This editorial refers to ‘Coronary CT angiography characteristics of culprit lesions in acute coronary syndromes not related to plaque rupture as defined by optical coherence tomography and angioscopy’, by Y. Ozaki et al., on page 2814

Prospective identification of high-risk plaque (or vulnerable plaque) prior to the occurrence of coronary thrombosis has for years been compared with the quest for the Holy Grail, since this would be the necessary initial step for the focal treatment of the high-risk lesion and subsequent prevention of progression to an acute coronary syndrome (ACS).1–3

The most common cause of coronary thrombosis is plaque rupture (in 55–60% of cases) or plaque erosion (in 30–35% of cases) and much less frequently calcific nodules.4 From post-mortem studies we know that ruptured plaques have specific features: a thin fibrous cap (<65 µm) overlaying a lipid/necrotic core (>10% of the plaque area) that is inflamed and often accompanied by expansive remodelling.4–6 These plaques usually have a stenosis diameter < 50% and contain spotty calcifications. The precursor lesion of the ruptured plaque is the thin cap fibroatheroma (TCFA), which resembles the morphology of the ruptured plaque except that there is no rupture or thrombosis. The ruptured plaque is distinct from the eroded plaque, and retrospective pathological studies of plaque erosion found that an acute thrombus was in direct contact with the intima in an area of absent endothelium. This plaque is often rich in proteoglycans, a lipid pool or necrotic core is often lacking, the fibrous cap is thick and rich in smooth muscle cells, and constrictive remodelling of the plaque is often seen.4 The precursor lesions of the eroded plaque are a heterogeneous group of plaques that consists of plaques with pathological intimal thickening (PIT) or a thick fibrous cap atheroma (ThCFA).4,7

Post-mortem studies are by definition single observational studies that do not allow the study of the natural course of high-risk or eroded plaques. However, the dynamic nature of thrombosed plaques can also be gleaned from histological studies. Ruptured or eroded plaques may heal, but repeated rupture and erosion may occur, as can be reconstructed from the multilayered appearance of plaques in histological cross-sections.4 The dynamic nature of coronary plaques was also demonstrated in a study of 99 patients in whom intravascular ultrasound virtual histology (IVUS-VH) was performed at baseline and again 12 months later.8 The authors found that approximately three-quarters of the IVUS- VH-defined TCFAs heal, i.e. they evolved to (presumably) less rupture-prone plaques. ‘New’ TCFAs developed from plaques with PIT, and some plaque types such as PIT, TCFAs, and ThCFAs increased in plaque volume whereas this was not noted among fibrous and fibrocalcific plaques.8 Although this study increased our insights into the natural history of plaques we have to extend these imaging observations and directly link plaque progression or regression to clinical outcome. The dynamic nature of plaques can also be inferred indirectly from the fact that patients who survived an ACS may progress to a repeat episode of instability or to a clinically quiescent phase of the disease with a favourable long-term outcome.

Currently we have different imaging modalities that are able to identify various morphological features associated with plaque instability (Figure 1). Each imaging modality has its strengths and weaknesses, and none can fully identify all features of plaque vulnerability and differentiate TCFAs, erosion-prone plaques (ThCFAs or PIT), and stable plaques.

Figure 1

Imaging modalities to identify morphological features of coronary plaque instability.

Figure 1

Imaging modalities to identify morphological features of coronary plaque instability.

Each imaging modality uses a unique definition of a high-risk plaque, which is based on the specific identification of the morphological features of the plaque by that imaging technique. IVUS defines a high-risk plaque as a hypolucent zone within the plaque and the presence of spotty calcification.9,10 However, IVUS cannot distinguish specific plaque components very well, nor is its spatial resolution (>100 µm) sufficient to detect a thin fibrous cap (<65 µm). IVUS-VH defines the TCFA as a focal lesion with a large necrotic core (>10%) in direct contact with the lumen (suggesting a thin fibrous cap) and area obstruction >40%.9,11,12 Palpography defines the high-risk plaque as a high strain pattern (deformability of the lesion), angioscopy as a yellow plaque, and optical coherence tomography (OCT) with an unmatched resolution of 10–20 µm as a thin fibrous cap (<60 µm) overlying a lipid core.13–15 Although combined approaches of, for instance IVUS-VH and OCT, are more accurate in identifying TFCAs than either modality alone,16 there is currently no imaging modality that is able to identify features of plaques prone to erosion.

