Online October 22, 2018 Journal of Neuroendovascular Therapy 2018; 12: 603–608 DOI: 10.5797/jnet.ra.2018-0070

Special Issue: Carotid Plaque Diagnosis Usefulness of Plaque Diagnosis Using during Carotid Artery Stenting

Takeshi Wada,1 Katsutoshi Takayhama,2 Kaoru Myouchin,2 and Kimihiko Kichikawa1

The preoperative plaque diagnosis and evaluation of plaque protrusion (PP) into the lumen after stent placement or postdilatation are very important for the prevention of ischemic complications in carotid artery stenting (CAS). The usefulness of intravascular ultrasound (IVUS), which makes these evaluations during CAS possible, is discussed.

Keywords▶ intravascular ultrasound, carotid artery stenting, plaque protrusion

Introduction so the accurate diagnosis of PP is required for the preven- tion of ischemic complications. In this article, the useful- The clinical application of intravascular ultrasound (IVUS) ness of IVUS in CAS and, particularly, for the diagnosis of began as Yock et al. reported IVUS images of human plaques and PP is discussed. peripheral blood vessels in 1988 and the human coronary artery in 1989,1) and the technique has since been applied Types of IVUS Devices Used in CAS widely to not only the coronary artery and peripheral blood vessel territories but also carotid artery stenting (CAS). The IVUS consoles and catheters presently in wide used in Since IVUS clearly visualizes plaques and permits accu- Japan are provided by three companies: Philips Volcano rate measurements of the luminal diameter of the normal as (San Diego, CA, USA), Boston Scientific (Natick, MA, well as stenosed part of the blood vessel, it provides infor- USA), and Terumo Corporation (Tokyo, Japan).3) IVUS mation concerning the localization and properties of the catheters are classified into the electronic scanning and plaques and information useful for the determination of the mechanical scanning types. OptiCross of Boston Scientific diameter, size, and type of the balloon or stent to be used. and ViewIT of Terumo are mechanical scanning types, and It has been reported recently that plaque protrusion (PP) Eagle Eye and Visions of Volcano are electronic scanning into the stent lumen after postdilatation during CAS is types. Each type has its merits and demerits. In mechanical closely related to perioperative ischemic complications,2) scanning IVUS catheters, a single transducer is rotated at 1800 rpm, and as a high frequency (40–45 MHz) is used, 1Department of Radiology, Nara Medical University, Kashihara, images of higher resolution can be obtained compared with Nara, Japan electron scanning types. Presently, mainly mechanical 2Department of Radiology and Interventional Neuroradiology, scanning type IVUS catheters are used for percutaneous Ishinkai-Yao General Hospital, Yao, Osaka, Japan coronary intervention (PCI). However, in mechanical scan- Received: April 26, 2018; Accepted: August 7, 2018 ning IVUS, the rotation speed of the transducer becomes Corresponding author: Takeshi Wada. Department of Radiology, irregular in tortuous blood vessels, occasionally resulting Nara Medical University, 840 Shijo-cho, Kashihara-shi, Nara in distorted images (non-uniform rotation distortion 634-8521, Japan [NURD]). In electronic scanning types, the frequency of Email: [email protected] the transducer is 20 MHz, and while the resolution is infe- This work is licensed under a Creative Commons Attribution-NonCommercial- rior to that of mechanical scanning types, there are merits NoDerivatives International License. such as exclusion of the guidewire from the image, no ©2018 The Japanese Society for Neuroendovascular Therapy NURD, and a short distance from the catheter tip to the

