Stroke remains a major cause of death and disability worldwide, with approximately one-third of ischaemic strokes being a consequence of carotid atherosclerotic plaque rupture. Thus, diagnostic strategies that could identify those patients at highest risk of events are of critical importance.This work is supported by Heart Research UK (RG2638/14/16)

Brown, AJ

Gillard, JH

Teng, Z

EBioMedicine

PubMed

Teng, Zhongzhao

Brown, Adam J.

Gillard, Jonathan H.

Elsevier - Publisher Connector 

From Ultrasonography to High Resolution Magnetic Resonance Imaging: Towards an Optimal Management Strategy for Vulnerable Carotid Atherosclerotic Plaques 

Zhongzhao Teng

Adam J. Brown

Jonathan H. Gillard

Directory of Open Access Journals

From Ultrasonography to High Resolution Magnetic Resonance Imaging: Towards an Optimal Management Strategy for Vulnerable Carotid Atherosclerotic Plaques

EBioMedicine 3 (2016) 2–3
Contents lists available at ScienceDirect
EBioMedicine
j ourna l homepage: www.eb iomed ic ine.comIn FocusFrom Ultrasonography to High Resolution Magnetic Resonance Imaging:
Towards an Optimal Management Strategy for Vulnerable Carotid
Atherosclerotic PlaquesZhongzhao Teng a,⁎, Adam J. Brown b, Jonathan H. Gillard a
a Department of Radiology, University of Cambridge, United Kingdom
b Division of Cardiovascular Medicine, University of Cambridge, United KingdomStroke remains a major cause of death and disability worldwide, Two multicentre randomised trials, European Carotid Surgery Trial
with approximately one-third of ischaemic strokes being a consequence
of carotid atherosclerotic plaque rupture. Thus, diagnostic strategies
that could identify those patients at highest risk of events are of critical
importance.
Severity of carotid luminal stenosis, as characterized by ultrasonog-
raphy, continues to be the major determinant for assessing stroke risk,
based on the results of historical trials. Here, ultrasound was used to
quantify the degree of carotid stenosis, as it was one of few non-
invasive imaging options available when these studies were designed
and conducted. Furthermore, carotid ultrasound is relatively reproduc-
ible in quantifying the severity of luminal stenosis in experienced
hands and remains relatively inexpensive when compared with con-
temporary cross-sectional imaging options. Based on measurements
derived from ultrasound, studies showed that surgery only beneﬁtted
patients with severe luminal stenosis (≥70%; North American Symp-
tomatic Carotid Endarterectomy Trial (NASCET) (Anon., 1991a) de-
ﬁned). However, the majority of patients who sustain strokes have
carotid luminal stenosis ≤50% (NASCET-deﬁned), suggesting severe
luminal stenosis alone is insufﬁcient to predict risk. Indeed, histo-
pathological studies indicate that plaque stability is not simply due
to luminal stenosis, but also dependent on necrotic core size, active
inﬂammation and overlying ﬁbrous cap (FC) thickness. Emerging
imaging technologies, including high-resolutionmagnetic resonance
imaging (MRI) and molecular imaging, have far surpassed luminal
assessment and allow visualisation of plaque structure and the un-
derlying biological process in far greater detail than ultrasonography
(Underhill et al., 2010). This has led to suggestions that speciﬁc fea-
tures on plaque imaging should be used as selection criteria, in addi-
tion to systemic risk factors, for future clinical studies in the hope of
improving patient care.
Soon after carotid endarterectomy (CEA)was introduced for thepre-
vention of ischemic stroke, enthusiasm for the procedure increased.
However, CEA carries a 2–3% risk of causing death or a disabling stroke
(Anon., 1991a, 1991b) and, as such, the operation can only be justiﬁed if
the future net beneﬁt is clearly larger than the immediate risk.⁎ Corresponding author at: Level 5, Box 218, Addenbrooke's Hospital, Hills Rd.,
Cambridge, CB2 0QQ, UK.
E-mail address: zt215@cam.ac.uk (Z. Teng).
http://dx.doi.org/10.1016/j.ebiom.2016.01.001
2352-3964/© 2016 The Authors. Published by Elsevier B.V. This is an open access article under(ECST) and NASCET, were designed to answer this fundamental ques-
tion in symptomatic patients. Interim results from ECST demonstrated
that for patients with severe stenosis (70–99%; ECST-deﬁned) total
risk of surgical death and any stroke was 12.3% for surgery and 21.9%
for control (Anon., 1991b). CEA conferred no beneﬁt in patients with
