Original Contribution

Emerging Risk Factors for Recurrent Vascular Events in

Patients With Embolic Stroke of Undetermined Source
Yuji Ueno, MD, PhD; Kazuo Yamashiro, MD, PhD; Ryota Tanaka, MD, PhD;
Takuma Kuroki, MD; Kenichiro Hira, MD; Naohide Kurita, MD; Takao Urabe, MD, PhD;
Nobutaka Hattori, MD, PhD

Background and PurposeUnderlying embolic causes diagnosed by transesophageal echocardiography could be implicated
in mechanisms of embolic stroke of undetermined source. We aimed to explore factors, including underlying embolic
causes, related to recurrent vascular events in embolic stroke of undetermined source.
MethodsPatients who fulfilled the diagnostic criteria for embolic stroke of undetermined source and whose potential
embolic sources were examined by transesophageal echocardiography were included. Recurrent vascular events, including
ischemic stroke, cardiovascular and peripheral artery diseases, and vascular death, were retrospectively analyzed. Cox
proportional hazards regression analysis was used to explore factors, including clinical characteristics, embolic causes
on transesophageal echocardiography, and the Calcification in the Aortic Arch, Age, Multiple Infarction score (CAM),
Downloaded from http://stroke.ahajournals.org/ by guest on October 6, 2016

based on the degree of aortic arch calcification on chest radiograph (03 points), age (70 years; 1 point), and multiple
infarctions on magnetic resonance imaging (multiple infarcts in 1, 2, or 3 territories of large intracranial arteries, 1, 2,
or 3 points) associated with recurrent vascular events.
ResultsA total of 177 patients (age, 64.114.2 years; 127 men) were enrolled. Thirty-one patients had recurrent vascular
events (follow-up, 3.52.7 years; annualized rate, 5.0% per person-year). Among embolic causes on transesophageal
echocardiography, incidence of recurrent vascular events was high in patients with large aortic arch plaques (7.5% per
person-year). Diabetes mellitus (hazard ratio, 2.56; 95% confidence interval, 1.235.32; P=0.012) and CAM score grade
(hazard ratio, 2.29; 95% confidence interval, 1.114.72; P=0.026) predicted recurrent vascular events.
ConclusionsHistory of diabetes mellitus and the CAM score could be novel risk factors for recurrent vascular events in
embolic stroke of undetermined source.(Stroke. 2016;47:00-00. DOI: 10.1161/STROKEAHA.116.013878.)
Key Words: aorta, thoracic echocardiography, transesophageal infarction recurrence stroke

E mbolic stroke of undetermined source (ESUS) is a

new clinical entity with specific diagnostic criteria
including (1) nonlacunar stroke on neuroradiological imag-
ing, (2) no arterial stenosis >50% or occlusion in a cor-
responding large artery, (3) lack of major cardioembolic
source, and (4) lack of other determined stroke causes.1
Diagnostic modalities to investigate cardioembolic sources
in the ESUS criteria involved 12-lead ECG, cardiac moni-
toring for 24 hours, and transthoracic echocardiography.
Transesophageal echocardiography (TEE) has presumably
not been required to standardize the diagnosis of ESUS.
In contrast, TEE clearly detected underlying embolic
causes, including patent foramen ovale (PFO), atrial septal
aneurysm (ASA), and aortic arch plaques, in unexplained
stroke.25 Several studies using TEE have shown that these
embolic causes increased the risk of recurrence in stroke
patients.48 In ESUS, these embolic sources could also be
latent, and thus, it is suggested that the identification of
potential embolic causes could be critical in the prognosis
for patients with ESUS.
To date, no studies have investigated the potential embolic
sources using TEE and long-term prognosis in association
with potential embolic sources on TEE in an ESUS popula-
tion. The present study was conducted on ischemic stroke
patients who fulfilled the diagnostic criteria for ESUS and
were undergoing TEE examinations, and we investigated
the factors, including clinical characteristics and poten-
tial embolic sources on TEE related to recurrent ischemic
stroke, as well as cardiovascular events in ESUS patients, in
a retrospective manner.

