【每日动态】冠状动脉CT血管造影——评估斑块的新战术

冠状动脉CT血管造影——评估斑块的新战术
Abstract | Most acute coronary syndromes are caused by sudden luminal thrombosis due to atherosclerotic plaque rupture or erosion. Preventing such an event seems to be the only effective strategy to reduce mortality and morbidity of coronary heart disease. Coronary lesions prone to rupture have a distinct morphology compared with stable plaques, and provide a unique opportunity for noninvasive imaging to identify vulnerable plaques before they lead to clinical events. The submillimeter spatial resolution and excellent image quality of modern computed tomography (CT) scanners allow coronary atherosclerotic lesions to be detected, characterized, and quantified. Large plaque volume, low CT attenuation, napkin-ring sign, positive remodelling, and spotty calcification are all associated with a high risk of acute cardiovascular events in patients. Computation fluid dynamics allow the calculation of lesion-specific endothelial shear stress and fractional flow reserve, which add functional information to plaque assessment using CT. The combination of morphologic and functional characteristics of coronary plaques might enable noninvasive detection of vulnerable plaques in the future.
【编者按】大多数急性冠脉综合症都是由于动脉粥样硬化斑块破裂或糜烂而引起的突发管内血栓形成所导致的。而预防急性冠脉综合症的的发生发展，或许也成为了降低冠心病死亡率和发病率唯一有效的策略。
易于破裂的冠状动脉病变斑块在形态上与稳定型斑块截然不同，利用这点，可以在早期采用非有创的影像学检查来鉴别不稳定的斑块。现代CT扫描仪有着亚毫米级别的高空间分辨率和出色的图像质量，能早期探测、标记并定量分析冠状动脉粥样硬化病变。
本文主要阐述冠状动脉CT血管造影作为一种非有创的在早期诊断粥样斑块方面的临床意义。
Introduction
Cardiovascular diseases are the number one cause of death globally. The number of people who die from cardiovascular diseases, mainly from coronary heart disease and stroke, will increase to reach 23.3 million by 2030 from an estimated 17.3 million deaths in 2008. Cardiovascular diseases are projected to remain the single leading cause of death by 2030 globally.
引言
心血管疾病已经成为全球第一死因。大多数心血管病患者都是死于冠心病和卒中，死亡人数将从2008年的1730万激增到2030年的2330万。长此以往，到了2013年，心血管疾病仍是人类的第一杀手！
In 2014, an estimated 1.1 million people in the USA will have a major adverse coronary event, which will lead to death in ~34% of those individuals,despite many effective treatment strategies existing to lower cardiovascular risk.Furthermore, by 2030, the prevalence of coronary artery disease (CAD) in the USA is predicted to increase by 16.6%—from 8.0% (based on2010 estimates) to nearly 9.5%. Acute myocardial infarction and sudden cardiac death remain the first manifestations of coronary atherosclerosis in the majority of the population (in 50% of men and 64% of women), which accounts for these unfavourable statistics.Most individuals do not, therefore, experience any symptoms or warning signs before the coronary event (acute coronary syndromes [ACS] or sudden cardiac death) occurs.
尽管已有很多有效的措施可以降低心血管疾病的发病率，但是在2014年就估计有110万美国人将患上心血管疾病，其中有34%的患者因此丧命。而且，预计2030年，美冠状动脉疾病（CAD）患者将增加16.6%。急性心肌梗死和心脏性猝死导致患者数量急剧上升的罪魁祸首，所以大多数患者在冠脉事件（急性冠脉综合症【ACS】或突发心脏性猝死）急性发作之前都没有任何症状或者警示征兆。
Prevention of acute coronary events seems to be the only effective strategy to reduce the burden of cardiovascular disease and improve mortality and morbidity rates.Considerable efforts are ongoing to predict where acute coronary events will happen on an individual plaque level. The identification of patients at high risk of developing acute coronary events remains a major challenge in cardiovascular imaging. Current diagnostic strategies focus predominantly on the detection of myocardial ischaemia and haemodynamic luminal narrowing,but not the detection and characterization of coronary atherosclerotic plaques.This strategy is based on the evaluation of symptomatic patients and ignores the larger problem of a major adverse coronary events occurring as the first (and only) manifestation of CAD.
目前看来，想有效地减轻心血管疾病所带来的负担以及降低死亡率和发病率，只有做好急性冠脉事件的预防。为此，研究人员投入了大量的精力去探究斑块水平与急性冠脉事件的相关性。但是，如何使用心血管影像学来确诊患者是否处于急性冠脉事件的边缘，也是一个急需解决的问题。当下的诊断策略显然侧重于检测有无心肌缺血和血流动力学管腔狭窄，而不是针对冠状动脉粥样硬化斑块。这种策略适合有症状的患者，却忽略了以急性冠脉事件为始发症状的CAD患者。
In post-mortem studies, most acute coronary events are found to be caused by sudden luminal thrombosis due to plaque rupture.The morphology of atherosclerotic plaques that are prone to rupture is distinct from stablelesions (Figure 1), which provides a unique opportunity for noninvasive imaging to identify high-risk plaques before they lead to adverse clinical events. Moreover,the assessment of coronary plaque composition and size are potentially more important than traditional detection of luminal stenosis for predicting devastating acute coronary events.
验尸报告显示，大多数急性冠脉事件的发生，是由于斑块破裂，导致突发管腔内血栓形成所诱发的。易于破裂的冠状动脉病变斑块在形态上与稳定型斑块截然不同，利用这点，可以在早期采用非有创的影像学检查来鉴别易损斑块。而且，相对于传统的检测官腔狭窄，检测冠脉斑块的组成和尺寸更有利于早期诊断急性冠脉事件。
Coronary computed tomography angiography (CCTA) permits the noninvasive evaluation of the coronary atherosclerotic plaque, not just the coronary lumen.CCTA provides information regarding the coronary tree and atherosclerotic plaques beyond simple luminal narrowing and plaque type defined by calcium content.These novel applications will improve image-guided prevention, medical therapy, and coronary interventions. The ability to interpret CCTA images beyond the coronary lumen and stenosis is of utmost importance as we develop personalized medical care to enable therapeutic interventions stratified on the basis of plaque characteristics.
冠状动脉CT血管造影（CCTA）可以对冠状动脉粥样硬化斑块进行无创性评估，而不仅限于检测冠脉官腔。CCTA可以明确冠脉的分支走向和动脉粥样硬化斑块的整体情况，而一般的检测方法只能辨别官腔狭窄与否或者根据钙离子水平判断斑块类型。有了新的应用设备，影像引导预防、药物治疗和冠脉介入治疗效果都能得到相应的改善。根据斑块特性进行分层，并制定相应的个性治疗方案，因此，我们需要掌握解析CCTA的能力，而不仅仅是判断官腔狭窄情况。
In this Review, we describe the morphological and functional features of vulnerable plaques, as potential targets of conventional CCTA imaging. We also highlight novel image post-processing techniques and integrated computational fluid dynamics simulations to characterize coronary plaques and stenoses. Finally, we discuss future imaging techniques for atherosclerotic plaque detection and potential strategies to identify patients at highest risk of developing ACS.
本文既描述了CCTA如何检测并描述易损斑块的形态和功能特性，也展示了最新的图像后处理技术和计算机流体力学模拟技术如何评估冠脉斑块与狭窄。最后，文章还探讨未来的成像技术如何在检测动脉粥样硬化斑块和早期诊断ACS患者方面有着重大的临床意义。
Plaque morphology
Histological investigations have revealed three distinct features of plaques associated with acute coronary events: rupture; erosion; and calcified nodule.Two-thirds of luminal thrombi in acute events result from ruptured atherosclerotic lesions characterized by a necrotic core covered by a thin layer of fibrous cap(Figure 1b). Plaques vulnerable to rupture might have the same morphological characteristics as ruptured plaques, but with an intact thin fibrous cap.These lesions—termed thin-cap fibroatheroma (TCFA), with a cap thickness of <65 μm—are considered to be the precursor lesions of plaque rupture.The limited spatial resolution of current CT scanners (≈ 400 μm) precludes the morphometric analysis of fibrous cap by CCTA.Histopathological investigations suggest that plaques prone to rupture are enlarged in all three spatial dimensions. In TCFAs the necrotic core length is ~2–17 mm(mean 8 mm) and the area of the necrotic core in 80%of cases is >1.0 mm.These dimensions are over the plaque detection threshold (>1 mm plaque thickness) for CCTA. Moreover, the majority of TCFAs occur in the proximal portions of the main coronary arteries, where vessel diameter is largest, and CCTA has the highest image quality and accuracy for the plaque detection.In modern CT scanners, the detection and quantification of some features of high-risk lesions might, therefore, be feasible.
