REVIEWS

Clinical classification of plaque morphology

in coronary disease
Fumiyuki Otsuka, Michael Joner, Francesco Prati, Renu Virmani and Jagat Narula
Abstract | In published post-mortem pathological studies, more than two-thirds of acute coronary events are
associated with the rupture of lipid-rich, voluminous, and outwardly remodelled plaques covered by attenuated
and inflamed fibrous caps in the proximal part of coronary arteries. Superficial erosion of the plaques is
responsible for most of the remaining events; the eroded plaques usually do not demonstrate much lipid
burden, do not have thin fibrous caps, are not positively remodelled, and are not critically occlusive. Both
noninvasive and invasive imaging studies have been performed to clinically define the plaque characteristics in
acute coronary syndromes in an attempt to identify the high-risk plaque substrate susceptible to development
of an acute coronary event. Optical coherence tomography (OCT)an intravascular imaging modality with
high resolutioncan be used to define various stages of plaque morphology, which might allow its use for the
identification of high-risk plaques vulnerable to rupture, and their amenability to pre-emptive interventional
treatment. OCT might also be employed to characterize plaque pathology at the time of intervention, to provide
apriori knowledge of the mechanism of the acute coronary syndrome and, therefore, to enable improved
management of the condition.
Otsuka, F. etal. Nat. Rev. Cardiol. advance online publication 29 April 2014; doi:10.1038/nrcardio.2014.62

Introduction

Cardiovascular
Pathology Inc.,
19Firstfield Road,
Gaithersburg,
MD20878, USA
(F.O.,M.J., R.V.).
SanGiovanni
Addolorata Hospital
and CLI Foundation,
ViaAmba Aradam, 8,
Rome 00184, Italy
(F.P.). Icahn School
ofMedicine at Mount
Sinai, One Gustave L.
Levy Place, New York,
NY 10029, USA (J.N.).
Correspondence to:J.N.
jagat.narula@
mountsinai.org

The course of atherosclerosis is considered a dynamic

process, with early lesions developing into moreadvanced atherosclerotic plaques. Although the major
coronary plaque types underlying sudden cardiac death
are well defined in the literature, debate continues about
the mechanisms explaining the transition of stable
atherosclerotic lesions, such as fibroatheroma, to unstable vulnerable plaques (that is, thin-cap fibroatheroma
[TCFA]). The pathological mechanisms associated with
plaque instability include extensive positive remodelling,
increased inflammation of a thin fibrous cap, expanding necrotic core, and intraplaque haemorrhage.15 The
macrophage infiltration and increased lipid content
within the necrotic core of atherosclerotic coronary
lesions are associated with positive vessel remodelling,68
which has been considered a convenient surrogate for
imaging of coronary plaque instability.9 In this Review,
Competing interests
M.J. receives honoraria from Abbott Vascular, Biotronik,
Medtronic, and St. Jude Medical, and is a consultant for
Biotronik and Cardionovum. R.V. receives research support from
Abbott Vascular, BioSensors International, Biotronik, Boston
Scientific, Medtronic, MicroPort Medical, OrbusNeich Medical,
SINO Medical Technology, and Terumo Corporation. She also
has speaking engagements with Merck, receives honoraria from
Abbott Vascular, Boston Scientific, Lutonix, Medtronic, and
Terumo Corporation, and is a consultant for 480 Biomedical,
Abbott Vascular, Medtronic, and W.L. Gore. J.N. has received
research grants (to his institution in the form of imaging
equipment) from GE Healthcare and Philips Healthcare, and has
received honoraria from GE Healthcare and Philips Healthcare
as a member of their advisory boards. F.O. and F.P. declare no
competing interests.

we discuss how optical coherence tomography (OCT),

atype of intravascular imaging that provides high resolution, can be used to visualize the stepwise pathological
progression of atherosclerotic plaques. We also highlight
how OCT can potentially be used to identify high-risk
plaques and aid in the management of acute coronary
syndromes(ACS).

Optical coherence tomography

OCT is an innovative intravascular imaging tool that can
be used to examine coronary atherosclerotic lesions at
a resolution (1015m) that far exceeds existing standards, such as intravascular ultrasonography (IVUS), by
an order of magnitude. OCT processes backscattering
infrared light to generate real-time tomographic images.
The imaging catheter is made up of an inner imaging core
surrounded by an outer sheath. The imaging core comprises an optic fibre with a prism and microlens at the
distal tip that generate a scanning beam perpendicular to
the axis of the inner core, which rotates within the outer
sheath to produce cross-sectional images.10 The older
versions of this technology used time-domain detection,
but current technology has applied frequency-domain
detection.11 The latter strategy allows the backscattering
light from various locations to be measured simultaneously, enabling a rapid pullback and shorter acquisition
time during nonocclusive luminal flush with contrast.
Of note, the very high resolution of OCT restricts the
depth of penetration of the light beam through blood and
tissue (to 13mm), resulting in the incomplete reflection
from the deeper arterial layers. This major drawback of

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Key points
Exvivo studies of the coronary arteries have demonstrated the accuracy of
optical coherence tomography imaging for definition of plaque characteristics
Whereas thin fibrous caps and necrotic cores indicate that plaques are
susceptible to rupture, no characteristic features are known to identify plaques
amenable to erosion
Clinical identification of plaques that cause acute coronary events is now
feasible; such events might be characterized as being associated with ruptured
or intact fibrous caps
Randomized studies might enable us to establish the safety of avoiding stent
implantation in acute coronary events associated with intact fibrous caps
Randomized studies might also establish whether pre-emptive treatment of
plaques vulnerable to rupture would prevent acute events

a
b

c
I
M
A

I
M
A

e
I

I
M
A

M
200 m

200 m

Figure 1 | Intimal thickening and intimal xanthoma. a| Low-power and b,c| highpower exvivo OCT images showing intimal thickening (panelsa and b) and intimal
xanthoma (panelsa and c) in a human coronary artery. Three layersA, I, and M
are apparent in the arterial wall. A focal signal-rich confluent punctate region (white
arrows in panelc) is observed close to the luminal surface, which is accompanied
by signal attenuation (white arrow heads in panel c). d,e | Corresponding
histological images showing intimal thickening without macrophages (paneld), and
intimal xanthoma characterized by the presence of foamy macrophages (black
arrows) within the thin neointima (panele). Abbreviations: A, adventitia; I, intima;
M, media; OCT, optical coherence tomography.