moderate stenosis (30–69%; ECST-deﬁned) (Anon., 1996) and any 3-
year beneﬁt of surgery for patient with mild stenosis (0–29%; ECST-
deﬁned) was outweighed by procedural risk (Anon., 1991b). 6-year
ECST follow-up reported that for patients with ≥80% luminal stenosis,
the frequency of amajor stroke or death at 3 years was 26.5% for control
and 14.9% for CEA (absolute beneﬁt 11.6%) (Anon., 1998). NASCET re-
ported that CEA conferred an absolute risk reduction of 10.6% in
preventing major stroke and death in patients with luminal stenosis
≥70% (NASCET-deﬁned) (Anon., 1991a). However, CEA only yielded
marginal risk reduction (6.5%; p = 0.045) in preventing ipsilateral
stroke at 5-years for patients with moderate luminal stenosis (50–
69%) (Barnett et al., 1998).
The potential of CEA for stroke reduction in patients with asymp-
tomatic carotid atherosclerosis has also been studied. Here, the beneﬁt
of CEA was unclear until the publication of two landmark randomised
trials, the Asymptomatic Carotid Atherosclerosis Study (ACAS) (Anon.,
1995) and the Asymptomatic Carotid Surgery Trial (ACST) (Halliday
et al., 2004). Both trials reported similar ﬁndings, showing a 50% relative
risk reduction in 5-year risk of stroke from 11–12% to 5–6% from CEA in
patient with luminal stenosis ≥60% (NASCET-deﬁned)/70% (ECST-
deﬁned).
The results of trials in patients with symptomatic and asymptomatic
lesions are therefore in general agreement. Surgery only beneﬁts
symptomatic patients with severe luminal stenosis (≥80% ECST-
deﬁned or ≥70% NASCET-deﬁned) at 3 years. Despite this, around 85–
90% of procedures may not yield clear clinical beneﬁt and the utility of
CEA for symptomatic patients with mild/moderate luminal stenosis or
in asymptomatic patients is questionable. As the majority of symptom-
atic patients do not have severe luminal stenosis, this leaves clinicians
with a signiﬁcant challenge. Although CEAmay confer beneﬁt in specif-
ically selected patient subgroups, the majority of clinical events cannot
be predicted by the degree of stenosis alone. Accordingly, screening
asymptomatic patients using ultrasonography in the general population
for carotid stenosis is not recommended (LeFevre and Force, 2014).the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
3Z. Teng et al. / EBioMedicine 3 (2016) 2–3Histological analysis of CEA specimens from symptomatic patients
has suggested that ‘vulnerable plaque’ is associatedwith speciﬁc charac-
teristics, including FC rupture, intraplaque hemorrhage (IPH), large
lipid-rich necrotic cores, erosions with overlying mural thrombus,
neovasculature and inﬂammatory cell inﬁltration. Recent developments
in MR imaging have enabled us to identify these components quantita-
tively (Underhill et al., 2010). MRI-identiﬁed IPH and FC defects are
associated with clinical presentation and subsequent ischaemic cere-
brovascular events. In a prospective study of asymptomatic patients
withmoderate luminal stenosis, investigators found a signiﬁcant associ-
ation between the presence of thin or ruptured ﬁbrous cap at baseline
and the subsequent development of an ipsilateral ischemic event
(Hazard ratio (HR) = 17.0) (Underhill et al., 2010). The presence of
IPH was associated with an increased risk for subsequent ischemic
events (HR ranges from 3.6 to 9.8) (Underhill et al., 2010).
These ﬁndings suggest that larger prospective studies with long-
term follow-up are required to fully quantify the annual risk of stroke
related to plaque morphological/compositional features, especially,
IPH. Additionally, high mechanical loading due to blood pressure may
be useful in identifying those lesions at highest risk of stroke (Sadat
et al., 2010), as FC rupture is likely to occur when such loading exceeds
cap strength. Clinical trials are now required to quantify the beneﬁt of
such combined plaque-speciﬁc approaches, so that modern advanced
imaging techniques may eventually beneﬁt individuals with symptom-
atic and asymptomatic carotid atherosclerotic diseases.
Disclosure
Authors do not have any conﬂict of interest to declare.Acknowledgment
This work is supported by Heart Research UK (RG2638/14/16).
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From Ultrasonography to High Resolution Magnetic Resonance Imaging: Towards an Optimal Management Strategy for Vulnerable Carotid Atherosclerotic Plaques

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