Innovative natriuretic peptide-based therapy for hypertrophic cardiomyopathy

项目概要/摘要 肥厚型心肌病（HCM）是最常见的遗传性心脏疾病，每200- 500个人HCM中的心脏纤维化是心力衰竭（HF）、心律失常和心功能不全风险的关键决定因素。 心源性猝死大约5%的HCM患者进展为终末期疾病， 心脏移植是唯一持久的治疗选择。没有经过证实的医学证据 HCM的治疗，改变纤维化，一个关键的病理生理过程，导致临床代偿失调， 不良后果。针对HCM纤维化的疗法存在严重未满足的需求。c型利钠肽 (CNP)是最有效的抗纤维化利钠肽，CNP已被证明可以减轻 其他HCM尚不清楚HCM患者的CNP水平是否改变。此外，它是未知的 以CNP为基础的治疗是否对HCM有效。我们将尝试解决这些问题与目前 项目首先，我们将比较HCM患者与健康对照组的CNP水平。这些数据将 提供CNP在HCM纤维化发展中作用的关键信息。第二，使用鼠标 在HCM模型中，我们将测试施用基于CNP的肽是否可以预防或逆转心脏纤维化。在 除了关注CNP外，我们还将测量CNP信号传导中的其他关键酶。脑啡肽酶是 CNP的酶促降解机制，因此抑制脑啡肽酶可能是一种替代策略 以防止HCM中的纤维化。使用临床标本和小鼠模型的组合， 该项目将为HCM中基于CNP的创新疗法和人体测试奠定基础。发展 靶向纤维化的基于CNP的新型治疗剂的研究也将提供未来的发明性，以将该策略应用于其他疾病。 扩张型心肌病和致瘤性心肌病等疾病。总的来说，我们的翻译 该方法将确定CNP在HCM中的作用，并确定增加CNP是否是一种可行的治疗策略 以防止HCM中的纤维化。

Project Summary/Abstract Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder, affecting 1 in every 200- 500 individuals. Cardiac fibrosis in HCM is a key determinant of the risk of heart failure (HF), arrhythmia and sudden cardiac death. Approximately 5% of patients with HCM progress to end-stage disease with systolic dysfunction, for which cardiac transplantation is the only durable therapeutic option. There is no proven medical therapy for HCM that modifies fibrosis, a key pathophysiologic process that leads to clinical decompensation and adverse outcome. There is a critical unmet need for therapies targeting fibrosis in HCM. C-type natriuretic peptide (CNP) is the most potent anti-fibrotic natriuretic peptide, and CNP has been shown to attenuate fibrosis in disease other HCM. It is unknown if levels of CNP are altered in patients with HCM. Furthermore, it is unknown if CNP-based therapy could be effective in HCM. We will attempt to address these questions with the present project. First, we will compare levels of CNP in humans with HCM compared to healthy controls. These data will provide critical information on the role of CNP in the development of fibrosis in HCM. Second, using a mouse model of HCM, we will test if administering CNP-based peptides can prevent or reverse cardiac fibrosis. In addition to focusing on CNP, we will also measure other key enzymes in CNP signaling. Neprilysin is the principle mechanism for enzymatic degradation of CNP, and therefore inhibiting neprilysin may be an alternative strategy to prevent fibrosis in HCM. Using a combination of clinical specimens and mouse models, this translational project will lay the foundation for innovative CNP-based therapy in HCM and testing in humans. The development of novel CNP-based therapeutics targeting fibrosis will also provide future inventive to apply this strategy to other diseases such as dilated cardiomyopathy and arrhythmogenic cardiomyopathy. Overall, our translational approach will identify the role of CNP in HCM, and determine if augmenting CNP is a viable therapeutic strategy to prevent fibrosis in HCM.