OCT technology precludes the determination of exact

vessel dimensions in areas of large plaque burden.11
Nevertheless, OCT has been successfully used to identify
various stages of atherosclerotic coronary plaques,including TCFA.12 Lipid-rich and necrotic plaques have been
visualized as areas with low backscattering signal within
the arterial wall, whereas fibrous plaque show a homogenous high backscattering signal.The calcified lesions
produce low backscatteringsignal with sharp borders
within the surrounding fibrous tissue.13 Detection of
macrophage accumulation in atherosclerotic plaques
might also be possible.14 OCT has become accepted as
a promising strategy to study plaque progression invivo.

Imaging stages of plaque progression

OCT imaging can be useful for the classification of
atherosclerotic plaque progression, because it enables
visualization of features that define the various stages.
Of note, this imaging modality is particularly useful at
defining the later stages of plaque progression; its utility
in the initial stages is somewhat limited. Here, we describe

how OCT can be used to visualize features of each of the

standard stages of the plaque progression as defined
in the pathological classification of at herosclerotic
coronarydisease.15

Intimal thickening and intimal xanthoma

Intimal thickening or intimal xanthoma is often considered to be the index manifestation of atherosclerotic
disease in coronary arteries.16 Some of these plaques might
form as fatty-streaks. The intimal thickening usually
regresses over time; however, these lesions are thought to
evolve early and, in children, are seen at similar locations
to where more-advanced lesions are expected to develop
in adults.17 Histologically, regions of intimal thickening contain focal accumulation of smooth muscle cells,
with proteoglycan-rich extracellular matrix and without
inflammation. Although some evidence supports the
idea that intimal proliferation is a precursor of a moreadvanced atherosclerotic lesion,15,17 another theory is that
intimal proliferation is an adaptive vascular reaction to
altered blood flow in coronary arteries.15
Correlative histopathological imaging data addressing the occurrence and fate of intimal thickening and
xanthoma are lacking, especially data from longitudinal, observational studies. From our experience, intimal
thickening is most often seen via OCT as focal intimal
thickening with a high backscattering signal-rich appearance in the absence of shadowing or attenuation of the
light beam (Figure1). The latter characterizes the intimal
xanthoma that corresponds with the histological presence
of foamy macrophages.
Pathological intimal thickening
Pathological intimal thickening has often been referred
to as the first atherosclerotic lesion showing progression over time, and is characterized by the presence of
an acellular lipid pool, consisting of proteoglycans and
lipid, that is located close to the medial wall (Figure2).15,16
The luminal intima consists of smooth muscle cells in a
proteoglycan-rich and collagen-rich extracellular matrix,
and might contain macrophages and Tlymphocytes,
which are usually remote from the lipid pool. Early calcification is visualized within the lipid pool as stippling
by vonKossa staining, and is likely to originate from the
death of smooth muscle cells.18
Pathological intimal thickening in the absence of
macrophages typically appears using OCT as focal thickening of the intimal layer exhibiting high backscattering
signal, with moderate attenuation of the light beam in the
deeper intimal layers (Figure2). Therefore, the utility of
OCT in detecting lipid pool in these lesions is limited,
probably because the lipid pool always forms within the
deeper intimal regions, close to the medial layer, where
the attenuated light beam results in insufficient resolution to depict anatomical details. When macrophages
are present in the more-superficial intimal layers, signalrich, distinct, or confluent punctate areas with shadowing of the underlying tissue structure14,19 are observed via
OCT. Rapid attenuation of the penetrating light beam
is an important component of macrophage-rich lesions

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a

early from more-advanced atherosclerotic plaques using

OCT imaging.

LP
1.0 mm

Movat

200 m

LP

200 m

1.0 mm

Movat

Figure 2 | Pathological intimal thickening. ac| Images showing macrophage-poor

pathological intimal thickening. df| Images showing pathological intimal
thickening containing macrophages. Focal signal-poor region with diffuse border
(white arrow heads) in exvivo OCT images (panelsa and d) correspond with the
presence of LP in low-powered (panelsb and e) and high-powered (panelsc and f)
images of histological sections of human coronary plaques (all sections are
stained with Movat Pentachrome). Signal-rich confluent punctate area with
attenuation is observed in the OCT image in paneld (white arrows), which
corresponds with the presence of foamy macrophages in the histology in panelf
(black arrows). Abbreviations: LP, lipid pool; OCT, optical coherence tomography.
a

LP
NC

NC
1.0 mm

Movat

200 m

NC
Movat

Fibroatheroma
In accordance with the AHA consensus classification
of coronary atherosclerotic plaques, fibroatheroma
(Figure3) are the first clearly distinguishable plaque
consisting of demarcated lipid-rich necrotic core encapsulated by surrounding fibrous tissue.15,20 Fibroatheroma
can be further subdivided into early and late stages.
The early stage of fibroatheroma is characterized by the
infiltration of macrophages into the lipid pool, together
with focal loss of proteoglycans, collagen, or both. Focal
regions of free cholesterol are present in early fibro
atheroma. In late fibroatheroma, discrete collections of
cellular debris and increased amounts of free cholesterol
exist, and the extracellular matrix is almost completely
depleted. The late fibroatheroma can result in substantial
luminal stenosis from episodes of intraplaque haemor
rhage, probably resulting from an increase in vasa
vasorum within the intimal plaque. The fibroatheroma
can be accompanied by focal calcification.
Both stages of fibroatheroma are characterized by
superficial high backscattering bright signal on OCT
(Figure3), with pronounced signal attenuation of light
in the deeper plaque regions, which is probably secondary to the presence of activated macrophages, calcification, or both. As mentioned above, the major drawback
of OCT technology is the limited tissue penetration
(13mm), which precludes the determination of exact
vessel dimensions in areas of large plaque burden. 11
Plaque area, lipid pool, necrotic core areas, and intraplaque haemorrhage cannot be completely demarcated
using OCT.