Received April 26, 2016; final revision received September 8, 2016; accepted September 16, 2016.
From the Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan (Y.U., K.Y., R.T., T.K., K.H., N.K., N.H.); and Department
of Neurology, Juntendo University Urayasu Hospital, Tokyo, Japan (T.U.).
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
116.013878/-/DC1.
Correspondence to Yuji Ueno, MD, PhD, Department of Neurology, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-
8421, Japan. E-mail yuji-u@juntendo.ac.jp
2016 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.116.013878

1
 2StrokeNovember 2016
Methods
Study Subjects
The present case series involved 1158 patients with acute ischemic
stroke who had presented within 7 days of onset, and baseline data
were derived from the Inpatient Registry of the Department of
Neurology at Juntendo University Hospital, a secondary referral cen-
ter, from April 2008 to March 2014. The Inpatient Registry included
the patients characteristics (age, sex, atherosclerotic risk factors, and
previous history of stroke); brain computed tomographic and mag-
netic resonance imaging findings involving the size, number, and
locations of infarcts on diffusion-weighted imaging; periventricular
hyperintensity and deep and subcortical white matter hyperintensity
on fluid-attenuated inversion recovery imaging; stenosis of intracra-
nial arteries >50% on magnetic resonance angiography; chest radio-
graph involving the degree of aortic arch calcification; 12-lead ECG;
and carotid ultrasonography. Transthoracic echocardiography was
also performed to obtain cardiac function and to screen for the pres-
ence of intracardiac thrombus, and continuous electrocardiographic
monitoring for at least 24 hours was started during admission. On
the basis of the aforementioned initial stroke examinations, whether
patients fulfilled the diagnostic criteria of ESUS was retrospec-
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tively analyzed, and patients with ESUS who had undergone TEE
were enrolled.1 Patients were excluded if paroxysmal atrial fibrilla-
tion or other stroke causes or advanced cancer was detected during
hospitalization. Survey questionnaires were distributed in the outpa-
tient department and mailed to patients or families, or results were
obtained by telephone in the follow-up study period from January
2015 to November 2015. The questionnaire included inquiries about
recurrent vascular events (ischemic stroke, cardiovascular and periph-
eral artery diseases, and vascular death) that had occurred since dis-
charge from our hospital and information on the use of antiplatelet
or anticoagulant agents, statins, and other medications during the
observation period. Those treatments were performed in our hospital
or by their referring physicians according to our or their best medical
judgment and were not randomized. Functional performance using
the modified Rankin scale was assessed at follow-up. This study was
conducted in accordance with the Declaration of Helsinki. The inde-
pendent ethics committee of Juntendo University Hospital approved
this study. Patients or their relatives received full explanations of the
study, and their written informed consent was obtained during the
follow-up study period but before enrollment.
Risk Factors
At baseline, atherosclerotic vascular risk factors were defined accord-
ing to the previous literature.2,9
CAM Score
The Calcification in the Aortic Arch, Age, Multiple Infarction score
(CAM) is based on the degree of aortic arch calcification on chest
radiograph (no visible calcification, 0 points; small spots or a single
thin area of calcification, 1 point; 1 or more areas of thick calcification,
2 points; and circumferential calcification, 3 points), age (70 years,
1 point), and diffusion-weighted imaging findings (single infarct, 0
points; multiple infarcts in 1 vascular territory, 1 point; 2 vascular terri-
tories, 2 points; 3 vascular territories, 3 points).9,10 A maximum CAM
score is 7 points, and the CAM scores were stratified into 3 grades (02,
low CAM; 34, intermediate CAM; and 57, high CAM grade).9
TEE Study
TEE was conducted using a Vivid S6 system equipped with a mul-
tiplane 5.0-MHz transducer (GE Medical Systems, Milwaukee, WI)
according to the previous protocol.2,3,9
Statistical Analysis
