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上篇 | 动脉粥样硬化性心血管疾病发病机制中是否存在性别差异

国际循环  · 公众号  ·  · 2024-04-30 19:11

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泰达国际心血管病医院 郑 刚

动脉粥样硬化性心血管疾病（ASCVD）是女性和男性死亡的主要原因，随着肥胖和心脏代谢疾病的流行，其发病率持续增加 [1-3] 。在<65岁的成年人中，男性的绝对ASCVD事件率高于女性，但在欧洲和美国，ASCVD死亡率相对增长最快的是中年女性（45~64岁） [1-2] 。因此，关注女性ASCVD风险很重要。ASCVD的漏诊或延迟诊断和治疗不足是关键因素 [4-5] ，有证据表明，女性接受指南推荐的预防性治疗的可能性低于男性 [6-10] 。家族性高胆固醇血症（FH）就是一个例子。全球数据显示 [11] ，女性诊断较晚且治疗不足，在怀孕和哺乳期间使用非降脂治疗（LLT），其累积胆固醇暴露量高于FH男性 [12] ，这可能解释了为什么FH对心血管风险的相对影响在女性中高于男性 [13-14] 。传统和风险增强因素的影响在女性和男性中也有所不同 [15-16] 。妊娠相关并发症、多囊卵巢综合征（PCOS）和过早绝经等性别特异性因素也对心脏代谢风险因素产生不利影响，并影响动脉粥样硬化 [17-19] 。评估女性的心血管风险，最好是从中年开始 [20] ，将提高对可改变风险因素或性别特异性风险因素升高者的早期识别，并促使尽早开始指南建议的治疗。

01

性别对心血管风险因素的影响


虽然两性都有许多传统的心血管风险因素，但这些因素对女性和男性的影响可能不同 [21] 。例如，尽管糖尿病在男性中更为普遍 [22] ，但糖尿病具有更大的相对性（尽管不一定是绝对的）与所有年龄段的男性相比，女性心血管风险增加 [23-27] 。在一定程度上，这可能与诊断时女性比男性更肥胖、更多的心血管风险因素有关 [27-29] ，以及糖尿病的性别特异性风险因素（如多囊卵巢综合征和妊娠期糖尿病） [27] 。女性通常也较男性更不喜欢运动，体重指数（BMI）更高 [30] ，已知这与ASCVD风险有关 [31] 。将更年期雌二醇水平下降与衰老的影响分开很困难，也有很多争论。大多数在更年期过渡之前、期间和之后进行测量的大型纵向研究显示，心血管风险因素的变化，包括体重增加、内脏肥胖、对脂质的不良影响 [32] ，以及炎症标志物和血压的增加，尤其是收缩压 [33-37] 。这些变化是否也与ASCVD风险增加有关，这一点更具争议性。两项纵向研究（249名和890名受试者） [38-39] 报告了与更年期相关的颈动脉内膜-中膜厚度（CIMT）的进展，与基线年龄无关，尽管另一项研究（多达3892名受试人）显示更年期过渡与CIMT进展没有关联 [37] 。然而，后一项研究确实，这表明，随着更年期过渡，肥胖和血糖的增加可能会影响糖尿病风险 [37] 。除此之外，与没有提前绝经的同龄女性相比，提前绝经与发生ASCVD的相对风险增加有关，尤其是40岁之前绝经的卵巢早衰患者 [18,40-41] 。患有多囊卵巢综合征的女性发生脑血管事件的相对风险增加，但不发生ASCVD事件 [19] 。

观察性研究表明，低密度脂蛋白胆固醇（LDL-C）作为女性和男性ASCVD风险的决定因素并不重要，因为女性患ASCVD的风险较低，特别是心肌梗死（MI） [42] 。然而，在世界卫生组织心血管疾病风险图工作组的报告中，总胆固醇每增加1 mmol/L，两性患致命性和非致命性MI、冠心病（CHD）和卒中的风险相似 [43] 。哥本哈根城市心脏研究和哥本哈根普通人群研究的数据也显示，LDL-C对两性患MI和缺血性心脏病（IHD）风险的因果遗传影响相似 [44-45] 。因此，这些发现支持LDL-C对女性和男性心血管疾病的因果影响相似 [46] 。女性的性别特异性因素值得考虑 [47-48] 。在美国指南中，先兆子痫和更年期提前等因素被视为“风险增加”，建议对处于临界或中等风险的女性进行他汀类药物治疗 [49] 。2021年欧洲心脏病学会（ESC）预防指南建议对有妊娠高血压、多囊卵巢综合征和妊娠期糖尿病病史的女性进行高血压和糖尿病筛查 [16] 。女性患慢性肾脏疾病的风险也不成比例，慢性肾脏疾病本身就是ASCVD的一个风险因素 [16] ，较男性更早出现 [50] 。自身免疫炎症疾病对女性的影响较男性更大 [15] ，增加过早ASCVD风险 [51-52] ，依赖于传统风险因素 [53-59] ，也被指南视为“危险增加”因素 [16,49,60] 。

