P297. Serum Neprilysin Levels in Patients with Marfan Syndrome are Associated with Ascending Aortic Diameter.

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Objective: Marfan syndrome (MFS) is the most common hereditary disorder causing lethal aortic syndrome by degradation of the aortic wall. The underlying mutation in the fibrillin-1 gene affects multiple organs and their function and the aorta's mechanical stability. Recently, neprilysin (NEP)/angiotensin II receptor blockers sacubitril/valsartan have been shown to improve cardiac function in heart failure and positively affect the aortic wall in mouse models of MFS. NEP degrades and inactivates apelin peptides, which have been reported to be protective in terms of aortic aneurysm formation. Here, we aimed to investigate possible correlations between NEP and MFS in aortic specimens and serum of patients with MFS.
Methods: We collected serum and aortic specimens from patients with MFS (age 19-64 years) in the outpatient MFS centre at the University Hospital Heidelberg and resected tissue from patients with MFS undergoing valve sparing aortic root replacement. Control samples were collected from the aortic tissue of patients undergoing routine coronary artery bypass grafting. Enzyme-linked immunosorbent assay (ELISA) was used to analyze blood serum soluble NEP (sNEP) and apelin levels. sNEP activity in the serum was assessed using a fluorogenic peptide substrate. Aortic tissue was examined using immunofluorescence microscopy.
Results: Soluble neprilysin activity was significantly higher in patients with MFS than in control individuals without a connective tissue disorder diagnosis (n=36-76, p=0.0047). We observed a positive correlation between aortic root diameter and sNEP activity (r=0.46, p=0.0137), predominantly driven by the male gender (r=0.5178, p=0.0399), whereas it was not relevant in female patients with MFS. Furthermore, elevated sNEP levels correlated negatively with apelin concentration in patients with MFS (r=0.4083, p=0.0251) compared to control individuals (r=0.3417, p=0.1023). Exemplary NEP immunofluorescent staining of aortic tissue derived from MFS patients (n=2) revealed a 47% higher NEP protein abundance in the AAo media than in control individuals (n=2). However, in MFS patients, sNEP plasma levels were 78% higher (p=0.004, n=24-29), independent of gender, age, aortic diameter, and clinical data such as pre-/ post-surgery.
Conclusions: Elevated serum neprilysin levels may play a pivotal role in developing and progressing aortic aneurysm formation in patients with MFS. The addition of neprilysin receptor blockers may influence the progression of aneurysm formation in patients with MFS, reducing the need for early aortic replacement surgery.

Authors
Rawa Arif (1), Elisa Krieg (2), Franziska Rehberg (2), Jasmin Soethoff (3), Marcin Zaradzki (3), Markus Hecker (2), Matthias Karck (4), Andreas H Wagner (2)
Institutions
(1) Department of Cardiac Surgery, Heidelberg, Germany, (2) Institute of Physiology and Pathophysiology, Heidelberg, NA, (3) Department of Cardiac Surgery, Heidelberg, NA, (4) N/A, Heidelberg

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