Non-stenotic Carotid Plaques in Embolic Stroke of Unknown Source

Abstract

Embolic stroke of unknown source (ESUS) represents one in five ischemic strokes. Ipsilateral non-stenotic carotid plaques are identified in 40% of all ESUS. In this narrative review, we summarize the evidence supporting the potential causal relationship between ESUS and non-stenotic carotid plaques; discuss the remaining challenges in establishing the causal link between non-stenotic plaques and ESUS and describe biomarkers of potential interest for future research. In support of the causal relationship between ESUS and non-stenotic carotid plaques, studies have shown that plaques with high-risk features are five times more prevalent in the ipsilateral vs. the contralateral carotid and there is a lower incidence of atrial fibrillation during follow-up in patients with ipsilateral non-stenotic carotid plaques. However, non-stenotic carotid plaques with or without high-risk features often coexist with other potential etiologies of stroke, notably atrial fibrillation (8.5%), intracranial atherosclerosis (8.4%), patent foramen ovale (5–9%), and atrial cardiopathy (2.4%). Such puzzling clinical associations make it challenging to confirm the causal link between non-stenotic plaques and ESUS. There are several ongoing studies exploring whether select protein and RNA biomarkers of plaque progression or vulnerability could facilitate the reclassification of some ESUS as large vessel strokes or help to optimize secondary prevention strategies.

Full text

MINI REVIEW
published: 22 September 2021
doi: 10.3389/fneur.2021.719329
Frontiers in Neurology | www.frontiersin.org 1September 2021 | Volume 12 | Article 719329
Edited by:
Christopher Bladin,
Monash University, Australia
Reviewed by:
Klearchos Psychogios,
Metropolitan Hospital, Greece
Patricia Martínez Sánchez,
Torrecárdenas University
Hospital, Spain
Jae Won Song,
University of Pennsylvania,
United States
*Correspondence:
Joseph Kamtchum-Tatuene
kamtchum@ualberta.ca
Specialty section:
This article was submitted to
Stroke,
a section of the journal
Frontiers in Neurology
Received: 02 June 2021
Accepted: 30 August 2021
Published: 22 September 2021
Citation:
Kamtchum-Tatuene J, Nomani AZ,
Falcione S, Munsterman D, Sykes G,
Joy T, Spronk E, Vargas MI and
Jickling GC (2021) Non-stenotic
Carotid Plaques in Embolic Stroke of
Unknown Source.
Front. Neurol. 12:719329.
doi: 10.3389/fneur.2021.719329
Non-stenotic Carotid Plaques in
Embolic Stroke of Unknown Source
Joseph Kamtchum-Tatuene 1
*, Ali Z. Nomani 2, Sarina Falcione 2, Danielle Munsterman 2,
Gina Sykes 2, Twinkle Joy 2, Elena Spronk 2, Maria Isabel Vargas 3and Glen C. Jickling 2
1Faculty of Medicine and Dentistry, Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada,
2Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada, 3Division of
Neuroradiology, Department of Radiology and Medical Imaging, Geneva University Hospital, Geneva, Switzerland
Embolic stroke of unknown source (ESUS) represents one in five ischemic strokes.
Ipsilateral non-stenotic carotid plaques are identified in 40% of all ESUS. In this narrative
review, we summarize the evidence supporting the potential causal relationship between
ESUS and non-stenotic carotid plaques; discuss the remaining challenges in establishing
the causal link between non-stenotic plaques and ESUS and describe biomarkers of
potential interest for future research. In support of the causal relationship between
ESUS and non-stenotic carotid plaques, studies have shown that plaques with high-risk
features are five times more prevalent in the ipsilateral vs. the contralateral carotid and
there is a lower incidence of atrial fibrillation during follow-up in patients with ipsilateral
non-stenotic carotid plaques. However, non-stenotic carotid plaques with or without
high-risk features often coexist with other potential etiologies of stroke, notably atrial
fibrillation (8.5%), intracranial atherosclerosis (8.4%), patent foramen ovale (5–9%), and
atrial cardiopathy (2.4%). Such puzzling clinical associations make it challenging to
confirm the causal link between non-stenotic plaques and ESUS. There are several
ongoing studies exploring whether select protein and RNA biomarkers of plaque
progression or vulnerability could facilitate the reclassification of some ESUS as large
vessel strokes or help to optimize secondary prevention strategies.
Keywords: stroke, carotid stenosis, carotid plaque, biomarkers, atherosclerosis
INTRODUCTION
Ischemic stroke is considered cryptogenic when no definite cause is identified during the baseline
etiological workup (1). According to the Cryptogenic Stroke/Embolic Stroke of Undetermined
Source International Working Group, the baseline etiological workup should include brain
imaging with computed tomography (CT) or magnetic resonance imaging (MRI), assessment
of the heart rhythm with 12-lead ECG and continuous cardiac monitoring for at least 24 h
with automated rhythm detection, transthoracic cardiac ultrasound, and imaging of cervical and
intracranial vessels supplying the infarcted brain region (using CT, MRI, conventional angiography,
or ultrasonography) (2).

Kamtchum-Tatuene et al. Non-stenotic Carotid Plaques in ESUS
Cryptogenic strokes represent ∼30% of all ischemic strokes.