1.0 mm

NC

200 m

Figure 3 | Fibroatheroma. ac| Images showing early fibroatheroma. df| Images

showing late fibroatheroma. Low backscattering, signal-poor regions with diffuse
border (white arrow heads) in exvivo optical coherence tomography images
(panelsa and d) correspond with the presence of LP or NC in low-powered (panelb
and e) and high-powered (panelc and f) images of histological sections of human
coronary plaques (all sections are stained with Movat Pentachrome). Early NC in
panelc is characterized by the infiltration of foamy macrophages into the LP, with
focal loss of proteoglycan and/or collagen matrix and cholesterol cleft. Late NC in
panelf consists of discrete collections of cellular debris with extensive cholesterol
cleft and intraplaque haemorrhage (black arrows) where extracellular matrix is
almost completely depleted. Abbreviations: LP, lipid pool; NC, necrotic core.

and explains the difficulty to distinguish lipid pool from

necrotic core. The former characterizes pathological
intimal thickening (Figure2), whereas the latter is an
important feature of fibroatheroma and TCFA (described
below). Therefore, more correlative imaging studies
employing consecutive histopathological sectioning
ofborderline lesions are needed to foster delineation of

Thin-cap fibroatheroma
A TCFA (Figure4), conceptually often referred to as a
vulnerable plaque, is characterized by a large necrotic
core (usually >25% of the plaque area9) encased by a
thin fibrous cap. The thin fibrous cap is traditionally
defined as being <65m thick, and is heavily infiltrated
by macrophages and, to a lesser extent, Tlymphocytes,
but contains few, if any, smooth muscle cells.19,21,22 The
thinning or weakening of the fibrous cap is an important precursor to plaque rupture.15,23 Although similar,
TCFAs differ from ruptured plaques, because they tend
to have a smaller necrotic core, fewer macrophages within
the fibrous cap, less plaque burden, and less luminal
encroachment than plaques that have ruptured.22
OCT can be used to measure fibrous cap thickness
and, therefore, can be employed to identify TCFA using
a <85m cut-off for the thin cap.1,24 This cut-off has been
chosen from histopathological studies, but might need
adjustment when applied to OCT imaging to account for
the effect of the tissue shrinkage that occurs during histo
pathological processing.19,24 Others have used a threshold of 65m for diagnosing TCFA, which is similar to
the cut-off established by histopathology.26 Although an
appropriate threshold remains to be validated, several
OCT studies have also used the arc of necrotic core as an

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a

b
NC
NC
1.0 mm

Movat

NC

200 m

f
NC

50.0 m

CD68

200 m

Figure 4 | Thin-cap fibroatheroma with extensive

haemorrhage. ac| Low-powered images. df| Highpowered images. A low backscattering, signal-poor region
with diffuse border (white arrow heads) in an exvivo
OCTimage (panela) corresponds with a large NC with
extensiveintraplaque haemorrhage in histological
sections of human coronary plaques (panelb; section
stained with Movat Pentachrome). A high-power OCT
image in panelc showsdistinct superficial high
backscattering, signal-richregion (white arrows) and thin
fibrous cap (double arrow=70m). Acorresponding highpower histological image in paneld shows thin fibrous cap
that is heavily infiltrated by macrophages. The infiltrated
macrophages inthe blacksquare are further highlighted in
an even higherpower image (panele), and also confirmed
in panelf byimmunostaining for CD68+ macrophages
(blackarrows).Abbreviations: NC, necrotic core; OCT,
optical coherencetomography.

additional parameter for detecting TCFA;19 most TCFA

in the autopsy cases of sudden coronary death demonstrate arcs of necrotic core that exceed 120.27 Although
the definition of necrotic core arc to detect TCFA as an
adjunct to measuring fibrous cap thickness seems reasonable, clinicians should consider the possibility of artificial
attenuation of OCT signal with feint of TCFA secondary to tangential signal dropout in instances of eccentric
catheter position.28 A change in OCT catheter position
can help to distinguish signal attenuation owing to the
necrotic core formation from artificial signaldropout.

Ruptured plaques
Ruptured plaques (Figure5) are distinguished from
TCFA by the presence of a luminal thrombus overlying
a thin, disrupted fibrous cap. In ruptured plaques, the
underlying necrotic core is usually large in size (>30% of
the plaque area).9,15,22 The fibrous cap consists mainly
of typeI collagen, with greater numbers of macrophages
and lymphocytes than in TCFA, and with sparse distribution of smooth muscle cells. The thickness of the fibrous