斑块的形态学特征
组织学调查研究表明斑块的三个特点与急性冠脉事件相关：斑块破裂，糜烂，钙化。3分之2的急性血栓形成性心血管事件与薄层纤维帽覆盖的粥样斑块破裂有关（见图1b）。不稳定性斑块和破裂的斑块除了前者有薄层纤维帽覆盖，其余形态上相似。这些覆有薄层纤维帽的斑块（TCFA）(纤维帽厚度<65um）的被认为是破裂的前兆。目前的CT扫描仪空间分辨率有限（ ≈ 400微米），使得CCTA无法对纤维帽进行形态学分析。组织病理上认为倾向于破裂的斑块在空间三维上均有增大。TCFA的脂质坏死中心长度约为2-17mm(平均8mm)，80%的长度会超过1.0mm.这些尺寸在CCTA的检测范围之内（＞1mm），而且绝大多数不稳定斑块会出现在主要的冠状动脉近端，这些地方血管直径较大，CCTA能更加准确地检测并更好地成像。因此，现代CT扫描在检测并量化高危斑块损伤上或许是可行的。
Coronary plaque burden
Large plaque volume was associated with the diagnosis of ACS in cross-sectional studies, and quantification of noncalcified plaques (NCP) can improve risk stratification and improve the prognostic value of CCTA to predict future cardiovascular events. The multicentre Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) trial is the first and largest natural-history study of coronary plaques using invasive angiography and intravascularultrasound (IVUS) to identify plaques vulnerable to rupture on a per-lesion basis.The prospective study included 697 patients with ACS in whom 3?vessel greyscale IVUS and IVUS with radiofrequency backscatter analysis (known as virtual histology IVUS [VH-IVUS])were performed to characterize nonculprit (that is unruptured) lesions. After a median of 3.4 years followup,the strongest predictor of future events was the IVUS-derived plaque burden of ≥70% (HR 5.03; 95% CI2.51–10.11; P <0.001).CT data sets can provide submillimeter isotropic spatial resolution, and the possibility of CT attenuation based tissue characterization enable the quantification of total coronary plaque burden and individual plaque components, which is similar to the results obtained with IVUS.
冠脉斑块负荷
横断面研究表明：体积较大的斑块与急性冠脉综合征诊断相关。对于非钙化斑块的定量分析（NCP）有助于危险分层，并提高CCTA预测心血管事件的分析价值。PROSPECT试验是一项前瞻性、多中心的研究，
是第一个同时也是最大的针对冠脉斑块的自然史研究，目的是评估易损斑块的自然进程，利用有创性的血管造影和血管内超声（IVUS）检测易损斑块。该研究共入选697例ACS患者，所有患者均接受灰阶IVUS及虚拟组织学IVUS（VH-IVUS）检查，以检测非罪犯病变。随访3.4年后，发现IVUS结果提示狭窄面积≥70%(HR 5.03; 95% CI2.51–10.11; P <0.001)对未来心血管事件有很好的预测作用。CT具有亚毫米同质空间分辨率，且能够量化整体的冠脉斑块负荷和分析斑块成分，血管内超声也具有类似的功能。
Automated software tools are now availablefor plaque quantification and characterization (Figure 2).Automated quantification of plaques is desirable to improve the reproducibility, accuracy and efficiency of CCTA plaque analysis. The reproducibility of automated 3D quantification software for plaque burden was risk stratification of patients over conventional CCTA reading.A cross-sectional clinical investigation demonstrated that the culprit plaques in patients with ACS have larger volume than stable lesions in patients with stable angina pectoris (SAP; 193 mm3 versus 104 mm3;P = 0.001).In patients with unstable angina, quantitative CCTA revealed that plaques with morphological features of plaque disruption (such as intraplaque contrast dye penetration) had a larger volume compared with plaques that had no signs of disruption (313 ± 356mm3 versus118 ± 93 mm3; P <0.0001). These lesions also contained more low CT attenuation components characteristic to lipid-rich plaques (99 ± 161 mm3 versus 19 ± 18 mm3;P <0.0001) than undisrupted plaques.In patients with acute chest pain and obstructive coronary lesions, the total volume of plaques leading to stenosis was not significantly different between those individuals with and those without ACS (212 mm3 versus 171 mm3; P = 0.24). Interestingly, the volume of NCP with low CT attenuation density, (<90 Hounsfield units [HU], a measure of CT attenuation) was significantly larger in patients with ACS compared with patients who did not have ACS (91 mm3 versus 49 mm3; P = 0.03).
具有自动化软件的工具已经运用于斑块的定量与定性。自动化的定量分析斑块能够提高CCTA在斑块分析上的可重现性，准确性与效率。斑块负荷自动化三维重现在危险分层方面优于传统阅片。横向临床研究表明ACS患者的罪犯斑块的体积比稳定性心绞痛的患者更大 (SAP; 193 mm3 对104 mm3;P = 0.001)。对于不稳定性心绞痛的病人，CCTA显示破裂的斑块的体积比没有破裂的斑块大（313 ± 356mm3 vs 118 ± 93 mm3; P <0.0001)，而且破裂斑块的低CT衰减区域（即斑块中富含脂质的部分）也比非破裂斑块大。 (99 ± 161 mm3 vs 19 ± 18 mm3;P <0.0001) 。而在患有胸痛和冠脉阻塞性病变的患者中，ACS患者与非ＡＣＳ患者在造成狭窄的斑块尺寸方面，没有显著差异 (212 mm3 vs 171 mm3; P = 0.24)。值得关注的是，ACS患者的NCP的体积却明显大于非ACS患者。
Longitudinal clinical investigations indicate a strong prognostic value of CCTA derived plaque volume for future coronary events. In a retrospective study of 1,059 patients with stable chest pain, the coronary plaque volume was larger in those patients who developed ACS compared with patients who did not during a follow-up period of 27 ± 10 months (134.9 ± 14.1 mm3 versus 57.8 ± 5.7 mm3; P <0.001).The authors of a study published in 2013 elegantly demonstrated that semiautomatic plaque quantification—whereby plaques are manually identified before automatic segmentation, characterization, and quantification, with optional manual corrections—provided additional prognostic value for ACS over both clinical risk factors and traditional CT reading (including calcium score, segment stenosis score, lesion severity, and number of segments with NCP). The patients who developed ACS had a higher total plaque volume (median 94 mm3 versus 29 mm3; P <0.001) and total NCP volume (28 mm3 versus 4 mm3; P <0.001) at baseline compared with those individuals who did not develop ACS.
纵向临床研究显示：通过CCTA检测斑块体积可以有效地早期诊断未来的心血管事件。一项纳入1059例有稳定型胸痛的患者的回顾性研究显示：在27 ± 10个月的随访期间，冠脉斑块体积较大的患者更容易发展为ACS(134.9 ± 14.1 mm3 vs 57.8 ± 5.7 mm3; P <0.001)。另外一项研究表明：除了检测临床危险因素和传统的CT阅片，半自动斑块定量分析技术也可以发挥诊断作用（包括钙分数，部分狭窄分数，病变程度和NCP数目）。与没有进展为ACS的患者而言，进展为ACS的患者总斑块体积相对较大 (平均94 mm3 vs 29 mm3; P <0.001)，总NCP体积也相对较大(28 mm3 vs 4 mm3; P <0.001)。
The volume of nonobstructive NCP measured by CCTA was a strong predictor of future coronary events in a prospective study of 312 patients with non-ST-segment elevation myocardial infarction who underwent CCTA before invasive coronary angiography. In total, 23 patients had a coronary event after a median follow-up of 16 months and the total volume of nonobstructive NCP was independently associated with the events with an HR of 1.18 per 100 mm3 plaque volume increase. Interestingly, neither Agatston score (a measure of calcium content in a CT scan), nor calcified plaque volume were associated with an increased risk of coronary event. A subset of patients (n = 32) underwent CCTA in the PROSPECT study. The authors of this exploratory substudy observed a higher total atheroma volume at baseline in patients with subsequent cardiac events during the mean 39 months follow-up (970 mm3 versus 811 mm3; P <0.01).However, despite these promising results, further software improvements are warranted to maximize accuracy, reproducibility, and time-efficiency before automated plaque burden quantification is implemented in the clinic.Moreover, industry standards should be developed to enable reproducible plaque assessments with CCTA regardless of the software tool used.
