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中国脑卒中一级预防CSPPT研究证实:同时降压和补充叶酸可以进一步显著降低 21% 的脑卒中风险

2026-05-11 04:28:27

我们的数据进一步发现携带有适度Hcy水平 Hcy ≤ 20 mol / L 的受试人群，MTHFR 677TT基因型和高血压的联合效应对脑卒中风险的预测更加显著。Saraswathy等的研究结果与我们的类似，他们发现当患者Hcy在 10~ 15 mol / L 时，会使高血压的发生风险增加8倍多，当 Hcy ≥ 15 mol / L 时，仅仅使高血压的发生风险增加3倍。对于造成上述现象的确切的生物学机制还不是很清楚。有研究显示，高同型半胱氨酸血症与DNA的低甲基化状态紧密相关，且这种关系受到不断增加的甲基转移酶抑制剂S- 腺苷高半胱氨酸的调控。Castro 等发现高同型半胱氨酸血症Hcy ≥ 75 μmol/ / L 会使DNA的甲基化程度降低 35% ,且能增加动脉粥样硬化的发生风险。另一个基因组DNA甲基化研究也表明,DNA的甲基化程度与叶酸的状态呈正相关,而与血浆中Hcy的水平呈负相关。此外,与MTHFR 677CC野生型相比较,TT基因型携带者的甲基化水平明显偏低。研究者发现只有TT基因型合并低叶酸水平患者DNA甲基化水平更低。这些结果表明了MTHFR C677T多态性与叶酸状态对基因组的DNA甲基化状态有交互影响。然而,最近的一项研究得到了一个相反结论:一个不育的男性连续6个月服用高剂量的叶酸后,发现其精子基因组不同区域的甲基化全部缺失。携带MTHFR 677TT基因型患者的精子基因组的启动子,外显子、内含子以及基因间的一些区域的DNA甲基化缺失的程度更加严重。最近的一个针对亚洲人群的脑卒中研究表明,MTHFR 基因特异性的CpG A的甲基化介导血清叶酸和维生素B12水平使得脑卒中易感性风险增加4.73倍。因此,叶酸以及MTHFR C677T基因型特异性的甲基化和表达的相关关系对于血管疾病的影响尚需进一步研究。

此外,另一个能合理解释我们研究结果的假设是:高浓度的Hcy ≥ 20 μmol/ / L 能够下调MTHFR 677TT基因型的表达或者能够把677CT二元杂合等位基因转变成677TT一元等位基因进行表达,反之适度的或低浓度的Hcy ≤ 20 μmol/ / L 与MTHFR基因稳定的表达是显著相关的。因而,高血压患者在高浓度的Hcy条件下,下调或是转变MTHFR 基因的表达都能够一定程度消减脑卒中和脑卒中死亡的额外风险。相似的证据也表明,MTHFR 基因的突变使得绝经前的妇女患乳腺癌的风险增加了3倍,但是对于采用激素替代疗法的绝经后的妇女来说却是个保护因素,这也充分暗示了基因和环境的影响是互相依存的。

已有报道表明,不同血管风险因素可协同增加血管事件的风险。Graham及同事发现Hcy水平升高能显著增加高血压患者和吸烟人群血管疾病的风险。Pezzini等在意大利人群中观察到:MTHFR C677T基因多态性和可修饰的风险因素如高血压和吸烟对缺血性脑卒中的发生风险有协同作用。这些发现表明了多重风险因素之间的相互作用可能在血管疾病的发病机制中扮演重要的作用。对于携带MTHFR C677T基因型的患者来说,同时服用B族维生素和降压药治疗可能是降低血管事件发生风险的有效策略。

图2 CSPPT研究：依那普利叶酸片与依那普利片治疗4.5年首发卒中风险K-M曲线

一项前瞻性研究的Meta分析表明,血浆中的Hcy浓度每降低 3 μmol/ / L ,会使缺血性心脏病的发生风险降低 11% ,使脑卒中发生风险降低 19%。这些结果凸显心脑血管疾病一级预防中有效降低Hcy浓度的重要性,特别适合高血压和Hcy升高普遍流行并缺乏叶酸摄入的中国人群。我们在柳叶刀杂志上发表的Meta分析首次指出,补充叶酸可以有效降低脑卒中风险（RR = 0.82；95% CI : 0.68~ 1.00；P = 0.045）,并且对于尚未进行食物强化补充叶酸的人群疗效更佳（RR = 0.75；95% C I : 0.62~ 0.91；P = 0.003）。为了进一步验证Meta分析的结果,我们研究组开展了中国脑卒中一级预防研究CSPPT,结果同样表明,与单纯使用依那普利降压比较,使用依叶同时降压和补充叶酸可以进一步显著降低我国高血压人群 21% 的脑卒中风险（HR = 0.79；95% CI : 0.68~ 0.93）。

我们的研究提供了有力的证据,表明H型高血压是由多个独立的、可干预的危险因素组成,其相互作用会进一步协同增加脑卒中发生和死亡的风险。我们的研究结果将为高血压患者个体化精准治疗方案的制定提供科学依据。

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