cap at the rupture site is 2319m, and 95% of the cap

measures <64m.21 Although fibrous cap rupture is
widely thought to occur at its weakest point, often near
shoulder regions, autopsy studies using serial sections
demonstrate an equal number of ruptures occurring at the
mid-portion of the fibrous cap, especially when rupture
occurs afterexercise.29
A luminal disruption of the thin fibrous cap allows
circulating cellular and noncellular elements to come
into direct contact with the highly thrombogenic components of the necrotic core, and this contact results in
thrombus formation (Figure5). Focal calcification or
larger calcified sheets are frequently observed in ruptured plaques, and are mostly located towards the abluminal surface of the necrotic core.30 At the rupture site,
the luminal thrombus is platelet-rich and grossly appears
as white thrombus; a predominance of red thrombus is
apparent at the proximal and distal propagation sites.
Thrombus organization is characterized by an infiltration
of inflammatory cells, smooth muscle cells, and endothelial cells, with surrounding extracellular matrix (that is,
proteoglycans and typeIII collagen).
Several clinical OCT imaging studies confirmed the
presence of plaque rupture as the most-frequent eventcausing lesion identified in patients with ACS. 24,31 In
these studies, the disrupted fibrous cap was <70m
thick and was observed in 67% of the examined patients;
median cap thickness was 54m (interquartile range
[IQR] 5060m), and 95% of the thinnest cap measured <80m. These clinical observations conform with
the pathology data described above. An important difference in the definition of plaque rupture by histology
versus OCT existsthe presence of an intraplaque cavity.
Whereas most contemporary imaging studies applied a
definition of plaque rupture covering a disrupted thin
fibrous cap along with an intraplaque cavity, the mandatory presence of intraplaque cavity has not been reported
in histopathology studies. We believe that high-pressure
contrast flush along with overlying thrombus obscuring
the underlying plaque morphology might result in a false
impression of intraplaque cavity when imaging plaque
rupture using OCT. Alternatively, necrotic core material
might also have embolized downstream in particular
patients, which would help to explain the presence of
intraplaque cavities.

Plaque erosion
Plaque erosionthe second-most-prevalent cause of coronary thrombosisdiffers substantially from rupture of
coronary plaques, because fibrous cap disruption does not
occur 32 and the luminal surface underneath the thrombus lacks endothelium and is rich in proteoglycans and
smooth muscle cells (Figure6). The underlying lesion
is usually less advanced than in ruptured plaques, and
mostly exhibits characteristics of early lesions (that
is, pathological intimal thickening or fibroatheromas
without an extensive necrotic core, haemorrhage, or calci
fication). Therefore, the most-relevant features of plaque
erosion include an abundance of smooth muscle cells
within a proteoglycan matrix and the absence of surface

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a
LM

LCX
B
C
D, E

RI

LAD

NC
Thr

Movat

Thr

1.0 mm

CD68

200 m

Figure 5 | Ruptured plaque associated with nonocclusive luminal thrombus.

Amanaged 45years with a history of hypertension, diabetes mellitus, and
hyperlipidaemia, died suddenly after jogging during his lunch break. a| Postmortem angiography showed mild luminal narrowing with haziness at proximal RI.
bd| Serial OCT images revealed the presence of plaque rupture (in panelsc and
d) with nonocclusive luminal thrombus (white arrow headin paneld), and an
adjacent distinct superficial signal-rich region (white arrows in panelb) with rapid
attenuation (white arrow heads in panelb) indicating thin-cap fibroatheroma.
Disrupted fibrous cap also shows distinct superficial signal-rich region (white
arrows in panelc and d). e| Histology confirmed the presence of plaque rupture
with an acute fibrin-rich thrombus (shown as Thr) overlying the NC (section
stainedwith Movat Pentachrome). f| Immunostaining for CD68+ macrophages
demonstrated substantial infiltration of macrophages within the disrupted fibrous
cap (black arrows). Abbreviations: LAD, left anterior descending coronary artery;
LCX, left circumflex coronary artery; LM, left main coronary artery; NC, necrotic
core; OCT, optical coherence tomography; RI, ramus intermedius.

endothelium or a prominent lipid core.33 Usually, few

macrophages and Tlymphocytes are close to the lumen
and the plaque is not disrupted.
Substantial hurdles have limited the clinical utility of
OCT in reliably distinguishing plaque erosion from other
causes of coronary thrombosis; in particular, its limited
axial resolution in detecting a disrupted endothelial
monolayer. Additionally, the presence of luminal thrombus further amplifies the hindrance of light and sound
into deeper tissue regions of the underlying plaque,
making a reliable judgement of plaque morphology
impossible. Clinical OCT studies have suggested that, in
the setting of an acute coronary event, the presence of
luminal thrombus over an intact fibrous cap is indicative of plaque erosion.34 Although presumptive clinical
documentation of plaque erosion is now available, demonstrating OCT characteristics of pathologically-verified
plaque erosion will be important. No post-mortem cases
of OCT validation have yet been reported.

Calcified nodule
Calcified nodule (Figure7) is the least-frequent cause
of luminal thrombus.15 This type of pathology is composed of fibrocalcific plaque with little or no underlying

necrotic core, luminal surface that is disrupted by

nodules of dense calcium, and overlying thrombus.
Calcified nodules often occur in severely calcified arteries
and have large plates of calcified matrix with surrounding
areas of fibrosis, inflammation, and neovascularization.
Although the precise nature of this lesion remains incompletely understood, fragmentation of calcified plates is
believed to be the aetiology of the nodular calcification.
These lesions are generally more prevalent in older men,
and in patients with tortuous coronary arteries, diabetes
mellitus, or chronic renalfailure.
When OCT imaging is applied, the prevailing feature
of calcified nodules is the disruption of a fibrous cap by
dense, calcified nodular tissue, with unique backscattering properties (Figure7).35 However, by definition, calcified nodules have an overlying thrombus and disruption
of the luminal surface, which helps to differentiate this
type of plaque from nodular calcification, a more-stable
form of calcified plaque. Nevertheless, we believe that
OCT can be used to capture the most-relevant features
of calcified nodule and, therefore, remains the mostpromisingimaging technology for the identification of
this type of pathology. Studies to further validate the
utility of this imaging modality in the identification of
calcified nodules are required.

