虚拟组织学血管内超声的临床应用现状和研究展望

吴小凡 马长生

近年来,血管内超声(intravascular ultrasound,IVUS)在心血管病学领域得到了广泛应用。但灰阶IVUS表达的仅仅是超声波的振幅信息而不能反映频率信息,不能对冠状动脉斑块的成分进行有效的评价。虚拟组织学 IVUS(virtual histology IVUS,VH-IVUS)综合反映了超声波的振幅和频率信息,能有效识别富含脂质坏死核(necrotic core,NC),从而弥补了灰阶IVUS的不足。本文旨在综述VH-IVUS在心血管疾病尤其介入心脏病学领域的临床应用和研究热点。

1.VH-IVUS的基本原理:目前IVUS的频率范围在20～45 MHz,轴向分辨率为70～200 μ m,纵向穿透距离达5 mm以上[1-2]。而血液成分在 >40 MHz时才会出现容易混淆血管界面的斑点图像。因此,灰阶IVUS可以准确地显示血管腔的边界以及发现支架内的新生内膜组织,并对血管腔、外弹力膜的横截面积和斑块面积进行定量测定以及对斑块性质做定性分析。但是由于灰阶IVUS提供的仅仅是超声波的振幅信息而不能反映频率信息,因此灰阶IVUS发现富含脂质斑块的敏感性仅为67%[3]。VH-IVUS综合反映了超声波的振幅和频率信息,其识别富含脂质坏死核(necrotic core,NC)的敏感性和特异性提高到91.7%和96.6%[4-5]。基于病理对照研究,VH-IVUS将冠状动脉动脉粥样硬化分为5类:薄帽纤维粥样硬化(thin-cap fibroatheroma,TCFA),厚帽纤维粥样硬化(thick-cap fibroatheroma,ThCFA),病理性内膜增厚(pathological intimal thickening,PIT),纤维斑块和纤维钙化斑块(图1)。但是由于“薄帽”的病理学概念是≤65 μ m,而VH-IVUS的轴向分辨率大约为 200 μ m,因此 VHIVUS规定连续性NC>10%的斑块面积,与血管腔中心的角度 >30°,且与血管腔直接接触时,称为 TCFA。与 VH-IVUS类似,背向散射IVUS(integrated backscatter IVUS,IB-IVUS)和iMAP也能提供斑块的组成信息。IB-IVUS在体识别脂质池的敏感度和特异度达到90%和92%[6-7],iMAP在猪模型离体识别脂质核心的准确性达97%,其在人体识别斑块成分的准确性还有待进一步研究证实[8]。

但是,VH-IVUS尚不能有效地识别血栓形成,因此,含有血栓的罪犯病变可能被误判为PIT或纤维斑块,当TCFA覆盖血栓时可能被错误诊断为ThCFA,从而遗漏易损斑块[9]。此外,钙化背后由于超声波发生的角度不同以及频率信号的传播,80%的兴趣区仍然有超声信号伴随着较低的声噪比,但是20%的兴趣区只有噪音而无超声信号,这样就导致钙化背后的病变可能会错判为 NC(65%)、纤维组织(18%)或纤维脂肪组织(14%)[10]。

图1 动脉粥样硬化斑块的VH-IVUS分型以及灰阶IVUS对照。红色代表坏死核,白色代表钙化组织,绿色代表纤维组织,黄绿色代表纤维脂肪组织。依据各种组织占斑块的面积百分比可以将动脉粥样硬化斑块分为5型,薄帽纤维粥样硬化(A,a),厚帽纤维粥样硬化(B,b),病理性内膜增厚(C,c),纤维斑块(D,d),纤维钙化斑块(E,e)

2.VH-IVUS与易损斑块:总的来说,冠状动脉粥样硬化斑块分为2种,即稳定性斑块和不稳定性斑块。基于病理研究,前者以小的脂质核心覆盖厚纤维帽为特征,后者表现为大的脂质核心覆盖薄纤维帽,亦称为“易损斑块”(vulnerable plaque,VP)。易损斑块是斑块破裂继发血栓形成导致急性冠脉综合症(acute coronary syndromes,ACS),或内膜增生致介入术后再狭窄的重要原因之一[11-12]。众多调脂试验显示较小的斑块形态改变可以获得明显的ACS事件减少的获益,而这一获益得益于斑块中脂质的移除[13-15]。因此,在体评价斑块性质在冠心病的防治链中显得尤为重要。VHIVUS能有效识别冠状动脉粥样硬化斑块的脂质核心,因而成为识别易损斑块和建立斑块发生发展动态体系的重要手段之一。

