Prognostic Value Of Elevated Levels Of Plasma N-acetylneuraminic Acid And Thereputic Efficacy Of Neuraminidase Inhibitor In Heart Failure Patients

Background:In recent years,it is increasingly recognised that aberrant cardiac sialyation may also represent an important contributor to heart failure(HF)pathogenesis.Sialic acids are frequently attached to the end of glycoconjugates on the cell surface or secreted proteins to mediate various physiological processes,such as serve as the binding sites for a variety of ligands.The presence of terminal sialic acid in gly coconjugates is vital to the normal cellular function and cardiovascular homeostasis.With ongoing pathologies,sialidase,also called neuraminidases,are modulated to catalyse the removal of α-glycosidic bonds linked sialic acid residues from glycoproteins and glycolipids,resulting in the disturbance of cell adhesion and transmembrane signaling.Previous works have observed a mechanistic link between sialic acid and cardiomyocyte apoptosis and inflammation.In HF patients,the relationships between free sialic acid and both cardiac and inflammatory indexes,and long-term clinical prognosis have not been evaluated.Meanwhile,the potential effect of modulation of cardiac sialylation(application of neuraminidase inhibitor)on HF worth exploring.Methods:Firstly,N-acetylneuraminic acid(Neu5Ac)level,which accounts for 80%of total sialic acids,were measured by liquid chromatograph-mass spectrometry,and its associations with HF and both cardiac and inflammatory indexes were investigated in 955 cases and 1000 controls,and look for validation in another independent 744 cases and 700 controls.Next,we visualized α-(2,6)-linked sialic acid and detected neuraminidase expression in human heart tissue.Finally,the therapeutic effects of a neuraminidase inhibitor were evaluated on HF animal models.Results:The median Neu5Ac level was 0.82 μM in HF patients,which was significantly higher than that in controls(0.59 μM;p<0.001).Elevated Neu5Ac level was independently associated with a higher risk of incident cardiovascular death and heart transplantation over a median follow-up period of 33 months in HF patients(3rd tertile adjusted hazard ratio(HR),2.20,95%confidence interval(CI),1.62-2.99,p<0.001).Furthermore,there were significant correlations between Neu5Ac levels and cardiac(NT-proBNP)and inflammatory(hsCRP)indexes.Validation studies confirmed these findings.In addition,in HF patients’ heart tissues,neuraminidase expression was upregulated and desialylation occurred.Oseltamivir,a neuraminidase inhibitor,was effective in inhibiting desialylation and improving cardiac dysfunction in isoproterenol-and angiotensin Ⅱ-induced HF mice.Conclusions:This study demonstrated a relationship of elevated Neu5Ac level with both an increased risk of HF and its subsequent cardiovascular events.Our data support the notion that desialylation represents an important contributor to the development and progression of HF,and application of neuraminidase inhibitor may be a potential therapeutic strategy in HF.