Numeric values are reported as meansSD. Data were analyzed using
the 2 test for categorical variables and the Mann-Whitney U test for
nonparametric analyses. Periods between stroke onset and the day of
outcome were calculated, and overall survival and presence of recur-
rent vascular events were calculated from stroke onset to the date of
last follow-up available or until the date of death, referring to the
method in the previous literature.11 The incidence of recurrent vascu-
lar events was estimated per 100 person-years of observation among
the potential embolic causes. The Cox proportional hazards model
was used to explore the factors, including clinical characteristics, as
well as embolic causes on TEE, associated with recurrent vascular
events. After univariate analysis of all clinically relevant covariates,
those with a P<0.05 were included in the multivariable Cox model.
The Kaplan-Meier method and log-rank test were used to estimate
cumulative event rates of recurrent vascular events. A 2-sided P<0.05
was considered significant. All data were analyzed using SPSS statis-
tical software version 15.0 for Windows (SPSS, Chicago, IL).
Results
In 1158 patients with ischemic stroke, 866 patients were cat-
egorized into groups with small vessel disease, large artery
atherosclerosis, cardioembolic stroke, or other determined
cause according to the Trial of Org 10172 in Acute Stroke
Treatment criteria.12 The remaining 292 patients fulfilled the
diagnostic criteria for ESUS, and TEE was performed for 213
patients in whom follow-up study was performed. Of those
patients, complete therapy data could not be obtained in 6
patients; 23 patients were lost during the follow-up period;
5 patients declined to participate in the study; 2 patients
developed other neurological diseases, including encephali-
tis and chronic subdural hematoma; and thus, final data were
successfully obtained in 177 patients (mean age 64.114.2
years; 127 men; Figure I in online-only Data Supplement).
During the follow-up period of 3.52.7 years, 31 patients had
recurrent vascular events: 24 patients had recurrent ischemic
stroke and 7 had major cardiovascular events including coro-
nary artery disease (n=5), aortic dissection (n=1), and arte-
riosclerosis obliterans (n=1). Eight patients died during the
follow-up. The incidence of recurrent vascular events was
5.0% per person-year.
Clinical Characteristics of Patients
With Recurrent Vascular Events
Baseline characteristics for all patients with and without
recurrent vascular events are summarized in Table1. Previous
history of ischemic stroke was more common in patients with
recurrent vascular events than in those without recurrent vas-
cular events (P=0.012). Hypertension and diabetes mellitus
(DM) were more common in patients with recurrent vascu-
lar events (P=0.021 and P<0.001, respectively). Multiple
infarcts and cortical infarcts on diffusion-weighted imaging
were more frequent in patients with recurrent vascular events
(P=0.046 and P=0.045, respectively). Degrees of deep and
subcortical white matter hyperintensity were higher in
patients with recurrent vascular events (P=0.040). On TEE
examinations, patients with recurrent vascular events had a
significantly higher frequency of large aortic arch plaques
4 mm compared with patients without recurrent vascu-
lar events (P=0.025), whereas no significant differences
were observed in frequencies of PFO, ASA, coexistence of
PFO and ASA, or valvular abnormalities between groups.
Frequency of low, intermediate, and high CAM grades were
71%, 25%, and 4% in patients without recurrent vascular
 Ueno et al Emerging Risk Factors and Prognosis in ESUS 3

Table 1. Baseline Characteristics and Radiological and TEE Findings According to

Classification by Recurrent Ischemic Stroke or Vascular Events
Recurrent Vascular Events
All Absent Present
Variables n=177 n=146, 82% n=31, 18% P Value
Demographics
Age, meanSD 64.114.2 63.014.8 69.39.3 0.092
Male sex, n (%) 127 (72) 101 (69) 26 (84) 0.099
Previous history of stroke, n (%) 18 (10) 11 (8) 7 (23) 0.012
Risk factors, n (%)
Hypertension 117 (66) 91 (62) 26 (84) 0.021
Diabetes mellitus 56 (32) 38 (26) 18 (58) <0.001
Dyslipidemia 103 (58) 86 (59) 17 (55) 0.677
Cigarette smoking, current 54 (31) 45 (31) 9 (29) 0.746
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Coronary artery disease 26 (15) 21 (14) 5 (16) 0.803

