Geographical predisposition influences on the distribution and tissue characterisation of eccentric coronary plaques in non-branching coronary arteries: cross-sectional study of coronary plaques analysed by intravascular ultrasound
Komiyama et al. Cardiovascular Ultrasound
Geographical predisposition influences on the distribution and tissue characterisation of eccentric coronary plaques in non- branching coronary arteries: cross-sectional study of coronary plaques analysed by intravascular ultrasound
Hidenori Komiyama 0 1
Hitoshi Takano 0
Shunichi Nakamura 0
Masamichi Takano 1
Noritake Hata 1
Miyauchi Yasushi 1
Yoshihiko Seino 1
Kyoichi Mizuno 0
Wataru Shimizu 0
0 Cardiovascular Medicine, Nippon Medical School , Tokyo 113-8603 , Japan
1 Cardiovascular Centre, Nippon Medical School Chiba Hokusou Hospital , Tokyo 270-1613, Chiba , Japan
Background: We investigated the influence of geographical predisposition on the spatial distribution and composition of coronary plaques. Methods: Thirty coronary arteries were evaluated. A total of 1441 cross-sections were collected from intravascular ultrasound (IVUS) and radio-frequency signal-based virtual histology (VH-IVUS) imaging. To exclude complex geographical effects of side branches and to localise the plaque distribution, we analysed only eccentric plaques in non-branching regions. The spatial distribution of eccentric plaques in the coronary artery was classified into myocardial, lateral, and epicardial regions. The composition of eccentric plaques was analysed using VH-IVUS. Results: The plaque was concentric in 723 sections (50.2%) and eccentric in 718 (49.9%). Eccentric plaques were more frequently distributed towards the myocardial side than towards the epicardial side (46.7 ± 7.5% vs. 12.5 ± 4. 2%, p = 0.003). No significant difference was observed between the myocardial and lateral sides (46.7 ± 7.5% vs. 20.8 ± 5. 0%) or between the lateral and epicardial sides. Eccentric thin-capped fibroatheromas were more frequently distributed towards the myocardial side than towards the lateral side (p = 0.024) or epicardial side (p = 0.005). Conclusion: Geographical predisposition is associated with distribution, tissue characterisation, and vulnerability of plaques in non-branching coronary arteries.
Atherosclerosis; Plaque distribution; Virtual histology; Vulnerable plaque
The central mechanism of atherosclerosis is chronic
inflammation in the presence of damaged vascular
endothelium and lipid-laden foamy macrophages derived
from infiltration of monocytes into the arterial wall. This
mechanism can lead to coronary stenosis and thrombotic
obstruction after disruption of the resulting
atherosclerotic plaque . Accumulation of leukocytes
and lipids, and proliferation of smooth muscle cells, cell
death, and fibrosis occur on the damaged endothelium .
Although the arterial wall is exposed to risk factors, such
as systemic hypertension, hypercholesterolaemia, and
diabetes, atherosclerotic plaques develop preferentially at
specific areas . In patients with acute coronary
syndrome (ACS), the distribution of ruptured coronary artery
plaques in the lumen is significantly more eccentric than
that of non-ruptured plaques. This finding suggests that
blood flow influences the location of ruptured plaques
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and may even contribute to plaque rupture . The
relationship between the spatial distribution and the
phenotype of plaques under conditions where blood
flow influences atherosclerosis in stable patients has
not been fully elucidated. In this study, we used
greyscale intravascular ultrasound (IVUS) to identify spatial
plaque distribution, and virtual histology (VH)-IVUS to
evaluate the plaque phenotype in 30 consecutive patients
who underwent elective percutaneous coronary
intervention (PCI), in an attempt to clarify the association between
geographical predisposition and plaque phenotype.
