Review Article Acta Cardiol Sin 2014;30:1-9

Assessment of Coronary Plaque Vulnerability with Optical Coherence Tomography

Shiro Uemura, Tsunenari Soeda, Yu Sugawara, Tomoya Ueda, Makoto Watanabe and Yoshihiko Saito

Several catheter-based imaging modalities have been developed over the past 2 decades for visualizing the morphological features of coronary atherosclerotic plaques that are susceptible to future development of serious cardiovascular events. Optical coherence tomography (OCT) is a new high-resolution intracoronary imaging modality based on near-infrared interferometry, and it has been shown to be able to identify various components of atheromatous plaques. In this review, we examine the histopathology of vulnerable plaques as a target for imaging technology, and discuss the evidence of OCT in identifying vulnerable atherosclerotic lesions in patients with coronary disease.

Key Words: · Optical coherence tomography · Vulnerable plaque

It is well recognized that the culprit lesions in pa- image processing. This review focuses on the usefulness tients with acute coronary syndrome (ACS) are usually of OCT for the evaluation of plaque vulnerability in pa- characterized by advanced atherosclerotic changes with tients with coronary artery disease. concomitant formation.1-3 The term “vulnera- ble plaque” is used to specify a high-risk plaque suscep- tible to the development of either rapid luminal OCT TECHNOLOGY or occlusive intraluminal thrombus, those lead to cata- strophic cardiovascular events.4-6 Over the past 2 de- OCT is a relatively new high-resolution intraco- cades, considerable effort has been made to identify ronary imaging technology based on near-infrared inter- such high-risk coronary plaques before their rupture for ferometry. The spatial resolution of OCT, nearly 10 mm the prevention of the critical coronary events. In recent on the lateral axis, is almost 10 times greater than that years, catheter-based intravascular imaging techno- of (IVUS). At present, 2 types of logies, especially intravascular optical coherence tomo- OCT systems, time domain (TD)- and Fourier domain graphy (OCT), have shown particular progress. Com- (FD)-OCT, are available for clinical use. TD-OCT is a con- pared with non-invasive or other invasive technologies, ventional type of intravascular device, and this system intravascular OCT has advantages in terms of higher spa- incorporates near infrared light source and optic al com- tial resolution, precise plaque localization, and real-time ponents that operate in a wavelength on 1,310 nm. Rather than using a broadband light source as in con- ventional TD-OCT systems, FD-OCT imaging systems employ a wavelength-swept laser as a light source, and Received: April 17, 2013 Accepted: August 28, 2013 First Department of Internal Medicine, Nara Medical University, this improvement enables faster image acquisition Nara, Japan. speeds and greater scan depths (Table 1). In addition, Address correspondence and reprint requests to: Dr. Shiro Uemura, the higher pull-back speed of FD-OCT can prevent heart First Department of Internal Medicine, Nara Medical University, 840 Shijo-cho Kashihara, Nara Japan 634-8522. E-mail: suemura@ motion artifacts and thus allow precise assessment of naramed-u.ac.jp the longitudinal distribution of plaque components.

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Table 1. Platform comparison between time domain (TD)- and Fourier domain (FD)-optical coherence tomography (OCT) TD-OCT FD-OCT (ILUMIEN OPTIS) Pullback Mode Nominal Survey mode High resolution mode Engine speed 15.6 fps 180 fps 180 fps Pullback speed 2.0 mm/sec 36 mm/sec 18 mm/sec Frame rate 7.8 frames/mm 5 frames/mm 10 frames/mm Pullbacklength 20mm 75mm 54mm Lines/frame 200 500 500 Scan diameter 6.8 mm 10.5 mm 10.5 mm