NIHSS score on admission, meanSD 3.12.9 3.02.8 3.43.8 0.736
mRS on follow-up, meanSD 1.11.4 1.01.4 1.51.6 0.084
Brain MRI
Number of infarcts, n (%)

Multiple lesions 69 (39) 52 (36) 17 (55) 0.046
Size of infarcts, n (%)

>15 mm 98 (55) 79 (54) 19 (61) 0.465
Location of infarcts, n (%)

Cortical lesions 91 (51) 70 (48) 21 (68) 0.045
White matter abnormality, grade 03

PVH 1.00.9 0.90.9 1.30.9 0.059

DSWMH 0.80.9 0.80.8 1.10.9 0.040
Intracranial stenosis, n (%) 50 (28) 41 (28) 9 (29) 0.915
Chest radiograph
Aortic arch calcification, grade 03 0.90.9 0.80.9 1.30.9 0.007
TEE findings
Embolic sources, n (%)

PFO 102 (58) 88 (60) 14 (45) 0.122

ASA 47 (27) 38 (26) 9 (29) 0.731
PFO with ASA 41 (23) 36 (25) 5 (16) 0.307
Aortic arch plaques 71 (40) 53 (36) 18 (58) 0.025
Valvular abnormality, n (%)
Mitral annular calcification 12 (7) 9 (6) 3 (10) 0.754

Mitral regurgitation 0.150

None 43 (24) 39 (27) 4 (13)

Trivial to mild 104 (59) 85 (58) 19 (61)

Moderate to severe 30 (17) 22 (15) 8 (26)
Aortic valvular calcification 23 (13) 17 (12) 6 (19) 0.246
Aortic regurgitation
 0.212

None 132 (75) 112 (77) 20 (65)
(Continued)
 4StrokeNovember 2016
Table 1. Continued
All
Variables n=177

Trivial to mild 42 (24)

Moderate to severe 3 (2)
CAM score grade
Low CAM, 02 points 114 (64)
Intermediate CAM, 34 points 53 (30)
High CAM, 57 points 10 (6)
Treatment, n (%)
Antiplatelet agents
 128 (72)
Anticoagulant agents
 51 (29)