PROSPECT研究(Providing Regional Observations to Study Predictiors of Events in the Coronary Tree:An Imaging Study in Patients with Unstable Atherosclerotic Lesions,PROSPECT)是第一个前瞻性评价易损斑块进展的多中心临床研究,旨在采用多种冠脉内影像手段尤其是VH-IVUS来早期识别导致未来不良事件的易损斑块[16]。该研究在美国和欧洲的40个中心入选了700例ACS患者,在成功对罪犯病变置入支架后,对3支主要冠状动脉进行QCA和IVUS序列分析,所有患者均接受优化药物治疗并随访3年,对发生事件者再次进行QCA和IVUS分析和评价。PROSPECT研究结果显示,VH-IVUS发现的易损斑块能够预测未来的不良冠脉事件。对未置入支架的非罪犯病变的亚组分析揭示导致不良冠状动脉事件的3个独立预测因子:TCFA,斑块负荷>70%以及最小管腔面积(minimal lumen area,MLA)≤4 mm2,而且这些因子存在累加效应。TCFA是VH-IVUS诊断的易损斑块,51.2%的患者含有至少1个TCFA,48%的事件相关病变显示存在 TCFA,16%同时存在 TCFA和 MLA≤4 mm2,而4.2%同时存在TCFA,MLA≤4 mm2和斑块负荷 >70%。对冠状动脉斑块形态和组成的自然进程的VH-IVUS研究显示,在9个月的随访期间,多数(3/4)未行支架置入的非罪犯病变的TCFA可以愈合,而部分位于冠状动脉近段且斑块负荷较大的TCFA仍未愈合;此外,PIT或ThCFA可发展为新的TCFA,提示相对于纤维斑块或纤维钙化斑块而言,PIT、TCFA和ThCFA更易于进展,表现为斑块负荷增大,管腔面积减小[17]。

3.VH-IVUS在介入治疗中的应用:灰阶IVUS在引导经皮冠脉介入治疗方面已经积累了丰富的经验,包括术前评价病变性质、范围,术中明确支架直径、长度,术后评价支架扩张和贴壁以及及时识别并发症等。VH-IVUS发展至今,关于其在介入治疗中的应用,也积累了一定的经验,包括对于易损斑块的处理、支架长度的选择以及病变特点与无复流之间的关系以及支架术后内膜覆盖和再狭窄的评价等。含易损斑块的临界病变是否置入支架,是近年来介入治疗策略的一个重要挑战。一方面,易损斑块容易破裂造成恶性心血管事件,有效的覆盖可建立易损斑块与血液的屏障,减少血栓事件的发生;另一方面,尽管VH-IVUS能有效识别TCFA,但现有的影像手段还不能明确斑块纤维帽的炎性侵润情况,而后者是斑块破裂的一个重要环节。同时,大多数ACS患者含有一个以上的易损斑块[18],尽管四分之三的易损斑块可能愈合,但何种易损斑块不会破裂目前仍不明确。此外,易损斑块的支架置入尤其需要考虑到组织脱垂、支架扩张和支架贴壁的问题。2009年,荷兰鹿特丹中心的SECRITT I研究进行了第一例易损斑块(TCFA)的支架置入,于前降支低压释放vProtect自膨胀支架,IVUS和OCT显示支架扩张及贴壁良好,且无组织脱垂,6个月随访显示TCFA已被增生的血管内膜完全覆盖,且无支架内再狭窄[19]

支架大小和长度的选择对于介入治疗尤为关键。对于急性心肌梗死(AMI)患者,冠状动脉造影显示罪犯病变通常位于血栓负荷最大处,而真正的罪犯病变(culprit of the culprit)常位于造影最狭窄处的近端或远端,因此冠脉造影指导的支架置入往往不能完全覆盖罪犯病变。来自波兰的一项针对40例AMI患者的VH-IVUS研究证实,STEMI有50%的薄帽纤维粥样硬化(TCFA)未被完全覆盖,其中35%存在于支架近端,15%同时存在于支架近端和远端;而NSTEMI有35%的TCFA未被完全覆盖,20%存在于支架近端,5%存在于支架远端,10%同时存在于支架近端和远端。罪犯病变未完全覆盖对远端栓塞、支架血栓、再狭窄以及病变进展等的影响需要进一步的大规模临床研究加以证实。

