男性和女性在心血管疾病(CVD)方面的差异是心血管医学领域最近才认识到的。尽管关于动脉粥样硬化过程及其后果的大量文献已经有几十年的历史了,但直到最近,研究人员才证明性别对CVD的病理生理和临床表现有很大的影响。矛盾的是,了解性别差异的第一步必须是意识到男女之间的相似之处。换句话说,是时候认识到心血管疾病可能发生在两性身上了。事实上,直到几年前,冠状动脉心脏病(CHD)一直被广泛认为是男性的典型影响因素,而且大多数医学论文都传递了这样一种观点,即女性更容易患乳腺癌,而不是心血管疾病和冠心病。因此,很长一段时间以来,大多数心脏病专家都错误地忽视了女性心脏可能会出现心肌缺血,而血管造影中没有发现任何冠状动脉疾病,这被用作排除女性心肌缺血的理由。遵循这样的文化传统,心血管研究将注意力从女性转移,因此不幸的是,缺乏适当的女性心血管疾病管理策略导致女性死亡率惊人地增加。
如今,冠心病不仅是男性死亡的主要原因,而且也是女性死亡的主要原因,占女性死亡总数的三分之一。值得注意的是,这些证据在很大程度上仍然不为大多数医生所知[1]。大多数妇女完全不知道心血管风险的含义,通常是因为医疗保健提供者没有充分地向她们提出这方面的建议。女性似乎比男性更不清楚自己的心血管风险状况,但每2名女性中就有1名最终可能死于心脏病或中风(相比之下,每25名女性中就有1名可能死于乳腺癌[2])。在世界上许多国家,女性每年死于心血管疾病的可能性高于男性。在美国,自1984年以来,女性心血管疾病死亡人数已经超过男性[3]。同样,世界卫生组织2004年报告,欧洲心血管疾病总死亡率为女性的55%,男性的43%。缺血性心脏病、中风和其他心血管疾病在女性中分别占23%、18%和15%,在男性中分别占21%、11%和11%[4]。鉴于科学和医学的进步使许多妇女能够从心脏病中存活下来并受到慢性心血管疾病的影响,女性心血管疾病对公共卫生的影响肯定也与发病率有关。如今,每3名成年女性中就有1人患有某种形式的心血管疾病[3]。 As life expectancy in female gender is longer than in male gender, the loss of disability-adjusted life years in women is significantly growing up. In 2006 it has been estimated that 34% (> 38 million) of women in the United States lived with CVD. Nowadays it represents a global health issue: in most Countries, including China, the proportion of women 35 to 74 years of age affected by dyslipidemia and hypertension has reached 53% and 25%, respectively [5]. Medical interventions tailored on individual patients can effectively prevent CVD. Such goal is in the first place in women, but needs an appropriate acknowledge of gender differences lying behind risk factors, pathophysiology and clinical manifestation of CVD.
在男性和女性中,传统的心血管危险因素决定心血管疾病的进展相似。然而,一些性别差异已被记录在案。年龄、高血压、总胆固醇和低密度脂蛋白(LDL)-胆固醇对男性的影响较大,而绝经、收缩期高血压、吸烟、糖尿病、甘油三酯和高密度脂蛋白(HDL)-胆固醇水平对女性的影响主要。在男性中,心血管风险随时间线性增加,动脉粥样硬化过程不断发展。相反,由于雌激素通过基因组和非基因组机制对心血管系统发挥有益作用,育龄期的女性免受动脉粥样硬化的侵害。绝经后,雌激素缺乏导致心血管风险指数增加,因为它引起心血管系统的一些结构和功能变化:内皮功能障碍,自主神经活动失衡,肾上腺素能状态增加,内脏肥胖,全身性炎症增强。所有这些因素都有助于全身性高血压、糖耐量受损、血脂异常和胰岛素抵抗的发展。从这个角度来看,更年期本身代表了CVD的独立预测因子。综上所述,女性的年龄特异性风险仅明显低于男性:女性和男性表现出相似的心血管状况,相差10岁[1]。绝经后动脉血压每年自然升高0.5 mmHg,通过降压治疗将其降低至最佳水平(如收缩期值为120 mmHg)而不是正常水平(如收缩期值为130 mmHg),从而使女性比男性预防更多的冠心病事件[6]。 Diabetes increases cardiovascular risk of threefold to sevenfold in women and of twofold to threefold in men [7]. Moreover, in response to adequate anti-diabetic therapy, women display a worse metabolic control than men. Total cholesterol is an important cardiovascular risk factor in both sexes, but elevated LDL-cholesterol levels enhance cardiovascular risk more in men than in women. High LDL-cholesterol predicts cardiovascular mortality in women younger than 65 years but not in older women [8]. On the other hand, reduced HDL-cholesterol is responsible for CHD in both young and old women and predicts CHD mortality more in women than in men. Although the role of triglycerides in cardiovascular risk remains controversial, their strict relationship with abdominal fat, insulin resistance and metabolic syndrome makes them an important risk factor in women. Incidence of metabolic syndrome is higher in women than in men: in female patients, it is responsible for more than 50% of cardiovascular events. Finally, more than 50% of myocardial infarctions among middle-aged women is attributable to tobacco smoking [9]. Smoking status is more detrimental in women than in men, with a relative risk of cardiovascular events of 3.6 in female and 2.4 in male subjects. Smoking habit shortens time of menopause onset by two years, while smoking cessation brings forward menopause advent only by one year. Of note, while cardiovascular risk in men remains similar irrespectively of cigarette amount, such risk increases in women with the number of cigarettes, ranging from 2.3 relative risk for 1–9 cigarettes/day to 5.9 relative risk for more than 20 cigarettes/day. Over the traditional cardiovascular risk factors, abdominal adiposity, characterized by a waist circumpherence greater than 88 cm in women and 122 cm in men, is an important risk factor for CHD in both sexes, independently of index of body weight. Prevalence of weight gain is increasing among women, so that obesity is by now considered an epidemic issue with about one third of adult women being obese, mainly because of physical inactivity.