This cross-sectional observational study was carried out
in a single centre. We studied 30 consecutive patients
who underwent elective PCI under the diagnosis of
stable effort angina pectoris and from whom satisfactory
grey-scale and VH-IVUS images were obtained. This study
was approved by the Nippon Medical School institutional
review board, and informed consent was obtained from all
IVUS image acquisition and analysis
According to our standard protocol and previous report
, all patients without contraindications were
administered aspirin (100 mg/day) and ticlopidine (100 mg B.I.D.)
for at least 7 days before the procedure. Per the protocol,
clopidogrel (75 mg/day) was also administered in some
cases, for at least 4 days before the procedure. At the start
of the procedure, weight-adjusted intravenous heparin was
given with a target activated clotting time of >250 s. All
patients underwent IVUS imaging before any
catheterbased intervention, and none of the patients had undergone
prior intracoronary intervention in the target vessel. All the
lesions were located in native coronary arteries, not in
grafted vessels. Intracoronary nitroglycerin (100–200 mg)
was administered during all IVUS studies before imaging.
Grey-scale and VH-IVUS images were acquired using
a phased array 20 MHz, 3.2 Fr IVUS catheter (EagleEye;
Volcano Corporation, Rancho Cordova, CA, USA) with
an automated pullback of 0.5 mm/s. The IVUS catheter
was tracked over a 0.014-inch guide wire up to a position
distal to the diseased segment. The VH-IVUS data were
recorded onto the imaging system’s hard disk, and
analyses were performed independently by experienced
analysts. The analysts were unaware of the angiographic
findings and the patients’ baseline clinical and lesion
characteristics. All measurements were derived automatically
using Volcano imaging system pcVH 2.1 software. The
VHIVUS data analysis was based on grey-scale border contour
calculation, and the tissue maps were provided by the
software (green = fibrous, yellow = fibro-fatty, red = necrotic
core, and white = dense calcium). All cross-sections located
near a side branch (within twice the vessel diameter) were
excluded from analysis to minimise confounding by flow
turbulence. The plaque eccentricity index was the ratio of
maximum to minimum plaque thicknesses calculated as
previously suggested . An eccentric lesion was defined by
an eccentricity index of ≥3, or by the presence of an arc of
disease-free arterial wall within the lesion. A three-layered
appearance with an intimal thickening of <0.2 mm was
considered the upper limit of a ‘normal’ arterial wall
. Cross-sections with excessive calcification (calcium
arc ≥90°) were excluded from the analysis because of
acoustic shadowing of deeper structures, precluding
accurate analysis of the vessel area. Lesions with <90°
of calcium arc were analysed by extrapolation,
assuming that the vessel circumference was circular, and by
axial movement of the transducer to identify the vessel
area of adjacent non-calcified segments, as described
Perivascular IVUS landmarks—coronary veins,
pericardium, myocardium, and side branches—were used for
vessel orientation, as previously described . Based on these
landmarks, the vessel was divided into myocardial (inner
curve of the vessel), epicardial (outer curve of the vessel),
and two lateral (intermediate) quadrants. All cross-sections
with eccentric plaque distribution were classified according
to whether their plaque orientation was centred on the
pericardial, myocardial, or either lateral side of the vessel
(Fig. 1). In cases where the plaque angle exceeded 90° or
the plaque was distributed in between two quadrants, the
quadrant with the greater plaque thickness was selected for
VH-thin-cap fibroatheroma (VH-TCFA) was defined
according to a previous study, in which VH-TCFA was a
plaque burden (plaque area/external elastic membrane
area) exceeding 40% over three consecutive frames, with
a confluent necrotic core whose arc was in contact with
the lumen for 36° along the lumen circumference .
We counted the cross-sections of VH-TCFA morphology
and expressed the total as a percentage of all distributed
eccentric plaques in each individual patient.
All IVUS images were analysed by two experienced
investigators who were blinded to the angiographic data
and clinical presentations. When discordance occurred
between the observers, a consensus reading was obtained
from another investigator.
All data were analysed using SPSS version 21.0 (IBM,
Corp, Armonk, NY). All data were analysed by the
Shapiro-Wilk test for distribution of normality, and the
test showed that the data were not distributed normally.