Statins 94 (53)
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Chi-square test and the Mann-Whitney U test were used for comparison. ASA indicates atrial septal aneurysm; CAM,
Calcification in the Aortic Arch, Age, Multiple Infarctions; DSWMH, deep and subcortical white matter hyperintensity; MRI,
magnetic resonance imaging; mRS, modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale; PFO, patent
foramen ovale; PVH, periventricular hyperintensity; and TEE, transesophageal echocardiography.
events and 35%, 52%, and 13% in patients with recurrent
vascular events, respectively, which reached statistical sig-
nificance (P<0.001). There were no significant differences
in histories of treatment with antithrombotic therapies or
statins between the groups.
Potential Embolic Sources and
Recurrent Vascular Events
PFO, PFO with ASA, and aortic arch plaques 4 mm were
found in 102, 41, and 71 patients, respectively. The incidences
of recurrent vascular events in patients with PFO, PFO with
ASA, and aortic arch plaques 4 mm were 3.4%, 3.0%, and
7.5% per person-year, respectively.
Factors Associated With Recurrent Vascular Events
In Table2, age, previous history of stroke, hypertension, DM,
aortic arch calcification, and aortic arch plaques were linked
with recurrent vascular events, whereas PFO was negatively
related to recurrent vascular events in a univariate Cox
regression analysis (P<0.05). A higher CAM score grade
was associated with recurrent vascular events (P<0.001).
Age, previous history of stroke, hypertension, DM, aortic
arch calcification, PFO, aortic arch plaques, and CAM score
grade were entered into the multivariate Cox regression
analysis as covariates to explore the predictors for recurrent
vascular events. The CAM score exhibited significant asso-
ciation with recurrent vascular events (hazard ratio, 2.29;
95% confidence interval, 1.114.72; P=0.026). DM was also
predictive of recurrent vascular events (hazard ratio, 2.56;
95% confidence interval, 1.235.32; P=0.012; Table3). The
Kaplan-Meier survival curves showed that cumulative event-
free rates were significantly lower in patients with DM than
in patients without DM (log-rank test, P=0.001) and lower
according to less severe CAM score grade (log-rank test,
P<0.001; Figure).
Recurrent Vascular Events
Absent Present
n=146, 82% n=31, 18% P Value
31 (21) 11 (35)
3 (2) 0 (0)
<0.001
103 (71) 11 (35)
37 (25) 16 (52)
6 (4) 4 (13)
102 (70) 26 (84) 0.113
46 (32) 5 (16) 0.086
80 (55) 14 (45) 0.329
Discussion
In the present study, the longitudinal outcomes of ESUS
patients whose embolic sources were documented by TEE
were investigated, and the factors associated with recurrent
vascular events were explored in a single-center retrospective
study. The major findings of the present study were (1) the
incidence of recurrent vascular events was 5.0% per person-
year, and (2) DM and the CAM score predicted recurrent
vascular events in ESUS. Although patients with large aortic
arch plaques exhibited a high incidence of recurrent vascu-
lar events (7.5% per person-year), no significant association
between large aortic arch plaques and recurrent vascular
events was shown on multivariate Cox proportional hazards
regression analysis.
In cryptogenic stroke, large-scale stroke registries and
studies have demonstrated that underlying paroxysmal
atrial fibrillation was newly diagnosed during follow-up in
30% of patients.1315 Likewise, paroxysmal atrial fibril-
lation was considered latent in ESUS. Stroke recurrence
in ESUS was as high as that in cardioembolic stroke and
was significantly higher than in other ischemic stroke
subtypes.16 In the current study, paroxysmal atrial fibrilla-
tion was detected in some patients, but cardiac monitoring
was not done during the follow-up period in all patients.
However, the potential embolic causes demonstrated on
TEE immediately after stroke onset could be fundamental
factors related to the pathogenesis of ESUS. To date, no
studies have been performed to evaluate the association of
recurrent vascular events with underlying embolic causes
in ESUS. Although the design of this study is retrospective
in nature, the emphasis of the current study is that we were
able to clearly diagnose potential embolic sources using
TEE in ESUS patients, and we first investigated the fac-
tors associated with recurrent vascular events in patients
with ESUS.
 Ueno et al Emerging Risk Factors and Prognosis in ESUS 5

Table 2. Univariate Analysis of Baseline Characteristics and Radiological and TEE

Findings According to Classification by Recurrent Ischemic Stroke or Vascular Events
Univariate Cox Regression
Variables HR 95% CI P Value
Demographics
Age 1.03 1.001.06 0.041
Male sex 2.34 0.906.12 0.082
Previous history of stroke 2.61 1.126.11 0.027
Risk factors
Hypertension 2.75 1.067.17 0.038
Diabetes mellitus 3.24 1.596.62 0.001
Dyslipidemia 1.06 0.522.17 0.871
Cigarette smoking, current 0.79 0.411.95 0.899
Coronary artery disease 1.44 0.553.77 0.456
NIHSS score on admission 1.04 0.931.15 0.510
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mRS score on follow-up 1.23 0.991.53 0.067