Healed lesions
Healed lesions (Figure8) are observed at sites previously
associated with thrombi. Healed plaque ruptures in coronary arteries are identified by a disrupted fibrous cap with
a surrounding repair phenomenon.36 The provisional
matrix at the site of healing typically consists of an organizing thrombus that is rich in platelets and fibrin, infiltrated smooth muscle cells, and granulation tissue with
accumulated proteoglycans and typeIII collagen. When
complete healing occurs, typeIII collagen might gradually convert into typeI collagen. The luminal surface will
eventually be fully endothelialized, and the underlying
plaque consists of smooth muscle cells and proteoglycanrich extracellular matrix. Healed ruptures often exhibit
multiple layers of necrotic core interspersed by fibrous
tissue. The earliest rupture site is always located in the
deepest intima, suggestive of previous thrombotic events,
which sequentially results in lesion progression.36 On the
basis of autopsy findings for individuals who experienced
sudden coronary deaths, healed ruptures are thought to
contribute to a considerable increase in plaque burden
and also to luminalnarrowing.
Healed ruptured plaques can be detected by OCT using
the landmark of multiple tissue layers of different optical
density overlying a large necrotic core in the presence
or absence of calcification (Figure8). When healing of
ruptured plaque is complete, and typeIII collagen has
been replaced by typeI collagen, a typical band of high
backscattering signal occurs between individual tissue
layers, probably because of the greater optical density of
typeI than typeIII collagen. Furthermore, as corroborated in clinical studies, luminal stenosis is more severe
in healed ruptured plaques than in other plaque types,
because the narrowing effect of sequentially healing

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a

b
Ca2+

Thr

NC
Thr

b
c
1.0 mm
Movat

Movat

Movat

Thr

100 m

Movat

d
Thr

200 m

NC

CD34

Thr

100 m

100 m

CD34

VE-Cadherin

100 m

100 m

VE-Cadherin

100 m

Figure 6 | Plaque erosion. ae| Histological sections showing plaque erosion with
acute thrombus. fh| Histological sections showing an adjacent lesion without
thrombus. A man aged 46years, with a history of non-ST-segment elevation acute
myocardial infarction and sirolimus-eluting stent placement in the proximal LAD
5years ante-mortem, died suddenly and was sent to autopsy for suspected stent
thrombosis. Histology showed patent stented segment with no thrombosis in
theLAD; acute plaque erosion with a nonocclusive thrombus was identified in the
proximal LCX. A low-power image of the proximal LCX (panela) shows plaque
erosion with nonocclusive platelet rich thrombi (shown as Thr) and underlying
fibroatheroma with early NC and focal mild calcification (shown as Ca2+; section
stained with Movat Pentachrome). A high-power image (panelb) highlights luminal
thrombus and underlying early NC with foamy macrophages. A high power image
(panelc) shows luminal surface lacking endothelium, which is in contact with acute
thrombus. Lack of endothelium at luminal surface is confirmed by immunostaining
for two endothelial markers: CD34 (paneld) and VECadherin (panele). A highpower image of an adjacent section (panelf) shows normal endothelialized surface,
which is confirmed by immunostaining for CD34 (panelg) and VECadherin
(panelh) (arrows). Unfortunately, we have not had the opportunity to perform
exvivo OCT imaging in coronary artery with plaque erosion as the event-causing
lesion. Abbreviations: LAD, left anterior descending coronary artery; LCX, left
circumflex coronary artery; OCT, optical coherence tomography; NC, necrotic core.

tissue layers cannot be appropriately compensated by

positive remodelling in the presence of severely diseased
arterialtissue.

Imaging of plaque instability

Acute coronary events are often the first manifestation of
coronary disease in otherwise asymptomatic individuals,
and identification of those at risk of developing acute
events is of paramount importance.1 As discussed above,
plaque rupture is the underlying substrate in at least twothirds of individuals who have ACS, and usually occurs
in plaques with a large necrotic core and a thin, but substantially inflamed, fibrous cap. Lesions with similar
histomorphological characteristics, but intact fibrous
caps (that is, TCFA), are expected to be high-risk plaques
that are vulnerable to rupture.

Pathology of plaque instability

In a study published in 2013, Narula etal. analysed
295coronary atherosclerotic plaques (105 fibroatheroma,
88TCFA, and 102 ruptured plaques) from individuals
who had experienced sudden cardiac death, to determine the hierarchical importance of various pathological characteristics (including fibrous cap thickness,
luminal stenosis, plaque area, necrotic core area, macro
phage area, and calcification) that might differentiate
stable plaques (fibroatheroma) from TCFA and ruptured
plaques.1 Fibrous cap thickness was found to be the mostimportant plaque characteristic to discriminate between
fibroatheroma, TCFA, and ruptured plaques. The fibrous
cap was almost always >85m thick in the fibroatheroma,
and all the disrupted plaques were <55m at their thinnest diameter. In most of the TCFAs, the fibrous caps were
5585m thick; a minority of the TCFAs with fibrous cap
<55m were less occlusive (<75% cross-sectional area
narrowing). In the absence of availabilityof information about fibrous cap thickness, the intensity of macrophage inflammation and the necrotic core size emerged
as discriminatory characteristics of plaque instability.
Clinically, the fibrous cap thickness can be measured
using OCT, as described above. The necrotic cores can
be appreciated using noninvasive modalities such as CT
angiography. The reliable assessment of inflammation is
not yet possible at the plaque level and, although radio
labelled deoxyglucose imaging is being investigated,
measures of the systemic biomarkers currently might
provide the presumptive or circumstantial evidence of
plaqueinflammation.
Observations in the Narula etal. study 1 suggested
that the culprit plaques that rupture usually cause clinically significant compromise of the lumen, and that the
TCFA need to grow considerably before they are likely
to rupture. A post-hoc analysis of the US National Heart,
Lung, and Blood Institute registry, wherein paired angio
graphy data were available,37 supports the conclusion
that plaques progressively expand before they rupture.
Although high-risk plaques have tacitly been believed not
to cause critical narrowing of the coronary lumen because
of the positive remodelling that occurs,38 the Narula etal.
study 1 demonstrated that disrupted plaques were almost
always associated with a large plaque size and artery
stenosis. Indeed, >75% cross-sectional vascular area sten
osis was observed in 70% of ruptured plaques and 40%
of TCFA, and only 5% of ruptured plaques and 10% of
TCFA had <50% cross-sectional area involvement. The
findings that luminally occlusive lesions are more likely
to rupture do not contradict the belief that the plaques
responsible for acute coronary events are more likely to
be mildly obstructive.38 Lesions that are mildly occlusive
at the time of early diagnosis might evolve to become
substantially larger when they rupture. In angiography
studies, the lesions that resulted in an event were shown
to be more occlusive at the time of a preceding coronary
angiogram, if obtained shortly before the event. However,
if the interval between the event and the preceding angiogram was longer, a milder lesion on the angiogram could
be identified as the future culprit plaque.39,40