The data were analysed by a non-parametric statistical
method, the Kruskal-Wallis test. The post-hoc multiple
comparison was performed automatically in SPSS. Data
Fig. 1 Intravascular ultrasound (IVUS) images of plaque. a Landmarks for IVUS orientation. The pericardium appears as a bright and relatively thick
structure with varying degrees of spokelike reverberations created by the interwoven fibrous strands. The cardiac vein was observed on the left
side of left anterior descending artery. b Orientation of plaque distribution was determined by IVUS landmarks. The eccentricity index of the plaque
was 3, and it was classified as myocardial plaque. c The virtual histology (VH) analysis of plaque composition was divided into four elements (fibrous
area, fibro-fatty area, necrotic core, and calcified area). d This cross-section was excluded from analysis because of diagonal branching
are presented as mean ± SEM. Statistical significance was
considered as p < 0.05.
The baseline characteristics of the patient population are
presented in Table 1. Of the 30 vessels subjected to IVUS
morphometric analysis, 11 were left anterior descending,
8 were left circumflex, and 11 were right coronary arteries.
A total of 1441 cross-sections were analysed, comprising
497 (34.5%) in the left anterior descending artery, 325
(22.6%) in the left circumflex artery, and 619 (43.0%) in
the right coronary artery.
Orientation of distributed atherosclerotic plaque
The results of the grey-scale IVUS data are summarised
in Table 2. Plaque distribution was found to be concentric
in 723 (50.2%) and eccentric in 718 (49.8%) cross-sections.
Imaging of landmarks, such as the pericardium, one or
more accompanying veins, and side branches, allowed for
spatial orientation . Of the 718 eccentric plaques, 401
cross-sections were oriented towards the myocardial side,
compared with only 80 that were oriented towards the
epicardial side, and 237 that were oriented towards the
two lateral quadrants. With regard to the plaque
distribution in each individual patient, plaque was more
frequently oriented towards the myocardial side (50.2 ±
7.0%) than towards the epicardial (25.6 ± 5.4%) or lateral
(14.2 ± 4.4%) side (Fig. 2). Eccentric plaques were more
frequently distributed towards the myocardial than
towards the epicardial side (p = 0.003). The minimum vessel
diameter was significantly smaller at sites where lateral
Table 1 Baseline clinical characteristics of patients
Total patients n = 30
Age, mean ± SEM, years
Silent myocardial ischaemia
Old myocardial infarction
Ischaemic cardiac myopathy
Table 2 Grey-scale IVUS data
Number of cross-sections (number)
Minimum lumen diameter (mm)
Minimum vessel diameter (mm)
Maximum lumen diameter (mm)
Maximum vessel diameter (mm)
Average lumen diameter (mm)
Average vessel diameter (mm)
Lumen area (mm2)
side plaque was observed, compared with sites with
epicardial side plaque. The maximum vessel diameter was
significantly smaller at sites with lateral side plaque than
at sites with myocardial side plaque. The plaque area of
lateral side plaques was significantly smaller than that of
myocardial or epicardial plaques.
Composition of eccentric plaques analysed by VH
We analysed the composition of eccentric plaque by
using VH-IVUS and classified it into four categories:
Fibrous, fibro-fatty, necrotic core, and calcification.
The results are summarised in Table 3. The plaque
area of lateral side plaques was significantly smaller
than that of myocardial or epicardial plaques. Lateral
and epicardial plaques contained significantly more
fibrous plaque component than myocardial plaques.
Myocardial side plaques contained less fibrous
component than lateral and epicardial side plaques, whereas
myocardial side plaques contained more fibro-fatty
area than lateral plaques. Myocardial and lateral side
plaques contained more necrotic core component than
the epicardial side plaques, and epicardial plaques
contained more calcium than lateral plaques.
Distribution of VH-IVUS-defined TCFAs
We observed TCFAs significantly more frequently in
myocardial side plaques (4.99 ± 1.61%) than in lateral
side plaques (0.80 ± 0.77%, p = 0.024) or in epicardial
side plaques (0%, p = 0.005) (Fig. 3).
