Abstract 11451: Myocardial Neprilysin Expression in Patients With Obstructive Hypertrophic Cardiomyopathy

Introduction: Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy and fibrosis, the underlying mechanisms of which remain poorly understood. Neprilysin (NEP) inhibition has been shown to attenuate hypertrophy and fibrosis in animal models of heart failure, and NEP inhibition is an established therapeutic target in dilated and ischemic cardiomyopathy. However, the myocardial expression of NEP in HCM has not been previously reported. Hypothesis: The expression of NEP is increased in patients with obstructive HCM (oHCM). Methods/Results: We analyzed publicly available gene expression data from two independent cohorts that used myectomy samples from patients with oHCM, and healthy unused donor hearts served as controls. Cohort #1 (NCBI GEO accession number GSE36961) included 107 patients with oHCM and 39 controls and used microarray to assess gene expression. Cohort #2 (NCBI GEO accession number GSE160997) included 18 patients with oHCM and 5 controls and used RNA-Seq to assess gene expression. Both cohorts showed NEP gene expression was significantly increased in oHCM compared to controls (P<0.0001 and P<0.001, respectively). We then examined NEP expression in our surgical cohort (#3), which included 40 patients with oHCM and 8 controls. Using qPCR we showed NEP gene expression was significantly elevated in oHCM compared to controls (P<0.001, see Figure 1). Conclusions: Myocardial NEP gene expression is significantly increased in patients with oHCM undergoing septal myectomy. Future studies are needed to determine if increased myocardial NEP gene expression is accompanied by elevated NEP protein expression and/or activity. Furthermore, future studies are required to determine the mechanism of increased NEP, and whether these findings extend to HCM patients who have not progressed to symptomatic obstruction.