Mechanisms of Left Ventricular Fibrosis in Mitral Valve Prolapse

二尖瓣脱垂引起左心室纤维化的机制

• 批准号: 10603587
• 负责人: Jordan E. Morningstar
• 金额: $ 5万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10603587
• 关键词: ATAC-seq; Adherence; Affect; American; Animal Model; Aorta; Apical; Automobile Driving; Autopsy; Benign; Biological; Biopsy; Bioreactors; Cardiac; Cardiac Death; Cardiovascular system; Cells; Cellular Assay; Cessation of life; Clinical; Collagen; Connexin 43; Data; Data Set; Deposition; Development; Disease; Dose; Echocardiography; Failure; Family; Fellowship; Fibroblasts; Fibrosis; Functional disorder; Gadolinium; Genetic; Genetic Transcription; Genomic Segment; Genomics; Goals; Guidelines; Heart; Human; Incidence; Individual; Knowledge; Left; Left Ventricular Dysfunction; Left atrial structure; Left ventricular structure; Link; Magnetic Resonance Imaging; Mechanical Stress; Mechanics; Mitral Valve; Mitral Valve Insufficiency; Mitral Valve Prolapse; Modeling; Modification; Molecular; Morbidity - disease rate; Mutation; Myocardial; Myocardium; Operative Surgical Procedures; Pathogenicity; Pathologic; Pathway interactions; Patients; Pattern; Physicians; Postoperative Period; Process; Ptosis; Reporter; Research; Research Training; Risk Factors; Role; Sampling; Scientist; Signal Transduction; Stimulus; Stress; Stretching; Structure of chordae tendineae cordis; Sudden Death; Surgical Management; Systole; Testing; Therapeutic; Time; Traction; Translating; United States; Ventricular; Work; cell type; clinical training; coronary fibrosis; early screening; experience; fibrogenesis; human model; imaging study; in vitro Assay; in vivo; insight; loss of function; mechanical force; mortality; mouse model; papillary muscle; pharmacologic; pre-doctoral; prevent; programs; repaired; response; routine screening; success; sudden cardiac death; transcriptome sequencing; transcriptomics

Abstract One in 40 Americans are estimated to have mitral valve prolapse (MVP). This disease is characterized by enlargement and mechanical incompetence of the mitral valve, eventually leading to billowing of the leaflets into the left atrium during systole and failure to properly coapt. It is a major contributor to morbidity and mortality, causing an estimated 35,000 deaths per year as well as 90,000 major surgeries in the United States. Currently, the only treatment for MVP is surgical correction. Despite adherence to current guidelines, one in five patients will develop new onset left ventricular dysfunction postoperatively, and this is associated with a decrease in long- term survival. A possible cause of postoperative LV dysfunction is myocardial fibrosis (MF), which has been described cross-sectionally in both autopsy studies of patients with MVP, as well as in MRI-based imaging studies. However, no studies exist that have mechanistically demonstrated how MVP, myocardial fibrosis, and LV dysfunction are linked. We have recently demonstrated that myocardial fibrosis is present with a regionalized distribution in patients who underwent surgical repair for severe MVP. Fibrosis is localized to the inferobasal myocardium and papillary muscles and is undetectable from apical and septal biopsies taken from the same patients. This regionalized pattern of fibrosis was validated in genetic mouse models of human MVP. The distribution of fibrosis within the myocardium supports our overarching hypothesis that regionalized myocardial fibrosis is a reactive process to increased mechanical tension in the setting of MVP. In this fellowship application, we aim to study the cellular and molecular mechanisms that translate pathogenic mechanical forces into myocardial fibrogenesis in MVP. In Aim 1, we will test the hypothesis that mitral valve prolapse can cause regionalized left ventricular fibrosis. In Aim 2, we will test the hypothesis that mechanical stress activates fibrogenesis through a mechanosensitive-ATP-Purinergic signaling mechanism. In Aim 3, we will test the hypothesis that integration of genomic and transcriptomic data can identify transcriptional regulators that initiate and sustain fibrosis programs. We will take advantage of available human samples, mouse models, and bioreactors developed by our group to define a mechano-molecular landscape underlying LV dysfunction in MVP. Through completion of these three aims, we will identify new cellular pathways involved in mechanically- induced fibrogenesis that could be manipulated in order to prevent or reverse myocardial fibrosis. Finally, a better understanding of how myocardial fibrosis occurs in MVP will be clinically informative and may encourage revision of current surgical guidelines in order to intervene earlier and decrease postoperative LV dysfunction. Collectively, the scientific approaches and experiences outlined in this fellowship will bring me to the cutting edge of cardiovascular research, significantly enhancing my clinical and research training, and serve as a springboard for success as I work towards achieving my goal of becoming an independent physician-scientist.

抽象的 据估计，有40个美国人中有二尖瓣脱垂（MVP）。该疾病的特征是 二尖瓣的扩大和机械无能，最终导致传单滚滚到 收缩期间的左心房，无法正确旋转。它是发病率和死亡率的主要因素， 估计每年造成35,000例死亡以及美国90,000次重大手术。现在， MVP的唯一治疗方法是手术校正。尽管遵守当前指南，但五分之一的患者 术后会出现新的左心室功能障碍，这与长期减少有关 术语生存。术后LV功能障碍的可能原因是心肌纤维化（MF）， 描述了MVP患者以及基于MRI的成像的横截面研究 研究。但是，没有任何研究能够从机械上证明MVP，心肌纤维化和如何 LV功能障碍链接。我们最近证明，心肌纤维化存在于区域化 进行严重MVP手术修复的患者的分布。纤维化本地化与地下浮游生物 心肌和乳头状肌肉，从同一动物中取出的根尖和隔膜活检是无法检测的 患者。这种纤维化的区域化模式在人类MVP的遗传小鼠模型中得到了验证。这 心肌内纤维化的分布支持我们的总体假设 心肌纤维化是在MVP中增加机械张力的反应性过程。在这个 奖学金应用，我们旨在研究翻译致病性的细胞和分子机制 在MVP中进入心肌纤维发生的机械力。在AIM 1中，我们将测试二尖瓣的假设 脱垂会导致区域化的左心室纤维化。在AIM 2中，我们将测试机械的假设 应力通过机械敏感-ATP-Purinergic信号传导机制激活纤维发生。在AIM 3中，我们 将检验以下假设：基因组和转录组数据的整合可以识别转录调节剂 启动和维持纤维化计划。我们将利用可用的人类样品，鼠标模型， 和我们小组开发的生物反应器，以定义机械分子景观的LV功能障碍 MVP。通过完成这三个目标，我们将确定与机械性有关的新细胞途径 为了预防或逆转心肌纤维化而可以操纵的诱导纤维发生。最后，一个 更好地了解MVP中心肌纤维化如何在临床上有用，并可能鼓励 修订当前的手术指南，以便更早干预并降低术后LV功能障碍。 总的来说，这项奖学金中概述的科学方法和经验将使我进入最前沿 心血管研究的大幅度增强了我的临床和研究培训，并充当跳板 为了成功，我努力实现成为独立医师科学家的目标。