Fig. 2 Plaque distribution (%) of the intravascular ultrasound (IVUS) cross-sections in the four quadrants. Of the total plaques, 46.7 ± 7.5% were
distributed towards the myocardial side, 20.8 ± 5.0% towards the lateral side, and 12.5 ± 4.2% towards the epicardial side. Data are shown as
mean ± SEM. N.S., not significant
Table 3 VH-IVUS data
Plaque area (mm2)
Necrotic core area (%) 18.26 ± 0.45†
(*p < 0.05, †p < 0.01)
The major findings of this study are as follows. (1) Eccentric
plaques were more frequently distributed towards the
myocardial side than towards the lateral and epicardial sides of
the coronary artery. (2) A significant difference was
observed in the diameters of the eccentric plaque vessels
between the distributed sides. (3) The difference in the
plaque component between the distributed sides was
also significant. TCFAs were more frequently observed
in myocardial side plaques than in lateral or epicardial
Coronary arteries are continually subjected to mechanical
force, such as tensile or compressive stress and shear stress
generated by the heartbeat and pulsatile blood flow during
each cardiac cycle [11, 12]. Among the biomechanical
forces, flow generates tangential drag force and resultant
shear stress. The magnitude of shear stress is determined
by changes in luminal geometry, blood flow velocity, and
plasma viscosity . Blood flow is disturbed by vessel
curvature; it is fast in the outer curvature and slow in the
inner curvature. Shear stress is high in the outer curvature
and low in the inner curvature [13–15]. Endothelial cells
sense shear stress and alter their shape and phenotype .
The shear stress is controlled by adapting vessel size to suit
the blood flow in response to sustained changes .
Hypothetically, if coronary arteries were classified geometrically,
myocardial, epicardial, and lateral sides would be
exposed to low, high, and intermediate shear stress,
respectively. Although shear stress may change over time
as plaque progression into the lumen changes coronary
flow, we found that eccentric plaques were more
frequently distributed towards the myocardial side than
towards the epicardial side or lateral side, which is
consistent with the hypothesis mentioned above.
Vascular adaptation by shear stress allows the arterial
tree to deviate from a straight-tube geometry to another
morphology. This phenomenon permits the shear stress
to remain unchanged, which provides the predilection
site for eccentric plaque development . Human autopsy
data showed compensatory enlargement of human
coronary arteries in relation to plaque area, and lumen stenosis
was delayed until the lesion occupied 40% of the internal
elastic lamina, which is termed Glagov’s phenomenon .
In the present study, the plaque area in the myocardial
and epicardial sides was significantly larger than that in
Myocardial side Lateral side
Fig. 3 Distribution of thin-capped fibroatheromas (TCFAs). Of the total TCFAs, 4.19 ± 1.49% were distributed towards the myocardial side, 0.80 ± 0.77%
towards the lateral side, and none towards the epicardial side. Data are shown as mean ± SEM. N.S., not significant
the lateral side, although no significant difference was
found in the lumen area between the distributed sides;
this finding indicates compensatory enlargement of the
myocardial and epicardial vessels. We also confirmed
that the minimum vessel diameter was significantly larger
on the epicardial side than on the lateral side, and that the
maximum lumen diameter was significantly larger on the
myocardial side than on the lateral side. Although the
difference was not statistically significant, the average vessel
diameter was numerically larger on the myocardial side
than on the lateral side (4.43 ± 0.04 mm vs. 4.15 ± 0.05 mm,
p = 0.108), and numerically larger on the epicardial side
than on the lateral side (4.48 ± 0.07 mm vs. 4.15 ± 0.05 mm,
p = 0.0814). The average plaque area was approximately
40% (44.83 ± 0.75%), and the compensatory vascular
remodelling was associated with geographical predisposition.
Using VH-IVUS imaging, a spatial relationship between
low shear stress and the necrotic core was observed in early
plaques (plaque burden <40%) , while increases in the
necrotic core percentage occurring at the site were typically
affected by low shear stress . In serial observations of
endothelial shear stress and plaque composition, low-stress
segments had greater plaque and necrotic core progression
compared with intermediate-stress coronary segments, and
high-stress segments had greater necrotic core and calcium
progression . In the present study, analysis of plaque
composition by VH-IVUS revealed that lateral and
epicardial plaques contained significantly more fibrous plaque
component than myocardial plaques. Myocardial side
plaques contained less fibrous component than the lateral and
epicardial side plaques, whereas myocardial side plaques
contained more fibro-fatty area than lateral plaques.
Myocardial and lateral side plaques contained more
necrotic core component than the epicardial side plaques,
and epicardial plaques contained more calcium than the
lateral plaque. The actual proportion of each plaque
component correlated well with assumed shear stress being
high on the epicardial side, intermediate on the lateral
side, and low on myocardial side (Table 3).
