摘 要：冠状动脉功能学评估是经皮冠状动脉介入治疗(PCI)临床决策的主要依据。血流储备分数(FFR)是功能学评估的金标准，但限于操作复杂、耗时长等原因，其临床应用十分有限。随着计算流体力学的发展，基于影像衍生的功能学指标(CT-FFR、QFR、caFFR、caIMR等)应运而生，其无创、高效且诊断准确率较高，在介入术前评估和术中指导中逐渐体现出优势。本文将介绍不同功能学衍生技术的应用场景，并对影像与功能学联合应用的价值进行展望。
关键词:冠状动脉疾病;血流储备分数; CT-FFR; QFR; caFFR; calMR;
Application scenarios and prospects of coronary functional derived techniques
NIE Shaoping XU Yang WANG Xiao
Beijing Anzhen Hospital, Capital Medical University
Abstract：
Coronary function assessment has become the cornerstone of clinical decision-making in percutaneous coronary intervention(PCI). Fractional flow reserve(FFR) is the gold standard for functional assessment, but its clinical application is limited due to the complicated and time-consuming procedure. With the development of computational fluid dynamics technology, imaging-derived functional indicators(CT-FFR, QFR, caFFR, caIMR, etc.) have emerged, which are non-invasive, efficient and have high diagnostic accuracy, and have advantages in pre-assessment and guidance of PCI. This article will introduce the application scenarios of different functional derived techniques, and discuss the value of the combined use of imaging and functional techniques.
Keyword: coronary artery disease; fractional flow reserve; CT-FFR， QFR; CaFFR; calMR;
冠状动脉(冠脉)功能学评估是经皮冠脉介入治疗(PCI)临床决策的基石。大量研究证实，与冠脉造影相比，基于压力导丝的血流储备分数(FFR)指导的介入治疗策略能显著改善患者预后。然而，由于操作复杂、耗时长等诸多原因，国内临床应用比例仍较低。随着计算流体力学的发展，基于无创或有创影像的各种功能学衍生技术应运而生，无论心外膜冠脉还是微血管功能评估，均体现出良好的应用前景(图1)。
1 传统基于冠脉导丝的功能学评估及其存在的问题
20世纪90年代，FFR的出现推动了冠脉功能学的发展[1],实现了从单纯解剖学评估到功能学评估的新阶段。随着DEFER[2]、FAME[3]、FAME2[4]、FAMOUS[5]及COMPARE-ACUTE[6]等研究的公布，FFR的适应证从稳定型心绞痛扩展到不稳定型心绞痛、非ST段抬高型心肌梗死和ST段抬高型心肌梗死(STEMI)的非罪犯血管。目前，FFR已被公认为冠脉功能学评估的金标准，在国内外介入治疗指南中也被列为ⅠA类推荐[7,8]。
然而，2021年发表的FLOWER-MI研究[9]显示，对于STEMI合并多支病变患者，FFR指导的完全血运重建较冠脉造影指导并未显示出临床获益。2022年发表的FAME 3研究[10]结果显示，对于3支病变患者，FFR指导的PCI策略较CABG在1年复合终点事件(包括死亡、心肌梗死、卒中或再次血运重建)方面并未显示出非劣效性；因此，对于高危或不稳定的病变，采用FFR指导介入策略仍存在争议。另外，在临床实践中，FFR并未得到广泛应用，主要原因包括操作时间长、费用较高以及血管扩张药物的副作用，此外还与导丝操控性和压力波形需精准调控等因素有关[11]。尽管先后出现瞬时无波形比值(iFR)、静息全周期比值(RFR)、舒张期比值(DFR)等无需充血的评价方法，但仍需压力导丝和冠脉内操作，因此其使用率仍较低。
2 冠脉功能学评估的衍生技术与应用场景