They could be further classified into three subgroups: stroke with
no cause despite complete baseline workup, stroke with multiple
possible underlying causes, and stroke with incomplete baseline
workup (3). In the subgroup of cryptogenic strokes with complete
workup, embolic stroke of unknown source (ESUS) is a clinical
construct referring to non-lacunar ischemic strokes (size >1.5 cm
on CT or >2.0 cm on diffusion MRI) of presumable embolic
origin (superficial/cortical brain lesion) despite the absence of
any obvious sources of cardiac or arterial embolism (e.g., atrial
fibrillation, carotid, or intracranial stenosis >50%) (Figure 1)
(2). ESUS represent ∼17% of all ischemic strokes with a recurrent
stroke rate of 4.5% per year despite antithrombotic therapy (4–6).
The definition of ESUS was based on the assumptions that
cryptogenic strokes may be related to covert atrial fibrillation
and that a relationship between non-stenotic atherosclerotic
plaques (causing <50% stenosis) and stroke was unlikely.
However, there is now evidence to suggest that ESUS represents
a heterogeneous group including patients with various other
potential causes of stroke besides atrial fibrillation (7–9). Such
causes include atrial cardiopathy (10), patent foramen ovale
(PFO) (11), cancer (12), and non-stenotic plaques affecting
the aortic arch or carotid, vertebral, or intracranial arteries
(7,13,14). Atrial cardiopathy is a concept referring to
a dysfunction of the left atrium that is thought to favor
and precede the onset of atrial fibrillation and its eventual
detection by electrocardiographic devices. The diagnosis is
based on the identification of imaging markers (e.g., left atrial
enlargement, spontaneous echocontrast in the left atrium or
the left atrial appendage, atrial fibrosis with delayed gadolinium
enhancement on MRI), electrocardiographic markers (e.g.,
paroxysmal supraventricular tachycardia, increased P-wave
terminal force in V1, interatrial block, prolonged PR), and
blood biomarkers (e.g., N-terminal pro-brain natriuretic peptide,
highly sensitive cardiac troponin T) (10).
Non-stenotic carotid plaques are found in 40% of patients
with ESUS and 10–15% of patients with ESUS have mild stenosis
(20–49%) (2,15–17). Here we review the evidence supporting
the relationship between non-stenotic carotid plaques with high-
risk features and stroke in patients with ESUS. We present the
remaining challenges in the process of formally establishing the
causal link between non-stenotic plaques and ESUS, notably
those related to the identification of blood biomarkers of
vulnerable plaque. Finally, we discuss the management of non-
stenotic carotid plaques in patients with ESUS and highlight areas
for future research.
NON-STENOTIC CAROTID PLAQUES AS A
POTENTIAL CAUSE OF ESUS
The relationship between non-stenotic carotid plaques and ESUS
is supported by a set of three clinical observations.
First, in patients with ESUS, carotid plaques are more
prevalent on the side of the stroke than on the contralateral
side. In a cross-sectional study of 85 patients with ESUS,
non-stenotic carotid plaques thicker than 3 mm were
present in 35% of ipsilateral carotid arteries vs. 15% of
the contralateral carotid arteries (18). A similar finding
was observed in a review of 138 ESUS cases from the
prospective multicenter INTERRSeCT study (The Predicting
Early Recanalization and Reperfusion With IV Alteplase
and Other Treatments Using Serial CT Angiography). The
investigators found a non-stenotic carotid plaque ipsilateral to
the stroke in 29.2% of patients and contralateral to the stroke
in 18.7% (17).
Second, in patients with ESUS, there is a lower incidence
of atrial fibrillation detected during follow-up in patients with
ipsilateral non-stenotic carotid plaques than in those without,
thus suggesting that non-stenotic carotid plaques may be
related to the stroke. In 777 participants of the New Approach
Rivaroxaban Inhibition of Factor Xa in a Global Trial vs.
ASA to Prevent Embolism in Embolic Stroke of Undetermined
Source (NAVIGATE-ESUS) trial who were followed up for a
median of 2 years, the incidence of atrial fibrillation was 2.9
per 100 person-years in patients with ipsilateral non-stenotic
carotid plaques vs. 5.0 per 100 person-years in those without
(overall rate: 8.5 vs. 19.0%; adjusted hazard ratio: 0.57, 95%
CI 0.37–0.84) (15).
Third, plaques with high-risk features are more prevalent
on the side of the stroke in patients with ESUS. In a
meta-analysis of 8 studies enrolling 323 patients with ESUS,
plaques with high-risk features were present in 32.5% of
the ipsilateral carotid arteries vs. 4.6% of the contralateral
carotid arteries. More specifically, the odds of finding a
non-stenotic carotid plaque with a ruptured fibrous cap in
the ipsilateral vs. the contralateral carotid artery was 17.5,
reinforcing the idea that non-stenotic carotid plaques should
not be considered as benign coincidental findings in patients
with ESUS (13).