AsshowninFigure1,OCTvisualizes3layerstruc- lesions, which instead showed features such as plaque tures of normal coronary artery as well as plaque com- erosion or calcified nodules. In current clinical practice, ponent of atherosclerotic lesions. The ability of OCT in these non-rupture-type features in baseline lesions are tissue characterization of coronary atherosclerotic also considered to be characteristics of vulnerable coro- lesions has been well validated in clinicopathological nary plaques (Table 2). In clinical setting, OCT is able to studies.7-9 In addition, the drawback points of OCT are visualize plaque morphology possibly agree with au- the relatively shallow depth of light penetration into the topsy findings (Figure 2). Furthermore, recent studies arterial wall in the comparison with ultrasound, and the have shown that vulnerable plaques can develop not necessity of blood removal by contrast medium during only in native coronary but also in the neo- image acquisition. intima after long-term coronary implantation.14,15

Table 2. Pathological features of vulnerable plaque PATHOLOGICAL BACKGROUND OF PLAQUE I. Macroscopic features VULNERABILITY Large necrotic or lipid core Luminal thrombus Plaque hemorrhage Medical term “vulnerable plaque” was first used by Spotty calcification Muller et al. in defining the plaque with rupture that is Positive vascular remodeling oneofthetriggersfortheonsetofacutecardiovascular II. Microscopic features disease.10,11 In fact, pathological studies of the victims of Thin fibrous cap covering lipid core sudden cardiac death have revealed that more than 70% infiltration of ACS are attributable to the formation of occlusive Plaque neovasculization Endothelial denudation thrombus that is preceded by plaque rupture.3,12,13 How- Smooth muscle cell apoptosis ever, as noted in these autopsy studies, plaque rupture Protease expression is not the sole pathological cause of coronary events; no Endothelial adhesion molecule expression rupture was seen in the remaining 30% of the culprit III. Heat generation

FigureA 2. RepresentativeBC OCT findings plaque observed in patients with acute coronary syndrome. (A) Plaque rupture. Arrow indicates disrupted fibrous cap. * Represents space previously contained lipid Figure 1. OCT findings of normal coronary artery. Note. Clear pool. (B) Plaque erosion with thrombus formation (arrow). (C) Calcified differentiation of 3 layers in vessel wall. nodule (arrow).

Acta Cardiol Sin 2014;30:1-9 2 OCT Assessment of Plaque Vulnerability

Plaque rupture caps,23,24 development of calcification,25 and heat gener- As previously described in the scientific literature, ation.26 Intraplaque new blood vessel formation is an- coronary arterial wall often develops significant athero- other unique morphological feature of TCFA, usually sclerotic changes before the progression of luminal ste- originating from the adventitial .27,28 Intra- nosis. Figure 3 shows the representative cross-sectional plaque microvessels are immature and leaky due to the OCT images obtained from non-stenotic coronary pla- lack of basement membranes and pericytes,29,30 and que in patients with coronary artery disease (CAD). their deterioration is known to cause intraplaque hemo- Among these complex characteristics, thin-cap fibro- rrhage. This phenomena results in both rapid enlarge- (TCFA) is known as a vulnerable plaque sub- ment of plaque size and luminal stenosis.31-33 These type which is susceptible to rupture. TCFA is patho- histopathological features observed within TCFA are logically diagnosed when the plaque has a large lipid or candidate targets for coronary artery imaging with the necrotic core (> 40% of total lesion cross-sectional area) goal of detecting plaque vulnerability. However, it and a thin fibrous cap (< 65 mmthick).3,16 An autopsy should also be noted that clinically silent plaque rupture study of ruptured plaques in patients with sudden car- is not rare.33-35 diac death found that 95% of these caps measured < 64 mmthick.3 Notably, a recent computer simulation study Non-rupture type vulnerable plaque showed that fibrous cap thickness and necrotic core size Plaque erosion is characterized pathologically by a are independent determinants for plaque disruption.17 continuous intimal layer without rupture or discon- Additionally, TCFA is frequently accompanied by macro- tinuation, usually accompanied by an intraluminal phage infiltration and matrix metalloproteinase (MMP) thrombus overlying a modestly occlusive plaque, al- expression in the fibrous cap covering the lipid core.18,19 though standard diagnostic criteria have not been de- Many studies have pointed out that high macrophage fined.3,36 Typically, the endothelial cell layer is denuded density is characteristic of lesions vulnerable to rupture. andtheexposedfibrouscapconsistsofsmoothmuscle Ex vivo studies of human coronary artery plaques have cells, rich proteoglycans, and varying numbers of inflam- shown that the density and pattern of macrophage infil- matory cells. Autopsy data have demonstrated that tration at plaque shoulders correlate with degree of plaque erosion is more frequent in women < 50 years of vulnerability.20-22 Chronic inflammation within TCFA also age, and lesions with such erosion are often negatively stimulates smooth muscle cell apoptosis within fibrous remodeled.9 Autopsy studies have shown that 20% to