随着计算流体力学和人工智能技术的发展，通过冠脉三维重建，可以计算出基于影像的FFR,包括无创CT血管造影(CTA)衍生的FFR(CT-FFR)和有创冠状动脉造影衍生的FFR,它们克服了基于导丝的FFR的诸多缺陷，诊断准确性与FFR一致性较高，无论在介入术前临床决策还是术中指导均体现出优势，目前已逐渐应用于临床实践。
2.1 介入术前无创功能学评估：CT-FFR
对于疑诊冠心病患者，CTA是最常用的诊断手段，其敏感性高，但因特异性不足，常导致不必要的冠脉造影。过去10年，多种CT-FFR技术如雨后春笋般出现，通过计算流体力学或人工智能与冠脉生理学参数相结合，计算出一个心动周期内冠脉树任一点的CT-FFR值，明确CTA冠脉狭窄的功能学意义[12]。
早期大型前瞻性临床研究证实，与单纯CTA相比，CT-FFR对FFR<0.8的诊断准确性显著提高[13,14]。与传统SPECT和PET相比，CT-FFR对血管特异性缺血的诊断性能更高[15]。我们的研究显示，基于“由粗到精”血管分割技术的Ruixin CT-FFR对于缺血的诊断敏感性、特异性和准确率分别为95%、90%和92%。对于临界病变、“灰区”病变和钙化病变的诊断效能也均高于80%,显著优于冠脉CTA[16]。
对冠心病患者进行CT-FFR评估可以减少不必要的有创治疗风险，并可能降低医疗费用。一项前瞻性队列研究显示，在接受了CTA与CT-FFR评估的新发胸痛患者中，有61%的患者取消了不必要的有创冠脉造影[17]。在ADVANCE多中心注册登记的5083例患者中，与单独使用CTA相比，有2/3的受试者根据CT-FFR的结果修改了治疗策略[18]。PLATFORM研究[19]显示，采用CTA/CT-FFR减少了33%的医疗费用。然而，新近发表的FORECAST研究[20]显示，CT-FFR指导策略虽然减少了有创冠脉造影，但并未降低医疗费用。PRECISE研究[21]将进一步评估CT-FFR指导策略与传统策略对临床结局的影响。此外，针对左主干或3支血管病变患者，基于CTA/CT-FFR的心脏团队的治疗决策与传统冠脉造影得出的决策高度一致，这表明基于CTA的功能学评估方式在临床治疗决策和规划方面具有潜在的可行性[22]。
2019年ESC慢性冠脉综合征指南推荐冠状动脉CTA作为疑诊冠心病患者的一线检查手段，对于CTA功能学意义不明确者，建议功能性影像学检查明确有无心肌缺血(Ⅰ类推荐)[23],相信CT-FFR同其他经典无创影像学检查一样，有望成为侵入性冠脉造影的“守门人”。当然，CT-FFR也存在着自身局限性，比如CTA图像质量会干扰CT-FFR的分析。未来期待通过技术与算法的进一步优化，在导管室外利用无创手段为患者提供更精准的功能学评估和指导。
2.2 基于冠脉造影的导管室功能学评估
2.2.1 心外膜冠脉功能学评估
由于不需要压力导丝和充血药物，基于冠脉造影衍生的功能学评估逐渐体现出优势，也成为近年研究热点。目前主要技术包括：定量血流分数(quantitative flow ratio, QFR)、基于计算流体力学的FFR(computational pressure-flow derived FFR,caFFR)、基于冠脉造影的血流储备分数(coronary angiography-derived FFR,FFRangio)等。其中，QFR和caFFR是研究最广泛的两种技术，不同的是caFFR结合实时主动脉压力，利用优化的流体力学公式进行计算从而模拟压力导丝回撤过程。FAVOR Ⅱ China研究显示，QFR在线评估冠脉狭窄功能学意义的准确率为92.4%[24]。flash FFR研究显示，与金标准FFR相比，caFFR的诊断准确率高达95.7%[25]。
FAVOR Ⅲ China是一项在中国26家医院进行的多中心、盲法、随机、对照试验。该研究共纳入3825例冠心病患者，结果显示，与传统造影指导治疗组相比，QFR指导组1年全因死亡、心肌梗死和缺血驱动的血运重建显著降低[26]。正在进行的FLASH Ⅱ研究(NCT04575207)预计入选2134例患者，将探讨caFFR指导对比FFR指导策略对中度冠脉狭窄患者1年临床结局的影响，该研究将进一步为基于造影的功能学评估手段提供有力证据。