性别的社会文化组成部分还影响ASCVD风险。与男性相比，女性不太可能寻求所需的医疗保健。对于具有更传统角色的人来说尤其如此 [61] ，他们可能将家庭、家庭和照顾者的责任置于自身健康之上 [62] 。心理社会压力在女性中也较男性更明显，这反映出低教育程度、抑郁症、以及焦虑导致ASCVD风险 [63-65] 。非高加索人种的女性尤其如此 [66] ，她们不太可能意识到ASCVD是死亡原因 [67] 并寻求治疗 [68] 。

02

性别对于心血管风险预测的影响


由于ASCVD的第一种表现更可能是男性的CHD，而女性的卒中 [69-70] ，因此最近对指南中的风险评分进行修订，将心血管结果以及致命和非致命事件更好地反映了女性临床ASCVD的总负担 [16,71] 。尽管如此，目前基于传统风险因素的心血管风险预测模型与10年而非终身风险相关，并且由于对女性事件的诊断不足而存在偏见，从而低估了风险 [72-76] 。即使是亚临床动脉粥样硬化负担重大的女性也更有可能被归类为低风险 [77] 。鉴于所有预测模型都基于现有数据，并且大多使用回顾性事件率来预测未来事件，过去研究中对事件的诊断不当会导致事件率较低，从而低估基于这些数据的模型中的风险 [72,78] 。女性通常在更晚的年龄经历ASCVD事件，且事件率低于男性 [79] ，但鉴于预期寿命较长 [80] ，具有相似的终身心血管风险 [69] 。风险因素的演变在一生中，性别之间也有所不同 [81-82] 。此外，女性鉴于支持性证据有限，在开发心血管风险预测模型时很少纳入特定的风险因素 [83-84] 。因此，终身心血管风险和治疗益处的概念是调整女性ASCVD预防的有希望的方法 [16] 。英国生物库的最新发现确定了CMIT基因座的性别差异，以及与BMI和糖代谢特征的相关性 [85-86] ，利用“大数据”为女性ASCVD的预测和预防提供增量价值的潜力很高。

03

动脉粥样硬化的发病机制存在性别差异



男性和女性的一个关键差异与性激素17β雌二醇、孕酮和睾酮的水平和比例有关。尽管没有随机对照试验明确证明这些性激素对ASCVD风险的影响，但实验研究表明，这三种激素都会影响与动脉粥样硬化相关的生物过程 [87] 。在动脉粥样硬化模型中，雌激素可降低动脉粥样硬化斑块负担 [88-89] 。雌二醇可以增加体外内皮一氧化氮的产生 [90-91] ，导致小鼠模型中血管舒张增加和内皮细胞功能改善 [92] ，在分离的人类小动脉中 [93] ，以及用雌二醇治疗的顺式和转基因人类女性中 [94-95] 。雌激素也会影响炎症途径，因为它们可以减少内皮细胞中细胞因子诱导的E-选择素、血管细胞和细胞间粘附分子的上调 [96] ，在（动脉粥样硬化）小鼠中减少白细胞募集 [97] 和白细胞介素-6的表达 [98] ，并已被证明可以防止血管平滑肌细胞（SMC）增殖和细胞外基质沉积 [99] ，所有驱动动脉粥样硬化形成的关键过程。

雌二醇还参与维持脂质稳态。随着脂质负荷的增加，雌激素可以调节胆固醇的反向转运机制，从而降低LDL-C和高密度脂蛋白胆固醇（HDL-C）水平，并防止巨噬细胞过度摄取脂质 [100] 。然而，尽管雌二醇似乎对动脉粥样硬化中的许多重要致病机制有有利影响，但这些现象的细胞和分子基础，并且这些现象的串扰在很大程度上未知。

实验数据与观察结果非常吻合，即绝经后，当雌激素水平下降时，绝经后女性的脂质状况不如绝经前女性，血管舒张效率较低，抑制炎症的效率较低。这表明，绝经后妇女ASCVD的增加可能是由更复杂的机制引起，而不仅仅是雌激素耗竭或雌激素对ASCVD的其他未明确的影响。绝经后激素替代疗法（HRT）的临床试验结果对于绝经后妇女ASCVD一级预防的净效果没有定论，尽管对试验和队列研究的系统回顾确实表明卒中风险增加 [101] 。然而，雌激素预防动脉粥样硬化试验（EPAT）确实，提示动脉粥样硬化进展中雌激素依赖性减少 [102] 。

