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

三尖瓣适应不良：其刺激、对瓣膜功能的影响及其对治疗的反应

• 批准号: 10650421
• 负责人: MANUEL Karl RAUSCH
• 金额: $ 70.03万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-20 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650421
• 关键词: Acute; American; Animals; Area; Benefits and Risks; Biological; Chronic; Computer Simulation; Dilatation - action; Disease; Extravasation; Fibrosis; Future; Growth; Health; Heart; Heart Valve Diseases; Human; Image; Implant; In Vitro; Individual; Intervention; Knowledge; Measures; Mechanics; Morbidity - disease rate; Operative Surgical Procedures; Outcome; Pathologic; Patient-Focused Outcomes; Patients; Phenotype; Public Health; Pulmonary Hypertension; Recording of previous events; Recurrence; Repeat Surgery; Right atrial structure; Right ventricular structure; Sheep; Speed; Stimulus; Techniques; Testing; Therapeutic; Thick; Three-Dimensional Imaging; Tissues; Tricuspid Valve Insufficiency; Tricuspid valve structure; Ultrasonics; Visualization; Work; clinically relevant; experience; high risk; improved; innovation; journal article; member; minimally invasive; mortality; new therapeutic target; patient population; prophylactic; repair strategy; right ventricular remodeling; sheep model; standard care; success; therapeutic target; treatment response

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.

摘要。1.6 100万美国人患有功能性三尖瓣反流（FTR），即三尖瓣反流， 由于瓣膜外在因素（如肺动脉高压诱导的右心室）导致的瓣膜泄漏 重塑在这些患者中，只有大约8 - 10万人接受手术治疗。这种对 FTR患者已被宣布为“公共卫生危机”。虽然治疗不足的原因是多方面的， 一个是无可争议的是，现有的治疗方案有次优的结果，而高风险;因此，倾斜 保守治疗的风险-收益比例。例如，FTR在多达10 - 30%的患者中复发 通过金标准手术技术三尖瓣环成形术治疗。此外，死亡率再- 手术率过高（> 30%）。显然，需要更好的治疗方法来治疗FTR， 停止对大量患者的治疗不足。我们的合作团队最近在两个独立的 绵羊模型，三尖瓣小叶生长和纤维化重塑FTR。三尖瓣的发现 瓣膜（错误）适应现在提高了利用瓣膜的天然生长能力，从而 对抗疾病，并治疗靶向小叶纤维化。然而，在能够使用我们的新 改善FTR治疗和克服当今大量治疗不足、三尖瓣 瓣膜适应不良必须得到更好的理解：到目前为止，我们不知道它的刺激，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。的目的 目前的建议是克服这些知识差距。为此，我们将测试我们的中心假设， 疾病引起的瓣叶应变刺激瓣叶适应不良，这反过来又阻碍瓣膜接合， 有助于FTR，并且瓣叶适应不良可以通过抵消疾病诱导的刺激来停止。我们 我们将从三个方面来实现我们的目标：1）识别三尖瓣适应不良的刺激，2）描绘三尖瓣适应不良的刺激。 适应不良阻碍瓣膜功能的机制，3）测试预防性干预是否 停止适应不良为了实现这些目标，我们将结合联合收割机创新，慢性羊模型与体外 使用高速3D成像和广泛的机械、成分和 生物组织表型分析我们的团队在研究三尖瓣功能方面有着长期的合作记录 和疾病，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，我们希望已经确定了三尖瓣适应不良的刺激， 了解它阻碍阀门功能的机制，并表明它可以停止 通过手术干预。因此，我们将阐明最近确定的疾病机制， 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 更好地理解和更好地处理FTR作为公共卫生危机。虽然我们的工作是以医疗为重点， 同样重要的是经导管修复策略，它放大了我们工作的重要性及其影响。