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.