For many years coronary plaque imaging was limited to intracoronary catheter-based modalities, which are expensive and time-consuming, associated with complications and patient discomfort, and therefore its use is restricted to imaging of (large) culprit vessels in the context of clinical coronary disease. Usually intracoronary imaging is performed in only one of the larger coronary branches and is not suitable for repeated imaging of plaque progression. Recently CT coronary imaging has emerged as an imaging modality able to evaluate the coronary plaque morphology and composition non-invasively within all three major coronary branches.

Association between plaque rupture and several features of plaque on CT images has been demonstrated in culprit lesions of patients with an acute coronary disease, including non-calcified plaque, outward vessel remodelling, large plaque area, low plaque attenuation (suggesting lipid-rich plaque), and spotty calcification,17–20 all of which were observed more often in unstable culprit lesions compared with those in patients with stable angina.

In a prospective study of 1059 symptomatic patients (10 037 coronary segments) who underwent CT coronary angiography, Motoyama et al. demonstrated that two CT features, i.e. low plaque attenuation and outward vessel remodelling, were associated with an adverse event, defined as the development of an ACS.21 At 27 ± 10 months, patients with both, either one, or neither of these two CT features of plaque vulnerability had an adverse event rate of 22, 11, and 0.5%, respectively.

The same group of investigators have now reported a next important step in the investigation of the ability of CT to identify distinct characteristics of culprit lesions in patients with ACS that have an intact fibrous cap, i.e. an eroded plaque as opposed to a plaque with a ruptured cap or culprit lesions in patients with stable angina pectoris.22 They devised a sophisticated, multi-imaging modality study using intracoronary OCT, IVUS, angioscopy, quantitative coronary angiography (QCA), and multislice CT (MSCT). Studies of this format can only be safely performed in a high-tech environment with very experienced operators, and the investigators of this study are commended for their high level of skills. OCT was used to demonstrate fibrous cap integrity or rupture. The presence of intracoronary thrombus was confirmed by OCT or angioscopy. All patients underwent 64-slice multidetector CT. Plaques were classified as calcified or non-calcified. The non-calcified plaques were divided into two groups: low attenuation plaques (<30 HU; lipid plaque) and intermediate attenuating plaques (30–150 HU; fibrous plaques). Calcific plaques were classified as spotty (<3 mm in size) or large calcification. CT coronary remodelling was defined as positive remodelling when the outer vessel contour at the plaque was >10% larger than at the reference site. In addition, IVUS and QCA were performed to provide confirmatory measurements to CT measurements. The culprit lesion was studied in 57 patients, of whom 35 had an ACS and 22 stable angina. The fibrous cap was ruptured in 25 but intact (eroded plaque) in 10 unstable culprit lesions. OCT revealed that the fibrous cap was thinner, and the frequency of TCFAs and large lipid pools was higher in ruptured plaques than in eroded or stable plaques. Low attenuation plaques and spotty calcification were more frequent and the outward vessel remodelling index was greater in ruptured plaques than in eroded or stable plaques. This study confirmed a previous study by the same group of investigators that low attenuation plaques and positive remodelling were associated with unstable plaques (ruptured and eroded plaques).21 Important was the fact that CT features were not able to distinguish between eroded plaques and stable plaques. Apparently the morphological differences between erosion-prone plaques and stable plaques are too subtle to be detectable by CT imaging, and perhaps also many of the invasive coronary imaging techniques. CT coronary imaging is a rather crude imaging modality with a resolution of 0.5 mm in all spatial dimensions under optimal clinical imaging conditions, which may be insufficient to differentiate lipid and fibrous plaque components in small plaques. As expected, CT imaging is not able to assess the thin cap thickness nor detect denudation of eroded plaques. Other methods pertaining to the processes underlying erosion or active thrombosis together with functional assessment of absence of endothelium may be the target of further research that may rely on biomarkers rather than imaging.