High-risk plaques have features on brain or vascular imaging
that are associated with a higher risk of stroke in patients with
either symptomatic or asymptomatic carotid atherosclerosis,
independent of the grade of stenosis (19–24). The most
common high-risk plaque features are echolucency, impaired
cerebrovascular reserve, intraplaque hemorrhage (Figure 1),
silent brain infarcts, lipid-rich necrotic core, large juxtaluminal
black hypoechoic area, large plaque volume, plaque thickness,
microembolic signals, mural thrombus, neovascularization,
plaque irregularity, plaque inflammation or hypermetabolism,
thin or ruptured fibrous cap, and ulceration (19,21,25–
31). The American Heart Association combines some of these
features to derive a classification of atherosclerotic plaques into
6 types reflecting increasing instability and risk of cardiovascular
events (Table 1) (32–37). On average, high-risk plaque features
are three times more prevalent in patients with symptomatic
vs. asymptomatic carotid stenosis (OR =3.4, 95% CI: 2.5–
4.6) (19). They are detected using various vascular imaging
modalities (Table 2). To date, there are no data on the risk
of recurrent stroke associated with each of the high-risk
features in patients with ESUS. Analysis of secondary outcome
data from the Carotid Plaque Imaging in Acute Stroke study
(CAPIAS; NCT01284933) might help to address this knowledge
gap (35,39).
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Kamtchum-Tatuene et al. Non-stenotic Carotid Plaques in ESUS
FIGURE 1 | Brain and plaque imaging findings in a 64-year-old man with ESUS. (A) Axial angio-CT scan slice showing a hypodense non-stenotic carotid plaque in the
right internal carotid artery (white arrow). (B–E) Axial diffusion-weighted imaging slices (with corresponding ADC maps) showing multiple embolic strokes in the right
pre-and post-central area. (F,G) Coronal and axial T1-weighted black blood sequence showing hyperintensity of the non-stenotic plaque in the right internal carotid
artery (white arrow), thus confirming the presence of intraplaque hemorrhage.
CHALLENGES OF ESTABLISHING CAUSAL
LINK WITH STROKE
Puzzling Clinical Associations
Although studies of high-risk features have provided evidence of
an association between non-stenotic carotid plaques and brain
infarction in patients with ESUS, establishing causality remains
challenging in most cases. The dilemma rests on four clinical
observations. First, high-risk features are often found in plaques
in the absence of related clinical symptoms (19,40). In a meta-
analysis of eight studies enrolling 323 patients with ESUS, a non-
stenotic carotid plaque with high-risk features was identified in
the contralateral carotid artery in 4.6% of cases (95% CI: 0.1–
13.1) (13). Likewise, in a meta-analysis of 64 studies enrolling
20,571 patients with asymptomatic carotid stenosis of various
grades, 26.5% of patients were found to have at least one high-
risk plaque feature (95% CI: 22.9–30.3). The highest prevalence
was observed for neovascularization (43.4%, 95% CI: 31.4–55.8)
and the lowest for mural thrombus (7.3%, 95% CI: 2.5–19.4).
On average, intraplaque hemorrhage was found in 1 out of 5
patients (19). Second, high-risk plaque features are not specific
for symptomatic carotid plaques. In a meta-analysis of data from
20 prospective studies enrolling 1,652 patients with symptomatic
carotid stenosis, high-risk plaque features were identified in <1
in 2 patients (43.3%, 95% CI: 33.6–53.2) (19). Third, in patients
with stroke, there is an association between the presence of high-
risk plaque features and atrial fibrillation. In a study of 68 patients
with embolic stroke, including 45 ESUS, the presence of high-
risk plaque features on carotid ultrasound (ulceration, thickness
≥3 mm, and echolucency) was independently associated with
detection of atrial fibrillation on admission or during follow-
up (OR =4.5, 95% CI: 1.0–19.6) (41). Fourth, in some patients
with ESUS diagnosed using the current clinical definition, non-
stenotic carotid plaques often coexist with other potential causes
of stroke, including atrial fibrillation (8.5%) (15), intracranial
atherosclerosis (8.4%) (42), PFO (5–9%) (43,44), and atrial
cardiopathy (2.4%) (45).
Lack of Reliable Biomarkers
The identification of an ipsilateral non-stenotic carotid plaque
with or without high-risk features is not sufficient to reclassify
ESUS as stroke due to large vessel disease. Further research is,
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Kamtchum-Tatuene et al. Non-stenotic Carotid Plaques in ESUS
TABLE 1 | American Heart Association comprehensive morphological classification scheme for atherosclerotic lesions (32–34).
Plaque type Description
Lipid rich
necrotic core
Fibrous cap Calcification Erosion/rupture Intraplaque
hemorrhage
Thrombus Regression to
normal
Type I (Initial lesion) Initial lesion, accumulation of
smooth muscle cells and isolated
foam cells, absence of a necrotic
core.
Absent Absent Absent Absent Absent Absent Possible
Type II (Intimal
xanthoma)
Multiple layers of foam cells,
previously referred to as “fatty
streak”
Absent Absent Absent Absent Absent Absent Possible
Type III
(pre-atheroma)
Smooth muscle cells in a
proteoglycan-rich extracellular
matrix, multiple layers of foam
cells, non-confluent extracellular
lipid pools
Absent Present (ill-defined) Absent Absent Absent Absent Possible
Type IV (atheroma) Confluent extracellular lipids Present
(well-formed)
Present
(well-defined)
Absent Absent Absent Absent Not possible
Type Va
(Fibroatheroma)
Confluent extracellular lipids with
prominent proliferative
fibromuscular layer
Present
(well-formed)
Present (thick) PossibleaAbsent Absent Absent Not possible
Type VI
(Complicated
atheroma)b
Inflammatory lesion with at least
one high-risk feature
Present (large) Present (thin or
eroded)
Possible (partial
calcification)
Possible (VIa if
present alone)
Possible (VIb if
present alone)
Possible (VIc if
present alone)
Not possible
aThe plaque is assigned category Vb if predominantly calcified (fibro-calcific) or category Vc if predominantly fibrous (collagen-rich atheroma with smaller lipid core).
bThe plaque is assigned category VIabc if erosion/ulceration, intraplaque hemorrhage and luminal thrombus are present concurrently.