功能学评估在PCI术后同样发挥着不容忽视的作用。一方面，术后功能学评估能有效预测PCI后的远期临床结果。DK CRUSH Ⅶ研究[27]证实，PCI术后FFR值与靶血管失败密切相关。随后HAWKEYE研究[28]与SYNTAX Ⅱ研究[29]进一步发现，PCI术后QFR越高，随访心血管不良事件的发生率越低。另一方面，术后功能学评估可能进一步优化PCI结果。Agarwal等[30]研究发现，PCI术后造影结果满意的病变有20%根据术后FFR值进行了重新分类，需要进一步干预。DEFINE PCI研究[31]对PCI成功的500例患者进行盲法iFR回撤，结果发现，近1/4的患者在PCI术后仍存在残余缺血；值得注意的是，这些在血管造影上并不明显的狭窄仅有38.4%位于支架节段内，这表明PCI术后功能学检查在支架节段外残余病变的评估和定位中发挥更重要的作用。TARGET FFR研究[32]显示，在采用冠脉造影指导的PCI患者中，高达2/3以上的患者冠脉功能学评估结果不理想。FFR指导的优化策略尽管未能显著增高最终FFR ≥0.90的患者占比，但却明显降低了最终FFR ≤0.80的患者占比。关于术后功能学评估指导优化PCI能否改善患者临床结局仍需进一步研究，目前正在进行的FFR REACT研究[33]和DEFINE-gps研究(NCT04451044)有望回答上述问题。
2.2.2 微血管功能评估
既往研究多关注心外膜冠脉，目前研究认为，微血管功能不全是非阻塞性冠心病(nonobstructive coronary artery disease, NOCAD)的主要原因。同时，对于PCI术后残余心绞痛的患者也应考虑微血管功能评估。目前已经开发了多种技术评估微血管功能，包括无创的超声心动图、PET-CT、CMR等，以及有创的冠脉血流储备(CFR)、微循环阻力指数(IMR)等方法。既往研究证实，PCI术后即刻IMR可预测稳定型冠心病和STEMI患者的心血管不良事件[34,35]。
然而，由于IMR操作复杂、耗时并需要充血药物或0.9%氯化钠，其临床应用受到限制，尤其对于心肌梗死患者存在潜在风险。为了克服IMR的局限性，一种基于冠脉造影衍生的微循环阻力指数应运而生——caIMR。caIMR与传统IMR相关性良好，诊断准确率达85%[36,37]。对于STEMI患者，caIMR与术后急性期CMR测量的微血管功能不全有较好的一致性[38];同时，STEMI术后caIMR>40 U的患者心源性死亡或心力衰竭再入院的风险显著升高[39]。这种无需压力导丝的非充血方法可以在术后早期识别高风险患者，从而指导临床医师制定更精准的治疗方案。
3 冠脉功能学评估的未来发展方向
3.1 基于OCT衍生的FFR
血管内光学相干断层扫描(optical coherence tomography, OCT)在评估冠脉病变形态学方面具有极高的分辨率，成为优化PCI治疗的重要工具，但其预测冠脉狭窄功能学意义的准确性有限，因此衍生出了基于OCT图像自动计算的FFR,即OFR。OCT成像后，利用软件自动描绘冠脉及其侧支的管腔轮廓进行三维重建，随后计算出沿冠脉每个位置的FFR,计算得出的OFR值叠加在三维重建的冠状动脉和管腔直径曲线上，同时呈现出解剖学和功能学评估结果[40]。在一项事后分析中发现，与传统有创FFR相比，OFR具有良好的诊断准确性和较低的观察者变异性[41]。另外一项前瞻性评估也显示，OFR在真实世界中的测量结果与FFR保持高度一致性[42]。OFR在提供高分辨率血管成像的同时，对狭窄病变的功能性缺血也有很好的诊断能力，可以在无诱发充血的情况下快速实现病变形态和功能学信息的整合。
3.2 基于血管内超声衍生的FFR
血管内超声(intravascular ultrasound, IVUS)利用超声波成像原理对血管的横截面进行实时成像，可以评估斑块形态、负荷并指导PCI治疗[43]。2018年，Seike等[44]开发出一种利用IVUS获得的解剖信息计算FFR的方法，用于评估心肌缺血，并且发现IVUS-FFR与FFR的线性相关性优于IVUS衍生的最小管腔面积。之后，通过IVUS影像进行血管重建也可计算FFR(IVUSFFR),并且与有创FFR相比表现出良好的一致性[45]。基于类似OFR的计算方法，通过流体力学计算的UFR与FFR表现出很强的相关性与一致性。UFR的计算速度快、可重复性好，有望更广泛地应用于导管室影像和功能学的综合评估[46]。
3.3 冠脉影像学与功能学的联合应用
冠脉斑块形态和功能学代表冠心病的不同特征，在冠心病发生发展过程中密不可分，两者相互作用形成不同的解剖和功能学特征。尽管FFR阴性的患者可能有较好的预后，但同时存在高危病变的患者仍可能发生临床事件。FAME 2研究5年随访发现，FFR>0.8的延迟血运重建患者中仍有15.7%发生了主要终点事件[47]。一项研究对299例患者进行CTA与FFR分析发现，在FFR>0.80组中，高危特征≥3个的病变显示出更高的缺血事件风险[48]。COMBINE研究显示，对于FFR>0.80行保守治疗的糖尿病患者，合并薄纤维帽动脉粥样硬化(TCFA)显著增加复合缺血事件风险。因此，综合考虑局部斑块负荷、高危斑块特征、局部生理学等能更好地定义易损特征，从而根据危险分层选择优化治疗策略[49],而简单、无创的功能学评估新手段为联合应用提供了技术支撑。
利益冲突 所有作者均声明不存在利益冲突
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