作者:泰达国际心血管病医院 郑刚
1 冠状动脉成像
冠状动脉成像能够发现冠状动脉斑块特征以及与易损性和失稳性相关的机制。血管内超声(IVUS)和光学相干断层扫描(OCT)都有助于理解与性别相关的CAD机制。IVUS是评估斑块负荷、左主干狭窄严重程度和钙化斑块的金标准[1]。使用虚拟组织学血管内超声(VH-IVUS)能够识别四种不同的斑块类型:钙化、坏死、纤维和混合/纤维脂肪斑块。然而,低空间分辨率、噪声增强以及系统伪影可能会影响对斑块微观结构和薄帽纤维粥样斑块(TCFA)的识别,这是易损斑块的形态标志[2]。
冠状动脉内OCT使用近红外光提供冠状动脉壁的高分辨率横断面图像。与IVUS相比,OCT技术的波长更短,穿透深度更低,但轴向分辨率更高,从而有可能识别VH-IVUS上看不到的斑块特征,与组织病理学发现的一致程度最高,导致“体内双视”[3]。特别是,OCT能够评估微血管、血栓和巨噬细胞浸润,并能够准确测量纤维帽厚度、钙和脂质范围。另一方面,OCT在评估斑块负荷和左主干狭窄意义方面不如IVUS准确[4]。近红外光谱(NIRS)是一种新型成像工具,它依赖于组织的特性,根据波长不同吸收和散射近红外光(波长为800至2500 nm)。NIRS是检测斑块内脂质核心的金标准技术[5]。最近,有人提出将NIRS和IVUS相结合,以将IVUS的穿透力与NIRS的化学特征相结合[6]。
血管造影和冠状动脉内成像研究的报告显示,与男性相比,女性平均表现出较少的冠心病和严重的冠心病,尽管心血管危险因素特征较差。这一发现在CAD的整个临床范围内是一致的[7]。具有里程碑意义的NCDR研究发现,与男性相比,慢性冠状动脉综合征(CCS)女性的阻塞性CAD血管造影患病率显著降低,并且在急性冠状动脉综合征(ACS)背景下,与男性患者相比,女性患非阻塞性CAD的情况发生了双重变化[8]。根据这一发现,一项包括535例CCS的血管造影研究与男性相比,女性患者的CAD程度和复杂性较低,SYNTAX评分也较低[9]。因此,在一项大型的法国ACS观察性研究中,近23%的女性和16%的男性患有非梗阻性CAD[10]。
基于有限的穿透深度阻碍OCT斑块负荷测量的假设,绝大多数冠状动脉内成像证据是通过IVUS评估收集的[4]。对3项主要IVUS研究(REVERSAL研究[51]、CAMELOT研究[12]和ACTIVATE研究[13])的事后分析,共包括978名患者(251名女性,727名男性),确定女性的CAD负担较低,与男性相比,动脉粥样硬化体积百分比较低,总动脉粥样硬化体积较小[14]。结合AtheroRemo IVUS研究[15]和IBIS-3研究[16]的具有里程碑意义的分析,支持了CCS和ACS女性的这一发现,显示与男性相比,IVUS的绝对和标准化总斑块体积较低,NIRS衍生的脂质核心负荷指数较低。值得注意的是,即使在调整了潜在的混杂因素后,性别差异仍然显著[17]。
几项研究发现,随着时间的推移,阻塞性CAD患病率中与性别相关的差距持续减弱,主要原因是与老年男性相比,老年女性的动脉粥样硬化加速;Pundziute等[18]调查了93名CAD患者(34名女性比59名男性)的IVUS斑块负荷,发现年龄>65岁的患者没有任何差异,而年龄<65岁的男性斑块负荷比女性更大。同样,在Qian等[19]的一项大型研究中,包括990名按三个年龄组(<58岁、58~68岁和>68岁)分层的患者,与女性同龄人相比,男性在任何年龄段都有更高的梗阻性CAD程度和复杂性,但在最年长的三分位组中,性别差距不太明显[19]。开创性的PROSPECT研究通过三支血管IVUS评估在697名ACS受试者队列中证实了这一发现:与女性相比,年龄<65岁的男性表现出明显更高的非罪犯病变数量、更大的病变长度和体积,但在老年亚组中,这种性别差异消失了[20]。尽管这些观察的病理生理基础尚未完全阐明,但可以推测雌激素戒断与更年期的主要作用以及更重的心血管风险特征[21]。
女性和男性存在如下在四种差异:a)根据临床表现的冠状动脉斑块表型;b) 冠状动脉斑块易损性;c) 冠状动脉斑块不稳定的机制;d)冠状动脉斑块愈合。
1.2.1.1慢性冠状动脉综合征 关于CCS患者的研究结果相互矛盾。Kornowski等[22]之前的IVUS研究未能显示斑块内钙成分和程度的性别差异。Bharadwaj等[23]通过多模式冠状动脉内成像(OCT、IVUS、NIRS)研究了383名CCS患者(268名男性,115名女性)的动脉粥样硬化斑块特征,发现OCT显示脂质和钙化斑块的分布相似,IVUS显示重塑指数相似,NIRS显示女性与男性的最大脂质核心负荷指数相似。其他IVUS研究报告了冠状动脉斑块组成的性别差异。Inoue等[24]发现,在364名CCS患者(72名女性比292名男性)的队列中,女性钙化和斑块的频率较高,坏死核心丰富,纤维斑块的患病率较低。