女性和男性的另一个主要区别是X和Y染色体，它们包含许多（X）基因和很少（Y）基因。动脉粥样硬化的实验小鼠模型表明，X染色体对脂质代谢产生不利影响，促进膳食脂肪的吸收和利用增加，导致动脉粥样硬化增加 [103] 。然而，与X染色体对心血管疾病影响有关的人类数据有限。其他途径导致女性和男性ASCVD的差异。全基因组关联研究确定了性别特异性单核苷酸多态性，特别是rs16986953（接近APOB）和rs7865618（CDKN2B-AS1），仅与男性心血管疾病相关。综合系统生物学方法揭示了性别之间基因网络的明显差异 [104-105] 。女性斑块包含更多与SMC表型调节和内皮间充质转化相关的网络，而男性斑块则表现出与免疫反应性相关的途径 [105] 。与此相一致，来自女性颈动脉内膜切除术标本显示炎症浸润较少，坏死核心较小，SMC和胶原含量增加 [106] 。影像学研究显示，CIMT和坏死核心较小的动脉粥样硬化斑块较少，胆固醇晶体较少，钙化较少，女性的斑块内出血或斑块破裂频率低于男性 [106] 。尽管缺乏人类数据，但新出现的实验证据表明，性别在动脉粥样硬化的发病机制中起重要作用。需要进一步的研究了解驱动这些差异的机制。

04

性别对动脉粥样硬化血栓形成风险的影响


血栓形成通常是动脉粥样硬化斑块转变为急性缺血性综合征的基础 [107-108] 。30多年前，研究表明女性对阿司匹林的血小板反应较差，尽管对血栓形成的潜在过程影响的确凿证据仍然缺乏 [109-110] 。尽管有证据表明女性的血小板活性、血小板计数和治疗时的血小板反应性更高，因此比男性更容易形成血栓 [111] ，但这些差异很小，不太可能带来更差的临床预后 [112] 。女性性激素（尤其是雌激素）调节促凝蛋白水平、血小板功能和血管壁生物学和组成，这可能会转化为血栓形成中基于性别的差异 [113] 。血小板和凝血的差异这些活动至少可以部分解释以下观察结果：女性更有可能对阿司匹林产生耐药性，在初级预防中从阿司匹林治疗中获得明显益处，以及呈现不同模式的静脉血栓形成和卒中 [113] 。尽管潜在机制尚不确定，但女性也有更高的高凝状态倾向。在一项使用显示不同性别依赖性信号传导和细胞激活的血小板的研究中，雌激素激活了血小板并增强了聚集和止血活性 [114] 。另一个重要的考虑因素是出血并发症，这种并发症在女性中较男性更普遍 [11,114-115] 。值得进一步研究基于性别的血栓形成调节机制。

小结

一些生活方式因素以及与性别影响风险相关的社会文化因素对妇女的影响尤为严重。激素和染色体效应也影响ASCVD的进展，尽管在理解潜在机制方面仍存在差距。在生命过程事件（妊娠、母乳喂养和更年期）中，脂质影响女性的ASCVD风险。在更年期过渡期间，LDL-C水平升高 [36] ，Lp（a）升高较男性更常见。在FH女性中，与FH男性相比，在妊娠和哺乳期间停止他汀类药物治疗会导致更大的累积胆固醇暴露该小组强调了早期评估女性心血管风险和早期治疗血脂异常的重要性。需要进一步研究女性性激素对动脉粥样硬化发展和进展的影响。采取有针对性的行动解决这些差距是减轻妇女ASCVD难以接受的高负担的优先事项。


专家简介


郑刚 教授



现任泰达国际心血管病医院特聘专家，济兴医院副院长


中国高血压联盟理事，中国心力衰竭学会委员，中国老年医学会高血压分会天津工作组副组长，中国医疗保健国际交流促进会高血压分会委员


天津医学会心血管病专业委员会委员，天津医学会老年病专业委员会常委，天津市医师协会高血压专业委员会常委，天津市医师协会老年病专业委员会委员，天津市医师协会心力衰竭专业委员，天津市医师协会心血管内科医师分会双心专业委员会委员，天津市心脏学会理事，天津市心律学会第一届委员会委员，天津市房颤中心联盟常委，天津市医药学专家协会第一届心血管专业委员会委员，天津市药理学会临床心血管药理专业委员会常委，天津市中西医结合学会心血管疾病专业委员会常委


《中华临床医师杂志（电子版）》特邀审稿专家，《中华诊断学电子杂志》《心血管外科杂志（电子版）》审稿专家，《华夏医学》副主编，《中国心血管杂志》常务编委，《中国心血管病研究》杂志第四届编委，《中华老年心脑血管病杂志》《世界临床药物》《医学综述》《中国医药导报》《中国现代医生》编委


本人在专业期刊和心血管网发表文章979篇，其中第一作者790篇，参加著书11部。获天津市2005年度“五一劳动奖章和奖状”和“天津市卫生行业第二届人民满意的好医生”称号


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