尽管个别研究显示纤维组织或纤维脂肪组织与支架术后无复流有关[20-21],但目前大多数的VH-IVUS研究显示NC与支架术后远端微栓塞致无复流有关[22-25]。灰阶IVUS发现的超声衰减斑块富含微钙化和胆固醇结晶,可广泛见于急性心肌梗死(40% ～70%)而极少见于稳定性心绞痛患者[26-27]。与VH-IVUS的比较分析发现,超声衰减斑块含有大量的NC,并与纤维粥样硬化有关[28]。而临床研究进一步证实,超声衰减斑块支架术后无复流/慢血流明显增多,与斑块在支架扩张过程中释放大量微栓塞物质损伤心肌有关[27,29-30]。与此一致,IB-IVUS研究显示脂质体积占斑块体积百分比越大,支架术后心肌酶谱升高越显著[31],光学相干断层造影(optical coherent tomography,OCT)研究显示斑块脂质大小(脂质弓)与ACS患者介入术后无复流有关[32],近红外波谱分光镜(near-infrared spectroscopy,NIS)研究也显示斑块脂质大小与介入术后无复流有关[33]。因此介入术前对斑块成分进行评价及早发现富含脂质斑块,对介入策略和防治无复流具有重要的临床意义。介入术后支架小梁在VH-IVUS往往显示为白色的钙化环绕红色的NC,因此基线IVUS影像是VH-IVUS评价术后内膜覆盖的重要参考。Leiden MISSION研究显示,支架置入术后9个月,雷帕霉素药物洗脱支架的新生内膜体积明显小于金属裸支架[34]。与之一致,支架置入后10个月的VH-IVUS随访研究显示,金属裸支架置入后由于内膜覆盖致使通过支架小梁接触管腔的NC明显减少(75%到19%,P<0.001),而药物支架置入后,保护性的内膜增生受到抑制,导致接触管腔的NC减少不明显(76%到61%,P=0.036),这种情况在参考节段也同样存在,提示在易损斑块置入药物支架由于内膜增生受到抑制,斑块的不稳定性可能长期存在[35]。对不同随访时期的再狭窄病例的新生内膜的VH-IVUS研究表明,随着随访时间的延长,NC和钙化组织占新生内膜的百分比成上升趋势,但是新生内膜组成成分的验证性研究还有待进一步的病例组织学对照研究加以证实。

4.新近研究热点:由于VH-IVUS能有效评价斑块性质,因此越来越广泛地应用于冠心病的基础和临床研究中。近年来的研究主要集中在以下几个方面:(1)结合流行病学和病理学研究识别高危冠心病患者;(2)评价药物对动脉粥样硬化斑块的治疗效果;(3)评价支架置入的安全性和有效性;(4)预测远期不良事件。

全球IVUS注册研究显示,VH-TCFA与Framingham危险分数相关,Framingham风险≥20%者,TCFA发生率高达21.4%,而Framingham风险<10%者,TCFA发生率下降一半,约11.3%[36]。糖尿病患者冠状动脉病变形态学研究显示,与非糖尿病患者相比,糖尿病患者冠状动脉粥样硬化斑块含有丰富的坏死核成分[37]。另一项VH-IVUS注册研究也证实了这一点,即糖尿病患者冠状动脉粥样硬化斑块坏死核体积百分比明显高于非糖尿病患者[38]。VH-IVUS能有效识别斑块性质,近年来越来越多地应用于评价药物对动脉粥样硬化斑块的治疗效果。对急性冠脉综合征患者应用脂蛋白相关磷脂酶A2(Lp-PLA2)Darapladib治疗的对照研究显示,与安慰剂比较,Darapladib能明显降低患者冠状动脉粥样硬化斑块的坏死核体积(-0.5±13.9)mm3比(4.5±17.9)mm3,P=0.012[39]。无复流是冠状动脉支架术最严重的并发症之一,VH-IVUS研究证实,富含坏死核心的斑块与支架术后无复流密切相关[22-25]。此外,PROSPECT研究证实VHIVUS发现的易损斑块能够预测未来的不良冠脉事件[16]。

随着VH-IVUS技术的不断完善,其对斑块组成的识别功能将会越来越广泛地应用于心脑血管疾病领域,包括对支架术后再狭窄、新生内膜组成,以及针对新药对斑块影响的在体动态评价等。

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