几十年来,动脉粥样硬化过程从不明显的冠状动脉狭窄到阻塞性冠状动脉疾病的进展一直被认为是解释心肌血液供需失衡导致缺血的独特范式。根据这一理论,在胸痛女性的血管造影中经常发现没有阻塞性冠状动脉疾病,这导致长期以来排除了女性可能患有心肌缺血的可能性。然而,急性冠状动脉综合征女性的住院预后比男性差。在Framingham Heart Study中,近三分之二的女性冠心病猝死发生在没有疾病症状的人群中,而男性的这一比例约为一半[10]。在过去的几年里,心血管研究已经确定了心肌缺血的不同病理生理机制。在男性中,冠状动脉容易发生阻塞性冠状动脉疾病,急性冠状动脉综合征在大多数情况下是由斑块破裂引起的。相反,在女性中,冠状动脉表现出较不严重的动脉粥样硬化疾病,急性冠状动脉综合征可能是由于斑块表面侵蚀、自发剥离、血管痉挛和血栓形成所致。在冠状动脉外科研究(CASS)中,因疑似冠心病接受冠状动脉造影的女性中,约有一半被发现有不显著的心外膜病变[11]。这些病例的不良预后是由于冠状动脉疾病的临床特征,这意味着诊断较晚,通常随后是对疾病的管理不足,并伴有高龄和许多合并症。此外,女性往往低估了这种疾病,很晚才去看医生。 More interestingly, most women with effort chest pain and normal coronary arteries manifest a functional impairment of coronary microcirculation. Primary coronary microvascular dysfunction typically characterizes some diseases [12], such as cardiac syndrome X [13,14] and tako-tsubo cardiomyopathy [15], which seems to involve almost exclusively female gender. As noteworthy, while obstructive atherosclerosis of the epicardial coronary arteries is well established to cause myocardial ischemia, the link between microvascular disease with normal coronary arteries and myocardial ischemia has been questioned for a long time. Nevertheless, in women with angiographically normal arteries, microvascular dysfunction is marked by reduction in coronary/myocardial blood flow, often related to endothelial and non-endothelial increased vasoconstriction and reduced vasodilatation: it actually results in myocardial ischemia, although the sequence of events is strikingly different from the classic ischemic cascade (Figure 1). The reason why cardiac syndrome X and takotsubo cardiomyopathy tipically affect female gender still remains unknown. One potential explanation may rely on some degree of psychological involvement, which is shared by both syndromes. Men and women have been widely demonstrated to differently respond to emotional or physical stress. During menopausal period, women have major risk to develop mental and somatic disorder. The particular interplay between heart and mind seems to be so much a female prerogative that depression and anxiety cause CVD especially in women. Two different pathways of cytokines production have been detected in men and women during an acute stress: in response to stressful stimuli, interestingly men have a pronounced catecholamine increase and peripheral cardiovascular reaction with elevated blood pressure, while women have a central cardiovascular reaction with elevated heart rate. Moreover, post-menopausal women show greater increase in cytokine production than pre-menopausal women or men.