A BCD

E FGH Figure 3. Plaque characterization of non-stenotic coronary atherosclerotic lesions with optical coherence tomography. (A) Normal coronary artery. (B) Stable fibrous plaque. (C) Thick cap fibroatheroma, two arrows indicate thickness of fibrous cap. (D) Thin cap fibroatheroma, two arrows indicate thickness of fibrous cap. (E) Calcium deposition (arrow). (F) Plaque neovasculization (arrow). (G) Macrophage infiltration at the surface of plaque (arrows). (H) Possible plaque erosion with luminal thrombus (asterisk).

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40% of acute coronary events are attributable to non- ral history of coronary plaques with vulnerable char- ruptured plaques,12,37,38 indicating that coronary throm- acteristics. bosis resulting from plaque erosions is not rare but is A recent clinical study using serial virtual his- rather an unexpectedly common phenomenon. In cur- tology IVUS (VH-IVUS) reported that 75% of TCFA rent clinical practice it is difficult to diagnose plaque healed and 25% of TCFA maintained baseline charac- erosion using imaging technologies, because the patho- teristics during 12-month follow-up.43 It is important genesis of plaque erosion has not been elucidated and to note that not all vulnerable plaques progress to no currently available imaging modalities can dif- rupture, although the mechanism of TCFA healing is ferentiate the existence of endothelial cells covering not well established. atherosclerotic plaques. As yet there have been very Motoyama et al. performed computed tomography few clinical studies targeting the role of plaque erosion (CT) angiographic examinations on 1059 patients and in the development of ACS, except for a few case re- prospectively followed them for 27 months for the ports using OCT.39,40 Furtherresearchinbothbasicand development of ACS.44 Coronary lesions were analyzed clinical fields will be needed to precisely define plaque for the presence of 2 features indicating plaque vulnera- erosion and to determine its clinical significance. bility: positive remodeling (lesion diameter at the Calcified nodules are a type of vulnerable plaque plaque site ³ 10% larger than that of the reference seg- that account for approximately 2% to 7% of all coronary ment) and low attenuation plaques (noncalcified pla- events.3 These nodules are defined pathologically as ques with a density < 30 Hounsfield units). Although fibrocalcific plaques with disruption of the luminal sur- these features are not completely consistent with face, little or no underlying necrotic core, and thrombus pathological studies, ACS developed in 22% of patients formation overlying the calcified surface and protruding who had plaques with both vulnerability features at into the vascular lumen. The underlying plaques are baseline, compared with 0.5% of patients who had usually characterized by heavy calcification and large plaques without these features. None of the patients plates of calcified matrix with surrounding areas of with normal CT developed ACS. The pre- fibrosis, inflammation, and neovascularization. Inter- sence of 1- or 2-feature positive plaques was the only estingly, pathological examination has shown that these significant independent predictor of ACS. lesions are found predominantly in the mid-right coro- nary artery, where coronary torsion stress is maximal.3 Intravascular ultrasound (IVUS) and OCT examination VULNERABLE PLAQUE IMAGING WITH OCT are able to diagnose calcified nodules in coronary ar- teries.41 Although the calcified nodule has been cate- Conventional gray-scale IVUS has been used in gorized as a vulnerable plaque, a recent prospective catheterization laboratories for over 20 years.45,46 It is an clinical study using 3-vessel IVUS reported that this established modality that is used not only for guidance nodule type was not a predictor for major adverse during percutaneous coronary intervention (PCI), but events during 3 years of follow-up.42 also, in the context of clinical studies, for evaluating the tissue characteristics of coronary plaques and assessing Natural course of vulnerable plaques plaque progression or regression.47,48 Its ability to pro- Until recently, morphological findings regarding vide precise qualitative and quantitative measurements vulnerable plaques had been limited in the context of of total plaque area and volume (burden), even in cases autopsy studies. Coronary specimens are retrospec- with positive vascular remodeling, make it invaluable for tively analyzed after event occurrence, so it is difficult evaluating the vulnerability of coronary plaques. How- for pathological studies to investigate longitudinal ever, since conventional IVUS is limited to relatively low changes in vulnerable plaques as well as the baseline spatial resolutions (100-150 mm) and cannot accurately plaque morphologies that cause future development differentiate plaque components. of coronary events. Only modern imaging techno- Because of its excellent spatial resolution, OCT is logies in clinical practice are able to observe the natu- currently the only imaging technology that can precisely