While the inability of CT to identify erosion-prone plaques may be felt as a disappointment by some, this does not disqualify non-invasive coronary imaging as a diagnostic test or prognostic tool in the context of acute coronary disease. While CT may not reliably assess focal plaque vulnerability, the ability to interrogate all main coronary branches non-invasively allows for a global evaluation of coronary atherosclerosis burden and identification of individuals at higher risk. Equally important is the ability of CT to exclude coronary disease, whether vulnerable or not, in patients presenting with acute chest pain at the emergency department.23 Symptomatic and asymptomatic individuals without detectable plaque by CT angiography have an excellent prognosis, which has recently been summarized in a paper by Hulten et al.24

For scientific purposes, coronary CT offers a powerful tool for repeated investigations as the radiation dose of modern CT has decreased to an effective dose of even less than 1 mSv. In addition CT can be incorporated in an algorithm to identify high-risk patients with coronary lesions of interest and provide a roadmap for targeted intracoronary investigation.

Following its ‘hype cycle’ past the peak of inflated expectations and through the trough of disillusionment, further research should develop the capabilities and establish the incremental value of cardiac CT in relation to high risk plaques.

Conflict of interest: none declared.

References

1
Naghavi
M
Libby
P
Falk
E
Casscells
SW
Litovsky
S
Rumberger
J
Badimon
JJ
Stefanadis
C
Moreno
P
Pasterkamp
G
Fayad
Z
Stone
PH
Waxman
S
Raggi
P
Madjid
M
Zarrabi
A
Burke
A
Yuan
C
Fitzgerald
PJ
Siscovick
DS
de Korte
CL
Aikawa
M
Juhani Airaksinen
KE
Assmann
G
Becker
CR
Chesebro
JH
Farb
A
Galis
ZS
Jackson
C
Jang
IK
Koenig
W
Lodder
RA
March
K
Demirovic
J
Navab
M
Priori
SG
Rekhter
MD
Bahr
R
Grundy
SM
Mehran
R
Colombo
A
Boerwinkle
E
Ballantyne
C
Insull
W
Jr.
Schwartz
RS
Vogel
R
Serruys
PW
Hansson
GK
Faxon
DP
Kaul
S
Drexler
H
Greenland
P
Muller
JE
Virmani
R
Ridker
PM
Zipes
DP
Shah
PK
Willerson
JT
From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: part I
Circulation
 , 
2003
, vol. 
108
 (pg. 
1664
-
1672
)
2
Naghavi
M
Libby
P
Falk
E
Casscells
SW
Litovsky
S
Rumberger
J
Badimon
JJ
Stefanadis
C
Moreno
P
Pasterkamp
G
Fayad
Z
Stone
PH
Waxman
S
Raggi
P
Madjid
M
Zarrabi
A
Burke
A
Yuan
C
Fitzgerald
PJ
Siscovick
DS
de Korte
CL
Aikawa
M
Airaksinen
KE
Assmann
G
Becker
CR
Chesebro
JH
Farb
A
Galis
ZS
Jackson
C
Jang
IK
Koenig
W
Lodder
RA
March
K
Demirovic
J
Navab
M
Priori
SG
Rekhter
MD
Bahr
R
Grundy
SM
Mehran
R
Colombo
A
Boerwinkle
E
Ballantyne
C
Insull
W
Jr.
Schwartz
RS
Vogel
R
Serruys
PW
Hansson
GK
Faxon
DP
Kaul
S
Drexler
H
Greenland
P
Muller
JE
Virmani
R
Ridker
PM
Zipes
DP
Shah
PK
Willerson
JT
From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: part II
Circulation
 , 
2003
, vol. 
108
 (pg. 
1772
-
1778
)
3
Schaar
JA
Muller
JE
Falk
E
Virmani
R
Fuster
V
Serruys
PW
Colombo
A
Stefanadis
C
Ward Casscells
S
Moreno
PR
Maseri
A
van der Steen
AF
Terminology for high-risk and vulnerable coronary artery plaques
Eur Heart J
 , 
2004
, vol. 
25
 (pg. 
1077
-
1082
Report of a meeting on the vulnerable plaque, June 17 and 18, 2003, Santorini, Greece
4
Virmani
R
Kolodgie
FD
Burke
AP
Farb
A
Schwartz
SM
Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions
Arterioscler Thromb Vasc Biol
 , 
2000
, vol. 
20
 (pg. 
1262
-
1275
)
5
Varnava
AM
Mills
PG
Davies
MJ
Relationship between coronary artery remodeling and plaque vulnerability
Circulation
 , 
2002
, vol. 
105
 (pg. 
939
-
943
)
6
Falk
E
Pathogenesis of atherosclerosis
J Am Coll Cardiol
 , 
2006
, vol. 
47
 