Brain MRI
Number of infarcts

Multiple lesions 2.01 0.994.10 0.054
Size of infarcts

>15 mm 1.28 0.622.64 0.506
Location of infarcts

Cortical lesions 1.96 0.924.17 0.081
White matter abnormality, grade 03

PVH 1.40 0.962.05 0.082

DSWMH 1.43 0.982.11 0.067
Intracranial stenosis on MRA 0.74 0.401.92 0.878
Chest radiograph
Aortic arch calcification, grade 03 1.70 1.192.43 0.003
TEE findings
Embolic sources

PFO 0.45 0.220.93 0.030

ASA 1.06 0.492.32 0.876
PFO with ASA 0.56 0.211.46 0.232
Aortic arch plaques 2.20 1.084.49 0.031
Valvular abnormality, n (%)
Mitral annular calcification 2.29 0.687.71 0.179

Mitral regurgitation 1.70 0.982.95 0.059
Aortic valvular calcification 1.95 0.794.78 0.145

Aortic regurgitation 1.33 0.702.52 0.383
Grade of the CAM score 2.67 1.624.35 <0.001
Treatment
Antiplatelet agents 2.37 0.916.20 0.079
Anticoagulant agents 0.40 0.151.03 0.058
Statins 0.77 0.381.56 0.461
ASA indicates atrial septal aneurysm; CAM, Calcification in the Aortic Arch, Age, Multiple Infarctions; CI, confidence
interval; DSWMH, deep and subcortical white matter hyperintensity; HR, hazard ratio; MRA, magnetic resonance
angiography; MRI, magnetic resonance imaging; mRS, modified Rankin scale; NIHSS, National Institute of Health Stroke
Scale; PFO, patent foramen ovale; PVH, periventricular hyperintensity; and TEE, transesophageal echocardiography.
 6StrokeNovember 2016

