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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3774_Библиотеки_им_академика_М_И_Перельмана
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3 Mechanisms oftheVulnerable Atherosclerotic Plaque andImaging
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3.3 Plaque Erosion
Plaque erosions account for approximately one-third of lesions causing ACS [32,
33]. Plaque erosion is dened by the presence of a thrombus in direct contact with
the intima, with absent endothelium and no identiable brous cap rupture [34]. In
contrast to plaque rupture, the underlying intima is rich in smooth muscle cells and
proteoglycans and has minimal inammatory cell inltrate [5]. Erosions are also
associated with a smaller plaque and necrotic core area, and lesser stenosis and
plaque burden than ruptures [35].
Plaque erosions are more common in younger men and women (<50-years-old)
and are associated with smoking, particularly in premenopausal women [5, 34].
Additionally, optical coherence tomography (OCT) studies have revealed that non ST elevated acute coronary syndromes (NSTEACs) are more commonly associated
with OCT-erosions and OCT-calcied nodules than ruptures [32].
The mechanism of plaque erosion has not been precisely elucidated. Proposed
mechanisms involve a complex simultaneous interplay between processes causing
endothelial cell loss, neutrophil recruitment, and thrombosis [36]. The underlying
intima in plaque erosions is rich in smooth muscle cells and proteoglycans.
Hyaluronan, a component of proteoglycans, has been shown to increase Toll-like
receptor- 2 (TLR-2) expression invivo. Additionally, erosions causing locally disturbed blood ow can increase endothelial TLR-2 expression and apoptosis [37].
Increased TLR-2 expression may lead to the accumulation of neutrophils, endothelial cell apoptosis and thrombosis.
3.4 Calcied Nodules
A calcied nodule is the least common cause of thrombosis [34]. Calcied nodules
can disrupt the overlying brous cap and cause thrombosis, however, it is not a common occurrence [5]. In an OCT study of 126 ACS patients, calcied nodules had an
incidence of 7.9% [32]. They are more commonly seen in elderly individuals with
heavily calcied arteries and most frequently found in the mid-right coronary artery
[5]. In the PROSPECT study, calcied nodules identied with intravascular ultrasound (IVUS) resulted in very few coronary events at 3years follow up [38].
3.5 Effect ofDiabetes onPlaque Morphology
Diabetes in patients without clinical CAD is associated with an atherosclerotic
burden equivalent to that of non-diabetics with clinical CAD, hence diabetes is
thought to be a ‘CAD equivalent’ in terms of risk factors. Differences in plaque
morphology have been shown between diabetic and non-diabetic patients.
Diabetes has been associated with more widespread diffuse atherosclerosis,
increased calcication [39], increased inammatory inltrate (macrophage,
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T-cells), HLA-DR expression [40], CRP elevation, larger necrotic core, greater
number of healed plaques [41], and increased presence of TCFAs [42, 43]. The
underlying cellular mechanisms behind this are multifactorial. Autopsy studies
have shown increased expression of receptors for advanced glycated end-products (RAGE) and RAGE-binding protein in plaques of diabetic patients.
Hyperglycaemia can result in increased production of advanced glycated endproducts (AGE) and AGE/RAGE signaling has been linked to increased calcication, oxidative stress and vascular inammation, thereby contributing to
accelerated atherosclerosis [41, 44].
K. Rana et al.
3.6 Carotid Imaging
3.6.1 Carotid Ultrasound
Intraplaque haemorrhage and the lipid-rich necrotic core appear echolucent on
ultrasound. Both of these plaque features cannot be distinguished on ultrasound.
Echolucent plaques are associated with an increased rate of cerebrovascular events,
independent of the degree of stenosis or cardiovascular risk factors [45, 46].
The grayscale median (GSM) score is a standardised way of characterising
plaques. The more echogenic the plaque, the higher the GSM score. GSM measurements can be made from a single longitudinal view (SLV-GSM) or from multiple cross-sectional views (MCSV-GSM). Plaques with a lower GSM score (i.e.
echolucent plaques) have been associated with an increased risk of stroke [47,
48]. In one study, the incidence of stroke was 9% for plaques with a GSM >50 and
40% in those with a GSM <50 (p < 0.001) [49]. Another study distinguished
plaques causing amaurosis fugax from asymptomatic plaques by the GSM features of increased plaque heterogeneity (highest MCSV-GSM minus the lowest
MCSV-GSM) and increased echolucency in plaques associated with amaurosis
fugax [50].