图1所示。男性阻塞性冠状动脉疾病(A)和女性tako-tsubo心肌病(B)的仪器诊断特征示例。尽管入院时st段改变模式相似(上),冠状动脉造影显示阻塞性冠状动脉疾病患者(中,A)的冠状动脉在心外膜水平严重狭窄,而tako-tsubo心肌病患者的冠状动脉正常或接近正常。此外,舒张期和收缩期的心室图清楚地显示壶腹状左心室,为该综合征的典型尖顶型(中,B)。标准超声心动图(下)可显示相同程度的壁运动异常。但超声造影剂显示冠状动脉疾病患者心内膜下灌注缺陷(箭头之间)和tako-tsubo心肌病患者心肌血流量经壁减少(箭头之间)。
CVD的临床表现在性别之间也存在差异,因此诊断具有挑战性。男性经常经历的症状,如压迫性或收缩性胸痛和呼吸困难,传统上被认为是心肌缺血的典型症状,因为它们与阻塞性冠状动脉疾病严格对应。相反,妇女更经常出现腹痛、头晕、呼吸短促、经常消化不良、不寻常的疲劳:在这种情况下,没有严重的冠状动脉疾病引起了重要的误解,因此,“非典型”症状一词通常被用作“心肌缺血概率低”的同义词。此外,有证据表明,女性心外膜冠状动脉疾病和微血管功能障碍可能表现出相同的症状,这在很大程度上造成了混淆。因此,女性胸痛的预后价值被大大低估了。部分原因是Framingham研究中的女性比男性更容易出现胸痛,但很少发展为心肌梗死[16]。心绞痛的预测价值仅在老年女性亚群中增加[17]。根据最近的文献资料,我们认为必须从另一个角度来关注这一重要问题:无论确切的病理生理机制如何,男性和女性可能同样遭受心肌缺血,值得适当治疗。医生对性别差异的认识对于确保在两性中采用最合适的治疗策略至关重要。与此同时,症状不应更多地被划分为“典型”和“非典型”:将临床表现重新定义为“男性典型”和“女性典型”的冲动,并可能潜在地改善预后(图2)。
图2。症状的示意图,通常发生在男性和女性,以及两性心肌缺血的病理生理机制。
- 1.Perk J, De Backer G, Gohlke H, Graham I, Reiner Z(2012)欧洲临床实践中心血管疾病预防指南(2012版):欧洲心脏病学会与其他学会第五次临床实践中心血管疾病预防联合工作组(由9个学会代表和特邀专家组成)。中华临床医学杂志,19(3):393 - 398。(Crossref)
- 2.张丽娟,张丽娟,张丽娟,等。(1997)女性心血管疾病的研究进展。美国心脏协会写作小组给医疗保健专业人员的声明,循环96: 2468 - 2482。(Crossref)
- 3.国家卫生统计中心(NCHS)和国家心肺血液研究所(NHLBI),《妇女和心血管疾病——2009年统计》。
- 4.Stramba-Badiale M, Fox KM, Priori SG, Collins P, Daly C等。(2006)女性心血管疾病:欧洲心脏病学会政策会议声明。欧洲心脏27日:994 - 1005。(Crossref)
- 5.Mosca L, Banka CL, Benjamin EJ, Berra K, Bushnell C,等。(2007)基于证据的女性心血管疾病预防指南:2007更新。循环115: 1481 - 1501。(Crossref)
- 6.王德明,王志强,王志强,等。(2003)代谢综合征患者血压和血脂优化控制预防冠状动脉事件的研究。我是卡迪罗吗?91: 1421 - 1426。(Crossref)
- 7.陈志强,陈志强,陈志强,等(1996)糖尿病患者的风险调整。预防心肌梗塞。牛津大学出版社,纽约,美国241-273。
- 8.Manolio TA, Pearson TA, Wenger NK, Barrett-Connor E, Payne GH等。(1992)老年人和妇女的胆固醇和心脏病:回顾NHLBI研讨会。安论文2: 161 - 176。(Crossref)
- 9.王晓明,王晓明,王晓明,等。(1987)吸烟妇女冠心病的相对和绝对风险。[英]医学317: 1303 - 1309。(Crossref)
- 10.美国心脏协会(1997)心脏和中风事实:统计更新。德克萨斯州达拉斯:美国心脏协会。
- 11.冠状动脉疾病的临床谱及其外科和内科治疗,1974-1979。冠状动脉手术研究。循环66: 16-23.(Crossref)
- 12.王晓明,王晓明,王晓明(2007)冠状动脉微血管功能障碍。[英]医学356: 830 - 840。(Crossref)
- 13.Lanza GA1, Buffon A, Sestito A, Natale L, Sgueglia GA等(2008)心脏综合征X患者应激性心肌磁共振灌注缺损与冠状动脉微血管功能障碍的关系。我是科尔·卡迪诺51: 466 - 472。(Crossref)
- 14.李建军,李建军,李建军,等。(2007)冠心病X综合征患者冠状动脉左前降支血流储备的无创评估。我是卡迪罗吗?[99] 1378 - 1383。(Crossref)
- 15.Galiuto L, De Caterina AR, Porfidia A, Paraggio L, Barchetta S等。(2010)可逆性冠状动脉微血管功能障碍:根尖球囊或Takotsubo综合征的常见发病机制。欧洲心脏31日:1319 - 1327。(Crossref)
- 16.Lerner DJ, Kannel WB(1986)冠心病发病率和死亡率的性别模式:对Framingham人群26年的随访。我的心111: 383 - 390。(Crossref)
- 版权所有OAT。版权所有。Kannel WB, Feinleib M (1972) Framingham研究中心绞痛的自然历史:预后和生存。我是卡迪罗吗?29日:154 - 163。(Crossref)