Clinical Investigative Study
Virtual Histology Analysis of Carotid Atherosclerotic Plaque:
Plaque Composition at the Minimum Lumen Site and of the Entire
Carotid PlaqueArihito Tsurumi, MD, PhD, Yuko Tsurumi, MD, Osamu Hososhima, MD, Noriaki Matsubara, MD, PhD,
Takashi Izumi, MD, PhD, Shigeru Miyachi, MD, PhD
From the Department of Neurosurgery, National Hospital Organization Nagoya Medical Center, Nagoya, Japan (AT); Department of Neurosurgery, Japanese Red Cross Nagoya
Daiichi Hospital, Nagoya, Japan (YT); Department of Neurosurgery, Tosei General Hospital, Seto, Japan (OH); Department of Neurosurgery, Nagoya University Graduate Schoolof Medicine, Nagoya, Japan (NM, TI, SM).

ABSTRACTBACKGROUND

Virtual Histology intravascular ultrasound (VH IVUS) volumetric analysis (analysis of
the entire plaque responsible for stenosis) has been used for carotid plaque diagnosis.
Knowing the carotid plaque characteristics by analyzing the plaque composition only at
the minimum lumen site will facilitate plaque diagnosis using VH IVUS.
PURPOSETo detect the relationship between the VH IVUS volumetric analysis of the entire plaqueresponsible for carotid artery stenosis and the VH IVUS cross-section plaque analysis at
the minimum lumen site.
METHODS

Forty-eight atherosclerotic cervical carotid stenoses in 45 consecutive patients were included in the study. VH IVUS was obtained during the carotid artery stenting procedure.
RESULTS

Keywords: Carotid stenosis, plaqueimaging, IVUS, Virtual Histology.
Acceptance: Received October 24,
2011, and in revised form May 22, 2012.
Accepted for publication June 22, 2012.
Correspondence: Address correspondence to Arihito Tsurumi, MD, PhD,
Department of Neurosurgery, National
Hospital Organization Nagoya Medical
Center, 4-1-1 San-no-maru, Nakaku,
Nagoya 460-0001, Japan. E-mail:tsurumi@med.nagoya-u.ac.jp.
J Neuroimaging 2013;23:12-17.
DOI: 10.1111/j.1552-6569.2012.00748.x

Simple regression analysis revealed that the volumetric proportion of each plaque typecorrelated significantly with the corresponding plaque-type area at the minimum lumensite. The adjusted coefficients of determination of the simple regression analyses were.782 (P < .001) for fibrous tissue, .741 (P < .001) for fibrofatty tissue, .864 (P < .001)
for dense calcium, and .918 (P < .001) for necrotic core.
CONCLUSION

The plaque composition at the minimum lumen site represents the volumetric compositionof the entire carotid plaque that causes atherosclerotic cervical carotid artery stenosis.

Introduction
Echolucent carotid plaque is associated with procedural embolization during carotid artery stenting and neurological complications, and this dangerous plaque is called vulnerable
plaque.1-3 For the treatment of patients with carotid arterystenosis, plaque imaging to analyze plaque characteristics isimportant to detect vulnerable plaque and avoid ischemic complications. Magnetic resonance imaging,4-7 computed tomography,8,9 positron emission tomography,10,11 carotid ultrasonography,5 and intravascular ultrasound (IVUS)12,13 have beenreported as carotid plaque imaging devices. Conventional
IVUS has been used for over a decade in carotid stenting, notonly to assess the plaque before treatment, but also to measurearterial diameters and subsequently to assess the completenessof stent deployment. Virtual Histology (VH; Volcano Corporation, Rancho Cordova, CA), which is based on spectral

12◦and amplitude analyses of the IVUS radiofrequency backscatter signals, is an advanced radiofrequency analysis of IVUS
signals.3 Several studies of coronary14-16 and carotid3 artery
plaque imaging have demonstrated that VH allows reliable
identification of four atherosclerotic plaque types: fibrous, fibrofatty, dense calcium, and necrotic core. In addition, thegeometric and compositional output of VH IVUS has beenreported to be reproducible.17 The VH cross-sectional images
are created from both the intensity and frequency of the reflected ultrasound, with the frequencies varying according to
the tissue types.14 VH IVUS provides color-coded maps offour different histological components of plaque (green, fibrous;
yellow, fibrofatty; white, dense calcium; and red, necrotic core)with the lumen colored black.3,18
VH IVUS has been used to evaluate plaque characteristics inboth coronary interventions19,20 and neurointerventions.21-25