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a

b g

P
L FA

P
LF
R

i
m

k
l

P R
L FA

L
A
R F

*
*

*
1 mm

Figure 7 | Calcified nodule. A man aged 57years underwent percutaneous coronary

intervention in the left anterior descending coronary artery for stable angina.
Theleft circumflex coronary artery was evaluated for the presence of clinically
significant lesions by OCT, and subsequent 3D reconstruction of OCT images was
performed. a| Coronary angiography of the left circumflex coronary artery. Black
lines indicate the studied segment. be| Upstream fly-through view (distal-toproximal) of 3D reconstruction of OCT images indicating the sites corresponding
topanelsfm. fm| OCT images show presence of red thrombus (white arrows)
inareas of fibrocalcific plaque (asterisks) in the absence of plaque rupture. Sharp
protrusions of calcium into the lumen are seen in parts g, j, and l (asterisks) with
very thin, or absent overlying intimal layer. Abbreviations: NC, necrotic core; OCT,
optical coherence tomography. The images in this figure were original published
inKaranasos, A., Ligthart, J.M., Witberg, K.T. & Regar, E. Calcified nodules:
anunderrated mechanism of coronary thrombosis? JACC Cardiovasc. Imaging
5(10), 10711072 (2012)35 American College of Cardiology.

IVUS confirmation of pathology

The findings described above were confirmed ina prospective IVUS imaging study of nonculprit plaques
PROSPECT.41 This study documented the incremental angiographic diameter stenosis associated with the
lesions that were subsequently responsible for major
adverse cardiovascular events.41 After successful and
uncomplicated percutaneous coronary intervention of
the index coronary lesions in 697 patients with ACS,
nonculprit lesions were imaged. The imaging assessment included coronary angiography followed by both
grey-scale and radiofrequency IVUS of the left main
coronary artery and the proximal parts of the major
epicardial coronary arteries. During a median follow-up
period of 3.4years, major adverse cardiovascular events
occurred in 74 patients (3year cumulative rate 11.6%).41
Most of the nonculprit lesions that were later responsible for a major adverse event appeared by angiography
to be mild at baseline, but evolved to cause substantial
stenosis. The mean angiographic diameter stenosis of
the 106 nonculprit-lesion-related adverse events was
3221% at baseline and 6516% at the time of the event.

Thestrongest lesion characteristics that were predictive of nonculprit-lesion-related major adverse cardio
vascular events at follow-up included baseline plaque
burden of >70%, a minimal luminal area of <4.0mm2,
and the presence ofTCFA.
Two other studies using virtual histology IVUS have
independently confirmed the feasibility of plaque
characterization for the prospective evaluation of highrisk plaques.42,43 In the VIVA study,42 the noncalcified
TCFA was associated with major adverse cardiovascular
events, driven predominantly by coronary revascularizations (unadjusted HR1.79, 95%CI 1.202.66, P=0.004).
The ATHEROREMO IVUS study 43 showed IVUSverified TCFA to be an independent predictor of major
adverse cardiovascular events (HR1.98, 95%CI 1.09
3.60, P=0.03), and acute cardiac events (composite of
death or ACS only; HR2.51, 95%CI 1.155.49, P=0.02).
These studies confirmed the observations of Narula
etal.1 and emphasized the critical importance of defining TCFA. Although TCFA was defined as the absence
of any intervening tissue between the necrotic core and
the lumen by virtual histology IVUS, the poor resolution
of IVUS does not allow precise definition of the fibrous
capthickness.

OCT imaging of plaque instability

Given that OCT can be used to precisely measure
fibrous cap thickness (in microns), and that high-risk
plaques have been described as those with the thinnest fibrous caps, the widest lipid arc, and the longest
lipid length, this imaging modality seems to be the
most useful for identifying plaques that are vulnerable
to rupture.44,45 Indeed, OCT has been used in multiple studies to assess plaque instability. Various OCT
studies have demonstrated that TCFAs are more commonly found in patients presenting with acute myocardial infarction and unstable angina than in those
presenting with stable CAD.46.47 In one such study, the
frequency of TCFAdefined by lipid-rich plaque with
OCT-measured cap thickness 65mwas 72% in the
patients who had experienced acute myocardial infarction, 50% in the group with unstable angina, and 20%
in the group of stable patients (P=0.01).47 The median
values of the minimum thicknesses of the fibrous cap
were 47m, 54m, and 103m, respectively (P=0.03).47
In another study, 103 lesions from patients with ACS
and 163 lesions from individuals with stable angina
were assessed using OCT before percutaneous coronary intervention.48 In the ruptured plaques, the median
thinnest cap thickness was 54m; in 95% of ruptured
plaques, the thinnest cap thickness was <80m.48 In
unruptured plaques, the median thinnest cap thickness
was 80m, and the median most-representative cap
thickness was 182m.48 The best OCT-measured cut-off
for predicting rupture was <67m (OR16.1, 95%CI
7.534.4, P<0.001) for the minimum cap thickness.48
One OCT study has shown that TCFAs are predisposed to rupture both at rest and during day-to-day
activity.49 The investigators also found that relatively
thicker fibrous caps could rupture with greater exertion,