Acta Cardiol Sin 2014;30:1-9 4 OCT Assessment of Plaque Vulnerability measure the thickness of the fibrous cap and also di- and TCFA and macrophage were frequent in patients rectly visualize microvessels within coronary athero- with inadequate glucose control of A1C > 8%.53 In CKD sclerotic plaques. Furthermore, OCT is able to identify patients, it is reported that compared to non-CKD pa- macrophage infiltration in the plaque, an important fea- tients, the patients with CKD had a larger lipid burden ture of continuous inflammation in TCFA (Figure 3).7,49 with a higher prevalence of calcium, -crystal The other advantage of OCT is its ability to detect and disruption.54 intracoronary thrombi that are not usually well vi- sualized by other imaging modalities. OCT not only vi- Neoatherosclerosis sualizes thrombi, but can also distinguish between red Recent studies have reported the development of and -rich white thrombi.50 neoatherosclerosis changes inside of both bare metal and drug eluting stents several years after im- Vulnerable plaque in native coronary arteries plantation.14,15 These changes include lipid accumula- In patients with CAD, TCFA was detected by OCT in tion, calcium deposition, macrophage infiltration de- 72% of cases with ST elevation myocardial velopment of neovascularization within neointima area (STEMI) and 50% of those with non-STEMI culprit le- ofthestent,andareassumedtoplayanimportantrole sions, as compared to 20% of cases with stable angina in the development of late in-stent restenosis and late pectoris lesions; the fibrous cap thicknesses in these 3 stent thrombosis that leads to secondary coronary groups were reported to be 47, 54, and 103 mm, respec- events related to the culprit lesion (Figure 4). Although tively.8 Furthermore, OCT examination after thrombus precise mechanisms in the development of neoathero- aspiration in patients with ACS revealed that 73% of pa- sclerosis, Kato et al. recently showed that several factors tients showed plaque rupture, and the mean thickness independently predicted neoatherosclerosis, including of the ruptured fibrous cap was 49 mm.51 These OCT stent age ³ 48 months [odds ratio (OR) 2.65, 95% confi- observations in patients with ACS correspond well with dence interval (CI) 1.43-4.92], drug-eluting stents (DES, established pathological findings of vulnerable plaques OR 2.65, 95% CI 2.41-13.24), age ³ 65 years old (OR that resulted in coronary events. 1.91, 95% CI 1.05-3.44), current smoking (OR 2.30, 95% The incidence of secondary cardiovascular events is CI 1.10-4.82), chronic kidney disease (CKD: OR 4.17, 95% substantially higher in patients with previous ACS than CI 1.42-12.23). In contrast, the use of angiotensin-con- in those with stable angina. Recent OCT study by Kato et verting enzyme inhibitors and angiotensin II receptor al. showed that compared with non-culprit plaques in antagonists was a protective factor against neo- non-ACS patients, the number of lipid-rich plaques was (OR 0.42, 95% CI 0.22-0.80).55 Although greaterintheACSpatients(1.9inACSpatientsvs.1.1in effective intervening treatment has not been estab- non-ACS patients, p = 0.022) In addition, it is reported lished on neoatherosclerosis, these results may support that non-culprit plaques in ACS patients had a wider the importance of secondary prevention after stent im- lipid arc, a longer lipid length, a thinner fibrous cap, and plantation. a higher prevalence of neovascularization. Moreover, Recent advance in OCT technology enable us to re- TCFA (67.4% vs. 14.9%, p < 0.001), macrophage (88.2% construct 3 dimensional images of neointimal tissue and vs. 37.9%, p < 0.001), and thrombus (23.5% vs. 0%, p < coronary stent. By using this technology, it is easy to 0.001) were more frequent in ACS patients, suggesting recognize the spatial distribution of neointimal cover- that non-culprit plaques in ACS patients are more vul- age of stent struts as well as neoatherosclerotic changes nerable than in non-ACS CAD patients.52 within the stent (Figure 5). Both diabetes mellitus (DM) and chronic kidney dis- ease (CKD) are established risk factors for the develop- Prediction of future development of ACS ment of ACS. Recent OCT study also has shown that In the recent longitudinal, multicenter PROSPECT compared with non-DM patients, DM patients have a study,56 693 ACS patients were evaluated using 3-vessel larger lipid pool and a higher prevalence of calcification grayscale and VH-IVUS, and the relation between base- and thrombus. Especially, the lipid burden was larger line IVUS characteristics of culprit and non-culprit

