Tricuspid Valve Maladaptation: Its Stimuli, its Effect on Valve Function, and itsResponse 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: 10852601
• 负责人: MANUEL Karl RAUSCH
• 金额: $ 19.77万
• 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/10852601
• 关键词: Administrative Supplement; Age; American; Area; Cadaver; Diagnostic; Disease; Disease Progression; Extravasation; Failure; Functional disorder; Funding; Future; Goals; Health; Heart; Heart Valve Diseases; Human; In Vitro; Knowledge; Outcome; Parents; Patient-Focused Outcomes; Patients; Physiology; Property; Research; Right atrial structure; Right ventricular structure; Sheep; Stimulus; Testing; Therapeutic; Thick; Translating; Tricuspid Valve Insufficiency; Tricuspid valve structure; Work; age related; computer studies; improved; insight; new therapeutic target; novel; parent grant; pharmacologic; repaired; sex; sheep model; success; treatment strategy

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.

摘要。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”或由于瓣膜外在因素。阀门本身被认为 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- 外在因素，忽略瓣膜本身。最近，我们发现三尖瓣反流可能不是这样的， 功能，毕竟。在两个独立的绵羊功能性三尖瓣反流模型中，我们发现， 三尖瓣小叶纤维性重塑，即，适应不良这些小叶面积增大， 更硬通过计算研究，我们进一步表明，适应不良会降低瓣叶顺应性 以及它们成功接合从而阻碍瓣膜功能的能力。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结局的预测因子。他们也可以解释 目前治疗策略的有限成功。也就是说，它们可以解释为什么三尖瓣修复术长期失败- 在多达30%的患者中。最后，三尖瓣适应不良也可作为药理学靶点 用于未来的治疗。虽然其他人已经表明，人类三尖瓣小叶可以在疾病中重塑， 增加它们的面积，但还没有证明它们也会生长和繁殖。因此，三尖瓣适应不良 尚未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差距。 三尖瓣反流的诊断和治疗策略。本行政区划的主要目标 补充就是填补这一知识空白。具体来说，我们的目标是证明人类三尖瓣也 由于变厚变硬而不适应。为此，我们将采用体外方法， 心中我们还将探索次要目标，并确定这些瓣膜特性是否是年龄和/或 性依赖因此，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;和2）测试人类三尖瓣厚度和刚度是否随年龄变化， 性别依赖这项工作的预期成果将是双重的。首先，在我们的工作结束时，我们将 知道人类的三尖瓣是否也适应不良。这对于将我们的研究转化为 羊（通过母公司R 01资助）给患者。因此，这一补充和 父母补助金将提供深入了解心脏瓣膜疾病的基本病理生理学。另外我们 从而确立三尖瓣适应不良作为患者的新治疗靶点。第二，我们将有 测试三尖瓣厚度和硬度是否与性别和年龄有关。这一点非常重要， 我们对基本瓣膜生理学/病理生理学的理解，也可能告知差异治疗 策略取决于患者的性别和年龄。总的来说，我们的努力将为一种致命的疾病提供新的线索， 在《卡罗尔法案》的帮助下，显然利用了我们的父母补助金。

项目成果

Valvular complex and tissue remodelling in ovine functional tricuspid regurgitation.

羊功能性三尖瓣反流的瓣膜复合体和组织重塑。

• DOI: 10.1093/ejcts/ezad115
• 发表时间: 2023
• 期刊: European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery
• 作者: Iwasieczko,Artur;Gaddam,Manikantam;Gaweda,Boguslaw;Goodyke,Austin;Mathur,Mrudang;Lin,Chien-Yu;Zagorski,Joseph;Solarewicz,Monica;Cohle,Stephen;Rausch,Manuel;Timek,TomaszA
• 通讯作者: Timek,TomaszA