另外一项前瞻性研究则表明了：利用CCTA对非阻塞性NCP的体积进行检测，对后期的心血管事件具有很好的预测作用。这项研究共纳312例非ST段抬高型心肌梗死患者，都在进行冠脉血管造影之前接受过CCTA检查。其中，有23例患者在平均随访16个月之后发生冠脉事件，非阻塞性NCP的总量是心血管事件的独立影响因素，每增加100mm3的斑块总量就有1.18的危险比率。无论是冠脉钙化分数（钙含量的CT扫描结果），还是钙化斑块体积，都与冠脉事件风险增加有关。还有一个仅纳入32例患者的PROSPECT研究，患者都接受过CCTA检查。该亚组研究发现：在平均39个月的随访期间，后期发生心血管事件的患者的总冠脉粥样化体积更大一些 (970 mm3 vs 811 mm3; P <0.01)。虽然研究结果看起来比较满意，但在自动斑块定量分析投入临床使用之前，还需进一步提升检测软件的性能，使检测结果更加准确、可重复和高效。当然，即使没有使用软件工具，产出的CCTA设备起码也要具备可再现的斑块评估功能。
Low CT attenuation plaques
Lesions leading to ACS often have a large necrotic lipid-rich core; therefore, the CT differentiation between plaques containing lipid-rich material and plaques with predominantly fibrous components is desirable for prediction of ACS. Traditionally, CCTA classifies plaques according to the presence or absence of calcified components, thereby differentiating between calcified, partially-calcified (mixed), and NCPs. The differentiation between calcified plaque components and NCPs was feasible even with early multidetector CT technology (such as 4?slice CTs used in the late 1990s). However, the classification of NCPs into lipid-rich and fibrous lesions on the basis of CT attenuation values (measured by HU) remains challenging.
低CT衰减斑块
导致ACS的病变往往有一个大且富含脂质的坏死中心，富含脂质的斑块与纤维成分为主的斑块在CT成像上有差别，利用这点对ACS进行预测是可行的。传统上来讲， CCTA根据有无钙化成分对斑块进行分类，从而分为钙化斑块，部分钙化斑块和非钙化斑块。即使是早期多排螺旋CT技术（如20世纪90年代后期使用的4-层CT）也可以鉴别钙化斑块成分与NCP成分。然而，根据CT衰减值将NCP分为富含脂质和纤维性病变仍然具有挑战性。
Some investigators have correlated CCTA plaque assessment with the clinical reference standard IVUS, and report low CT attenuation on average for lipid-rich plaques.NCPs with high CT attenuation correlated with fibrous tissue and those with low densities correlated with necrotic core and fibrofatty tissue as assessed by VH?IVUS. In histogram analysis of the intraplaque pixel CT numbers, lipid-rich plaques have a higher percentage of pixels with low HU values compared with plaques of predominantly fibrous components.This observation was validated in an ex vivo study that showed that the relative area (area >25%) of intraplaque pixels with <60 HU could accurately detect lipid-rich atherosclerotic lesions (sensitivity, 73%; specificity, 71%).
一些研究者将CCTA斑块评估技术与临床参考标准联系起来，并发布了富含脂质斑块的平均低CT衰减值。呈现高CT衰减值的NCP与纤维组织相关，而呈现低密度的NCP则与坏死中心和纤维脂肪组织相关。通过斑块像素CT值的直方图分析可知，与纤维成分为主的斑块比较而言，富含脂质斑块大多处于低HU值像素区域。以上的观察结果在一个临床试验中得到验证，其显示：低于60HU的斑块像素的相关区域，可以准确地富含脂质的动脉粥样硬化病变(敏感性, 73%; 特异性, 71%)。
Moreover, low CT numbers were measured in TCFAs identified by optical coherence tomography (OCT; the standard clinical reference for fibrous cap thickness measurements and necrotic lipid-rich core detection) compared with stable lesions (35–45 HU versus 62–79 HU; P <0.001).However, the variability of CT values within plaque types is wide. Despite the differences in mean densities between fibrous plaques and lipid-rich plaques, almost all investigators have reported a substantial overlap of densities, which prevented the reliable subclassification of NCPs.Furthermore, CT measurements of coronary plaques are influenced by several factors, such as the concentration of adjacent intraluminal iodinated contrast agent, plaque size, image noise, tube voltage, slice thickness, and the reconstruction filter.
此外，与稳定性病变相比较而言，光学相干断层扫描（OTC；为纤维帽的厚度测量和坏死富含脂质中心检测提供临床参考标准）可以识别TCFA病变处为低CT值(35–45 HU vs 62–79 HU; P <0.001)。 然而， 不同的斑块类型，所对应的CT值也不尽相同。尽管纤维斑块和富含脂质斑块之间的平均密度存在差异，但是几乎所有的研究者都报道了大量的重叠密度，使得NCP的细分类广受质疑。另外，冠状动脉斑块的CT测量受到以下几个因素的影响，如相邻管腔内的碘化造影剂的浓度，斑块大小，图像噪点，管电压，层厚和重建滤波器。
The reliable differentiation between lipid-rich and fibrous lesions made solely on the basis of CT attenuation is, therefore, not yet feasible.New automated plaque quantification software tools, with scan-specific adaptive attenuation threshold settings, can potentially overcome some of these limitations and might improve CT number-based plaque component quantification (Figure 2).Despite the challenges associated with CT number-based plaque characterization, low CT attenuation seems to be a consistent feature of lipid-rich plaques. Low-density plaques, defined by <30 HU average attenuation, were more often seen in patients with ACS than in those individuals with SAP (79% versus 9%; P <0.0001).
因此，目前仅靠CT衰减来区分富含脂质型和纤维性病变仍然行不通。而新研发的自动斑块量化软件具有随意调节衰减阈值的功能，可以突破以上所提到的部分限制，进一步改善以CT值为基础的斑块量化技术（见图二）。尽管目前仅靠CT值来检测残斑块面临着很多困难，但是低CT衰减所对应的富含脂质斑块的结果却始终如此。ACS患者身上发现低密度斑块（平均<30 HU）的概率高于SAP患者 (79% vs 9%; P <0.0001)。
The same investigators compared the characteristics of ruptured fibrous cap culprit lesions in patients with ACS with the intact fibrous cap plaques of patients with SAP. Again, the low plaque attenuation was defined as <30 HU, and 88% of ruptured plaques had a low CT attenuation, compared with 18% of the stable lesions (P <0.001). Similarly, other investigators have also reported lower mean CT densities of NCPs in patients with ACS versus SAP (40–86 HU versus 97–144 HU; P <0.01).Establishing a simple CT number cut-off value across an entire plaque that permits the reliable differentiation between lipid-rich and fibrous atherosclerotic lesions is difficult. However, quantification of CT number variability and identification of focal areas of low CT attenuation are methods that might aid a more-accurate differentiation of vulnerable plaques by CCTA. Moreover, culprit lesions in patients with ACS have significantly lower average CT numbers compared with patients who have SAP, suggesting that low CT attenuation is an established high-risk plaque feature.