In a previous study using integrated backscatter IVUS
, Sato et al. reported that in plaques with moderate
stenosis in non-branching lesions, lipid pools clustered in
the inner curvature and fibrous tissue clustered in the outer
curvature. In accordance with their findings, we also found
that fibro-fatty and necrotic contents identified by
VHIVUS were more often seen in myocardial side plaque.
Although they studied both eccentric and concentric
plaques, whereas we selected only the eccentric plaques for
analysis, different imaging modalities specifically useful for
plaque content characterisation confirmed similar results.
Longitudinal studies in porcine models have shown that
TCFAs, which develop more frequently in the coronary
regions, are exposed to low shear stress throughout their
evolution [24, 25]. Autopsy studies have shown that
atherosclerotic lesions are provoked by TCFA rupture,
which can lead to thrombosis, ACS, and sudden cardiac
death [26, 27]. In vitro studies using the finite element
method have demonstrated that the shear stress of the
vascular lumen is an important determinant of coronary
plaque vulnerability and plaque rupture [28, 29]. Fukumoto
et al. demonstrated that localised elevation of blood
pressure and shear stress are associated with coronary plaque
rupture in the proximal or top portion of the plaque in
ACS patients . The shear stress concentration is
frequently correlated with the plaque rupture site. Plaque
rupture may heal without any symptoms or lead to mural
thrombosis with subsequent asymptomatic healing [31, 32].
Although the precise mechanisms that promote the
focal formation of rupture-prone coronary plaques in vivo
remain to be elucidated, we found that eccentric TCFAs
were clustered towards the myocardial side. We only
analysed eccentric plaques, which may be predisposing
to future coronary events . The relationship between
rupture-prone TCFAs and subsequent thrombus
formation or clinical events is still unknown , as is whether
TCFA-induced plaque ruptures lead to lumen stenosis.
Although it is also still unclear whether TCFA clusters
towards the myocardial side actually rupture and lead
to clinical symptoms or lumen stenosis, the method for
the geographical classification of coronary plaques by
using IVUS in this study is simple and applicable in
clinical settings, and can be utilized to characterise the
complex profile of atherosclerotic plaque.
The limitations of this study are as follows. First, the
sample size was small; only 30 coronary arteries in 30 patients
were analysed. Second, all the patients were in stable
condition, and their plaque phenotype may have been
different from that of unstable patients. Third, we included
right arteries, in which atherosclerotic change may differ
from that in left coronary arteries . Fourth, we did not
calculate the absolute value of inter-observer variability in
identifying the distribution of plaque, although this does
not invalidate the findings because discordance in the
image reading was rare. Fifth, this study was designed as
an observational study, and the clinical importance of
geographical predisposition should be assessed prospectively.
Eccentric coronary plaques are more often observed on
the inner side of the coronary arteries. The geographical
predisposition of myocardial distribution in the human
coronary artery was associated with a larger lipid burden,
a thinner fibrous cap, and a higher prevalence of TCFA.
The geographical classification of coronary plaques using
IVUS is applicable in clinical settings to elucidate the
complex profile of atherosclerotic plaque.
ACS: Acute coronary syndrome; IVUS: Intravascular ultrasound; PCI: Percutaneous
coronary intervention; TCFA: Thin-capped fibroatheroma; VH: Virtual
histology; VH-IVUS: Virtual histology intravascular ultrasound
Availability of data and materials
The authors are prepared to share the data and materials on request.
HK: Conception and design of study, analysis and interpretation of data,
statistical analysis, drafting, revising, and finalizing the manuscript. HT:
Collection and analysis, interpretation of data, and critical revision of
manuscript for important intellectual content. SN, MT, NH, MY, YS: Critical
revision of manuscript for important intellectual content. KM, WS: Critical
revision of manuscript for important intellectual content, supervision. All
authors read and approved the final manuscript.
Consent for publication
All authors and participants consented in writing to publication of this study.
Ethics approval and consent to participate
Informed consent was obtained from all patients, and the Nippon Medical
School institutional review board approved the study. All participants signed
a consent form to participate in the study.
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