Abstract
The transmembrane zink-metalloendopeptidase neprilysin (NEP) is implicated in cardiovascular disease but also tumor biology. The aim of the study was to investigate the relationship of circulating NEP (cNEP) levels with established cardiovascular biomarkers and its effect on overall survival in an unselected cohort of treatment-naïve cancer patients. 555 consecutive cancer patients prior anticancer therapy were enrolled prospectively. NEP levels were determined alongside routine laboratory parameters, established cardiac biomarkers, i.e. NT-proBNP, hsTnT, MR-proANP, MR-proADM, CT-proET-1 and Copeptin, and inflammatory parameters, i.e. CRP, IL-6 and SAA, in venous plasma samples. All-cause mortality was the primary endpoint. cNEP levels of 276 pg/ml (IQR: 0–5981) displayed a weak inverse correlation with age [r = −0.12, p = 0.023] and inflammatory status [r = −0.14, p = 0.007 CRP; r = −0.20, p < 0.001 IL-6 and r = −0.18, p < 0.001 SAA]. cNEP was comparable between different tumor entities and stages and not related to functional parameters of other organ systems as kidney, liver or especially the heart. Moreover, cNEP was not associated with overall survival in the total cohort [adj.HR for ln (cNEP) 1.00, 95% CI: 0.94–1.06, p = 0.887] but in myelodysplatic malignancies [adj.HR for ln (cNEP) 1.27, 95% CI: 1.01–1.61, p = 0.044]. In conclusion, cNEP lacks association with outcome but for myelodysplastic disease. cNEP shows no correlation with established cardiovascular biomarkers related to prognosis, thereby holding a limited potential as a biomarker in cardio-oncology.
Highlights
Neprilysin inhibition (NEPi) as part of the therapy with angiotensin-receptor neprilysin inhibitor (ARNI) has recently been shown to impressively reduce hospitalization and all-cause mortality in patients with heart failure with reduced ejection fraction (HFrEF)[1], and represents standard of care[2]
NEP overexpression is not restricted to leukemias, but NEP staining is used for the diagnosis of B-lymphoblastic leukemia or lymphoma cells[11,12,13]
C-reactive protein (CRP) was determined with a median of 0 mg/dl (IQR 0–1), serum-amyloid A (SAA) with 8 μg/ml (IQR 4–16) and IL-6 with 2 pg/ml (IQR 2–3) for the total cohort
Summary
Neprilysin inhibition (NEPi) as part of the therapy with angiotensin-receptor neprilysin inhibitor (ARNI) has recently been shown to impressively reduce hospitalization and all-cause mortality in patients with heart failure with reduced ejection fraction (HFrEF)[1], and represents standard of care[2]. Cardiac research has been focusing on revealing the exact mechanisms of action of NEPi. Several reports on concentrations of the circulating form of the enzyme and its activity have been published in the last three years, and circulating NEP concentrations (cNEP) have been discussed controversially as a biomarker for heart failure patients[3,4]. Several studies have shown elevation of these markers in treatment-naïve cancer patients assumedly as a response to systemic inflammation, making the interpretation of these markers more complex[6] Molecules implicated in both cardiac and malignant disease could be good candidates for additional characterization of this special patient population. The relationship of cNEP with other established cardiac biomarkers in cancer patients is of interest to characterize the role of NEP in cardio-oncology. We aimed to determine the association of cNEP with other established cardiac biomarkers known to reflect cardiac dysfunction and holding prognostic information in this patient population
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