Copyright C 2012 by the American Society of Neuroimaging

Fig 1. A VH IVUS sample image of color-coded plaque compositional maps on transverse planes in a patient with symptomatic internal
carotid artery origin stenosis. VH IVUS shows a large fibrofatty necrotic core plaque with calcification. VH IVUS provides color-coded maps offour different histological components of plaque (green, fibrous; yellow, fibrofatty; white, dense calcium; and red, necrotic core), with the lumen
colored black.
Rupture of vulnerable plaque in the coronary arteries is thecause of most acute coronary syndromes. VH IVUS can identify the vulnerable plaque by its high content of necrotic lipid
core.26 In addition, the authors have previously reported thatperiprocedural hypotension in carotid artery stenting can bepredicted by VH IVUS volumetric analysis of the plaque responsible for the carotid artery stenosis. Fibrous plaque, inwhich fibrous tissue detected on VH IVUS is composed ofmore than 60% of the whole plaque volume on VH IVUS,
is the independent risk factor for periprocedural hypotension(systolic blood pressure ≤90 mm Hg) and prolonged periprocedural hypotension (requiring vasopressor for >3 hours) in
carotid artery stenting.27
VH IVUS volumetric analysis of the plaque, which can beachieved by performing integral analysis of the cross-sectional
plaque analyses, is a time-consuming task. In contrast, analyzing only one cross-section at the minimum lumen site is easierand faster than VH IVUS volumetric analysis. If it is possible toknow the carotid plaque characteristics by analyzing the plaquecomposition only at the minimum lumen site, plaque diagnosis
using VH IVUS will become easier, and easier prediction of patients who will have periprocedural hypotension during carotid
artery stenting will become possible. This study was conducted
to identify the relationship between the volumetric analysis of
the entire carotid plaque and one cross-section plaque analysis
at the minimum lumen site.

Methods
Study Design
A retrospective, cross-sectional study of patients who underwent interventional therapy for cervical carotid artery stenosis
in a tertiary referral hospital from April 1, 2006 to April 30,
2007 was conducted. All consecutive patients who underwent
interventional therapy for cervical carotid artery stenosis in our
hospital were registered and recorded in this study. Patientswith stenosis related to radiation therapy or with restenoses
after carotid endarterectomy (CEA) were excluded from thepresent study. All patients underwent both volumetric andcross-sectional analyses of the carotid plaque using VH IVUS.
The patients who had stenosis that was too severe for the VH
IVUS catheter to cross before predilatation for carotid arterystenting were also excluded from the study. The study was
conducted according to the requirements of the institutional
review board. The procedures of VH acquisition and periprocedural management were in agreement with the institutionalguidelines.

Virtual Histology Acquisition
All procedures were performed under local anesthesia. Stenotic
lesions with unstable and complex plaque were treated withproximal protection systems to avoid the risk of distal embolization by advancing the protection device and the VH IVUS

Tsurumi et al: Virtual Histology Analysis of Carotid Atherosclerotic Plaque13

catheter through the stenosis.28 The other lesions were treatedusing a distal embolic protection device. A VH IVUS was obtained before predilatation for the carotid artery stenting procedure. A VH IVUS catheter (Eagle Eye Gold, 3.5 F/20 MHz;
Volcano Corporation) was placed distal to the stenotic lesion
and manually pulled back proximal to the stenosis. During thispullback, color flow IVUS was recorded on the VH IVUS console. Then, the VH IVUS catheter was again advanced distal to
the stenosis, and it was subsequently pulled back proximal to thestenosis by a motorized pullback system set at .5 mm/second.
During this pullback, raw radiofrequency data were captured
on the VH IVUS console at the top of the R-wave of the electrocardiogram and recorded on a digital video disk. Each distance
between the captured images was also recorded.

