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40 S. Torii
et al.
the important differences in the definition of plaque rupture by histology
versus OCT is the presence of an intraplaque cavity seen in OCT but not in
histologic sections.
3
Although most contemporary imaging studies applied
a definition of plaque rupture covering a disrupted thin fibrous cap along
with an intraplaque cavity, our observations are not in agreement. We have
never seen on histology such a cavity in the coronary arteries of patients
presenting withacute plaque rupture at autopsy (without prior intervention).
In our examination of over 500 cases, all have a necrotic core with an
overlying disrupted fibrous cap and a thrombus. There are likely a few
explanations for this discrepancy: high-pressure contrast flush along with
an overlying thrombus obscuring the underlying plaque morphology might
result in a false impression of intraplaque cavity or excessive hemorrhage
29
in the necrotic core and OCT’s inability to discriminate red cells.
It is also
possible that necrotic core material might also have embolized downstream
in selected cases, which would help explain the presence of intraplaque
cavities.
Plaque erosion
Plaque erosion is the second-most-prevalent cause of coronary thrombosis and differs from rupture because it lacks a thin fibrous cap with
30
disruption
and the luminal surface underneath the thrombus is rich in
proteoglycans and smooth muscle cells with an absence of endothelial
lining (Figure 7). The underlying atherosclerotic lesion is usually less
advanced than in ruptured plaques and mostly exhibits characteristics of
early lesions (pathological intimal thickening in 16% and an early or late
fibroatheroma in 50% and 34%, respectively).
31
The majority of plaque
erosion lesions (56%) lack evidence of calcification, although microcalcification is observed in approximately 40% of the lesions. Fragmented calcification and sheets of calcification are rare (<2%).
31
Therefore, the most
relevant features of plaque erosion include an abundance of smooth muscle
cells within a proteoglycan matrix and the absence of surface endothelium
or a prominent large lipid core.
32
Thus far, OCT has failed to reliably distinguish plaque erosion from
other causes of coronary thrombosis, in particular, due to its limited axial
resolution for the detection of an absence of endothelial monolayer through
Coronary Arteries 41
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OFDI
OFDI
(a)
RCA
LAD
(b)
Th
LCX
Diagonal
(c)
Th
(d)
‘
‘
‘
‘
‘
‘
‘
‘
(e)
Figure 7. Plaque erosion. (a–c) A 34-year-old man died suddenly due to multiple plaque erosions
in three major coronary arteries. (a) Postmortem radiography showed focal mild calcification in all
major coronary arteries. (b) The right coronary artery (RCA) showed a luminal fibrin-rich organizing
thrombus with an underlying late fibroatheroma. (c) The diagonal branch artery also showed a luminal
fibrin-rich organizing thrombus with an underlying pathologic intimal thickening. High-power images
from boxed areas in (c and d) are shown on the right. Fibrin-rich thrombus with a few inflammatory
cells is seen on the luminal surface. Corresponding OFDI images (OFDI; Terumo, Tokyo, Japan) are
depicted on the right side. OFDI showed luminal surface irregularity with minimal attenuation because
the thrombus had focal areas of platelets interspersed by large areas of fibrin in the RCA and the
diagonal branch (white arrows) and a bright layer with attenuation (red arrowheads) indicating the
presence of macrophages in RCA Th = thrombus, *guidewire. (d) A 31-year-old man presented with
non-ST-segment elevation myocardial infarction. Angiographic image (left panel) shows a moderate
stenosis in the proximal left anterior descending coronary artery. Serial optical coherence tomography
(OCT) cross-sectional images from proximal to distal of the culprit lesion indicate that no rupture is
detected. Cross-sectional images indicate fibrous plaque (homogeneous high signal region) proximal
(A) and distal (D) to thrombus OCT-erosion is identified as an irregular lumen surface with attached
42 S. Torii
et al.
an overlying platelet-rich thrombus. Recently Jia et al. have reported on
OCT criteria for establishing the diagnosis of plaque erosion called as
“OCT-erosion” instead of erosion. Definite OCT-erosion is identified by the
presence of a luminal thrombus overlying a n intact and visualized plaque,
or probable OCT-erosion if (1) there is luminal surface irregularity at the
culprit lesion in the absence of thrombus or (2) attenuation of underlying
plaque by thrombus without superficial lipid or calcification immediately
proximal or distal to the site of thrombus.
33
Also, the presence of luminal thrombus hinders the penetration of light and sound into deeper tissue
regions of the underlying plaque, making a reliable judgment of plaque
34
morphology difficult.
Although, as noted above, a definite and probable clinical documentation of plaque erosion has been defined, we have
recently published a case report that demonstrated the comparison between
31
pathologically verified plaque erosions and OCT images
(Figure 7).