Nakamura等[25]证实与男性相比,女性更有可能出现钙化斑块,纤维脂肪斑块的比例也更低。与这一发现相一致,Mariani等[26]最近的一项OCT研究。观察到与男性相比,女性富脂斑块的患病率更高,钙体积指数也有上升的趋势。与之形成鲜明对比的是,在克利夫兰诊所OCT登记处的一项回顾性分析中,包括一个相对年轻的320名CCS受试者队列,与同龄人相比,女性的斑块中钙化和胆固醇晶体含量较低,脂质弧较小[27]。这些明显相互矛盾的结果可以部分解释为斑块组成随年龄增长而发生的与性别相关的变化。在Pundziute等[18]的IVUS研究中,仅在<65岁的受试者中观察到性别差异,男性钙化患病率较高,核心坏死趋势较多,而女性纤维化斑块更常见,在≥65岁的患者中没有明显差异。Qian等[19]在一项包括990名受试者的大型OCT研究中证实了这些观察结果,与同龄人相比,年龄最大的女性(>68岁)中具有丰富坏死核心和大钙化的斑块患病率更高,而在年轻患者中,性别差异变小。
1.2.1.2 ACS 在ACS的背景下,即使在调整了潜在的混杂因素后,女性的脂质核心和致密钙的程度也明显低于男性[17,28]。还证实了衰老与动脉粥样硬化斑块组成中与性别相关的差异之间的密切联系。具有里程碑意义的PROSPECT研究显示,通过IVUS检查,与男性相比,老年(≥65岁)女性的坏死核心患病率更高,纤维脂肪斑块的频率更低,而年轻患者没有差异[20]。随后,Ann等[29]在一组STEMI患者中证实了这些发现,与男性相比,66~75岁的女性显示出明显更大的坏死核心VH-IVUS检查方法。
“易损斑块”一词是指动脉粥样硬化斑块表型的一种特定模式,这种模式易导致斑块失稳,即所谓的薄纤维帽包括(TCFA)。这种斑块的特征是众所周知的形态特征:一个大的脂质池,上面有一个薄的纤维帽,伴随着巨噬细胞的浸润[30]。关于可能的性别差异,也存在相互矛盾的结果;Bharadwaj等[23]的多模态成像研究表明,患有CCS的女性与男性相比,TCFA和斑块微观结构(微血管、巨噬细胞浸润)的患病率相当,最近的IVUS、OCT和NIRS研究也报告了同样的发现[19,28,31]。另一方面,其他研究报告称,女性更频繁地表现出脆弱的斑块表型,这取决于年龄分布。在Pundziute等[18]的IVUS研究中,年龄<65岁的受试者TCFA在男性中的患病率较高,在老年时消失。ADAPT-DES的一项子研究通过OCT成像证实了这一发现[32]。随后,Sato等[33]最近对860名患者进行的OCT研究表明,只有老年(≥70岁)女性才有更多的TCFA病例。
最近的两项OCT研究探讨了衰老、性别和更年期对冠状动脉斑块易损性的影响。Seegers等[34]招募了1 368名ACS患者(1 082名男性和286名女性):虽然与男性相比,女性总体上表现出相似的斑块组成,但衰老与斑块易损性特征频率之间的显著正相关仅存在于女性中。Tang等[35]根据绝经状态将191名ACS女性分为两组,结果表明,与绝经前女性(n=97)相比,绝经后患者(n=94)更容易出现易损斑块表型,TCFA、巨噬细胞浸润、胆固醇晶体和微通道的患病率更高。
1.2.3. 冠状动脉斑块不稳定的机制 冠状动脉斑块稳定的机制是多种多样和复杂的。易损斑块的斑块破裂(PR)是ACS最常见的机制;相反,斑块侵蚀(PE)占ACS的三分之一,并涉及内皮单层暴露区域的血栓形成:这种机制与更稳定的罪犯斑块表型有关,具有完整的纤维帽。
最后,钙化结节是ACS最不常见的原因,表现为纤维帽被密集钙的喷发结节破坏,并伴有上覆管腔血栓[36]。绝大多数体内可用信息都是通过OCT获得的,OCT是探索冠状动脉斑块微观结构的金标准工具[4]。先前比较女性和男性ACS机制相对比例的研究尚未得出结论。Chia等[37]的一项小型OCT研究显示,斑块破裂和血栓在性别之间的患病率相当。同样,Jia等[38]未能在由126名患者(100名男性和26名女性)组成的异质性ACS人群中检测到罪犯斑块破裂和斑块侵蚀患病率的任何性别差异,Sun等[39]在相对年轻的211名STEMI患者(49名女性,平均年龄60.2±8.2岁,162名男性,平均年龄55.7±11.2岁)中也发现了同样的结果。具有里程碑意义的OCTAVIA研究是一项前瞻性、多中心、对照试验,招募了140名年龄匹配的STEMI患者(70名女性和70名男性),证实了这些数据,揭示了两性之间斑块破裂和斑块侵蚀的可比率[40]。随后,对大型OCT-FORMIDABLE注册表的子分析发现,只有微小的差异:在285名ACS患者(68名女性,127名男性)的队列中,与男性相比,患有STEMI的女性更有可能表现出更长的斑块破裂部位和更高的巨噬细胞浸润率[41]。相反,Prasad等[42]和Kataoka等[26]的原始数据指出,男性斑块破裂和女性斑块侵蚀的患病率较高,尽管这两项研究都没有足够的能力检测到较小的效应大小。