8 Suppl
(pg. 
C7
-
C12
)
7
Arbustini
E
Dal Bello
B
Morbini
P
Burke
AP
Bocciarelli
M
Specchia
G
Virmani
R
Plaque erosion is a major substrate for coronary thrombosis in acute myocardial infarction
Heart
 , 
1999
, vol. 
82
 (pg. 
269
-
272
)
8
Kubo
T
Maehara
A
Mintz
GS
Doi
H
Tsujita
K
Choi
SY
Katoh
O
Nasu
K
Koenig
A
Pieper
M
Rogers
JH
Wijns
W
Bose
D
Margolis
MP
Moses
JW
Stone
GW
Leon
MB
The dynamic nature of coronary artery lesion morphology assessed by serial virtual histology intravascular ultrasound tissue characterization
J Am Coll Cardiol
 , 
2010
, vol. 
55
 (pg. 
1590
-
1597
)
9
Garcia-Garcia
HM
Costa
MA
Serruys
PW
Imaging of coronary atherosclerosis: intravascular ultrasound
Eur Heart J
 , 
2010
, vol. 
31
 (pg. 
2456
-
2469
)
10
Ehara
S
Kobayashi
Y
Yoshiyama
M
Shimada
K
Shimada
Y
Fukuda
D
Nakamura
Y
Yamashita
H
Yamagishi
H
Takeuchi
K
Naruko
T
Haze
K
Becker
AE
Yoshikawa
J
Ueda
M
Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction: an intravascular ultrasound study
Circulation
 , 
2004
, vol. 
110
 (pg. 
3424
-
3429
)
11
Rodriguez-Granillo
GA
Garcia-Garcia
HM
Mc Fadden
EP
Valgimigli
M
Aoki
J
de Feyter
P
Serruys
PW
In vivo intravascular ultrasound-derived thin-cap fibroatheroma detection using ultrasound radiofrequency data analysis
J Am Coll Cardiol
 , 
2005
, vol. 
46
 (pg. 
2038
-
2042
)
12
Stone
GW
Maehara
A
Lansky
AJ
de Bruyne
B
Cristea
E
Mintz
GS
Mehran
R
McPherson
J
Farhat
N
Marso
SP
Parise
H
Templin
B
White
R
Zhang
Z
Serruys
PW
PROSPECT Investigators
A prospective natural-history study of coronary atherosclerosis
N Engl J Med
 , 
2011
, vol. 
364
 (pg. 
226
-
235
)
13
Schaar
JA
De Korte
CL
Mastik
F
Strijder
C
Pasterkamp
G
Boersma
E
Serruys
PW
Van Der Steen
AF
Characterizing vulnerable plaque features with intravascular elastography
Circulation
 , 
2003
, vol. 
108
 (pg. 
2636
-
2641
)
14
Ueda
Y
Asakura
M
Hirayama
A
Komamura
K
Hori
M
Komada
K
Intracoronary morphology of culprit lesions after reperfusion in acute myocardial infarction: serial angioscopic observations
J Am Coll Cardiol
 , 
1996
, vol. 
27
 (pg. 
606
-
610
)
15
Prati
F
Regar
E
Mintz
GS
Arbustini
E
Di Mario
C
Jang
IK
Akasaka
T
Costa
M
Guagliumi
G
Grube
E
Ozaki
Y
Pinto
F
Serruys
PW
Expert's OCT Review Document
Expert review document on methodology, terminology, and clinical applications of optical coherence tomography: physical principles, methodology of image acquisition, and clinical application for assessment of coronary arteries and atherosclerosis
Eur Heart J
 , 
2010
, vol. 
31
 (pg. 
401
-
415
)
16
Sawada
T
Shite
J
Garcia-Garcia
HM
Shinke
T
Watanabe
S
Otake
H
Matsumoto
D
Tanino
Y
Ogasawara
D
Kawamori
H
Kato
H
Miyoshi
N
Yokoyama
M
Serruys
PW
Hirata
K
Feasibility of combined use of intravascular ultrasound radiofrequency data analysis and optical coherence tomography for detecting thin-cap fibroatheroma
Eur Heart J
 , 
2008
, vol. 
29
 (pg. 
1136
-
1146
)
17
Hoffmann
U
Moselewski
F
Nieman
K
Jang
IK
Ferencik
M
Rahman
AM
Cury
RC
Abbara
S
Joneidi-Jafari
H
Achenbach
S
Brady
TJ
Noninvasive assessment of plaque morphology and composition in culprit and stable lesions in acute coronary syndrome and stable lesions in stable angina by multidetector computed tomography
J Am Coll Cardiol
 , 
2006
, vol. 
47
 (pg. 
1655
-
1662
)
18
Cordeiro
MA
Lima
JA
Atherosclerotic plaque characterization by multidetector row computed tomography angiography
J Am Coll Cardiol
 , 
2006
, vol. 
47
 