Analysis of Virtual Histology
The color-coded map superimposed on the gray-scale IVUS
tomographic image was reconstructed from the captured raw
radiofrequency data using the VH IVUS software (version 1.3;
Volcano Corporation). Using the VH IVUS software,
atherosclerotic plaques were classified into the four different
histological components of plaque (green, fibrous; yellow, fibrofatty; white, dense calcium; and red, necrotic core) by classification trees based on mathematical autoregressive spectral
analysis of IVUS backscattered data; a VH IVUS sample imageis shown in Figure 1. The distal/proximal end frames were defined as the frames where the plaque within the media line wasconcentric and the diameter of the lumen within the intima did
not change compared with more distal/proximal frames. Between the distal and proximal end frames, a media line and an
intima line were manually drawn in each frame by referring to
the adjacent frames and by referring to the corresponding color
flow IVUS image, respectively. Referring to adjacent frames
is useful in detecting the media line. The intima line can bedetected easily using the color flow IVUS images showing theblood flow in the vessel. Since the VH IVUS software could
not analyze the plaque within ulceration, the ulcerated area
was considered to be with an intima line in VH IVUS analyses.
The total volume of each plaque type (fibrous, fibrofatty,
dense calcium, and necrotic core) was calculated using the VH
IVUS software and expressed in cubic millimeters. The volumetric proportion of each plaque type was also determined.
The proportion of the area of each plaque type at the minimum
lumen site was also calculated using the VH IVUS software.

Statistical Analysis
A simple regression analysis was performed to examine the effects of the proportion of the four plaque types at the minimum
lumen site on the volumetric proportion of each plaque type. A
P value < .05 was considered significant. All statistical analyses
were performed with the IBM SPSS statistical software package(version 19.0; SPSS Inc., Chicago, IL).

Results
Fifty-six consecutive interventional therapies for cervicalcarotid artery stenosis in 52 patients were initially includedin this study. One patient with stenosis that was related to ra-

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Journal of Neuroimaging Vol 23 No 1 January 2013

Table 1. Patient Data and Characteristics
Variables

Clinical characteristics
Age (years)
FemaleHistory
Hypertension
Diabetes mellitus
Hyperlipidemia
Coronary artery disease
Congestive heart failure
Lesion-related characteristics
Lesion side: left
Distance between carotid bifurcation and
MLS ≤ 10 mm
Distance between carotid bifurcation and
MLS > 10 mm
Plaque ulceration deeper than 2 mm
Stenotic lesion involving both CCA & ICA
Stenotic lesion involving only ICA
Degree of stenosis (%)
Contralateral ICA stenosis (>50%) or
occlusion
Contralateral ICA occlusion
Symptomatic carotid stenosis, ipsilateral
Cerebral infarction, ipsilateral
Cerebral infarction, contralateral
Symptoms of carotid stenosis within 3 months,
ipsilateral
Cerebral infarction within 3 months, ipsilateral
History of CAS or CEA, contralateralData

68.8 (SD 7.1)
6 (13%)
33 (69%)20 (42%)28 (58%)15 (31%)4 (8%)
25 (52%)36 (75%)12 (25%)19 (40%)19 (40%)29 (60%)73.6 (SD 15.3)
8 (17%)
4 (8%)
25 (52%)18 (38%)7 (15%)
11 (23%)7 (15%)
5 (10%)

Continuous data are shown as the means (SD). Categorical data are shown ascounts (%).
SD = standard deviation; MLS = minimum lumen site; CCA = common carotid
artery; ICA = internal carotid artery; CAS= carotid artery stenting; CEA =carotid endarterectomy.

diation therapy and 1 patient with restenosis after CEA were
excluded from the study. Since the VH analyses of the plaquewere not available, six stenotic lesions (three stenoses that were
too severe for the VH IVUS catheter to cross before predilatation; three stenoses in which the raw radiofrequency data
captured in the VH IVUS console could not be recorded on adigital video disk because of technical difficulties) were also excluded. The remaining 48 stenotic lesions in 45 patients were analyzed in this study. The descriptive characteristics are shown in
Table 1.
All patients had successful dilatation of the carotid lesion
by carotid artery stenting. In the periprocedural period, nopatients suffered from major adverse events, including symptomatic cerebral infarction, myocardial infarction, or death. No
patients needed repeated procedures or blood transfusions after
the procedure.
The volumetric proportion of each plaque type (fibrous, fibrofatty, dense calcium, and necrotic core), and the proportionof the area of each plaque type at the minimum lumen site are
given in Table 2.
The scattergraphs of the volumetric proportion of eachplaque type against the proportion of the corresponding plaquetype area at the minimum lumen site were drawn (Fig 2). EachTable 2. Virtual Histology Findings
Variables

Data

Virtual Histology findings of plaque volumetriccomposition analysis
Fibrous tissue (%)
Fibrofatty tissue (%)
Dense calcium (%)
Necrotic core (%)
Virtual Histology findings of plaque composition
at MLS
Fibrous tissue (%)
Fibrofatty tissue (%)
Dense calcium (%)
Necrotic core (%)