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transducer because the setting is relatively simple, and the luminal diameter of the distal part of the common carotid guidewire can be passed through the center of the catheter. artery) and postdilatation balloons with a diameter ≤80% Electronic scanning IVUS is often used in PCI of chronic of the luminal diameter of the distal normal part are total occlusion lesions and peripheral blood vessels and also selected. After stenting and postdilatation, widely in CAS. In this article, primarily electronic scanning 1) detection of the insufficient expansion of the deployed IVUS of Philips Volcano is discussed. stent, stent thrombosis, and PP 2) evaluation of the diameter of the most stenosed part Significance of the Use of IVUS in and cross-sectional contour of the stenosed part after stent- CAS ing and vascular dilatation, and 3) evaluation of stent apposition to the vascular wall are In usual grayscale IVUS, a normal artery is visualized as a possible by IVUS. The relationship between the detection lumen surrounded by annular layers. As the intima is thick- of PP by IVUS and postoperative ischemic complications ened due to atherosclerosis, the vascular wall is visualized as is discussed later. a three-layer structure. The innermost layer histologically corresponds to the intima and internal elastic layer, and the Plaque Diagnosis by VH-IVUS outermost layer shows a layer with even higher echogenic- ity, which corresponds to the adventitia and external elastic By comparison with histopathological study of the coro- layer. Between these two layers is a thin layer with low nary artery, VH-IVUS has been reported to have high pre- echogenicity, which corresponds to the media. If a low dictive accuracy. Nair et al. examined whether the four echoic area is observed in a plaque, the plaque is considered histological types classified by VH-IVUS (FI, FF, DC, and likely to be a soft plaque that contains necrotic tissue and NC) agreed with actual histological classification in coro- intraplaque hemorrhage. Calcification is visualized as an nary artery samples (n = 51) and reported a high discrimi- area of extremely high echogenicity and is accompanied by nating power of VH-IVUS with sensitivities of 95.7, 72.3, an acoustic shadow. The echo level of fibrous plaques is 71.9, and 86.5% and specificities of 90.9, 97.9, 96.6, and between those of soft and calcified plaques.4) ChromaFlo 98.9%, respectively.5) Although studies in which the diag- presents the blood flow in the lumen in red and permits more nostic ability of VH-IVUS was examined by comparison distinct observation and assessment of the lumen (true with histological findings in the carotid artery have been lumen). In addition, by virtual histology IVUS (VH-IVUS), few, Diethrich et al. examined plaque properties by frequency analysis of the data obtained by IVUS is per- VH-IVUS in 15 patients who underwent carotid endarter- formed, and histopathological properties of plaques can be ectomy (CEA) after examination of coronary artery plaques presented in different colors (fibrous tissue [FI]: green, fibro- compared the following six categories based on VH-IVUS fatty [FF]: yellowish green, dense calcium [DC]: white, with the histopathological findings.6) necrotic core [NC]: red), making more detailed evaluation of Pathological intimal thickening, where the intimal plaque properties possible compared with grayscale IVUS.4) media thickness was >600 mm, the FF plaque component Generally, the objectives of the use of IVUS in CAS are was >10%, and there was confluent NC or calcium that as follows: amounted to <10% of the total plaque cross-sectional area; 1) to evaluate the localization, length, and flatness of the fibroatheroma, where there was confluent NC> 10% of the lesion; total plaque cross-sectional area; calcified fibroatheroma, 2) to accurately determine the luminal diameter of the dis- fibroatheromatous plaque with a confluent area of calcium; tal and proximal normal parts and media-to-media diameter thin-cap fibroatheroma, where there was NC >10% of the of the most stenosed part (minimal lumen diameter [MLD]); total plaque cross-sectional area, and the NC was confluent 3) to diagnose plaque properties (calcification and against the lumen; calcified thin-cap fibroatheroma, thin- necrosis, presence or absence of lipid pools, degree of cap fibroatheromatous plaque with a confluent area of cal- fibrosis, presence of unstable plaques), and cium; fibrocalcific, where there was a confluent area of 4) to accordingly decide the appropriate stent type, stent calcium >10%, with NC and FF plaque each <10% of the size, and size of pre- and postdilatation balloons. At our total plaque cross-sectional area. institution, with the smallest diameter not smaller The diagnostic accuracy of VH-IVUS was 99.4% for than the diameter of the proximal normal part (mostly the thin-cap fibroatheroma, 96.1% for calcified thin-cap

