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.

摘要 据估计，每40个美国人中就有一个患有二尖瓣脱垂（MVP）。是本病特征性表现 二尖瓣扩张和机械功能不全，最终导致瓣叶鼓起， 心脏收缩期的左心房和无法正确接合。它是发病率和死亡率的主要因素， 在美国，每年估计造成35，000人死亡以及90，000例大手术。目前， MVP的唯一治疗方法是手术矫正。尽管遵守了当前的指南， 术后将出现新发左心室功能障碍，这与长- 长期生存。术后LV功能障碍的一个可能原因是心肌纤维化（MF）， 在MVP患者的尸检研究以及基于MRI的成像中进行了横断面描述 问题研究然而，目前还没有研究从机制上证明MVP、心肌纤维化和 左心室功能障碍是相关的。我们最近证实心肌纤维化存在区域性的 重度MVP接受手术修复的患者中的分布。纤维化局限于下基底 心肌和乳头肌，从同一部位采集的心尖和间隔活检中无法检测到 患者这种纤维化的区域化模式在人MVP的遗传小鼠模型中得到验证。的 心肌纤维化的分布支持了我们的总体假设， 心肌纤维化是在MVP的情况下对增加的机械张力的反应过程。在这 奖学金申请，我们的目标是研究细胞和分子机制，翻译致病 机械力导致MVP心肌纤维化。在目标1中，我们将检验二尖瓣 脱垂可导致局部左心室纤维化。在目标2中，我们将检验机械 应激通过机械敏感性-ATP-嘌呤能信号传导机制激活纤维形成。在目标3中，我们 将检验基因组和转录组数据的整合可以识别转录调控因子的假设 启动和维持纤维化项目。我们将利用现有的人类样本，小鼠模型， 和生物反应器，以定义LV功能障碍的机械分子景观， 最有价值球员。通过完成这三个目标，我们将确定新的细胞途径参与机械- 诱导的纤维化，可以操纵，以防止或逆转心肌纤维化。最后 更好地了解MVP中心肌纤维化如何发生将具有临床信息，并可能鼓励 修订现行手术指南，以便早期干预，减少术后左室功能障碍。 总的来说，在这次奖学金中概述的科学方法和经验将使我走到最前沿 心血管研究，大大提高了我的临床和研究培训，并作为跳板 在我努力实现成为一名独立的物理学家和科学家的目标的过程中，