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Kamtchum-Tatuene et al. Non-stenotic Carotid Plaques in ESUS
TABLE 2 | High-risk plaque features commonly used in clinical practice (13,21,25–31).
High-risk plaque
featuresa
Imaging
modality of
choice
DescriptionbAlternative imaging
modalities
Prevalence (%)in patients with ESUS
AHA type IV, V, VI
(35–37)
MRI Plaque with large lipid-rich necrotic core
(>40% of the vessel circumference), ruptured
fibrous cap, mural thrombus, or intraplaque
hemorrhage (see below).
CT, US In three studies including 82 patients with
ESUS, an AHA plaque type IV-VI was
found in the ipsilateral carotid in 38% of
cases on average (35–37).
Echolucency US Hypoechoic area within the plaque on B-mode
(reference =sternocleidomastoid muscle)
Not applicable In a study of 44 patients with ESUS, an
ipsilateral echolucent non-stenotic carotid
plaque was found in 50.0% (38)
Impaired
cerebrovascular
reserve
TCD <10% increase of blood flow in the ipsilateral
MCA while breathing 5% CO2for 2 min.
BOLD-MRI Not applicable for non-stenotic plaques
Intraplaque
hemorrhage
MRI Intraplaque hyperintensity on T1W FAT SAT
(black blood) and 3D-TOF
MRI In five studies including 162 patients,
intraplaque hemorrhage was found in the
ipsilateral carotid in 24.4% of cases (13).
Ipsilateral silent brain
infarcts
MRI Non-lacunar hyperintensity of the brain
parenchyma, in the territory of the internal
carotid artery, visible on T2W and FLAIR, or
DWI (if acute)
CT (would appear as a
hypodensity)
No data available for patients with ESUS
Lipid-rich necrotic core MRI Collection of foam cells, cholesterol crystals
and apoptotic cells that appears
iso/hyper-intense on T1W and iso/hypo-intense
on T2W.
CT, US (although it is
difficult to make the
difference with
intraplaque
hemorrhage on these
modalities)
No data available for patients with ESUS
Microembolic signals TCD Random audible transient increase (variable
threshold) of the Doppler signal within the
monitored arterial blood flow, generating a
high-intensity signal on the doppler imaging
(PWV and M-Mode), visible and moving in the
direction of the flow. Duration of recording
≥1 h.c
Not applicable No data available for patients with ESUS
Mural thrombus MRI Filling defect on contrast MRI, hyperintense
signal adjacent to the lumen on T1W
CT, US In three studies enrolling 94 patients with
ESUS, plaque thrombus was identified in
the ipsilateral carotid in 6.9% of cases (13).
Neovascularization CEUS Enhancement of the plaque on pulse inversion
harmonic imaging (microbubbles carried into
the plaque by the blood entering the
neovessels)
DCE-MRI No data available for patients with ESUS
Plaque irregularity MRI 0.3–0.9 mm fluctuations of the surface of the
plaque
CT, CEUS No data available for patients with ESUS
Thin/ruptured fibrous
cap
MRI Disrupted or invisible dark band adjacent to the
lumen on 3D-TOF
CEUS In two studies enrolling 50 patients with
ESUS, a thin or ruptured fibrous cap was
found in the ipsilateral carotid in 23.6% of
cases (13).
Ulceration MRI Depression >1 mm on the surface of the
plaque
CTA, CEUS (the
threshold is 2 mm in
ultrasound studies)
No data available for patients with ESUS
aThe following high-risk features are used less often: juxta-luminal black hypoechoic area and plaque volume assessed by ultrasound, plaque inflammation measured by standardized
(18) F-FDG uptake on positron emission tomography-computed tomography, carotid temperature assessed by microwave radiometry.
bFor simplicity, the description of each high-risk feature is based on its appearance on the imaging modality of choice.
cThe sound threshold and the number of MES for a positive examination is variable across studies.
AHA, American Heart Association; BOLD, blood oxygen level-dependent; CEUS, contrast-enhanced ultrasound; CI, confidence interval; CT, computed tomography; DCE, dynamic
contrast-enhanced; ESUS, embolic stroke of undetermined source; FLAIR, fluid-attenuated inversion recovery; MCA, middle cerebral artery; MRI, Magnetic Resonance Imaging; T1W,
T1-weighted imaging; T2W, T2-weighted imaging; TCD, transcranial Doppler ultrasound; and 3D-TOF, 3-dimensional time of flight.