8 Suppl
(pg. 
C40
-
C47
)
19
Motoyama
S
Kondo
T
Sarai
M
Sugiura
A
Harigaya
H
Sato
T
Inoue
K
Okumura
M
Ishii
J
Anno
H
Virmani
R
Ozaki
Y
Hishida
H
Narula
J
Multislice computed tomographic characteristics of coronary lesions in acute coronary syndromes
J Am Coll Cardiol
 , 
2007
, vol. 
50
 (pg. 
319
-
326
)
20
Kashiwagi
M
Tanaka
A
Kitabata
H
Tsujioka
H
Kataiwa
H
Komukai
K
Tanimoto
T
Takemoto
K
Takarada
S
Kubo
T
Hirata
K
Nakamura
N
Mizukoshi
M
Imanishi
T
Akasaka
T
Feasibility of noninvasive assessment of thin-cap fibroatheroma by multidetector computed tomography
JACC Cardiovasc Imaging
 , 
2009
, vol. 
2
 (pg. 
1412
-
1419
)
21
Motoyama
S
Sarai
M
Harigaya
H
Anno
H
Inoue
K
Hara
T
Naruse
H
Ishii
J
Hishida
H
Wong
ND
Virmani
R
Kondo
T
Ozaki
Y
Narula
J
Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome
J Am Coll Cardiol
 , 
2009
, vol. 
54
 (pg. 
49
-
57
)
22
Ozaki
Y
Okumura
M
Ismail
TF
Motoyama
S
Naruse
H
Hattori
K
Kawai
H
Sarai
M
Takagi
Y
Ishii
J
Anno
H
Virmani
R
Serruys
PW
Narula
J
Coronary CT angiography characteristics of culprit lesions in acute coronary syndromes not related to plaque rupture as defined by optical coherence tomography and angioscopy
Eur Heart J
 , 
2011
, vol. 
32
 (pg. 
2814
-
2823
First published on 30 June 2011. doi:10.1093/eurheartj/ehr189.
23
Hoffmann
U
Bamberg
F
Chae
CU
Nichols
JH
Rogers
IS
Seneviratne
SK
Truong
QA
Cury
RC
Abbara
S
Shapiro
MD
Moloo
J
Butler
J
Ferencik
M
Lee
H
Jang
IK
Parry
BA
Brown
DF
Udelson
JE
Achenbach
S
Brady
TJ
Nagurney
JT
Coronary computed tomography angiography for early triage of patients with acute chest pain: the ROMICAT (Rule Out Myocardial Infarction using Computer Assisted Tomography) trial
J Am Coll Cardiol
 , 
2009
, vol. 
53
 (pg. 
1642
-
1650
)
24
Hulten
EA
Carbonaro
S
Petrillo
SP
Mitchell
JD
Villines
TC
Prognostic value of cardiac computed tomography angiography: a systematic review and meta-analysis
J Am Coll Cardiol
 , 
2011
, vol. 
57
 (pg. 
1237
-
1247
)

Author notes

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehr189.

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