Plaque calcication and the brous cap appear echogenic on ultrasonography.
Ultrasonographic brous cap thickness measurement has shown to have excellent
correlation with histological ndings [51]. The Oxford plaque study showed that
ruptured carotid plaques had a median representative cap thickness of 300μm and a
median minimum cap thickness of 150μm, compared to 500 μm and 250μm for
non-ruptured plaques respectively [52]. This study proposed a representative cap
thickness of less than 500μm and minimum cap thickness of less than 200μm to
identify ruptured plaques on carotid ultrasonography.
Plaque ulceration is dened as an area of surface irregularity in the plaquelumen border greater than 2mm in depth and with a well-dened back wall at its
base [53]. Standard and Doppler ultrasonography have a low sensitivity and specicity to detect plaque ulceration when compared with CT and MRI [54, 55], however contrast- enhanced ultrasonography has been shown to have improved
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Table 3.1 The detection of vulnerable plaque features by ultrasound
Morphological features Ultrasound ndings
Intraplaque haemorrhage and large lipid-rich
necrotic core (LR-NC)
Thin brous cap Echogenic brous cap with minimum cap
Plaque ulceration Surface irregularity >2mm depth, well-dened
Neovascularisation Enhancement with contrast
Echolucent plaque
thickness <200μm
back wall on colour doppler
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sensitivity and accuracy for the detection of plaque ulceration when compared to
standard ultrasound [56].
Plaque neovascularisation and inammation are active processes implicated in
plaque rupture. However, these processes are unable to be evaluated by simple
B-mode ultrasonography. Contrast-enhanced ultrasonography can however use an
intravenous microbubble agent that remains within the vascular space to enhance
areas of neovascularisation and inammation in the plaque [57]. Contrast enhancement indicating neovascularisation was seen in more than 93% of soft, echolucent
plaques [58]. These ultrasonography features may be used for the risk stratication
of carotid plaques (Table3.1).
Doppler imaging can be used to assess the haemodynamic signicance of internal carotid artery (ICA) lesions. The ICA peak systolic velocity (PSV) and the
visualisation of plaque on B-mode or Doppler are key determinants for the grading
of lesions. The Society of Radiologists has published consensus guidelines on the
grading of carotid artery lesions with ultrasonography [59]. The ICA/CCA ratio
and end diastolic velocity (EDV) are additional measurements used to assist in
grading lesions. The ICA is normal when PSV is <125cm/s and there is no plaque
visualised; there is <50% stenosis when PSV is <125cm/s and there is plaque or
intimal thickening visible; 50–69% stenosis is present when PSV is between 125
and 230cm/s and plaque is visible; >70% stenosis when PSV is >230 cm/s and
visible plaque and luminal narrowing is seen; near-occlusion is when there is
“trickle” ow on colour Doppler and total occlusion is when there is no detectable
lumen on B-mode ultrasound and no detectable ow on Doppler imaging [59]. It
should be noted that there is not a linear association between PSV and the degree
of stenosis—for a near-occlusion or complete occlusion, the PSV may be low or
undetectable.
3.6.2 Carotid Computed Tomography
Multidetector-row CT (MDCT) and dual-source CT (DSCT) are the two main CT
modalities used for carotid plaque imaging. Both techniques provide a high spatial
and temporal resolution and can be used for plaque characterisation.
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K. Rana et al.
CT angiography (CTA) of the carotid arteries has a higher spatial resolution and
quicker acquisition time than magnetic resonance angiography (MRA) [60]. CTA
can provide information on the degree of luminal narrowing, as well as plaque morphological features including plaque calcication, brous cap thickness, intraplaque
haemorrhage and lipid-rich necrotic core [60]. Comparison of carotid CTAs with
histological examination of endarterectomy specimens has allowed for the correlation of different plaque features with CT Hounseld densities [61]. Calcications
are readily identied due to their high density (HU >250). There is a signicant
degree of overlap between the CT Hounseld densities of lipid-rich necrotic core
(LR-NC) and connective tissue, as well as some overlap between connective tissue
and haemorrhage. However, as a general rule, LR-NC has a low density (HU<30)
whilst connective tissue and haemorrhage have an intermediate density (between 30
and 150HU) (Fig.3.2).