therefore, needed to determine whether combination of vascular
imaging findings, clinical data, and candidate biomarkers of
plaque progression/instability or atheroembolism (46–82) into
multiparameter scores could improve the ability to (1) establish a
causal link between ESUS and a non-stenotic carotid plaque, (2)
predict plaque progression or stroke recurrence, and (3) select
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Kamtchum-Tatuene et al. Non-stenotic Carotid Plaques in ESUS
patients who might benefit from adjuvant anti-inflammatory
and lipid-lowering therapies as briefly discussed in the next
section. Some biomarkers of plaque progression and instability
that warrant further investigation specifically in patients with
ESUS are presented in Table 3. There are several ongoing projects
exploring biomarkers in patients with ESUS or cryptogenic
stroke, notably the Searching for Explanations for Cryptogenic
Stroke in the Young: Revealing the Etiology, Triggers, and
Outcome study (SECRETO, NCT01934725) (95), the Carotid
Plaque Imaging in Acute Stroke study (CAPIAS, NCT01284933)
(35), and the Biomarkers of Acute Stroke Etiology study
(BASE, NCT02014896) (96). Efforts to establish a causal
relationship between non-stenotic carotid stenosis and ESUS
using biomarkers and multimodal vascular imaging in well-
phenotyped prospective cohorts will also benefit from research
aiming to identify alternative causes of stroke in patients with
ESUS (14,68,97–104).
CHALLENGES OF SECONDARY STROKE
PREVENTION
As a result of the challenges to determine the root cause of an
ESUS, the optimal treatment strategy for patients with ESUS
remains unclear, and a tailored approach would likely be the
most appropriate (9). In this section, we briefly describe the
strategies that have been explored so far and discuss possible
future directions.
Dual Antiplatelet Therapy and Antiplatelet
Switch
Following the results of the Platelet-Oriented Inhibition in
New TIA and Minor Ischemic Stroke (POINT) (105) and the
Clopidogrel in High-Risk Patients with Acute Non-disabling
Cerebrovascular Events (CHANCE) (106) trials, patients with
ESUS are treated with Aspirin-based dual antiplatelet therapy
for 21 days provided that their baseline NIHSS is low. After 3
weeks, patients ideally return to single antiplatelet therapy and
switching from Aspirin to Clopidogrel is considered in patients
who had an ESUS while on Aspirin (107). A meta-analysis
of data from CHANCE and POINT showed that extending
the treatment beyond 3 weeks might increase the bleeding
risk without additional benefit for secondary stroke prevention
(108). Whether the presence of ipsilateral non-stenotic carotid
plaque with or without high-risk features would modify the
magnitude (absolute risk reduction) and duration (beyond 21
days) of the benefits derived from dual antiplatelet therapy
in patients with ESUS remains unknown. In patients allergic
to Clopidogrel and in carriers of a CYP2C19 loss of function
allele, Ticagrelor might be an alternative according to findings
of the Acute Stroke or Transient Ischemic Attack Treated with
Ticagrelor and ASA [acetylsalicylic acid] for Prevention of Stroke
and Death (THALES) trial (109–112). The ongoing Clopidogrel
with Aspirin in High-risk patients with Acute Non-disabling
Cerebrovascular Events II (CHANCE-2, NCT04078737) trial is
evaluating the superiority of the Ticagrelor-Aspirin combination
over Clopidogrel-Aspirin therapy in CYP2C19 loss of function
carriers with minor stroke or transient ischemic attack (TIA)
(113). There is currently no evidence supporting the use of
dual antiplatelet therapies not containing Aspirin or triple
antiplatelet therapies (with or without Aspirin) for secondary
stroke prevention in patients with acute stroke or TIA (114).
Anticoagulation
The New Approach Rivaroxaban Inhibition of Factor Xa in a
Global Trial vs. ASA [Acetylsalicylic Acid] to Prevent Embolism
in Embolic Stroke of Undetermined Source (NAVIGATE-ESUS)
and the Randomized Double-Blind Evaluation in Secondary
Stroke Prevention Comparing The Efficacy Of Oral Thrombin
Inhibitor Dabigatran Etexilate for Secondary Stroke Prevention
in Patients With Embolic Stroke of Undetermined Source (RE-
SPECT-ESUS) trials have shown that universal full-dose oral
anticoagulation is not an effective strategy to reduce the risk of
stroke recurrence in patients with ESUS (5,6). These results are
likely explained by the heterogeneity of stroke mechanisms in
patients with ESUS as discussed earlier, with atrial fibrillation
being diagnosed in only 24.8% of cases at 24 months using
insertable cardiac monitors (115). Moreover, there is no evidence
that patients with ESUS and ipsilateral non-stenotic carotid
plaques should be treated differently than those without plaques.
In a subgroup analysis of data from 2,905 patients with non-
stenotic carotid plaques enrolled in the NAVIGATE-ESUS trial,
there was no difference between Rivaroxaban and Aspirin
with respect to the prevention of ipsilateral ischemic stroke
[Hazard ratio [HR] =0.6, 95% CI: 0.2–1.9]. Major bleeding
complications were significantly more frequent in patients taking
anticoagulation (HR =3.7, 95% CI: 1.6–8.7) (16).
In the Cardiovascular Outcomes for People Using
Anticoagulation Strategies (COMPASS) trial, the combination
Rivaroxaban-Aspirin (2.5 mg twice daily plus Aspirin 100 mg
once per day) was superior to Aspirin alone (100 mg once daily)
for the prevention of cardioembolic strokes (HR =0.4, 95% CI:
0.2–0.8) and ESUS (HR =0.3, 95% CI: 0.1–0.7) but there was
no effect on the incidence of stroke due to moderate-to-severe
carotid stenosis (HR =0.9, 95% CI: 0.5–1.6) (116). Although
these results suggest that the combination of Aspirin and
low-dose Rivaroxaban could be an effective secondary stroke
prevention strategy, they are not directly applicable to patients
with ESUS since all patients with acute stroke (<1 month)
were excluded from the trial due to the perceived higher risk
of major intracranial bleeding (117). Furthermore, the baseline
proportion of patients with non-stenotic carotid plaque, with or
without high-risk features, was not reported. The prevalence of
ipsilateral non-stenotic carotid plaque in participants diagnosed
with ESUS during follow-up was also not reported.
