Innovative natriuretic peptide-based therapy for hypertrophic cardiomyopathy

项目摘要/摘要 肥厚型心肌病(HCM)是最常见的遗传性心脏病，每200人中就有1人患病。 500个人。肥厚性心肌病的心脏纤维化是心力衰竭(HF)、心律失常和 心源性猝死。大约5%的肥厚型心肌炎患者进展为终末期疾病，伴有收缩 功能障碍，心脏移植是唯一持久的治疗选择。没有经过证实的医学上的 改变纤维化的肥厚性心肌病的治疗，这是导致临床失代偿和 不好的结果。针对肥厚性心肌炎的纤维化治疗存在严重的未得到满足的需求。C型利钠肽 (CNP)是最有效的抗纤维化钠尿肽，而且CNP已被证明可以减轻 其他肥厚型心肌炎的疾病。目前尚不清楚HCM患者的CNP水平是否发生了变化。此外，它是未知的 以CNP为基础的治疗方案是否能有效治疗肥厚性心肌病。我们将尝试用现在来解决这些问题 项目。首先，我们将比较患有肥厚性心肌炎的人与健康对照组的CNP水平。这些数据将 提供有关CNP在肥厚性心肌炎纤维化发展中的作用的关键信息。第二，使用鼠标 在HCM模型上，我们将测试给予以CNP为基础的多肽是否可以预防或逆转心肌纤维化。在……里面 除了关注CNP，我们还将测量CNP信号中的其他关键酶。奈普利辛是原则 酶降解CNP的机制，因此抑制Neprilysin可能是一种替代策略 预防肥厚性心肌炎的纤维化。使用临床样本和小鼠模型的组合，这一翻译 该项目将为在HCM中进行基于CNP的创新疗法和在人体上进行测试奠定基础。最新进展 针对纤维化的基于CNP的新型疗法的研究也将提供未来将这一策略应用于其他 扩张型心肌病和致心律失常性心肌病等疾病。总体而言，我们的翻译 方法将确定CNP在肥厚性心肌病中的作用，并确定增加CNP是否是一种可行的治疗策略 预防肥厚性心肌炎的纤维化。

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.