CTA does, however, show good reliability when considering large (>5-pixels)
LR-NC and haemorrhages. CTA is also reliable in detecting ulcerations as small as
1mm and measuring the brous cap thickness [61]. Fibrous cap thickness measurement on CTA was found to have excellent correlation with histological examination
ab c
Fig. 3.2 Computed tomography (CT) imaging of Carotid Plaque. CT reconstruction (a) and volume rendering (b) showing a wide ulcerated carotid plaque causing signicant stenosis. CTA axial
image (c) shows a hypodense plaque (white arrow). Histological section (d) reveals the presence
of neovessels (black arrows) and macrophages (black arrowheads). (Reprinted from Saba,
Anzidei [106])
d
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(P<0.001) [61]. Additionally, carotid plaque enhancement with contrast agents has
shown good correlation with intraplaque neovascularisation [62].
Plaque features derived from CTA have shown to be correlated with cerebrovascular events including strokes and TIAs. A higher risk of stroke was found with the
following features on CTA in one study: an increased wall volume, a thinner brous
cap, higher number of lipid clusters, lipid clusters closer to the lumen, and fewer
calcium clusters [63]. Other studies have also shown a correlation between noncalcied plaques or plaques with calcication at their base [64], carotid plaque
enhancement [62] and ssured brous caps [65] with cerebrovascular events. Plaque
morphological features derived from CTA can assist in determining the risk of
future cerebrovascular events. Interventions may be directed at those deemed to be
at high risk, however further studies are needed in this area.
3.6.3 Carotid Magnetic Resonance Imaging
Carotid MRI enables accurate visualisation of vulnerable carotid plaque features
including thin or ruptured brous caps, large lipid-rich necrotic core, intraplaque
haemorrhage, and carotid wall thickness. These features are associated with an
increased risk of future cerebrovascular events [66].
Histological correlation of endarterectomy specimens with carotid MRI features
has led to the development of a tissue type classication system linking MRI features
to the histological ndings (Table3.2, Fig.3.3). The lipid-rich necrotic core is seen
centrally and forms the bulk of the plaque. A lipid-rich necrotic core may be seen
with or without intraplaque haemorrhage (IPH). The intensities of IPH vary depending on whether it is acute (<1week), recent (1–6weeks), or old (>6weeks) [67].
Table 3.2 Correspondence of plaque features with invivo MRI ndings
Plaque features
LR/NC with no
IPH
LR/NC with
IPH—Fresh
LR/NC with
IPH—Recent
LR/NC with
IPH—Old
Calcication Hypointense Hypointense Hypointense Hypointense
Dense brous
tissue
Loose matrix Hypo/isointense Hyperintense Hyperintense Hypointense
LR/NC lipid rich necrotic core, IPH intraplaque haemorrhage
Chu, Kampschulte [67], Saam, Ferguson [112]
T1-weighted
sequence
Iso/hyperintense Hypo/isointense Iso/hyperintense Isointense
Hyperintense Hypointense/
Hyperintense Hyperintense Hyperintense Hyperintense
Hypointense Hypointense Hypointense Hypointense
Isointense Isointense Isointense Hypointense
T2-weighted
sequence
isointense
Proton densityweighted sequence
Hypointense/
isointense
Time of
ight
Hyperintense
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a
b
Fig. 3.3 T1-weighted (T1W) and time of ight (TOF) section through a left internal carotid artery
lesion. Baseline imaging (a) and follow-up imaging at 18months (b). The lesion contains intraplaque haemorrhage (arrow heads) and calcications (arrows). A reduction in lumen area and
increased wall thickness can be seen from (a–b). JV jugular vein. ∗Lumen of the internal carotid.
(Reprinted from Underhill, Yuan [107])
Gadolinium-based contrast agents can be administered intravenously in
carotid MRIs. The gadolinium enhances areas with increased vascularity. Thus,
contrast-enhanced magnetic resonance imaging (CEMRI) can be used to help
differentiate the brous cap which becomes enhanced, from the poorly vascularised LR-NC which does not enhance. CEMRI allows for quantication of the
plaque volume, brous cap thickness and LR-NC—important determinants of
plaque vulnerability [68]. Additionally, the rate of contrast enhancement is signicantly correlated with neovascularisation and macrophage content. Thus,
carotid MRIs can provide detailed information on the features of a vulnerable
plaque. But how do these imaging technologies correlate with the risk of future
clinical events?