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fibroatheroma, 85.9% for fibroatheroma, 85.5% for fibro- with pulse artifact, and it has disadvantages such as the dif- calcific, 83.4% for pathological intimal thickening, and ficulty in delineating fibrous capsules and calcified lesions. 72.4% for calcified fibroatheroma. While the diagnostic However, VH-IVUS is invasive and is not appropriate to accuracy for calcified fibroatheroma was relatively low, perform repeatedly, but it has the advantages that it pro- it was recognized as thin-cap fibroatheroma or calcified vides useful information about the accurate location of cal- thin-cap fibroatheroma, and the diagnostic accuracy of cification and fibrous lipid in the plaque as color maps and lesions considered to be vulnerable was reported to be has excellent reproducibility and objectivity.10) high. However, Tamakawa et al. performed VH-IVUS The evaluation of the properties of atheroma by VH- during CEA and compared the findings with true plaque IVUS is also considered useful for the prediction of the properties in six patients and reported that caution is nec- occurrence of perioperative bradycardia and hypotension. essary as intraplaque hemorrhage (two patients) and a Tamakawa et al. performed VH-IVUS immediately before thrombus attaching to a plaque (one patient) were also stent placement during CAS and evaluated plaque proper- visualized as stable fibrous lesions, possibly leading to ties in 20 patients. They reported that the percentage of DC underestimation of vulnerability. Also, calcified lesions determined by VH-IVUS was higher in the eight patients different in hardness and stability, such as nodular calcifi- who showed a decrease in blood pressure after CAS cation and sand-like calcification, in actual pathological (a decrease in the systolic blood pressure to ≤90 mmHg samples could not be distinguished by VH-IVUS.7) It is or by 30 mmHg compared with the preoperative level) necessary to remember these reports in the assessment of (0%–6%, mean: 2.9%) than in the 12 who showed no plaque properties by VH-IVUS. decrease in blood pressure after CAS (0%–2%, mean: 1.0%) There have also been a few studies about whether the and that a decrease in blood pressure after CAS occurred occurrence of distal embolism during CAS can be pre- more often in patients with highly calcified lesions.11) dicted by VH-IVUS. Matsumoto et al. compared the results of evaluation of plaque properties by intraoperative VH- PP during CAS IVUS with the amount of aspirated debris in 25 patients who underwent CAS with distal balloon protection and reported The projection of plaque into the stent lumen during PCI is that more debris was generated as the total plaque volume called PP or plaque prolapse. Reportedly, its incidence is (Rs = 0.480, p = 0.015) and FF volume (Rs = 0.561, p = 4.95%–22.5%,12,13) and it is unrelated to perioperative isch- 0.001) were larger.8) In addition, Yamada et al. performed emic complications.14) PP may also be observed during CAS, diffusion-weighted MRI (DWI) before and after CAS in 45 but reports of its incidence or relationship with periopera- patients who underwent VH-IVUS during CAS and exam- tive ischemic complications have been few. Concerning PP ined the relationship between plaque properties evaluated during CAS, Kotsugi et al. retrospectively analyzed 354 by VH-IVUS and the presence or absence of newly appear- lesions of cervical carotid artery treated by a stan- ing ipsilateral silent ischemic lesions (NISIL). Accord- dard procedure of CAS and reported: PP occurred in 2.6% ing to their results, the FF area was significantly larger (nine patients), cerebral infarction was noted in six (66.7%) in the NISIL-positive group (n = 18) than in the NISIL- of the nine patients with PP and was major in one negative group (n = 27) (32.7 ± 13.2 and 18.3 ± 9.8%, and minor stroke in five patients, the incidence of cerebral respectively; p <0.001), and the fibrous area was signifi- infarction was significantly higher in those who developed cantly narrower (59.2 ± 9.5 and 74.6 ± 9.1%, respectively; PP, and PP was closely associated with perioperative isch- p <0.001).9) emic complications.2) Accurate diagnosis of PP is consid- Tamakawa et al. obtained MR plaque images (black ered necessary for the prevention of perioperative ischemic blood imaging) before CAS, performed VH-IVUS imme- complications and have been reported. diately before stent placement during CAS, and compared Only papers concerning PP during CAS using IVUS15,16) plaque properties evaluated by each method in 10 patients. have been reported and its incidence has been reported to They reported that the black blood MRI and VH-IVUS be 7.8%–10%. While, according to Kotsugi et al.,2) the findings were closely correlated in FF lesions but that the incidence of PP observed by both IVUS and DSA was low diagnosis of calcification was difficult by black blood MRI. at 2.6%, which was lower than in previous reports, that of As a result, they concluded that black blood MRI can pro- PP observed by IVUS alone was 7.6% and was close to the vide high-contrast images of FF plaques but is associated figures reported previously. Shinozaki et al. also reported

