血浆多胺及抗氧化物质动态变化与脑卒中发病的巢式病例对照研究

Stroke has become the first cause of death and is an important public health problem in China. Recently, experimental studies indicated that the addition of spermidine (one type of the polyamine) into drinking water can improve the vascular function of mice by activating autophagy, which provides a new idea for stroke prevention and treatment. However, the relationship between polyamine and incident stroke has not been confirmed in prospective cohort studies, and there is no study reporting the dynamic changes in polyamine before the onset of stroke. Therefore, we will perform a 1:1 matched nested case-control study to validate the association between dynamic plasma polyamines, antioxidant substances and incident stroke using our longitudinal population cohort (n = 10394). During a median of 5-year follow-up period, we will identify more than 630 cases of newly stroke. With risk-set sampling, we will select controls from those who remain free from incident stroke and match them to case patients. The levels of plasma polyamines (putrescine, spermidine, spermine) and antioxidant substances will be dectected by UHPLC-MS / MS and ELISA, respectively. We will use the conditional logistic regression, generalized estimation equation, mixed effect model and mediator analysis to analyze the relationship between the dynamic changes of polyamines and the risk of stroke and to elucidate the role of antioxidant pathway in the relationship between polyamine and stroke. The present study is expected to provide profounding data support for new strategies for prevention and treatment of stroke.

脑卒中已成为我国居民第一位死因，是重要的公共卫生问题。近期，实验研究发现在饮用水中添加亚精胺（多胺类型之一）可通过激活细胞自噬提高小鼠的血管功能，这为脑卒中防治提供了全新思路。但是，多胺与脑卒中关系在前瞻性队列研究中尚未被证实，而且尚无脑卒中发病前多胺动态变化规律的文献报道。本研究拟利用已有的纵向人群队列（n=10394），采用1:1匹配巢式病例对照研究，以随访新发脑卒中为病例组，同时采用危险集随机抽取与之匹配的非脑卒中为对照组，通过UHPLC-MS/MS和ELISA检测研究对象血浆多胺（腐胺、亚精胺、精胺）和抗氧化物质（LPO、MDA、T-SOD、GSH-Px）动态变化水平，通过条件Logistic回归、广义估计方程、混合效应模型、中介分析等方法分析多胺动态变化与脑卒中发病风险的关系，阐明抗氧化通路在多胺和脑卒中发病关系中的作用。期望通过本项目，为开展脑卒中预防和治疗新策略提供数据支持。

动物实验研究发现在饮用水中添加亚精胺可通过激活细胞自噬提高小鼠的血管功能，这为脑卒中防治提供了全新思路。但是，亚精胺与脑卒中关系在前瞻性研究中尚未被证实。项目组通过巢式病例对照研究发现，脑卒中组的血清亚精胺平均水平高于对照组[Median（P25-P75）：182.8（141.8-231.5）nmol/L vs. 152.0（124.3-193.0）nmol/L，P < 0.001]；进一步多因素条件Logistic回归分析发现，亚精胺每增加10 nmol/L，脑卒中发病风险增加13%（OR及95% CI：1.13，1.04-1.23）；以亚精胺T1组为对照，T3组脑卒中发病风险显著增加（OR及95% CI：5.02，1.58-16.02）；外部人群病例对照研究同样验证这一关联。另外，项目组以急性心肌梗死专病队列为基础进行随访发现，以T1组为参照，T3和T2组发生MACE的调整HR及95%CI分别为0.566（0.329-0.974）和0.515（0.298~0.893）；限制性三次样条图建模发现亚精胺与MACE风险之间存在J型关联(P非线性=0.036)。进一步通过多因素分位数回归模型分析血清亚精胺与SOD、GSH-Px和MDA的关系，发现亚精胺对SOD及GSH-Px水平存在促进作用，而对MDA水平存在抑制作用；以血清亚精胺和抗氧化剂检测数据为分析集，通过中介分析抗氧化物质（SOD、GPX和MDA）在血清亚精胺与MACE事件预后关联中的中介效应，但是并没有发现统计学意义。本项目研究结果为未来研究亚精胺在细胞内外水平平衡状态、肠道菌群和膳食对血清亚精胺水平的影响，以及亚精胺对健康和疾病的影响机制提供了研究方向，同时为推广亚精胺在心脑血管疾病发病和预后提供了潜在治疗靶点，具有很好的科学价值和推广意义。项目共发表9篇代表性论著（5篇SCI），目前我国的这一研究领域居于世界前沿。