3 Mechanisms oftheVulnerable Atherosclerotic Plaque andImaging
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MRI allows for the visualisation of high-risk plaque features that are not detectable on standard carotid ultrasonography. High-risk plaque features derived from
MRI including IPH, large LR-NC and thin/ruptured brous caps have been associated with an increased risk of future ipsilateral ischaemic events [66, 69]. Detailed
information on plaque morphology may allow clinicians to monitor high-risk plaque
features and their response to medical therapy, as well as providing new indications
for medical and/or surgical therapy directed at high-risk plaques that may not be
symptomatic or signicantly obstructive. Conversely, moderate stenoses (50–70%)
on Doppler ultrasonography which do not have high-risk plaque features on MRI
are reassuring markers of plaque stability and hence aid in clinical decision making.
3.7 Molecular Imaging
Positron emission tomography (PET) scans can be used to image functional processes implicated in atherosclerosis and plaque rupture. PET scans involve the
administration of positron-emitting isotopes which decay resulting in the production of two photons that travel in opposite directions. The photons are detected and
used to produce an image reecting the location and density of the isotopes.
3.7.1 Imaging Inammation: Fluorodeoxyglucose (18F-FDG)
Fluorodeoxyglucose (18F-FDG) is a radioactive glucose analogue that accumulates
in cells in direct proportion to their rate of glycolysis and hence is a marker of glucose metabolism. In atherosclerosis, 18F-FDG can be exploited as a marker of macrophage activity (Fig. 3.4) [70, 71]. Histological studies have shown that the
intensity of
endarterectomy specimens [71, 72]. Increased macrophage activity predominantly
reects the degree of inammation in the plaque (Fig.3.5) [70, 71]. However, there
are also other factors that contribute to an increased signal. Hypoxia in atherosclerotic plaques can stimulate neoangiogenesis, glucose uptake by macrophages, and
inammation causing an increase in glycolysis and accumulation of 18F-FDG [73,
74]. The 18F-FDG signal may also be impacted by delivery. Increased microvascular
permeability and microvessel density may increase delivery of 18F-FDG and thus
the signal may not entirely reect the degree of inammation [75].
Clinically, the utility of 18F-FDG has not been well dened, however studies have
shown promise. 18F-FDG scans have been shown to help in predicting early stroke
recurrence [76], cardiovascular events in a cohort with neoplastic disease [77], and
can help predict the risk of cardiovascular disease beyond the Framingham risk
score in some populations [78]. However,
metabolism and can be taken up by the myocardium, making it difcult to clearly
assess the signals from the coronary arteries [70].
18
F-FDG uptake correlates well with the macrophage content of plaque
18
F-FDG is a non-specic marker of
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Large Necrotic Core
T1-weighted High Intensity
Black Blood Imaging
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Late Gadolinium Enhancement
Macrophage
Infiltration
USPIOs
18F-FDG PET/MRI
Microcalcification
18F-fluoride PET/MRI
Angiogenesis &
Intraplaque Hemorrhage
Plaque Imaging
Fig. 3.4 Vulnerable plaque features on MRI.Vulnerable plaque features that can be detected with
magnetic resonance imaging. (Reprinted from Dweck, Puntman [108])
Positive Remodeling
T1-weighted
K. Rana et al.
Thin Fibrous Ca
Sub-clinical
Plaque Rupture
T1-weighted
High Intensity
Plaque Imaging
18
F-FDG imaging has also been shown to play a role in assessing the clinical utility of drugs to reduce inammation in plaques. A FDG-PET study provided evidence for dose-dependent reductions in carotid plaque 18F-FDG uptake with statin
therapy, independent of changes in blood lipid proles [71]. This study showed that
patients randomized to atorvastatin 80mg had signicantly reduced inammation
in the index vessel as compared to patients randomized to atorvastatin 10mg at
12-weeks [71]. Additionally, 18F-FDG imaging can be used as an endpoint in clinical trials to test the efcacy of various anti-atherosclerotic or anti-inammatory
drugs for atherosclerosis.