According to currently available data, patients with
ESUS and features of atrial cardiopathy, notably atrial
enlargement, constitute the only subgroup that may benefit
from anticoagulation (118). However, since these results are
derived from a post-hoc analysis of the NAVIGATE-ESUS trial,
they might not be used to justify universal prescription of
anticoagulation until confirmation is obtained in dedicated
trials. The ongoing Atrial Cardiopathy and Antithrombotic
Drugs in Prevention After Cryptogenic Stroke (ARCADIA,
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Kamtchum-Tatuene et al. Non-stenotic Carotid Plaques in ESUS
TABLE 3 | Biomarkers of potential interest for the study of non-stenotic carotid plaques in ESUS.
Biomarker Type Main source Key evidence Specific target
of a drug
previously tested
in human trials
References
Lectin-like
oxidized LDL
receptor 1 (LOX-1)
Protein Endothelial cells,
smooth muscle
cells, fibroblasts
In 4,703 participants from the Malmo Diet and Cancer Cohort, higher plasma levels of soluble LOX-1
were associated with higher risk of stroke during a mean follow-up of 16.5 years (HR =1.5, 95% CI:
1.3–2.4).
In 202 patients undergoing carotid endarterectomy, plasma levels of soluble LOX-1 were correlated with
the plaque content of oxidized LDL, proinflammatory cytokines, and matrix metalloproteinases.
No (46–49,59,75)
Omentin-1 Protein Visceral adipose
tissue, stromal
vascular cells,
lung, heart,
placenta, ovaries
In 173 patients with acute ischemic stroke, serum levels of omentin-1 were lower in subjects with
unstable plaque (n=38, echolucent, thin fibrous cap, ulcerated) than in those with stable plaques
(median of 53 vs. 62 ng/mL).
No (69)
Lipoprotein-
associated
phospholipase A2
(Lp-PLA2)
Protein Monocytes,
macrophages, T
lymphocytes, and
mast cells
In 1,946 participants of the Northern Manhattan study, there was a dose-response relationship between
Lp-PLA2 mass and the risk of first-ever stroke due to large vessel atherosclerosis (HR =1.4, 4.5, and
5.1 for quartiles 2, 3, and 4 compared with quartile 1 in multivariable survival analysis).
Yes (Darapladib) (52,53,83)
Chitinase-3-like-1
(YKL-40)
Protein Inflammatory cells In 1,132 patients with carotid atherosclerotic plaques of various grades, higher levels of YKL-40 were
associated with plaque instability (n=855, echolucency) after adjusting for various demographic and
cardiovascular risk factors (OR =2.1 and 1.7 for quartiles 3 and 4, respectively).
No (56,59)
Granzyme B Protein T lymphocytes In 67 patients with severe carotid stenosis undergoing revascularization, higher plasma levels of
granzyme B were found in patients with unstable plaques (n=16, echolucent) than in those with stable
plaques (median of 492.0 vs. 143.8 pg/mL)
No (57)
Vimentin Protein Endothelial cells,
macrophages, and
astrocytes
In 4,514 patients with carotid plaques in the Malmo Diet and Cancer Cohort, higher plasma levels of
vimentin at baseline were associated with the incidence of ischemic stroke after a mean follow-up of 22
years (HR =1.66, 95% CI: 1.23–2.25).
Yes (Withaferin-A) (65,84)
Macrophage
chemoattractant
protein
(MCP-1/CCL2)
Protein Monocytes In the Athero-EXPRESS biobank, higher plaque levels of MCP-1 levels were found in symptomatic (vs.
asymptomatic) plaques and in vulnerable (vs. stable) plaques.
No (61)
Matrix
metalloproteinase
9 (MMP9)
Protein Macrophages,
foam cells
Serum levels of MMP9 were higher in large artery atherosclerosis strokes (n=26, 1,137 ng/mL) vs.
cardioembolic strokes (n=86, 517 ng/mL). MMP9 >1,110 ng/mL had 85% sensitivity and 52%
specificity for differentiating large vessel from cardioembolic strokes.
No (59,66)
Complement 5b-9 Protein Liver In 70 patients with acute ischemic stroke, serum C5b-9 levels were higher in patients with unstable
plaques (n=37) than in those with stable plaques (median of 875 vs. 786 ng/mL). There was also a
positive correlation with plaque burden and grade of stenosis.
Yes (Eculizumab) (76,85)
Interleukin 1β
(IL-1β)
Protein Monocytes,
macrophages
A higher expression of IL-1βand other components of the NLRP3 inflammasome was observed in 30
plaques when compared with 10 healthy mesenteric arteries, both at the protein and the mRNA level.
Yes (Anakinra,
Rilonacept,
Canakinumab)
(77,86–88)
Interleukin 6 (IL-6) Protein Monocytes,
macrophages
In a sub-analysis of data from 703 participants of the population-based Tromsø study, higher plasma
levels of IL-6 were independently associated with plaque progression after a 6-year follow-up (OR 1.4,
95% CI 1.1–1.8 per 1 SD increase in IL-6 level).