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a

NC
1.0 mm

Movat

NC

NC

200 m

Figure 8 | Healed plaque rupture. a| An exvivo OCT image shows a layered pattern
of the signals and underlying signal-poor region with diffuse border (white arrow
heads) and focal signal-rich confluent punctate area with rapid attenuation (white
arrows). b| A corresponding histological section of the human coronary plaque
(stained with Movat Pentachrome) shows healed plaque rupture and underlying NC
with extensive haemorrhage and the presence of foamy macrophages close to the
luminal surface (black arrows). c| The layered pattern of the OCT signals is
highlighted in a high-power image (white double arrows). d| A high-power
histological section (stained with Movat Pentachrome) shows numerous smooth
muscle cells within the newly formed proteoglycan-rich neointima (black double
arrows close to the luminal surface), with clear demarcation from the underlying old
collagen-rich fibrous cap. e| In a high-power image of a Sirius-red-stained section
(taken with polarized light) that corresponds with the image in paneld, dense
(typeI) collagen forms a fibrous cap, seen as areddish-yellow region, and is
overlaid with newer (typeIII) collagen, detected as a greenish area. Abbreviations:
NC, necrotic core; OCT, optical coherence tomography.

and that a culprit plaque is more likely to have ruptured

at the shoulder when rupture occurred with exertion.49
However, these finding are not in agreement with histological studies in which exertion-related ruptures tended
to occur in the thinnest portion of the cap, most often
located in the mid portion. 29 OCT studies have also
demonstrated a significant increase in the fibrous cap
thickness after statin therapy.50,51
The standard deviation of the OCT signal intensity
has been suggested as a way to identify cap macrophage
density.52 In an OCT image analysis of lipid-rich athero
sclerotic arterial segments post-mortem, this OCT
measure correlated well with histological measurements of fibrous cap macrophage density (r=0.84,
P<0.0001), and a range of OCT signal standard
deviation thresholds (6.156.35%) yielded excellent
diagnostic accuracy for identifying caps containing
>10% staining for macrophage markers. 52 In another
OCT study by the same group, a greater macrophage
density was found in the fibrous caps of patients with
ACS than in those with stable angina, and the sites
of plaque rupture had a greater macrophage density
than sites of unruptured plaques (6.951.60% versus
5.291.17%; P=0.002).53 For culprit lesions, but not for
remote lesions, surface macrophage infiltration was a
stronger predictor of unstable clinical presentation than
subsurfaceinfiltration.53

Although OCT imaging has demonstrated convincing correlations with the morphological determinants
of high-risk plaques, outcomes studies similar to the
PROSPECT trial41 are needed to establish the clinical
utility of OCT imaging, both in predicting plaque instability and in the management of patients with high-risk
plaques. Using OCT imaging, investigators in the pilot
SECRITT trial54 evaluated the feasibility and safety of
a pre-emptive interventional treatment targeting highrisk plaques by implantation of a self-expanding metallic
stent. The implanted bare-metal stent helped to develop
a thick fibrous layer in the stented region and presumably helped to stabilize the plaque.54 Bioresorbable vascular scaffolds might be superior to bare-metal stents
for pre-emptive treatment, because the polymer material is fully degraded within 23years of implantation,
and the location of the struts is no longer identifiable
by OCT after 4years.55 After scaffold resorption, symmetric neointimal tissue (mean thickness 220m) bereft
of remnants of polymeric struts might resemble a stable
fibroatheromatous plaque. 55 However, enthusiasm
for these theories needs to be tempered until studies
have demonstrated effects on outcome measures and
the absence of an increased restenosis rate with the
bioresorbable scaffold.

OCT imaging in ACS management

Pathology reports obtained from the autopsies of individuals who experienced sudden cardiac death have demonstrated that more than two-thirds of acute coronary
events are related to thrombotic occlusion secondary
to atherosclerotic plaque rupture, and that the remaining events are caused by thrombotic occlusion secondary to plaque erosion or, rarely, a calcified nodule.1,2
Interestingly, an OCT study demonstrated more-similar
proportions of plaque ruptures and erosions (44% versus
31%) in patients presenting with acute coronary events.56
Ozaki etal. have proposed that the classification
of acute coronary events should be based on clinical
imaging and have suggested that events associated with
plaque rupture (Figure9ac) or erosion (Figure9df)
two pathologically distinct entitiesbe defined as ACS
with ruptured fibrous caps (RFCs) or ACS with intact
fibrous caps (IFCs), respectively.34 For patients who
have experienced ACS, current treatment guidelines
dictate catheter-based reperfusion of the infarct-related
artery with intravascular stent placement, regardless of
the underlying plaque morphology.57 Whether the use
of imaging to provide apriori knowledge of the mechanism of ACS would allow improved management of the
conditions remains to be investigated.58
In erosive pathology, when stenosis of the arterial
lumen is not clinically significant and the vessel wall
not disrupted, the use of imaging to reliably characterize plaque morphology might enable justified avoidance
of coronary stent placement as the initial strategy.57 We
evaluated a series of patients in whom the acute event
was attributed to IFCs after aspiration thrombectomy.58
The decision of how these patients would be treated was
left to the interventionists. Standard-of-care treatment