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Fig. 1 Case 1: 68-year-old female. Asymptomatic right stenosis. (A) Preprocedural time of flight cervical MRA showed severe stenosis at the origin of the right internal carotid artery (arrow). (B) MRI plaque imaging (2D T1-weighted, transverse) showed a hyperintense area in the plaque at the site of stenosis, suggesting an unstable plaque (arrow). (C) Lateral view right angiogram showing severe stenosis at the origin of the internal carotid artery (arrow). (D) Luminal view of the internal carotid artery in the area distal to the site of stenosis. The luminal diameter was 4.9 × 4.9 mm, and a balloon 4 mm in diameter was selected for postdilatation. (E) VH-IVUS image of the narrowest part. NC was observed around the stenosed part, suggesting an unstable plaque. (F) Since the luminal diameter of the common carotid artery was 6.8 × 6.4 mm, Precise stent (7 × 40 mm) was selected. (G) Predilatation was performed using a balloon catheter 3.0 mm in diameter with filter protection (arrow). (H) Lateral view right common carotid artery angiogram obtained immediately before stenting. The stent is placed at the optimal position. (I) Lateral view right common carotid artery angiogram immediately after stenting showing residual stenosis (arrow). (J) Postdilatation was performed using a balloon 4.0 mm in diameter. (K) Right common carotid artery angiogram immediately after postdilatation showed a filling defect at the site of stenosis, suggesting PP (arrow). (L) PP was observed similarly by IVUS (arrow). (M) Carotid Wallstent (Boston Scientific, Natick, MA, USA) 6× 22 mm was additionally placed by the stent-in-stent technique. (N) PP was obliter- ated in the right common carotid artery angiogram (lateral view) after stent placement (arrow). (O) PP was also obliterated in the IVUS image. (P) A large amount of debris was observed in the recovered filter. (Q) Diffusion-weighted MRI of the brain on the day after the procedure. Many symptomatic ischemic lesions were observed in the right cerebral hemisphere. Although minor postoperative stroke was observed, neurological symptoms completely disappeared within 30 days. IVUS: intravascular ultrasound; NC: necrotic core; PP: plaque protrusion; VH: virtual histology

