Mechanisms of Left Ventricular Fibrosis in Mitral Valve Prolapse

摘要 据估计，每40名美国人中就有一人患有二尖瓣脱垂(MVP)。这种病的特点是 二尖瓣增大和机械功能不全，最终导致小叶滚滚进入 收缩过程中的左心房和不能正确接合。它是发病率和死亡率的主要贡献者， 据估计，在美国每年造成3.5万人死亡和9万例大手术。目前， MVP的唯一治疗方法是手术矫正。尽管遵循当前的指导方针，五分之一的患者 术后会出现新的左心功能不全，这与长时间心脏功能不全的减少有关。 长期生存。术后左心功能不全的一个可能原因是心肌纤维化(MF)，它已经被认为是 在MVP患者的尸检研究中以及在基于MRI的成像中进行了横断面描述 学习。然而，目前还没有研究机械地证明MVP、心肌纤维化和 左心室功能障碍是有联系的。我们最近证实，心肌纤维化表现为局部化的 严重MVP患者接受手术修复后的分布。纤维化局限于下基底区 心肌和乳头肌，从取自同一组织的心尖和间隔活检中检测不到 病人。这种区域化的纤维化模式在人类MVP的遗传小鼠模型中得到了验证。这个 心肌内纤维化的分布支持我们的主要假设，即区域化 心肌纤维化是MVP时机械张力增加的反应性过程。在这 奖学金申请，我们的目标是研究翻译致病病毒的细胞和分子机制 机械力在MVP心肌纤维化形成中的作用。在目标1中，我们将检验二尖瓣的假设 脱垂可导致局灶性左心室纤维化。在目标2中，我们将检验机械的假设 应激通过一种机械敏感的-ATP-嘌呤能信号机制激活纤维化形成。在目标3中，我们 将检验这样的假设，即基因组和转录数据的整合可以识别转录调控因子 启动并维持纤维化项目。我们将利用现有的人体样本，老鼠模型， 和我们团队开发的生物反应器，以定义导致左心功能障碍的机械-分子图景 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，涉及机械- 诱导纤维化，可以通过操纵来预防或逆转心肌纤维化。最后，一个 更好地了解MVP中心肌纤维化是如何发生的，将在临床上提供信息，并可能鼓励 修订目前的手术指南，以便更早地干预和减少术后左心功能不全。 总而言之，在这次奖学金中概述的科学方法和经验将把我带到前沿 心血管研究，大大提高了我的临床和研究培训，并作为一个跳板 为了成功，我努力实现了我成为一名独立内科科学家的目标。

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.