Calcified nodule
Calcified nodule (Figure 8) is the least-frequent cause of luminal throm-
2,15
bus.
thrombi in which risk factor analysis was also available, the incidence of
calcified nodules was only 5%.
ence of nodules of calcium that are protruding (convex) into the lumen and
the luminal surface is covered by a thrombus. The eruptive calcified nodules are usually eccentric, bulging into the lumen, with an absence of both
endothelial lining and collagen and an overlying usually a non-occlusive
thrombus. Although the precise mechanism remains unknown, mechanical
From the sudden coronary death registry of 236 cases of coronary
35
Calcified nodule is defined by the pres-
←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
Figure 7 (Continued). mural thrombus (arrows) overlying a fibrous plaque (B and C). (e) A 37year-old male smoker presented with ST-segment elevation myocardial infarction. The angiographic
image (left panel) shows a mild stenosis in the proximal left anterior descending coronary artery.
Serial optical coherence tomography (OCT) cross-sectional images from proximal to distal of the
culprit lesion show the absence of detectable rupture (A’ to D’). Underlying plaque morphology is not
well visualized, due to the presence of residual red thrombus (A’ to C’, arrows). The OCT images
in the distal and proximal segments of the thrombotic lesions show the absence of superficial lipid
and calcification (A’ and D’). Histological and OCT image in panel a reprinted with permission from
Ref. [33] and Ref. [31].
Coronary Arteries 43
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(a)
(f) (g) (h) (i)
(b)
g
(d)
h
f
l
k
m
(c)
(e)
i
*
*
(j) (k) (l) (m)
*
1mm
*
j
i
k
m
m
l
*
Figure 8. Calcified nodule. A man aged 57 years underwent percutaneous coronary intervention in
the left anterior des cending coronary artery for stable angina. The left circumflex coronary artery was
evaluated for the presence of clinically significant lesions by OCT, and subsequent 3D recons truction
of OCT images was performed. (a) Coronary angiography of the left circumflex coronary artery.
Black lines indicate the studied segment. (b–e) Upstream fly-through view (distal-to-proximal) of 3D
reconstruction of OCT images indicating the sites corresponding to panels f–m. (f–m) OCT images
show the presence of red thrombus (white arrows) in areas 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 in Ref. [37].
stress might fracture sheets of calcium, resulting in small nodules that could
break the collagen over the luminal surface and become surrounded by fibrin. The lesion is usually an underlying fibrocalcific plaque with little to no
underlying necrotic core, usually showing the presence of calcified sheets
44 S. Torii
et al.
with the luminal surface disrupted by the nodules of dense calcium with
an 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.These lesions are generally
more prevalent in older males and females and in patients with tortuous
coronary arteries, diabetes mellitus, and/or chronic renal failure.
On OCT imaging, the calcified nodule is defined when fibrous cap
disruption is detected over a calcified plaque that is characterized by protruding calcification, superficial calcium, and the presence of substantive
calcium proximal and/or distal to the lesion
36,37
(Figure 8). An overlying
thrombus and disruption of the luminal surface help differentiate calcified
nodule from nodular calcification, a more stable form of calcified plaque.
Nevertheless, we believe that OCT is the most relevant modality able to
clearly visualize the various features of calcified nodule and, therefore,
remains the most promising imaging technology for its identification.
Healed lesions
Healed lesions (Figure 9) are observed at sites previously associated with
thrombi, mainly from plaque rupture, although can be secondary to another
cause of thrombi, such as plaque erosion and calcified nodules. The majority of plaque ruptures that cause symptoms occur in lesions that occupy
greater than 75% cross-sectional vascular area narrowing.
all ruptures, especially those associated with less severe stenosis, result
in an overt event and may instead heal spontaneously
to plaque enlargement and progressive luminal narrowing.
plaque healed plaque rupture is characterized by the presence of a discrete defect in the fibrous cap collagen (yellow) with the area of the healed
thrombus filled by collagen staining green in the Sirius red stain viewed
under polarized light. Mann and Davies showed lesions with 0–20% diameter stenosis and had 16.2% healed plaque ruptures, while 21–50% diameter
stenosis had 18.6% healed with the maximum (73.2%) seen in lesions with
≥ 1%. We have s hown that healed ruptures often exhibit multiple layers of
necrotic core interspersed by fibrous tissue, representing multiple ruptures
at one location. The earliest rupture site is always located in the deepest
intima, suggestive of previous thrombotic events, which sequentially results
19
However, not
27
and contribute
38
Thesiteof
Coronary Arteries 45
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(a) (b)
Movat
NC
(c) (d) (e)
NC
Figure 9. Healed plaque rupture. (a) An ex vivo OCT image shows a layeredpattern of the signals and
underlying signal-poor region with diffuse border (white arrowheads) 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 hemorrhage 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 collagenrich fibrous cap. (e) In a high-power image of a Sirius-red-stained section (taken with polarized light)
that corresponds with the image in panel d, dense (type I) collagen forms a fibrous cap, seen as a
reddish-yellow region, and is overlaid with newer (type III) collagen, detected as a greenish area.
