitro valve experimentation. Upon conclusion of this work, we expect to have identified the stimuli for tricuspid valve maladaptation, understand the mechanisms through which it impedes valve function, and have shown that it can be halted through surgical intervention. Thus, we will have shed light on a recently identified disease mechanism of the tricuspid valve and suggested it as a novel therapeutic target. Our work will therefore pave the way toward a better understanding and better treatment of FTR as a public health crisis. While our work is surgically-focused, it is equally important to transcatheter repair strategies which amplifies the significance of our work and its impact.