Yes (Ziltivekimab,
Tocilizumab)
(71–74)
(Continued)
Frontiers in Neurology | www.frontiersin.org 7September 2021 | Volume 12 | Article 719329

Kamtchum-Tatuene et al. Non-stenotic Carotid Plaques in ESUS
TABLE 3 | Continued
Biomarker Type Main source Key evidence Specific target
of a drug
previously tested
in human trials
References
C-Reactive Protein
(CRP)
Protein Hepatocytes,
white blood cells,
adipocytes,
smooth muscle
cells
In a prospective observational study enrolling 271 participants, higher levels of CRP (quartile 4 vs. 1)
were associated with plaque progression after a follow-up of 37 months (OR =1.8, 95% CI: 1.03–2.99).
No (78,89)
CD36 Protein Various cells
including
monocytes,
endothelial cells,
adipocytes,
platelets.
In 62 patients with severe carotid stenosis undergoing revascularization, plasma levels of soluble CD36
were higher in those with symptomatic (n=31) and unstable (echolucent, n=20) plaques.
No (60)
Lipoprotein (a) Lipoprotein Food/Liver In 876 consecutive patients with carotid atherosclerosis (2.5% occlusions), plasma lipoprotein (a) was an
independent predictor of carotid occlusion (OR=1.7, 95% CI: 1.2–2.3 per 1 SD increase), suggesting
that it plays a role in plaque destabilization/rupture, thrombosis, and impaired fibrinolysis.
In 225 patients with coronary artery disease who underwent intra-coronary optical coherence
tomography imaging of culprit plaque, the prevalence of thin fibrous cap atheroma was significantly
higher in the group with higher serum lipoprotein (a) levels (>25 mg/dL, n=87): 23 vs. 11%.
Yes (AKCEA-
Apo(a)-LRx)
(79–81,90,91)
Non-HDL
cholesterol
Lipoproteins Food/Liver In 2,888 patients with carotid plaque, including 1,505 with vulnerable plaques (echolucent, irregular, or
ulcerated), higher serum levels of non-HDL cholesterol were independently associated with plaque
vulnerability (OR =1.5 for tertile 3 vs. 1, 95% CI: 1.2–1.8).
Yes (various class
of lipid lowering
drugs)
(51,92,93)
Uric acid Xanthine (purine
derivatives)
Various cells In a study including 88 patients with carotid plaques (44 symptomatic), serum uric acid levels were
significantly higher in patients with symptomatic plaques (7.4 vs. 5.4 mg/dL) who also had higher plaque
expression of xanthine oxidase as assessed by immunohistochemistry.
Yes (allopurinol) (82)
Neutrophil count Cells NA In 60 patients with recently symptomatic carotid artery disease, higher neutrophil count (>5,900/µL) was
associated with detection of microembolic signals on transcranial Doppler monitoring.
No (58)
miR-199b-3p,
miR-27b-3p,
miR-130a-3p,
miR- 221-3p, and
miR-24-3p
RNA Various cells In 60 patients with moderate or severe asymptomatic carotid stenosis, higher plasma levels of the
micro-RNAs were associated with plaque progression (n=19) after 2 years of follow-up.
No (62)
miR-200c RNA Various cells In 22 patients undergoing carotid endarterectomy, higher levels of miR-200c were found in patients with
unstable plaques (echolucent symptomatic) and were positively correlated with biomarkers of plaque
instability (matrix metalloproteinase—MMP1, MMP9; interleukin 6, macrophage chemoattractant protein
1—MCP-1)
No (59,94)
Resistin and
chimerin mRNA
RNA Various cells In an analysis of 165 carotid plaque (67% unstable based on histological criteria), Resistin and chemerin
mRNA expression was 80 and 32% lower, respectively, in unstable vs. stable plaques.
No (70)
Frontiers in Neurology | www.frontiersin.org 8September 2021 | Volume 12 | Article 719329

Kamtchum-Tatuene et al. Non-stenotic Carotid Plaques in ESUS
NCT03192215) (101), Apixaban for Treatment of Embolic
Stroke of Undetermined Source (ATTICUS, NCT02427126),
and A Study on BMS-986177 (oral factor XIa inhibitor) for
the Prevention of a Stroke in Patients Receiving Aspirin and
Clopidogrel (AXIOMATIC-SSP, NCT03766581) trials will,
hopefully, provide conclusive results to guide patient care.
Likewise, in the Oxford Vascular Study, a large patent foramen
ovale is present in 36% of patients with a cryptogenic stroke
aged >60 years (119) and associated with a 2.5 times higher risk
of recurrent ischemic stroke (120), thus suggesting it might be
worth trialing PFO closure or anticoagulation in elderly patients
with a large PFO. However, the causal relationship between
the PFO and the recurrent stroke was not formally established
and the prevalence of ipsilateral non-stenotic carotid plaque
not reported. Because PFO closure or anticoagulation are not
expected to prevent strokes due to large vessel atherosclerosis,
trials of PFO closure or anticoagulation in elderly patients with
a large PFO should carefully plan subgroup analyses according
to the presence of alternative candidate causes of the recurrent
stroke, notably an atrial cardiopathy or an ipsilateral non-stenotic
carotid plaque that may coexist with PFO (43,44,121).