研究人员又将ACS患者的破裂纤维帽罪犯斑块与SAP患者的完整纤维帽斑块进行对比，低斑块衰减值仍然额定为<30 HU。结果发现，88%的破裂斑块呈现低CT衰减，18%的稳定斑块呈现CT衰减(P <0.001)。其他研究人员也发现类似的现象，ACS患者的NCP平均CT密度值低于SAP患者 (40–86 HU versus 97–144 HU; P <0.01)。欲利用CT对一整个斑块建立截断值数据库，以此对富含脂质斑块和纤维化冠脉粥样硬化斑块进行区分，仍然存在很多困难。然而，对CT值波动的量化和对低CT衰减区域的重点识别，可以辅助CCTA更加准确地检测出各种易损斑块。此外，ACS患者的罪犯斑块的平均CT值明显低于SAP患者，提示低CT衰减可确定为高风险斑块的特征。
Napkin-ring sign
Histopathological analysis of culprit and nonculprit TCFAs with similar stenosis revealed that only fibrous cap thickness (OR 0.35; P <0.05), and necrotic core size (OR 2.0; P <0.02) are independent predictors of plaque rupture.A further analysis of the hierarchical importance of plaque features that are accessible by noninvasive imaging revealed that the size of necrotic core and the presence of macrophage infiltration are the two best discriminators between ruptured plaques or TCFAs and stable lesions. Furthermore, a large necrotic core cross-sectional area (>3.5 mm2) can differentiate a ruptured plaque or TCFA from a stable plaque.In 80% of plaques vulnerable to rupture, the area of necrotic core is >1.0 mm2.
一个关于造成同等狭窄程度的罪犯与非罪犯TCFA的组织病理学研究显示：只有纤维帽的厚度(OR 0.35; P <0.05)，坏死中心的大小 (OR 2.0; P <0.02) 是斑块破裂的独立预测因子。一个由非有创性影像检查分层分析斑块性质的研究表明，坏死中心的大小以及巨噬细胞浸润能很好地鉴别破裂斑块或TCFA与稳定型斑块。另外，仅凭大面积坏死中心(>3.5 mm2) 也能鉴别破裂斑块或TCFA与稳定斑块。80%的易损斑块里，坏死中心面积>1.0 mm2。
These dimensions are over the detection threshold of CCTA and, therefore, enable noninvasive risk stratification of individual coronary plaques according the presence or absence of large necrotic core. A plaque cross-section with low CT attenuation in the central part of the lesion might be indicative of the presence of a large lipid-rich necrotic core.A ring-like CT attenuation pattern of NCP was observed in ACS culprit plaques and in plaques associated with slow-flow and no re-flow phenomenon during percutaneous coronary intervention.The term napkin-ring sign (NRS) is used to describe this specific plaque attenuation pattern.The NRS is a qualitative plaque feature and can be defined in a noncalcified plaque cross-section by the presence of two features: a central area of low CT attenuation that is apparently in contact with the lumen; and a ring-like higher attenuation plaque tissue surrounding this central area (Figure 3).
这些坏死中心的面积都超过CCTA的检测阈，因此实现了通过有无大片坏死中心对冠脉斑块进行非有创性风险分层。病灶中心低CT衰减提示可能存在大块富含脂质坏死中心。在诱发ACS的斑块里以及PCI操作中发现的慢血流或无复流现象相关的斑块均可见非钙化斑块的环状低衰减影。餐巾环征 (NRS)就是用来描述这种特定的斑块CT衰减模式。NRS可描述斑块的性质，根据如下两个特征，能被定义成非钙化斑块：与腔内相接的中心性低CT衰减病变，周围有环状稍高衰减斑块组织包绕（见图3）。
Interestingly, NRS was present in both native (that is noncontrast-enhanced) and contrast-enhanced ex vivo CT images, suggesting that the feature is the result of differences in CT attenuation between the large necrotic core (a central low CT attenuation) and fibrous plaque tissue (ring-like higher attenuation).However, in vivo, some additional factors (such as the vasa vasorum) might influence the development of NRS.The area of necrotic core can be over twice the size in NRS plaques compared with non-NRS plaques (median 1.10 mm2 versus 0.46 mm2; P = 0.05).These values correlate with other histopathological observations that demonstrate the area of necrotic core in vulnerable plaques is >1.0 mm2 in the majority (~80%) of cases.In CT, the specificity of an NRS to identify an advanced coronary plaque and TCFA is excellent (98.9% and 94.1%, respectively).
有趣的是，NRS均出现于平扫与体内对比增强的CT影像，提示该特征是大片坏死中心（中心低衰减）与纤维斑块组织（环状稍高衰减）对比的结果。然而在体外，一些附加因素（如血管滋养管）可能影响NRS的发展。NRS斑块坏死中心面积比非NRS斑块大两倍(平均 1.10 mm2 vs 0.46 mm2; P = 0.05)。这些数值对应到组织病理学观察所显示的大部分病例（~80%）易损斑块坏死中心面积>1.0 mm2。在CT检查中，用NRS鉴定严重的冠脉斑块和TCFA，特异性非常好(分别是98.9% 和 94.1%)。
In a detailed plaque attenuation pattern analysis, a pattern-based plaque classification scheme has been proposed that classifies noncalcified plaques into homogeneous and heterogeneous, and stratifies heterogeneous plaques into NRS and non-NRS lesions (Figure 4).The diagnostic performance of pattern classification to identify advanced lesions was significantly better than conventional plaque classification made on the basis of calcified content (area under the receiver operating characteristics curve: 0.761 versus 0.678; P <0.001).In clinical investigations the NRS had 96–100% specificity for the identification of TCFA or culprit ACS lesions.
一个斑块衰减模式分析报告推荐应用斑块分类表，来把非钙化斑块细分成同质性、异质性斑块，把多层异质性斑块再细分成NRS和非NRS病变（见图4）。模式分类对鉴别严重病变的诊断价值远比传统的根据斑块钙化进行分类的方式高得多（受试者工作曲线的线下面积：0.761 vs 0.678; P <0.001）。临床调查发现，NRS检测TCFA或者ACS罪犯斑块有96–100%的特异性。
The NRS was more frequent in TCFA compared with non-TCFA plaques defined by OCT in two different clinical studies (TCFA 44–65% versus non-TCFA 4–16%; P <0.0001). NRS also independently predicted future ACS events (independently of positive remodelling and low attenuation) in a prospective study of 895 patients with a mean follow-up of 2.3 years(HR 5.6; P <0.001).The NRS seems to be a specific CT feature of plaques with a large necrotic core. However, the sensitivity of NRS is relatively low. A more-detailed analysis of different plaque attenuation patterns might provide means for the development of plaque classification scheme with improved diagnostic performance and identify vulnerable coronary plaques.
在2个不同的临床研究中，纳入了由OCT确诊斑块的患者，相对于非TCFA斑块，NRS更常应用于检测TCFA(TCFA 44–65% VS 非-TCFA 4–16%; P <0.0001)。一个纳入895例患者、平均随访期为2.3年的前瞻性研究(HR 5.6; P <0.001)也表明，NRS能独立预测ACS事件(同正性重构和低CT衰减)。NRS或许是大面积坏死斑块的特征性CT表现。然而，NRS的敏感度相对较低。因此，需要一个对不同斑块衰减模式的深入研究以提供更完善的斑块分类表，提高其诊断价值，识别易损斑块。
Positive remodelling
Rupture-prone plaques might not lead to significant luminal narrowing, owing to the effect of positive remodelling.Positive remodelling describes the compensatory enlargement of the vessel wall that occurs at the site of the atherosclerotic lesion as the plaque size increases, resulting in the preservation of luminal area. In histopathology studies, positive remodelling is associated with the abundance of macrophages and increased necrotic core. CCTA can measure the outer vessel wall and lumen dimension.The remodelling index is calculated as the vessel cross-sectional area at the site of maximal stenosis divided by the average of proximal and distal reference segments’ cross-sectional areas.A remodelling index threshold of ≥1.1 was suggested for the definition of positive remodelling visualized by CCTA, whereas some authors use ≥1.05 or >1.0 as the cut-off point on the basis of IVUS studies.Automated software now permits the easy quantification of the remodelling index.