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a

Figure 9 | Two pathologically distinct types of acute coronary event. ac| ACS with
a ruptured fibrous cap. Imaging of the coronary arteries in a man aged 59years
with anterior ST-segment elevation myocardial infarction shows a ruptured fibrous
cap, a clinical representation of plaque rupture described in autopsy specimens.
The angiogram (panela) shows a severe mid-LAD lesion (arrow). The OCT images
(panelsb and c) show a large thrombus associated with fibrous cap rupture
(arrowin panelc). df| ACS with an intact fibrous cap. Imaging of the coronary
arteries in a woman aged 65years with anterior non-ST-segment elevation
myocardial infarction shows an intact fibrous cap, a clinical representation of
plaque erosion described in autopsy specimens. The angiogram (paneld) shows
narrowing of the proximal LAD (arrow). An OCT image (panele) shows white
thrombus occurring at a site with mild disease, and no signs of ulceration (arrow).
In another OCT frame obtained just proximal to the site with thrombus (panelf),
thethrombus is attached to the luminal vascular surface (indicated by the arrow).
Abbreviations: ACS, acute coronary syndrome; LAD, left anterior descending
coronary artery; OCT, optical coherence tomography.

with stent placement was received by 60% of patients;

in the remaining patients, the interventionists reasoned
that the stenting might be superfluous in the absence of
a severely obstructive plaque, and obviating stent deployment might avoid potential procedure-related complications. These patients were treated with aspirin, heparin,
and a thienopyridine, with or without a glycoproteinIIb/
IIIa inhibitor. The residual coronary stenosis was similar
in the two groups. After a follow-up of >2years, none
of the patients treated by thrombectomy alone (that is,
without a stent) required an additional revascularization. Although promising, a prospective, randomized
study is needed to identify the benefit of the alternative
approach in the sizable subgroup of patients presenting with ST-segment elevation myocardial infarction
(STEMI).57 Definition of the optimal antithrombotic
treatment in patients who are not treated with a stent
is also necessary. We also presume that, in the absence
of plaque rupture, the lesion could be cleaned up with
intracoronary plasmin.59
As Eugene Braunwald wrote in an editorial that accompanied the publication of the aforementioned study
assessing the use of only medical therapy in patients
who have experienced an ACS with an IFC,57 although
plaque erosion is not the most common cause, it certainly
is not an infrequent cause of coronary thrombosis and
STEMI. The application of OCT in patients with STEMI
secondary to plaque erosion who were treated successfully without percutaneous coronary intervention should

lead to further investigation of this ingenious therapeutic

approach. Critical evaluation of the delay in revascularization procedure caused by adding OCT imaging to
the diagnostic regimen is necessary in patients eventually
treated with percutaneous coronary intervention with
stentingwe need to determine whether the benefit of
diagnostic OCT would outweigh the detrimental effects
of this time delay, and compare the strategy to simply
proceeding with stent placement in all patients regardless
of whether the ACS were with RFCs or IFCs.57 Owing
to their limited resolution, other intravascular imaging
modalities are unlikelyto be useful for clinically defining the plaque pathology to differentiate between an IFC
and a RFC.

Conclusions
Intravascular imaging, particularly OCT, has provided
unprecedented information about plaque morphology
invivo. Comparison of the plaque characteristics in
autopsy specimens exvivo and the invivo intracoronary
imaging data has allowed identification of pathological features of plaque vulnerability that are amenable to
clinical imaging. These features are likely to be used in
prospective, randomized trials of pre-emptive interventional therapy for potential prevention of acute coronary
events. Additionally, in patients who have experienced
an ACS, appropriate distinction between plaque rupture
(ACS with a RFC) and plaque erosion (ACS with an
IFC) using OCT imaging might enable the avoidance of
stent implantation in patients with an IFC, if the lumen
is not found to be substantially occluded after thrombus
aspiration. A multicentre, randomized study is being
initiated to prospectively evaluate the necessity for stent
placement in cases of plaqueerosion.
Notably, researchers are actively working on further
improving OCT imaging techniques. The resolution
of OCT imaging is expected to improve substantially,60
although the promising micro-OCT technology might
take some time to come to coronary clinics, because it is
dependent on contact of the probe and on the absence
of motion of the object that is being imaged. The definition of plaque characteristics might also be improved via
the use of a multimodality fluorescence and OCT probe
using a double-clad fibre combiner that might enable
targeted molecular imaging.61,62
Review criteria
A search for original articles and state-of-the-art review
articles published between 2004 and 2013 and focusing
on plaque vulnerability and intravascular imaging
was performed in MEDLINE and PubMed. The search
terms used were: IVUS, OCT, coronary artery
disease, atherosclerosis, and vulnerable plaque in
combination. All articles selected were English-language,
full-text papers. We also searched the reference lists
of identified articles for further relevant papers. Data
from some of the classic papers on plaque vulnerability
published earlier were also added without a systematic
search for additional papers reported during the same
time frame.

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NATURE REVIEWS | CARDIOLOGY

Acknowledgements
St. Jude Medical (USA) and Terumo Corporation
(Japan) provided the major source of research
fundsfor the exvivo optical coherence tomography/
optical frequency domain imaging study, with other
support from CVPath Institute, Inc., USA. F.O. is
supported by a researchfellowship from the Uehara
Memorial Foundation(Japan).
Author contributions
F.O., F.P., and J.N. researched data for the article.
M.J., R.V., and J.N. substantially contributed
todiscussion of content. F.O., M.J., R.V., and
J.N. wrote the manuscript. M.J., F.P., R.V.,
and J.N. reviewed and edited the manuscript
beforesubmission.

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