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that the incidence of PP was 7.8% by IVUS and 2.6% Kotsugi et al.,2) also, stent in stent was performed using by DSA, indicating that IVUS is more sensitive for PP Carotid Wallstent until PP disappeared in four patients who than DSA.16) developed PP during the procedure after approval of insur- In addition, Kotsugi et al. showed unstable plaque and ance coverage of Carotid Wallstent, but two showed cere- the use of an open-cell stent were related to the risk of PP.2) bral infarction (Fig. 1), which was a major stroke in one of If unstable plaque is suggested by preoperative examina- them. Since the risk of cerebral infarction increases once tion (MR plaque imaging or VH-IVUS) (Fig. 1B and 1E), PP occurs, it is considered important, first, to perform a the use of a closed-cell stent, in which is PP is less likely to procedure that does not induce PP. occur, is recommended. Summary Usefulness of IVUS in CAS In CAS, IVUS is useful for the plaque diagnosis and intrap- The significance of IVUS and VH-IVUS in CAS isas rocedural diagnosis of PP, and it is considered a device described above, and one of the advantages of the use of necessary to prevent ischemic complications and improve IVUS during CAS is that the optimal stent size can be the outcome of CAS. selected by the measurement of the exact vascular diame- ter. If a stent larger than the diameter of the normal vessel Disclosure Statement is selected, it causes overdilatation, which is considered to increase the possibility of PP. Particularly, one of the risk There are no particular conflicts of interest to disclose con- factors of the slow flow phenomenon caused by clogging cerning the contents of this paper. due to plaque rupture during the use of a filter protection device is reported to be the use of a stent with a large diam- References eter,17) suggesting that embolism is induced by the use of a large-diameter stent. Thus, PP and the slow flow phenome- 1) Yock PG, Linker DT, Angelsen BA: Two-dimensional non may be prevented by selecting the appropriate stent intravascular ultrasound: technical development and ini- size by accurate measurement of the blood vessel using tial clinical experience. J Am Soc Echocardiogr 1989; 2: IVUS. Moreover, with Volcano’s electronic scanning type 296–304. 2) Kotsugi M, Takayama K, Myouchin K, et al: Carotid artery IVUS, the blood flow in the stent lumen after stent place- stenting: investigation of plaque protrusion incidence and ment can be evaluated by ChromaFlo IVUS, and the pres- prognosis. JACC Cardiovasc Interv 2017; 10: 824–831. ence or absence of PP that is difficult to diagnose by usual 3) Hibi K, Honda Y, Kimura K, et al: [Atherosclerosis: prog- IVUS can be diagnosed more accurately. In addition, PP ress in diagnosis and treatments. Topics: III. Progress in that is difficult to diagnose by DSA is considered to become diagnosis of atherosclerosis; 5. IVUS (intravascular ultra- more diagnosable if it is combined with IVUS. If there is sound)]. Nippon Naika Gakkai Zasshi 2013; 102: 344–353. circumferential calcification at the site of stenosis, accurate (in Japanese) evaluation of the lumen is difficult by IVUS due to artifact. 4) Honye J: [Coronary plaque morphology evaluated by intra- In addition, there is the risk of distal embolism and vascu- vascular ultrasound]. NICHIDOKU-IHO 2008; 53: 70–75. lar damage due to the procedure of IVUS itself. In lesions (in Japanese) accompanied by marked circumferential calcification, the 5) Nair A, Kuban BD, Tuzcu EM, et al: Coronary plaque clas- IVUS catheter may not pass through the lesion. However, sification with intravascular ultrasound radiofrequency data according to our experience, although the measurement analysis. Circulation 2002; 106: 2200–2206. 6) Diethrich EB, Pauliina Margolis M, Reid DB, et al: Virtual was made impossible as the IVUS probe was disconnected histology intravascular ultrasound assessment of carotid during its passage through the calcified lesion in some artery disease: the Carotid Artery Plaque Virtual Histology patients, we have experienced no complications due to Evaluation (CAPITAL) study. J Endovasc Ther 2007; 14: IVUS such as distal embolism and vascular damage. As for 676–686. the treatment in the event of PP, Shinozaki et al. reported 7) Tamakawa N, Ishikawa T, Moroi J, et al: [Analysis of a case in which cerebral infarction could be prevented carotid plaque using virtual histology IVUS during carotid by obliterating PP that occurred during the procedure by : comparison with pathological findings]. the stent-in-stent technique.16) According to the report by Surg Cereb Stroke (Jpn) 2011; 39: 323–328. (in Japanese)

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