Other Therapies and Interventions
Currently, patients with ESUS receive intensive lipid-lowering
therapy (e.g., statins, ezetimibe) to achieve a level of LDL
cholesterol <70 mg/dL (1.8 mmol/L) as early as possible after
stroke (122–124). The treatment is maintained long-term if
well-tolerated, even in older adults (125–128). Specific targets
of LDL cholesterol have not been assessed in patients with
ESUS and it is unknown if the presence of an ipsilateral non-
stenotic carotid plaque would modify the effect of lipid-lowering
drugs as suggested by findings of the Stroke Prevention by
Aggressive Reduction in Cholesterol Levels (SPARCL) (129).
Furthermore, the potential role of newer classes of lipid-lowering
drugs for plaque stabilization and secondary stroke prevention
is yet to be defined. Such drugs include proprotein convertase
subtilisin/kexin type 9 (PCSK9) inhibitors (small interfering
RNA—inclisiran or monoclonal antibodies—evolocumab or
alirocumab) and Apo(a) antisense oligonucleotides that reduce
plasma levels of both LDL cholesterol and lipoprotein(a) [Lp(a)];
as well as anti- angiopoietin-like 3 monoclonal antibodies that
do not affect Lp(a) levels and bempedoic acid (92,130–135).
Like ezetimibe (93,136), the new lipid-lowering drugs may be
useful as add-on or statin-sparing agents in cases of allergy or
intolerance to statins, familial hypercholesterolemia, refractory
hypercholesterolemia, or in patients with high Lp(a) levels at
the time of stroke since statins increase plasma levels of Lp(a)
(90,137). There are reports of an association between high
Lp(a) levels and cryptogenic stroke (138,139) suggesting that
Lp(a) could represent a biomarker to guide optimization of lipid-
lowering therapy in patients with ESUS as is the case in other
cardiovascular diseases.
Systemic inflammation, a hallmark of atherosclerosis,
modulates the risk of stroke and the effect of lipid-lowering
agents (140–142). This explains the benefit of various anti-
inflammatory drugs (e.g., canakinumab, colchicine) for
the prevention of atherosclerotic cardiovascular diseases
(86,87,143). In patients with ESUS and ipsilateral non-stenotic
carotid plaque, the effect of anti-inflammatory agents is worth
exploring, especially in those with high-risk plaque features
since they would not be offered revascularization procedures as
first-line treatment according to current guidelines (144–146).
Data from the ongoing Colchicine for Prevention of Vascular
Inflammation in Non-Cardioembolic Stroke (CONVINCE,
NCT02898610) might answer the question of whether patients
with ESUS with or without ipsilateral non-stenotic carotid
plaques would benefit from the addition of low-dose colchicine
to best medical therapy for secondary stroke prevention (147).
The relevance of serial vascular imaging to monitor carotid
plaque progression and stability is another aspect of the
management that remains unexplored.
Besides pharmacological treatments, there is a variety of
lifestyle interventions that are beneficial for cardiovascular
risk reduction and are recommended by the American Heart
Association for secondary stroke prevention no matter the
suspected underlying etiology. Such interventions include
smoking cessation, regular physical activity, weight loss,
improved sleep hygiene, avoidance of noise and air pollution,
reduction of salt and sugar intake, higher consumption of fish,
fruits, and vegetables (148–155).
CONCLUSION
ESUS is a common subtype of stroke that is frequently associated
with an ipsilateral non-stenotic carotid plaque. Evidence suggests
that advanced multimodal vascular imaging and biomarkers
might help reclassify some ESUS as large vessel strokes. However,
the precise algorithm for this reclassification remains to be
designed. Despite significant research efforts since the term
ESUS was coined in 2014, the optimal management strategy
for patients with ESUS remains unclear. There are several
ongoing trials investigating various interventions. While waiting
for more evidence to support the design of tailored therapeutic
guidelines for the various well-phenotyped subgroups of patients
with ESUS, clinicians should continue to fully implement
all previously validated stroke prevention strategies, whether
an ipsilateral non-stenotic carotid plaque is present or not.
Such strategies include short-term dual antiplatelet therapy if
appropriate, long-term intensive lipid lowering therapy, control
of modifiable cardiovascular risk factors (e.g., hypertension,
diabetes, smoking, obesity), and lifestyle changes.
AUTHOR CONTRIBUTIONS
JK-T did the literature search and wrote the manuscript. MV
and JK-T prepared the figure. AN, SF, DM, GS, TJ, ES, MV, and
GJ critically revised the manuscript. All authors approved the
final version.
FUNDING
GJ received research grant support from Canadian Institutes
of Health Research (CIHR), Heart and Stroke Foundation,
Frontiers in Neurology | www.frontiersin.org 9September 2021 | Volume 12 | Article 719329

Kamtchum-Tatuene et al. Non-stenotic Carotid Plaques in ESUS
University Hospital Foundation, Canada Foundation for
Innovation (CFI), and National Institutes of Health (NIH).
JK-T was supported by the Faculty of Medicine and Dentistry
Motyl Graduate Studentship in Cardiac Sciences, an Alberta
Innovates Graduate Student Scholarship, the Ballermann
Translational Research Fellowship, the Izaak Walton Killam
Memorial Scholarship, and the Andrew Stewart Memorial
Graduate Prize.
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Frontiers in Neurology | www.frontiersin.org 14 September 2021 | Volume 12 | Article 719329