人类病理学研究描述了ACS机制中的性别差异。事实上,Burke等[43]的一项具有里程碑意义的研究表明,斑块破裂是男性ACS的主要机制,而斑块侵蚀在女性中更常见。此外,绝经后妇女比斑块侵蚀更容易发生斑块破裂,并且与绝经前妇女相比表现出脆弱的斑块特征[44],这再次突显了更年期在妇女生活中的关键作用。最近,两项OCT研究证实了这些仪器观察结果:Tang等[35]发现,与绝经前妇女相比,绝经后妇女的斑块破裂患病率更高,而Seegers等[34]描述了女性衰老与斑块破裂之间的密切关系。
1.2.4. 冠状动脉斑块愈合 斑块愈合是一种亚临床型斑块失稳,伴有非闭塞性血栓形成和随后血管完整性的恢复。因此,它被认为是ACS流产的标志,导致进行性斑块生长,最终在CCS中抑制[45]。几项研究调查了与斑块愈合相关的临床、血管造影和OCT斑块形态特征,发现不同性别的斑块愈合频率没有差异[46-47]。然而,Okamoto等[48]最近在205名CCS患者队列中的一项研究报告称,分层罪犯病变中男性的患病率明显更高。这一过程的潜在临床意义仍值得进一步研究。
2 心脏计算机断层扫描
冠状动脉计算机断层扫描血管造影(CCTA)是一种非侵入性技术,能够评估CAD的存在并表征冠状动脉斑块表型[49]。根据最新的ESC指南,CCTA适用于低至中等CAD可能性的急性胸痛患者[50]。几项CCTA研究报告了不同背景下CAD的显著性别差异。
冠状动脉钙化是亚临床动脉粥样硬化的标志物,也是冠状动脉粥样硬化负荷的指标。Agatston钙评分与不良事件之间存在明确的关联,该评分考虑了每个病变处的钙含量,按衰减系数进行缩放,并在所有病变中求和。McClelland等[51]的一项具有里程碑意义的研究发现,与男性相比,女性的钙动脉评分较低。最近,Kim等[52]研究结果表明,在传统的心血管危险因素频谱中,男性是钙动脉评分较高的最有力预测因素,HR为3.04。
几份CCTA报告表明,与男性相比,女性的阻塞性CAD程度较低。Nasir等[53]的一项研究包括268名男性和148名女性,报告称11%的女性和25%的男性患有阻塞性CAD。同样,在SCOT-HEART研究中(50%对26%)[54]和CONFIRM登记中(43%对26%),女性比男性更有可能拥有视觉评估的正常冠状动脉[55]。
心脏CCTA用于区分冠状动脉斑块的特征,传统上分为钙化、非钙化和混合斑块[49],并用于识别高风险斑块,其特征是低衰减、正重塑、斑点状钙化和餐巾环征,预后较差[49]。与男性相比,女性更有可能携带较少的混合斑块[18,54-55],而非钙化斑块的性别分布报告了相互矛盾的结果[52-55]。此外,虽然在ICONIC研究中,高危斑块的患病率没有性别差异[56],但其他研究发现,与女性相比,男性高危斑块的发生率明显更高(CONFIRM登记处为45%对20%[55],Plank等[57]研究中为41%对24%)。有趣的是,与同龄男性相比,女性冠状动脉钙化的进展更为显著[18],高危斑块预示着女性的预后更差[56-58]。最后,女性主动脉瓣钙浓度低于男性[59]。鉴于主动脉钙化是亚临床动脉粥样硬化的替代物[59],这一发现支持了血管钙化性别生物学差异的证据,并可能为CAD和主动脉狭窄的治疗开辟新的途径。
小结
与男性相比,女性CAD的临床表现、自然史和预后存在显著差异。然而,到目前为止,对潜在病理生理机制的有限了解阻碍了个性化CAD管理和治疗的实施。通过冠状动脉内成像技术揭示了病理生理机制和冠状动脉斑块特征中与性别相关的差异。特别是,生物、解剖和遗传特征以及社会心理发现是动脉粥样硬化加速的原因,随着年龄的增长,女性中观察到的易损斑块患病率更高。最后,鉴于女性患者的CAD病理生理学与男性患者相比更为复杂和多方面,前者需要更广泛和有针对性的治疗方法,该方法考虑了新兴的非传统RF的整个范围。
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