正性重构
由于正性重构的作用，有破裂倾向的斑块不一定导致严重的官腔狭窄。正性重构指的是在有冠脉粥样硬化的血管壁，当斑块持续增大，血管壁也会发生代偿性的增大，从而维持管腔内有效面积。组织病理学研究显示：正性重构与丰富的巨噬细胞和激增的坏死中心有关。CCTA可以检测血管壁的外部以及官腔直径尺寸。重构指数的计算方法为：血管最大狭窄部分的的横截面面积除以近端和远端参照段的截面积的平均值。目前，正性重构CCTA可视化普遍定义为重构指数的阈值≥1.1，而一些研究人员则在IVUS研究的基础上取≥1.05 或 >1.0作为临界点。自动化软件也使得重构指数的量化更加容易。
The remodelling index assessed by CCTA correlates well with IVUS measurements; however, CCTA has a trend towards overestimation of remodelling index (95% CI of the mean difference 0.01–0.08; P = 0.005). Consistent with histopathological data, lesions with positive remodelling on CCTA have a higher plaque burden, a larger amount of necrotic core and a higher prevalence of TCFA assessed by VH?IVUS when compared to lesions without positive remodelling. Furthermore, in two correlative studies comparing CCTA with OCT, the CT?derived remodelling index was higher in TCFA compared with non-TCFA lesions classified by OCT (1.14 versus 1.02, P <0.0001; and 1.14 versus 0.95, P <0.0001). A remodelling index threshold of 1.08, which had the best diagnostic performance to identify TCFA, has been suggested by some investigators.
虽然CCTA评估的重构指数与血管内超声所测量出来的重构指数紧密相关，但是CCTA有对重构指数高估的趋势。组织病理学数据亦表明：结合CCTA和VH-IVUS检查，与正性重构的病变相比较而言，有正性重构的病变斑块负荷更大，坏死中心更多，出现TCFA的概率更大。此外，在2个比较CCTA和OTC的相关研究中，OTC将斑块分为TCFA和非TCFA，TCFA病变的CT衍生重构指数高于非TCFA病变(1.14 vs 1.02, P <0.0001; 1.14 vs 0.95, P <0.0001)。部分学者认为，将1.08作为重构指数的阈值，可以准确地检测出TCFA病变。
In a study of 38 patients with ACS and 33 patients with SAP, positive remodelling was strongly associated with culprit plaques in ACS (87%), but not SAP (12%; P <0.0001), and had the best diagnostic performance among other high-risk CT plaque features (low attenuation and spotty calcification) to identify the culprit lesions (sensitivity 87%; specificity 88%).Several other cross-sectional CCTA studies have also found a higher remodelling index in patients with ACS compared with patients with SAP (1.14–1.6 versus 0.9–1.2; P = 0.001–0.04). Positive plaque remodelling and/or low plaque attenuation was an independent predictor of ACS in a clinical study with 27 ± 10 months follow-up (HR 22.8; 95% CI 6.9–75.2; P <0.001). Among patients with one of these high-risk CT features, one in five will have an adverse coronary event within 1–3 years, a similar rate to those with a three-feature positive plaque determined by VH?IVUS in the PROSPECT trial. The remodelling index can be reliably measured by CCTA. However, a more-conservative remodelling index threshold of 1.1 is preferred in the assessment of CCTA images.
一项纳入了38例ACS患者和33例SAP患者的研究表明：ACS患者的罪犯斑块与正性重构密切相关(87%)，但SAP患者却不然(12%; P <0.0001)。而且相对于其他的高危CT斑块特征（如低CT衰减和点状钙化斑），正性重构对鉴别诊断罪犯斑块的的价值更高(敏感性87%; 特异性88%)。其他几个横断面CCTA研究还发现，ACS患者的重构指数高于SAP患者(1.14–1.6 vs 0.9–1.2; P = 0.001–0.04)。另一个随访期为27 ± 10个月的临床研究发现，斑块的正性重构和/或低CT衰减斑块是ACS的独立预测因素(HR 22.8; 95% CI 6.9–75.2; P <0.001)。PROSPECT试验也表明：有这些高风险的CT特征之一的患者中，五分之一的患者在1-3年内会出现不良的心血管事件，由VH-IVUS检测出的有3个高危斑块特征的患者也有类似的发病率。虽然通过CCTA可以准确地计算重构指数，但是实际的CCTA图像评估仍较为保守，首选1.1作为重构指数阈值。
Spotty calcium in plaques
Calcification is an ever-present feature of advanced coronary atherosclerosis.Coronary calcification assessed by CT is highly associated with plaque burden and related to poor clinical prognosis.However, the effect of calcification on plaque instability is controversial . Although most acute plaque ruptures in individuals with sudden cardiac death contain some calcification under histopathology, approximately two-thirds have only microcalcification, which is not detectable by CT. In a serial IVUS study, plaques with heavy calcification are clinically quiescent, whereas spotty (small) calcification was associated with accelerated disease progression in patients with SAP.Furthermore, the presence of spotty calcification was related to culprit plaques in patients with ACS in a study utilizing IVUS imaging.
斑块的点状钙化
钙化现象广泛存在于严重的冠脉粥样硬化斑块。冠脉钙化与斑块负荷密切相关，意味着临床预后差。然而，钙化对斑块不稳定性的影响却是众说纷纭。在心源性猝死的患者身上，通过组织病理学检查可以发现，大多数急性破裂的斑块都有钙化的现象，大约三分之二都只有CT无法检测到的微小钙化。系列IVUS研究发现，钙化严重的斑块在临床上处于非活动状态，而点状钙化却有加快SAP患者病情紧张的倾向。此外，点状钙化也与ACS患者的罪犯斑块有关。
In CCTA, spotty calcification is defined as a small, dense (>130 HU) plaque component surrounded by noncalcified plaque tissue. The typical cut-off to define a small calcification in CCTA as spotty is <3 mm. Spotty calcifications have been further differentiated into small (<1 mm), intermediate (1–3 mm), and large (>3 mm) calcifications.Small spotty calcification has the strongest association with vulnerable plaque features defined by VH?IVUS . Furthermore, in multiple cross-sectional studies in patients with ACS and SAP, spotty calcification is associated with ACS culprit lesions. However, results vary widely, and highlight the current uncertainty in the relationship between spotty calcification and plaque rupture.With further improvements in CT technology, detection of microcalcifications, which have been suggested to be a frequent feature in unstable angina, might be feasible.
通过CCTA，可以看到点状钙化是非钙化斑块组织包绕下的高密度 (>130 HU) 小成分。传统上，所谓“点状”的临界定义是CCTA视野下<3 mm的小钙化物质。如今，点状钙化又被进一步分为小型(<1 mm)、中型(1–3 mm)和大型(>3 mm)钙化。VH-IVUS检查发现的易损斑块特征与小型点状钙化密切相关。此外，多个纳入了ACS和SAP患者的横断面研究发现，点状钙化与ACS罪犯病变有关。然而，目前学术界的相关研究结果差异较大，难以确定点状钙化与斑块破裂有关。学术普遍认为微小钙化可作为不稳定型冠心病的常用检测指标，随着CT技术的提升，微小钙化在CT上显影也有望成为现实。
Functional plaque characteristics
Plaques develop at specific areas of coronary arteries where flow is disturbed, such as the outer walls of bifurcations, in side branches, and in the inner curve of arteries, despite risk factors for plaque formation (including smoking, high cholesterol levels, hypertension, and insulin resistance) affecting the whole vascular bed. Haemodynamic factors, such as endothelial shear stress (ESS), are pathologically important for the spatial localization and development of atherosclerotic plaques. Low ESS promotes an atherogenic milieu and high-risk plaque formation, whereas high ESS at stenotic vulnerable plaque sites promotes plaque rupture by destabilization of the fibrous cap. In the early 1990s, post-mortem studies indicated that more than two-thirds of infarctions evolve from nonobstructive lesions (that is lesions occupying <70% of the lumen).
