Li Chenze, Zhao Mingming, Xiao Lei, Wei Haoran, Wen Zheng, Hu Dong, Yu Bo, Sun Yang, Gao Jianing, Shen Xiaoqing, Zhang Qi, Cao Huanhuan, Huang Jin, Huang Wei, Li Ke, Huang Man, Ni Li, Yu Ting, Ji Liang, Xu Yangkai, Liu Gang, Konerman Matthew C, Zheng Lemin, Wen Wang Dao
Department of Cardiology, Zhongnan Hospital of Wuhan University, Institute of Myocardial Injury and Repair, Wuhan University, China (C.L.).
Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital (C.L., L.X., H.W., Z.W., D.H., B.Y., Y.S., X.S., J.H., K.L., M.H., L.N., T.Y., D.W.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Circ Heart Fail. 2021 Nov;14(11):e008459. doi: 10.1161/CIRCHEARTFAILURE.121.008459. Epub 2021 Oct 29.
Cardiac sialylation is involved in a variety of physiological processes in the heart. Altered sialylation has been implicated in heart failure (HF) mice. However, its role in patients with HF is unclear, and the potential effect of modulation of cardiac sialylation is worth exploring.
We first assessed the association between plasma N-acetylneuraminic acid levels and the incidence of adverse cardiovascular events in patients with HF over a median follow-up period of 2 years. Next, immunoblot analysis and lectin histochemistry were performed in cardiac tissue to determine the expression levels of neuraminidases and the extent of cardiac desialylation. Finally, the therapeutic impact of a neuraminidase inhibitor was evaluated in animal models of HF.
Among 1699 patients with HF, 464 (27%) died of cardiovascular-related deaths or underwent heart transplantation. We found that the elevated plasma N-acetylneuraminic acid level was independently associated with a higher risk of incident cardiovascular death and heart transplantation (third tertile adjusted hazard ratio, 2.11 [95% CI, 1.67-2.66], <0.001). In addition, in cardiac tissues from patients with HF, neuraminidase expression was upregulated, accompanied by desialylation. Treatment with oseltamivir, a neuraminidase inhibitor, in HF mice infused with isoproterenol and angiotensin II significantly inhibited desialylation and ameliorated cardiac dysfunction.
This study uncovered a significant association between elevated plasma N-acetylneuraminic acid level and an increased risk of a poor clinical outcome in patients with HF. Our data support the notion that desialylation represents an important contributor to the progression of HF, and neuraminidase inhibition may be a potential therapeutic strategy for HF.
心脏唾液酸化参与心脏的多种生理过程。唾液酸化改变与心力衰竭（HF）小鼠有关。然而，其在HF患者中的作用尚不清楚，调节心脏唾液酸化的潜在效果值得探索。
我们首先评估了在中位随访期2年的HF患者中，血浆N-乙酰神经氨酸水平与不良心血管事件发生率之间的关联。接下来，在心脏组织中进行免疫印迹分析和凝集素组织化学，以确定神经氨酸酶的表达水平和心脏去唾液酸化的程度。最后，在HF动物模型中评估神经氨酸酶抑制剂的治疗效果。
在1699例HF患者中，464例（27%）死于心血管相关死亡或接受了心脏移植。我们发现，血浆N-乙酰神经氨酸水平升高与心血管死亡和心脏移植事件的较高风险独立相关（第三三分位数调整后的风险比，2.11[95%CI，1.67-2.66]，P<0.001）。此外，在HF患者的心脏组织中，神经氨酸酶表达上调，伴有去唾液酸化。在注射异丙肾上腺素和血管紧张素II的HF小鼠中，用神经氨酸酶抑制剂奥司他韦治疗可显著抑制去唾液酸化并改善心脏功能障碍。
本研究揭示了HF患者血浆N-乙酰神经氨酸水平升高与临床不良结局风险增加之间的显著关联。我们的数据支持去唾液酸化是HF进展的重要因素这一观点，并且抑制神经氨酸酶可能是HF的一种潜在治疗策略。