3.7.2 Imaging Microcalcication: Sodium Fluoride (18F-NaF)
Spotty (micro) calcication is a feature of vulnerable plaques, whereas dense macrocalcication is associated with stable plaques [30]. Microcalcication cannot be
detected with plain CT-scans whilst macrocalcication can be detected on
CT.Sodium uoride (
tions that were previously not detectable on plain CT. NaF is incorporated into
hydroxyapatite at sites of active calcication [79]. It has traditionally been used to
image bone diseases and cancers, however its application is now being extended
18
F-NaF) is a promising isotope that can help image calcica-
a
a
b
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b
c
Fig. 3.5 Molecular imaging of vulnerable plaque with Fluorodeoxyglucose (left panels) and
Sodium Fluoride (NaF) (right panels). (Left panels) Fluorodeoxyglucose (FDG) uptake as a marker
of plaque inammation.
subjects with Coronary Artery Disease (CAD). F-FDG imaging in a patient with recent ACS and a
new stent (a) indicates a higher degree of tracer uptake than those with a stable syndrome and a
new or old stent (b, c). (d) shows
Syndrome (ACS) patient. Reprinted from Rogers, Nasir [109]. (Right panels) Sodium Fluoride
(NaF) as a marker of active plaque calcication.
activity in CAD patients. (a) Control subject with no calcication or NaF uptake. (b) Subject had
extensive calcication in the left anterior descending artery as demonstrated by the hyperdense
lesions however had no NaF uptake, indicating no current active calcication processes. (c) Shows
increased NaF uptake on top of existing calcication. (d) Shows increased NaF uptake in the LAD
adjacent to existing calcication. (Reprinted from Dweck, Chow [
d
18
F-FDG PET/CT preliminary imaging of coronary artery inammation in
18
F-FDG uptake at the LMCA trifurcation in an Acute Coronary
c
18
F-NaF PET/CT imaging of plaque osteogenic
d
80])
into the vascular arena. 18F-NaF uptake is a useful marker of active calcication and
does not represent the pre-existing calcium burden of a vessel (Fig.3.5).
Increased NaF uptake has been correlated with higher rates of prior cardiovascular
events, angina and Framingham risk scores [80]. Increased
18
F-NaF uptake has been
associated with histological evidence of active calcication, macrophage inltration,
apoptosis and necrosis [81]. It is further associated with other high-risk plaque features
on intravascular ultrasound (IVUS) including positive remodeling, microcalcication,
and necrotic core [81]. 18F-NaF PET-CT is a non-invasive method of imaging high-risk
plaques, however its role in altering management needs further investigation.
3.8 Intravascular Imaging
3.8.1 Intravascular Ultrasound (IVUS)
Intravascular ultrasound (IVUS) involves the same principle as conventional ultrasound but is able to take higher resolution images of atherosclerotic plaque. A transducer produces sound waves at 20–40MHz, and the amplitude of the reections are
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K. Rana et al.
digitised to produce gray-scale images [82]. Gray-scale IVUS has limited use in
dening plaque morphology. In GS-IVUS, lipid-rich plaques have low-echogeneity,
calcied plaques have high echogenicity with acoustic shadowing, brous plaques
have intermediate echogeneity between the soft plaques and the echogenic calcications and mixed plaques have a combination of the above. However, many of the
ndings in GS-IVUS are non-specic. For example, an area of echolucency may be
attributable to one of several plaque features including lipids, necrotic zone, intramural haemorrhage, or thrombus [83].
To counter these issues, post-processing modules including virtual histology IVUS
(VH-IVUS), iMAP-IVUS and integrated backscatter IVUS (IB-IVUS) have been
developed. VH-IVUS uses the amplitude and frequency of the reected waves to generate images. VH-IVUS has been shown to have reasonable accuracy (>90%) in identifying brous tissue, bro-fatty regions, necrotic core and calcium-dense regions in
plaques [84, 85]. VH-IVUS can also quantify plaque burden, lumen area, positive
remodelling, and identify VH thin-cap broatheromas (Fig.3.6). VH-TCFAs have been
dened as plaques with a necrotic core ≥10%in contact with the lumen without overlying brous tissue and percent atheroma volume≥40% [86]. VH-IVUS characterised
features including plaque burden >70%, minimal lumen area <4 mm2, VC-TCFAs,
necrotic core area, dense calcium area and remodelling index have been associated with
Fig. 3.6 Intravascular ultrasound, virtual histology and OCT to highlight plaque morphology. (A)
Grayscale IVUS, (B) Virtual Histology, (C) OCT imaging for four different types of plaque: (1)
broatheroma, (2) calcied broatheroma, (3) thin-cap broatheroma, (4) calcied thin-cap broatheroma. (Reprinted from Gonzalo, Garcia-Garcia [110])
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