斑块的功能特征
尽管理论上认为斑块形成的危险因素（包括吸烟，高胆固醇，高血压，和胰岛素抵抗性）对整个血管床都有影响，但是在冠脉的某些特殊部位（如分叉血管外壁，侧分支，动脉内弯处）干扰了血流的正常流动，导致斑块形成。此外，如血管内皮剪切力（ESS）之类的血流动力学因素也促进了动脉粥样硬化斑块的定植和演变。低ESS促进动脉粥样硬化的氛围和高风险的斑块形成，而在狭窄的易损斑块部位，高ESS可加剧纤维帽的不稳定性，促进斑块破裂。在上世纪90年代初，尸检报告显示，超过三分之二的梗死是从非梗阻性病变演变而来（即病变小于管腔的70％） 。
However, histopathological investigations have now challenged these studies, and a high portion of culprit lesions now seem to cause obstructive luminal narrowing (>75% area stenosis was seen in 70% of plaque ruptures), especially in late stages of plaque development before the disruption of the fibrous cap. These observations correlate with evidence that patients with ischaemic lesions have a poor prognosis. Indeed, increased plaque vulnerability might in part be a consequence of haemodynamic perturbations and altered shear stress owing to abnormal fractional flow reserve (FFR). Invasive FFR is the gold standard method for the identification of lesions that result in ischaemia, and the combination of ESS and FFR might, therefore, provide a novel functional dimension in plaque vulnerability assessment (Figure 1). Advances in computational fluid dynamics (CFD) have enabled the simulation of coronary flow and pressure-based metrics on the 3D geometry of the coronary artery tree.When CFD is added to standardly acquired CCTA dataset, ESS-CT and FFR-CT coronary maps can be calculated.
然而，如今组织病理学研究结果也开始质疑这些结论，大部分罪犯病变似乎也可以引起阻塞性的管腔狭窄（70%的斑块破裂病例发现>75%的管腔狭窄），尤其是纤维帽破裂前斑块形成的晚期。
再结合相关证据表明，有缺血性病变的患者预后不良。实际上，可能是由于血流储备分数异常，引起血流动力学紊乱以及剪切力改变，最终导致斑块易损性增加。目前，有创性FFR检查仍是诊断缺血性病变的金标准，而综合ESS和FFR的检查结果，或许可以作为用于检测斑块易损性的新方法（见图1）。计算流体动力学（CFD）的发展已经实现了在三维成像的冠脉树中，模拟冠脉血流和基于压力的度量。如果将CFD的数据补充到标配的CCTA数据集，ESS- CT和FFR - CT的冠状动脉图也可以通过计算得知。
ESS-CT
ESS is the tangential force generated by the friction of flowing blood on the endothelial surface of the arterial wall.In coronary artery segments with low and disturbed or turbulent flow—where ESS is low—the endothelial cell gene expression initiates a proatherogenic pattern.Persistently low ESS reduces nitric oxide production, increases LDL uptake, promotes endothelial cell apoptosis, and induces local oxidative stress and inflammation, which induce an atherogenic endothelial phenotype and subsequently leads to the development of high-risk lesions.By contrast, in straight arterial segments with undisturbed laminar flow—where ESS varies within a physiological range—endothelial cells express atheroprotective genes leading to plaque stability and quiescence.However, high shear stress at the stenotic portion of the plaque might initiate pathophysiologic processes that promote plaque destabilization and rupture. In serial IVUS studies of coronary arteries in diabetic pigs, the majority of vulnerable plaques developed in vessel segments characterized by persistently low ESS.
血管内皮剪切力的CT检查
ESS是指血流经过动脉壁与血管内皮摩擦产生的切线力。在冠状动脉低速血流段和乱流或湍流段，即ESS低的地方，内皮细胞启动促粥样硬化的基因表达。持续的低ESS可减少NO的生成，增加LDL的吸收，促进内皮细胞凋亡，引起局部氧化应激和炎症反应，从而介导粥样内皮表型，其后导致高危病灶的形成。相比之下，在层流的直动脉段，ESS随生理结构的变化而变化，内皮细胞表达粥样保护基因，使斑块稳定。然而，斑块狭窄部位的高剪切力会启动病理生理程序，使斑块稳定性降低并破裂。糖尿病猪冠脉血管内超声研究表明，大部分易损斑块发生在持续低ESS的血管段。
Furthermore, the magnitude of low ESS at baseline was significantly associated with the severity of high-risk plaque features at follow-up.Another animal study has refined the concept that low ESS promotes coronary plaque growth and vulnerability by demonstrating that dyslipidaemia and low ESS have a synergistic effect leading to the development of vulnerable atheromas.The first natural-history VH?IVUS study in humans assessed the left anterior descending artery in 20 patients with nonobstructive CAD at enrolment and at 6 months follow-up.Low ESS segments developed increased plaque area and necrotic core as well as constrictive remodelling, whereas high ESS segments developed greater necrotic core and regression of fibrous and fibrofatty tissue, and excessive positive remodelling, suggestive of transformation to a more-vulnerable phenotype.
并且，基线上低ESS的程度与随访高危斑块的严重程度密切相关。另一个动物研究展示了血脂异常和低ESS对易损粥样斑块的发展有协同作用，从而明确低ESS促进冠脉粥样斑块的进展与易损性。人类第一个VH-IVUS自然史研究收录了20个非梗阻性CAD病人，评估他们的冠脉左前降支，随访期为6个月。低ESS段的进展增加了斑块面积、坏死中心和缩窄重构，而高ESS段形成更大的坏死中心、纤维和纤维脂肪组织形成、过度重构，提示向更易损的斑块类型转变。
These observations highlight the importance of low ESS in vulnerable plaque development and high ESS in the destabilization of these plaques. In the Prediction of Progression of Coronary Artery Disease and Clinical Outcome Using Vascular Profiling of Shear Stress and Wall Morphology (PREDICTION) trial,a total of 506 patients underwent three-vessel IVUS examination and were assessed again at 1?year follow-up.The results demonstrated that large plaque burden and low ESS can independently predict plaques that progressively enlarge and develop substantial lumen narrowing.3D coronary geometry visualization by CCTA enables CFD to be applied to ESS-CT calculations and subsequent coronary wall behaviour assessment (Figure 5).These observations have been confirmed in a study using CCTA and IVUS for vascular profiling.
这些观察突出了低ESS促进易损斑块的发展、高ESS促进斑块失稳的重要性。用血管剪切力与管壁形态描述分析冠脉疾病进展预防与临床结果 (PREDICTION) 的试验中，506例患者行三支冠脉IVUS检查并随访1年。该结果显示，大斑块负荷和低ESS皆能预测进行性增大并发展为管腔阻塞的斑块。CCTA冠脉三维成像帮助CFD应用于ESS-CT，对冠脉壁运动情况进行评估（见图5）。以上观察结果已被一个CCTA和IVUS血管分析研究所证实。
CCTA was sufficiently accurate to determine ESS distribution in the main vessels and in the bifurcation regions.The CFD simulations in CCTA can be used to remove all plaques in a virtual environment to replicate the healthy vascular wall before the development of atherosclerotic plaques. In an exploratory investigation, static and dynamic parameters of ESS-CT were calculated in a virtual healthy coronary lumen to determine the best haemodynamic predictor of future plaque location. The results of this virtual experiment suggested that low ESS is a prerequisite for plaque formation; however, its presence alone is insufficient to predict future plaque locations. Dynamic factors that describe the time-dependent directional changes in ESS might, therefore, have an incremental prognostic value regarding plaque progression and vulnerability.
CCTA足以明确主血管以及分叉口处ESS的分布情况。CCTA里的CFD仿真技术能在虚拟环境中除去斑块，重构粥样斑块出现以前的健康血管壁。在一个探索性的调查研究中，ESS-CT的静态和动态参数被应用于虚拟健康冠脉管腔，来寻找最佳的血流动力学预测因子，预测斑块出现的位置。这个虚拟实验的结果提示：低ESS是斑块形成的先决条件，然而，它的单独出现不足以预测未来斑块形成的位置。就斑块进展与易损性而言，探究日后ESS发展方向的动态因素，也因此有着日益重要的诊断价值。
FFR-CT
Plaques that rupture cause substantial luminal narrowing at the time of the acute event. Histopathological investigations demonstrated that plaques that rupture but are nonstenotic are very rare. The assessment of luminal narrowing at the site of a large lipid-rich plaque might, therefore, be an important addition to high-risk plaque features and could aid the identification of vulnerable plaques.