Abbreviations: NC, necrotic core; OCT, optical coherence tomography. Histological image in panel a
reprinted with permission from Nature Publishing Group © Otsuka, F., et al. Clinical classification of
plaque morphology in coronary disease. Nature Reviews Cardiology, 11(7): 379–389 (2014).
e
NC
in lesion progression.27At the site of the thrombus (platelet/fibrin thrombus
with or without red cells), healing typically consists of infiltrated endothelial and inflammatory cells with granulation tissue consisting of smooth
muscle cells accumulating proteoglycans and type III collagen and areas of
angiogenesis. When full healing is complete, type III collagen is gradually
replaced by type I collagen. The luminal surface is eventually completely
46 S. Torii
covered by endothelial cells, and the underlying plaque consists of few
smooth muscle cells but the matrix is proteoglycan–collagen rich. In our
autopsy study, we showed that 61% of the hearts from individuals dying of
sudden coronary death had healed plaque ruptures and the luminal narrowing was 66±11%, whereas, for those dying with acute plaque rupture, the
luminal narrowing was 79 ±15%.
Healed ruptured plaques by OCT are difficult to detect, although we
have shown that multiple tissue layers of different optical densities overlying a large necrotic core in the presence or absence of calcification likely
represent a healed plaque rupture (Figure 9). When healing of a ruptured
plaque is complete, the type III collagen with a proteoglycan-rich matrix
formed at the site of the original thrombus (green on Movat stain) is typically seen as a distinct band of low scattered signal followed by a high
backscattering signal from the collagen type I layer of the underlying ruptured fibrous cap. This gives a multi-layered appearance on OCT, probably
because of the greater optical density of type I collagen compared with
type III collagen. Furthermore, as reported above, luminal stenosis is more
severein healed ruptured plaques compared with first-time plaque ruptures,
but because the narrowing impact of sequential healing occurs by collagenous tissue layers, there is negative remodeling seen in severely diseased
arteries.
et al.
Imaging of Plaque Instability
The main goal of imaging is to be able to predict which plaques will eventually leadto thrombosis in thefuture with the hope that either medical therapy
or invasive intervention will prevent future thrombosis. Of the three main
causes of coronary thrombosis, the only precursor lesion that is recognized
is that of TCFA which is thought to precede rupture and is identified by
the presence of three fundamental morphologic characteristics, i.e. large
necrotic core, a thin cap, and its infiltration by foamy macrophages. TCFA,
also known as the vulnerable plaque, is considered an unstable lesion that
is likely to rupture in the future although in vivo evidence of this is lacking.
OCT, as reported above, is the only modality with high enough resolution
(12–20 microns) to identify TCFA as shown in multiple studies, mostly due
Coronary Arteries 47
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to itsability to accuratelymeasure the cap thickness.Jang et al. measured the
fibrous cap thickness using OCT in patients with acute myocardial infarction (AMI, n = 20), acute coronary syndrome (ACS, n = 20, [NSTEACS
and unstable angina]), and stable angina pectoris (SAP, n = 17). The
median value of the minimum fibrous cap thickness was 47µm, 54µm,
and 103µm, respectively (P = 0.03).
39
Pathology of plaque instability
To determine the importance of variouspathological characteristics,we previously evaluated 295 coronary atherosclerotic plaques(105 fibroatheroma,
88 TCFA, and 102 ruptured plaques) from individuals who had experienced sudden cardiac death.
of fibrous cap thickness, percent stenosis, macrophage area, necrotic core
area, and calcified area were evaluatedusing recursive partitioning analysis.
Cap thickness emerged as the best predictor of plaque rupture (<55 uM),
whereas all fibroatheromas had cap thickness >84 microns. Majority of
the TCFAs were found to have a cap thickness of 54–84 microns, however,
those with cap thickness <54 microns were likely to show <74% luminal
stenosis. Macrophage infiltration was the second best predictor of TCFA.
