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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-023-02793-8

摘要内容如下：

尽管加强了心血管疾病（CVD）的预防工作，但即使对于接受所有指南推荐的干预措施的个体，仍存在大量的残余CVD风险。烟酸是一种在主食中强化的必需微量营养素，但其在心血管疾病中的作用还不是很清楚。在这项研究中，对前瞻性发现队列（n=1，162，女性n=422）中的稳定心脏病患者的空腹血浆进行非靶向代谢组学分析，表明烟酸代谢与主要不良心血管事件（MACE）事件相关。在两个验证队列中，过量烟酸的终末代谢物N1-甲基-2-吡啶酮-5-甲酰胺（2PY）和N1-甲基-4-吡啶酮-3-甲酰胺（4PY）的血清水平与3年MACE风险增加相关（美国总计N=2，331，女性N=774；欧洲N=832，女性N=249）（2PY的校正风险比（HR）（95%置信区间）分别为:1.64（1.10-2.42）和2.02（1.29-3.18）；对于4PY：分别为1.89（1.26-2.84）和1.99（1.26-3.14））。与2PY和4PY水平显著相关的遗传变异rs10496731的全表型关联分析揭示了该变异与可溶性血管粘附分子1（sVCAM-1）水平的相关性。进一步的荟萃分析证实rs10496731与sVCAM-1相关（n=106，000，女性n=53，075，P=3.6×10-18）。此外，在验证队列（n=974，n=333女性）中，sVCAM-1水平与2PY和4PY显著相关（2PY：ρ=0.13，p=7.7×10-5；4Py：ρ=0.18，P=1.1×10-8）。最后，用生理水平的4PY而不是其结构异构体2PY处理，诱导了小鼠中VCAM-1的表达和白细胞对血管内皮的粘附。总之，这些结果表明过量烟酸的终末分解产物2PY和4PY均与残余CVD风险相关。他们还提出了4PY和MACE之间临床相关性的炎症依赖性机制。

英文原文如下：

Abstracts

Despite intensive preventive cardiovascular disease (CVD) efforts, substantial residual CVD risk remains even for individuals receiving all guideline-recommended interventions. Niacin is an essential micronutrient fortified in food staples, but its role in CVD is not well understood. In this study, untargeted metabolomics analysis of fasting plasma from stable cardiac patients in a prospective discovery cohort (n = 1,162 total, n = 422 females) suggested that niacin metabolism was associated with incident major adverse cardiovascular events (MACE). Serum levels of the terminal metabolites of excess niacin, N1-methyl-2-pyridone-5-carboxamide (2PY) and N1-methyl-4-pyridone-3-carboxamide (4PY), were associated with increased 3-year MACE risk in two validation cohorts (US n = 2,331 total, n = 774 females; European n = 832 total, n = 249 females) (adjusted hazard ratio (HR) (95% confidence interval) for 2PY: 1.64 (1.10-2.42) and 2.02 (1.29-3.18), respectively; for 4PY: 1.89 (1.26-2.84) and 1.99 (1.26-3.14), respectively). Phenome-wide association analysis of the genetic variant rs10496731, which was significantly associated with both 2PY and 4PY levels, revealed an association of this variant with levels of soluble vascular adhesion molecule 1 (sVCAM-1). Further meta-analysis confirmed association of rs10496731 with sVCAM-1 (n = 106,000 total, n = 53,075 females, P = 3.6 × 10-18). Moreover, sVCAM-1 levels were significantly correlated with both 2PY and 4PY in a validation cohort (n = 974 total, n = 333 females) (2PY: rho = 0.13, P = 7.7 × 10-5; 4PY: rho = 0.18, P = 1.1 × 10-8). Lastly, treatment with physiological levels of 4PY, but not its structural isomer 2PY, induced expression of VCAM-1 and leukocyte adherence to vascular endothelium in mice. Collectively, these results indicate that the terminal breakdown products of excess niacin, 2PY and 4PY, are both associated with residual CVD risk. They also suggest an inflammation-dependent mechanism underlying the clinical association between 4PY and MACE.

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