5 Acta Cardiol Sin 2014;30:1-9 Shiro Uemura et al.

A BCD

E FGH Figure 4. Development of neoatherosclerotic changes observed within coronary stent. (A) Fibrous neointima. (B) Microchannel. (C) Lipid accumulation. (D) Intimal laceration. (E) Calcium deposition. (F) Thin cap fibroatheroma. (G, H) Luminal thrombus. Note. Each OCT image involves stent strut images. plaques and the secondary occurrence of major adverse cardiovascular events (MACE) at 3 years was studied. In this patient population, the MACE rate during 3 year follow-up was 20.4%, and these events were equally attributable to the progression of non-culprit lesions and to index culprit lesions treated by PCI. For MACE related to non-culprit lesions, no angiographic variables were associated with subsequent events. By contrast, the following IVUS and VH-IVUS baseline plaque para- A meters independently predicted the subsequent de- velopment of non-culprit lesion-related MACE: large plaque burden (³ 70%), higher stenosis rate (minimal luminal area £ 4.0 mm2),orthepresenceofVH-IVUS- detected TCFA. In addition, no events developed in coronary plaque segments with < 40% plaque cross- BCD sectional area. However, even when all 3 predictive variableswerepresent,theeventraterosetoonly Figure 5. 3D OCT image of coronary stent. In this case, bare metal stent (BMS) was implanted in the culprit lesion of acute myocardial 18.2%, indicating that although IVUS-derived character- infarction. FD-OCT examination was performed 8 months after istics suggest the occurrence of a subsequent event, implantation. (A) 3D image of BMS showing variety of neointimal they are not sufficient to predict which will coverage over coronary stent. (B) Cross-section of distal part of BMS undergo plaque progression. It is possible that the rela- showing uncovered stent strut. (C) Cross-section of middle part of BMS showing struts covered with fibrous neointima. (D) Cross-section of tively low spatial resolution of IVUS failed to dif- proximal part of BMS showing struts with malapposition. Note. Spatial ferentiate fine vulnerable structures in atheromatous distribution of various degree of neointimal coverage within stented non-culprit lesions, and that integration of systemic factors that influence plaque biology is necessary for Uemura et al. examined the baseline OCT findings in more precise estimation of future ACS development. non-stenotic coronary plaque within non-culprit coro- However, specific OCT findings for predicting the nary artery, and followed these plaques up to 12 months. future development of ACS have not been established. In their study, baseline OCT findings of TCFA and micro-

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