Percent narrowing >75% was seen in 70% of PR and 40% of TCFA, but
only 5% of PR and 10% of TCFA has less than <50% cross-sectional area
narrowing.As a result, fibrous capthickness was found to be the most important plaque characteristic to discriminate between fibroatheroma, TCFA,
and ruptured plaques. The intensity of macrophage inflammation and the
necrotic core size emerged as other discriminatory characteristics of plaque
instability. It has been shown by CT angiography that positive remodeling,
along with the presence of low attenuated plaque and spotty calcification,
represents high-riskplaques that have been shownto be a predictor of future
events.
40,41
19
In the study, the hierarchical importance
IVUS confirmation of pathology
The findings described both by CT angiography and autopsy were also
reported in a prospective IVUS imaging s tudy of the non-culprit plaques:
Providing Regional Observations to Study Predictors of Events in the
48 S. Torii
et al.
Coronary Tree (PROSPECT). This study had the limitation that IVUS
which does not have the resolution of OCT to either detect macrophages or
measure fibrous cap relied on vague criteriadeveloped for virtual histologyintravascular ultrasound (VH-IVUS) to define TCFA.
42
After successful
and uncomplicated percutaneous coronary intervention of index coronary
lesions in 697 patients with ACS, non-culprit lesions were subjected to
imaging. During a median follow-up period of 3.4 years, major adverse
cardiovascular events occurred in 74 patients (3-year cumulative rate of
11.6%). The strongest lesion characteristics that were predictive of nonculprit-lesion-related major adverse cardiovascular events at follow-up
included a baseline plaque burden of >70%, a minimal luminal area of
2
<4.0 mm
, and the presence of TCFA.
OCT imaging of plaque instability
Although IVUS can only suggest the presence of a thin-cap fibroatheroma
by identifyinga necrotic core alongside the lumen, OCT can identify fibrous
cap thickness of less than 65 µm, macrophages in the fibrous cap, and the
underlying lipid core. Therefore, OCT has been used in multiple studies
assessing plaque instability. Various OCT studies have demonstrated that
TCFA is more commonly found in patients presenting with acute MI and
unstable angina versus those presenting with stable CAD.
study, the frequency of TCFA — defined by lipid-rich plaque with OCTmeasured cap thickness ≤65 µm — was 72% in the patients who had experienced acute MI, 50% in the group with unstable angina, and 20% in the
39
stable group of patients (P = 0.01).
The median values of the minimum
thicknesses of the fibrous cap were 47µm, 54µm, and 103µ m, respectively (P = 0.03).
39
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.
20
median thinnest cap thickness was 54µm versus unruptured plaques which
has a mean cap thickness of 80 µm, and the median most representative
cap thickness for rupture was 116 µm vs. 182 µm for unruptured; in 95%
of ruptured plaques, the thinnest cap thickness was < 80µm.
tured plaques, the median thinnest cap thickness was 80 µm and the median
39,43
In one such
In ruptured plaques, the
20
In unrup-
Coronary Arteries 49
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most representative cap thickness was 182 µm.20The best OCT-measured
cut-off for predicting rupture was <67 µm (OR 16.1, 95% CI 7.5–34.4,
P < 0.001) for the minimum cap thickness.
20
One OCT study has shown that TCFAwas predisposed to rupture both
at rest and during day-to-day activity.
28
The investigators also found that
relatively thicker fibrous caps could rupture with greater exertion and that a
culprit plaque is more likely to have ruptured at the shoulder when rupture
occurred with exertion.
28
However, these findings are not in agreement
with histologic studies where exertion-related ruptures tended to occur in
the thinnest portion of the cap most often located in the mid portion.
26
Moreover, OCT studies have also demonstrated a significant increase in
the fibrous cap thickness after statin therapy.
44,45
We recently demonstrated the drawback of TCFA detection by OFDI,
of the 18 TCFA determined by histology, OFDI detected TCFA in 23, with
24
a positive predictive value of only 60.9%
primarily due to the presence
of surface macrophages that typically appear bright with a steep signal
attenuation by OFDI therefore over diagnosing TCFA. Macrophages play
an important role in various stages of atherosclerotic progression and also
invade the thin fibrous cap, either as a single layer or multiple layers, and
increase the susceptibility for the formation of TCFA which will eventually rupture. In OCT/OFDI, macrophages uniformly exhibit high-intensity
appearance with trailing shadow, making it difficult to correctly diagnose
24
tissues behind macrophages.
On the other hand, by utilizing integrated
backscatter-IVUS (IB-IVUS), all of OFDI-derived “pseudo” TCFA were
excluded, with a positive predictive value of TCFA detection reaching
100%. The combination of IB-IVUS with OFDI improved the accuracy
of TCFA detection, suggesting hybrid imaging will be required to identify
coronary lesions responsible for future events.
Pathological 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 acute
coronary events are caused by thrombotic occlusion secondary to plaque
erosion or, rarely, a calcified nodule.
16,19