血流储备分数的CT检查
急性心血管事件中，斑块破裂引起实质性的管腔狭窄。组织病理学研究显示斑块破裂却不引起狭窄的情况非常罕见。因此，对大块富含脂质斑块部位管腔狭窄程度的评估，应列为高危斑块的特征之一，有助于鉴别易损斑块。
In a histopathological study of ruptured plaques and TCFAs, 70% produced significant narrowing (>75%) of the cross-sectional luminal area.The remaining 30% of nonobstructive ruptured plaques were further subdivided into those with luminal narrowing of 50–75% and those with luminal narrowing <50% (25% and 5% of lesions respectively). Importantly, the investigators assessed the nonruptured TCFAs, which are the potential targets for noninvasive imaging, and found 40% also caused luminal narrowing of >75%. Because these lesions are likely to cause angina, they are probably more likely to be treated. However, lesions with an intermediate stenosis can be large, but not necessarily associated with symptoms of angina. Vulnerable plaques with a stenosis range of 50–75% (~50% of all TCFAs) are, therefore, the more-appropriate targets for noninvasive imaging (Figure 6).
一个关于破裂斑块和TCFAs的组织病理学研究显示：70%均引起管腔横断面的重度狭窄(>75%)，剩余30%的非梗阻性破裂斑块被进一步细分为中度狭窄（面积为50–75%，占25%）和轻度狭窄(面积<50%，占5%)。值得一提的是，作为非有创性影像检查的潜在目标，调查者评估非破裂TCFA时发现40%已引起管腔重度狭窄>75%。因为这些病变易于引起心绞痛，患者一般会积极治疗。然而，中度狭窄的病灶可能很大，却不一定引起心绞痛的症状。因此，狭窄程度为50–75% (＜50%的所有TCFAs)的易损斑块，都是非有创性影像检查的合理目标（见图6）。
Notably, the relationship between intermediate stenosis (50–75% diameter stenosis) and the presence of ischaemia is extremely unreliable—half of the lesions lead to ischaemia and the remaining half do not, as determined by invasive FFR measurement. In an intermediate lesion with abnormal FFR, the flow perturbations, altered ESS, and the physical strain changes placed on the plaque might be responsible for the development of a rupture-prone lesion. Furthermore, patients with an obstructive coronary plaque might develop an ACS owing to thrombus formation induced by high EES.In an investigation that included 70 patients with stable CAD, a strong association was observed between inflammatory cytokine activity and FFR; therefore, ischaemia might be involved in plaque progression and destabilization.
应当注意，中度狭窄(直径狭窄50–75%)与缺血表现，两者不是相关联的。半数的中度狭窄有缺血表现，其余则无，这是由有创性FFR检查所确定的。 在FFR异常的中度狭窄中，紊乱的血流、变化的ESS、机体过劳等作用于斑块，可能导致斑块发展成破裂倾向。由于高ESS介导的血栓形成，阻塞性冠脉斑块的患者可能发生ACS。一个纳入70例稳定型CAD患者的调查表明，炎症细胞因子的活性与FFR密切相关；因此，缺血可能参与了斑块进展与失稳的过程。
Moreover, in an explorative study, CCTA-visualized adverse features in obstructive plaques—that is, low attenuation plaque and positive remodelling—were strongly predictive of myocardial ischaemia. TCFAs with intermediate stenosis and positive FFR should be treated; however, the noninvasive identification of these lesions is challenging. Conversely, <1% of patients with a plaque resulting in an intermediate stenosis without ischaemia (FFR ≥0.8) have a myocardial infarction within 5 years, which is similar to a matched control population without diagnosed CAD.FFR-CT will help in the identification of lesions with ischaemia and likely improve CT accuracy for the detection of high-risk lesions. Importantly, FFR-CT can be derived from CCTA, without the need for additional imaging, extra radiation, or any medication (Figure 7).
在一个探究性研究中，CCTA观察下的阻塞性斑块的不良征象（即低衰减斑块与正性重构）有力地预测了心肌缺血的出现。中度狭窄与FFR阳性的TCFA应积极治疗，而对这些病变的非有创性检查结果却不尽如人意。相反地，斑块中度狭窄而无缺血症状(FFR ≥0.8)的病人，5年内发生心梗的人数却不到1%，这结果近似于无冠脉疾病的对照组。FFR-CT有助于诊断缺血性病变，有希望能提高CT检测高危病变的准确性。值得一提的是，FFR-CT数据可源自CCTA，无需接受重复的检查、额外的射线或者药物处理（见图7）。
Furthermore, FFR-CT provides a comprehensive three-vessel FFR from a single CCTA test, enabling FFR readings at any location of the coronary tree. Two prospective clinical trials have demonstrated that FFR-CT compares favourably to the reference standard invasive FFR measurements. In the Diagnosis of Ischemia-Causing Stenoses Obtained Via Noninvasive Fractional Flow Reserve (DISCOVER-FLOW) trial, FFR-CT was compared with invasive FFR, and had a per-vessel accuracy of 84.3%, sensitivity of 87.9%, and specificity of 82.2%. In addition, FFR-CT had better diagnostic performance than CCTA when identifying clinically significant coronary lesions; the area under the receiver-operator characteristics curve (AUC) were 0.90 for FFR-CT and 0.75 for CCTA (P = 0.001).
通过一次CCTA检查，FFR-CT可提供综合性的三支冠脉FFR数值，因此可以读取冠脉树任何部位的FFR。2个前瞻性临床试验表明，FFR-CT优于由有创性FFR检查所得的参考标准。在通过非有创性血流储备分数获悉引起缺血的狭窄(DISCOVER-FLOW)的临床试验中，对比有创性FFR检查，FFR-CT的总血管精确度为84.3%，敏感度为87.9%，特异度为82.2%。此外，鉴别临床上显著的冠脉病变时，FFR-CT比CCTA有更好的诊断价值；FFR-CT的受试者工作曲线的线下面积（AUC）为0.90，CCTA则为0.75(P = 0.001)。
Investigators in the Determination of Fractional Flow Reserve by Anatomic Computed Tomographic Angiography (DeFACTO) trial, a multicentre international study evaluating the diagnostic performance of FFR-CT, enrolled 252 patients. On a per-patient basis, FFR-CT was superior to CCTA in identifying ischaemic lesions (accuracy 73% versus 64%; sensitivity 90% versus 84%; specificity 54% versus 42%). Compared with obstructive CAD diagnosed by CCTA alone (AUC 0.68; 95% CI 0.62–0.74), FFR-CT was associated with improved discrimination of coronary stenosis with ischaemia (AUC 0.81; 95% CI 0.75–0.86; P <0.001).
在解剖性CT血管造影测定血流储备分数(DeFACTO)的临床试验中，一项多中心国际研究收录了252例患者，来评估FFR-CT的诊断绩效。以每个病人为基础，在诊断缺血性病变方面FFR-CT优于CCTA (准确度73% vs 64%; 敏感度90% vs 84%; 特异度54% vs 42%)。与单纯CCTA诊断梗阻性CAD相比(AUC 0.68; 95% CI 0.62–0.74)，FFR-CT能更好地辨别缺血性冠脉狭窄(AUC 0.81; 95% CI 0.75–0.86; P <0.001)。
Notably, in patients with intermediate stenosis, FFR-CT had more than a twofold increase in sensitivity compared with CCTA alone (82% versus 37%; no statistical data was reported), with no loss of specificity (66% versus 66%).A novel application of CFD is the possibility of implanting a stent in a virtual setting to test different stenting strategies and predict functional outcomes by changes in FFR.FFR-CT is an accurate new tool to assess lesion-specific ischaemia in a typically acquired CCTA exam and an improvement on the accuracy of CT alone.