61.0 (SD 12.8)
28.0 (SD 15.2)
3.9 (SD 6.2)
7.2 (SD 8.3)

57.9 (SD 14.7)
31.6 (SD 16.8)
3.3 (SD 7.0)
7.1 (SD 9.5)

Data are shown as the means (SD).
SD = standard deviation; MLS = minimum lumen site.

regression line, the adjusted coefficient of determination, and
its P value were also drawn in the graphs. The adjusted coefficients of determination of the simple regression analyses were.782 for fibrous tissue, .741 for fibrofatty tissue, .864 for dense
calcium, and .918 for necrotic core, which indicated a strong
correlation.

Discussion
In this study, the authors analyzed the relationship between thevolumetric composition of the entire carotid plaque and theplaque composition at the minimum lumen site using simple

regression analyses. The volumetric proportion of each plaquetype correlated significantly with the corresponding plaquetype area at the minimum lumen site (Fig 2). This result gives
support to the hypothesis that the plaque composition at theminimum lumen site represents the volumetric composition of
the entire plaque that causes the stenosis.
As described earlier, periprocedural hypotension in carotid
artery stenting can be predicted by VH IVUS volumetric analysis of the plaque responsible for carotid artery stenosis.27 While
VH IVUS volumetric analysis of the plaque is a time-consuming
task,3,16 analyzing only one cross-section at the minimum lumen site is easier and faster. The result of this study enables
easier and faster prediction of periprocedural hypotension during carotid artery stenting, which means quick and easy analysisof the relationships between carotid plaque composition and theclinical prognosis after carotid artery stenting.
Plaque characteristics are related to not only periprocedural
hypotension, but also ischemic complications in the periprocedural period of carotid artery stenting.29 Particularly in carotid
artery stenting using filter-type embolic protection devices, slow
flow behavior is associated with an excess risk of periprocedural
stroke and is known to be a serious complication.25,30 Significant embolization of vulnerable plaque elements produced by
the carotid artery stenting procedure is the cause of the slow
flow behavior. Detecting such vulnerable plaque is importantfor optimizing patient and lesion selection criteria for carotid
artery stenting.31,32 CEA is one of the safer treatment options
for the carotid stenosis with such vulnerable plaque. The results of this study may be useful for deciding the type of carotid

Fig 2. The scattergraphs and regression lines between the volumetric proportion of each plaque type (A) fibrous, (B) fibrofatty, (C) dense
calcium, and (D) necrotic core, and the proportion of corresponding plaque-type area at the minimum lumen site. FI = fibrous; FF = fibrofatty;
DC = dense calcium; NC = necrotic core; MLS = minimum lumen site; R 2 = adjusted coefficient of determination.

Tsurumi et al: Virtual Histology Analysis of Carotid Atherosclerotic Plaque15

intervention (carotid artery stenting or CEA) using the concept of plaque-guided patient selection in carotid arterydisease.33-36

Limitations of the Present StudyIn this study, the authors analyzed only atherosclerotic plaquein cervical carotid artery stenosis. Patients with stenosis related
to radiation therapy or with restenoses after CEA were excluded from this study, and there were no patients with carotid
artery stenosis caused by arterial dissections in the study period. Further investigation is required for the analysis of thesenonatherosclerotic plaques. In addition, VH IVUS does not
identify hemorrhage within the plaque but assigns hemorrhage
to fibrous or fibrofatty components via the available colors.37,38
Hemorrhage may therefore be contained within the fibrous or
fibrofatty components assessed by VH IVUS.25 The risk of intraplaque hemorrhage should be assessed by combination useof other plaque-imaging devices.

Conclusions
The result of this study indicates that the plaque composition at
the minimum lumen site represents the volumetric compositionof the entire carotid plaque responsible for atherosclerotic cervical carotid artery stenosis; this may be useful for deciding thetype of carotid intervention using the concept of plaque-guided
patient selection in carotid artery disease.
The authors thank Dr. Tatsuo Takahashi, Dr. Shinichiro Tsugane,
Dr. Noriyuki Susaki, Dr. Motoki Oheda, Dr. Toshiki Fukuoka, andDr. Yosuke Tamari (Department of Neurosurgery, Nagoya Medical
Center) for their helpful discussion.

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