尤其是对于中度狭窄的患者，FFR-CT检查的敏感度比单独CCTA检查增加了2倍以上(82% vs 37%; 暂无统计数据报告)，而不降低特异度(66% vs 66%)。现有望研发出一个新的CFD应用程序，能在虚拟环境中植入支架来测试不同植入方式地结果，以及通过FFR的改变来预测功能结果。传统上诊断斑块引起的缺血需要CCTA检查，FFR-CT是一个全新的精确诊断工具，同时也是CT准确性提高的体现。
Future directions for CCTA
Coupling individual plaque morphology with plaque specific functional data, including ESS and FFR, provide new opportunities for the noninvasive detection of plaques vulnerable to rupture. Combining morphological and functional metrics of coronary plaques (comprehensive plaque assessment) might lead to the development of a ‘vulnerable plaque score’ to indicate potential acute clinical events (Figure 8). Moreover, the high sensitivity and specificity of CCTA to identify atherosclerotic plaques can be combined with whole genome sequencing and epigenomics, whole transcriptome sequencing, unbiased proteomics, metabolomics, lipidomics, and lipoprotein proteomics to enable a stratified, step-wise approach (‘‘omics’ followed by CCTA if needed) to identify patients with subclinical CAD and vulnerable plaques.
Combining the complex information obtained from CT with bioinformatics analysis of genomic or proteomic data, as well as data derived from electronic medical records and drug information, might realize a personalized approach to cardiovascular disease prevention and care for each patient.Automated plaque assessment tools and computation fluid dynamics simulations will be necessary to provide multidimensional information on individual plaques. Importantly, the definition of vulnerable plaques by CCTA has not yet been established. Large, longitudinal imaging trials to test the prognostic value of comprehensive plaque assessment and derive standardized CT metrics of vulnerable plaques are also warranted.
Using hybrid scanners and novel contrast agents to acquire metabolic information might also improve CT plaque assessment. For example, inflammatory immune cell infiltration into the fibrous cap is a strong marker of plaque rupture vulnerability. In rabbits, the detection of inflammatory cells in atherosclerotic plaques by CCTA with iodinated nanoparticle contrast agent N1117 has been demonstrated. Furthermore, spectral CT imaging of gold-labelled HDL nanoparticles targeted to activated macrophages showed promising results in a mouse model of atherosclerosis. However, neither technique has been adapted for human patients.
The high metabolic activity of macrophages and their metabolic dependence on exogenous glucose provide opportunity for combined positron emission tomography and CT imaging using a radiolabelled glucose analogue—fluorine? 18-fluorodeoxyglucose(18F-FDG)—to noninvasively detect vulnerable, inflamed plaques. In a clinical investigation `culprit lesion site of patients with recent ACS as compared to stented lesions in patients with SAP. In a prospective clinical trial, 18F?sodim fluoride (18F-NaF) uptake co-localized to ruptured plaques in patients with ACS, and in patients with SAP 18F-NaF identified plaques with high-risk features, as determined by IVUS. The intriguing results showed that 18F-NaF positron emission tomography-CT imaging can detect metabolically active plaques by identifying areas of ongoing calcification activity.
结合个体斑块的形态与斑块详细的功能数据，如ESS和FFR，能提供新的无创性方式检查易损易破斑块。综合冠脉斑块的形态学与功能性指标（综合性斑块评估）有利于发展“易损斑块评分”，以早期诊断潜在的急性临床心血管事件（见图8）。CCTA对动脉粥样硬化斑块检查的高敏感度和高特异度，可与全基因组序列、表观基因组、全转录组排序、无偏倚蛋白质组学、代谢组学、脂类组学、脂蛋白组学结合，循序渐进地（如有必要，CCTA之后作“组学”的检查）识别亚临床CAD患者与易损斑块的患者。
结合CT获得的复杂信息与基因组学或蛋白组学的生物信息学分析，以及医学电子记录和药物信息数据，能实现为每个病人进行心血管疾病个体化预防与照料。为了提供每个斑块的多维信息，自动化斑块评估工具以及流体动力学模拟计算是必不可少的。值得一提的是，CCTA对易损斑块的定义还没确立，仍然需要大型的纵向成像试验来检测综合性斑块评估的预测价值以及获取易损斑块的标准化CT指标。
使用混合扫描仪以及新型对比增强剂来获得代谢信息也能改善CT对斑块的评估。例如，纤维帽内炎症性免疫细胞浸润，加剧了破裂斑块的易损性。在兔子模型实验中已证实，用碘化纳米颗粒造影剂N1117进行CCTA检查，可检测到动脉粥样硬化斑块中浸润的炎细胞。此外，老鼠动脉粥样硬化模型上也得到满意的结果，CT能谱成像显示金标记的高密度脂蛋白纳米颗粒聚集到激活的巨噬细胞。然而，两种技术均尚未做人类实验。
巨噬细胞高代谢活性和他们对外源性葡萄糖的需求，为使用放射性同位素标记的葡萄糖（18氟-脱氧葡萄糖）的PET-CT成像提供了可能，对易损、发炎的斑块进行无创性检查。在一个前瞻性临床试验中，18F氟化钠(18F-NaF)吸收共定位于ACS患者的破裂斑块中，以及有高危特征的SAP 18F-NaF鉴定斑块的患者中，并为IVUS检查结果所证实。这结果显示18F-NaF PET-CT成像能通过识别钙化活动区域来检测代谢活跃的斑块。
Conclusion
CCTA has the ability to depict all main epicardial coronary branches and, therefore, enables both individual plaques and global coronary plaque burden to be evaluated. Modern CCTA assessment can identify multiple high-risk features—such as NRS, positive remodelling, low CT attenuation, and low ESS—that make a plaque vulnerable to rupture and, therefore, put individuals at increased risk of an acute cardiovascular event. Conversely, the limited spatial and contrast resolutions of CT scanners prevent the detection of some histological features of vulnerable plaques, such as fibrous cap thickness or plaque rupture. Nanoparticle contrast agents and hybrid imaging provide valuable information regarding the metabolic activity of atherosclerotic plaques, but initial results, although encouraging, need to be confirmed in large prospective trials. Patients with acute and stable chest pain syndromes—and perhaps even asymptomatic patients—might receive improved, targeted therapy and derive the health benefits from such interventions. However, CCTA uses ionizing radiation and its current use must, therefore, be limited to symptomatic patients with established clinical indication for this noninvasive test.Generalized, large, prospective trials are needed to confirm the results of small, prospective or registry-based studies, because current data suggest that CCTA-based assessment of both individual and global coronary plaque features is highly predictive of future adverse events. Randomized trials testing whether interventions made on the basis of CCTA assessment can improve both health and economic outcomes should also be conducted. Further strategies targeting vulnerable plaques, or to treat patients more effectively, might also include medical therapy and/or plaque sealing with a biodegradable vascular scaffold.
结论
CCTA可以检测所有主要的心外膜冠状动脉分支，便于评估每个斑块以及整体的斑块负荷水平。现代的CCTA技术可以鉴别许多高危特征，比如NRS，正性重构，小幅度CT衰减和低ESS，这些都会导致斑块易于破裂，从而增加了急性心血管事件发生的风险。相反，CT扫描仪检测空间有限，无法检测出纤维帽厚度或斑块破裂等易损斑块的组织学特征。尽管初步结果表明，利用纳米造影剂和混合成像技术，可以了解动脉粥样硬化斑的代谢活性，但还需进一步的试验来证实结果。无论是急性稳定型胸痛综合征患者还是无症状患者，都可以在基于CCTA的检测中获益，得到更好的，更有针对性的治疗。然而，CCTA的使用终究会产生电离辐射，在临床应用中需加以限制，设定临床适应症。小型的、前瞻性或基于注册表的研究往往需要广义的、大型的前瞻性试验进一步证实结果，而目前的实验数据显示，CCTA可检测并评估每个斑块和整体斑块负荷水平，针对不利的心血管事件做出可靠的预测，那么，也有必要进行广义的、大型的前瞻性试验。至于这种基于CCTA的检测是否可以改善预后以及减少经济支出，还需要进一步的随机试验来确定。为了使处理易损斑块更具有针对性，或者使治疗更具效率，接下来还要探究药物治疗以及可降解药物支架治疗的相关领域。