Table 3. Multivariate Cox Analysis of Baseline linkage between aortic arch plaques and recurrent vascular
Characteristics and Radiological and TEE Findings Predicting events, the significance of aortic arch plaques on TEE for
Recurrent Ischemic Stroke or Vascular Events recurrent vascular events in ESUS should be investigated in
Multivariate Cox Regression large-scale clinical trials.
With regard to treatments for potential embolic sources,
Variables HR 95% CI P Value
there has been insufficient evidence to establish whether oral
Age 1.00 0.961.04 0.919 anticoagulants are superior to antiplatelet agents for second-
Previous history of stroke 2.11 0.835.32 0.115 ary stroke prevention in stroke patients with these underly-
ing embolic causes on TEE, while, in part, oral anticoagulants
Hypertension 1.69 0.614.73 0.314
could reduce the risk of stroke recurrence further than anti-
Diabetes mellitus 2.56 1.235.32 0.012 platelet agents in stroke patients with PFO with ASA and in
Aortic arch calcification on those with aortic arch plaques.4,5,8,17,2729 In the current study,
1.13 0.691.86 0.621
chest radiograph the following therapeutic interventions were applied. Warfarin
PFO 0.58 0.271.22 0.151 (target international normalized ratio, 1.62.6) was used for
patients with coexistence of PFO and ASA and paradoxical
Aortic arch plaques 0.79 0.321.96 0.607
brain embolism, as well as for those with the presence of
CAM score grade 2.29 1.114.72 0.026 PFO with deep venous thrombosis. Antiplatelet agents were
CAM indicates Calcification in the Aortic Arch, Age, Multiple Infarctions; CI, given to patients with PFO alone and aortic arch plaques. This
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confidence interval; HR, hazard ratio; PFO, patent foramen ovale; and TEE, might have affected our data, suggesting that oral anticoagu-
transesophageal echocardiography. lant therapy apparently reduces the risk of recurrent vascular
events. With regard to statin therapy, we recently elucidated
DM is a strong risk factor for stroke and is associated with that treatment with 5 mg rosuvastatin induced aortic arch
stroke recurrence, as well as disability.1720 In particular, DM
predicted stroke recurrence in the settings of lacunar stroke
and large artery atherosclerosis.19,20 Our data first show that
DM could be a risk factor for recurrent vascular events in
ESUS patients with any underlying embolic causes. On the
contrary, we show that the CAM score, based on the degree
of aortic arch calcification on chest radiograph, age, and mul-
tiple brain infarcts, is independently associated with recurrent
vascular events in patients with ESUS. Aortic arch calcifica-
tion could represent systemic atherosclerosis and has been
shown to be related to cardiovascular events, as well as isch-
emic stroke.10,21 Aging is associated with aortic stiffness and
atherosclerosis, as well as with recurrent ischemic stroke.2,22,23
Multiple brain infarcts indicate a high risk of potential embolic
sources.1,24 Thus, it is suggested that the CAM score reflects
systemic atherosclerosis and is also a relevant indicator of a
high risk for embolic stroke. A recent study indicated that a
risk stratification score for ischemic stroke in patients with AF
was associated with an increase in the risk of recurrent stroke
and death in ESUS.25 Current data revealed for the first time
that the CAM score could be a novel risk factor for recurrent
vascular events in patients with ESUS.
Aortic arch plaques 4 mm, especially those with large
plaques with complex morphology, exhibited a higher preva-
lence of recurrent ischemic stroke or death than plaques <4
mm in stroke patients, and large aortic arch plaques have been
shown to be related to cardiovascular events.5,26 In addition,
we previously demonstrated that the CAM score was closely
linked with the complex morphology of aortic arch plaques in
stroke patients.9 In the current study, large aortic arch plaques
4 mm were more frequently found in patients with recurrent Figure. Kaplan-Meier curves of freedom from recurrent vas-
cular events during follow-up. The x axis indicates time in days
vascular events and exhibited a high incidence of recurrent since inclusion in the study. The y axis indicates the proportion
vascular events (7.5% per person-year). However, multivariate of patients surviving free of vascular event or recurrent stroke.
Cox proportional hazards regression analysis did not reveal Cumulative event-free rates were compared based on the pres-
ence of diabetes mellitus (A); and among low-, intermediate-, and
that large aortic plaques predicted recurrent vascular events
high-grade Calcification in the Aortic Arch, Age, Multiple Infarc-
in ESUS. Although our data in a single-center retrospective tions (CAM) scores (B); showing P=0.001 and P<0.001 on the
study did not indicate statistically significant evidence of log-rank test, respectively.
 Ueno et al Emerging Risk Factors and Prognosis in ESUS 7
plaque stabilization together with a 40% reduction of low-
density lipoprotein-cholesterol in stroke patients.30 However,
intensity of statin therapy was not determined, and no efficacy
of statins for the prevention of recurrent vascular events was
shown in the present study. Currently, ongoing clinical trials
aim to compare the efficacy and safety of direct oral antico-
agulant agents with aspirin.31 However, antiplatelet agents and
statins have been recommended for stroke associated with
large aortic arch plaques in the American Heart Association/
American Stroke Association guidelines.32 Thus, in the ESUS
population, TEE is critical for the diagnosis of aortic arch
plaques, and future large-scale studies using TEE to explore
the efficacy of optimal antithrombotic therapy and intensive
statin therapy are warranted.
Some potential limitations of this study must be considered
when interpreting the present results. First, this study was
retrospective. The diagnosis of ESUS was made according to
the data from our registry, which might have influenced the
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accurate diagnosis of ESUS. Second, it was not possible to
obtain detailed information on treatment or daily compliance
with medications from the medical records or by survey ques-
tionnaire. Third, the data from the current study were derived
from a single center, and the number of patients with recur-
rent vascular events was small. Moreover, TEE examinations
were performed in a limited number of patients with ESUS
in consideration of the absence of severe stroke, pneumonia,
congestive heart failure, or severe dementia, and more than a
few patients dropped out during follow-up. Thus, there might
have been selection bias in the final analysis of patients and an
issue regarding the generalizability of the results to the entire
ESUS population.
In conclusion, this is the first study to elucidate the long-
term prognosis for ESUS patients in association with potential
embolic sources clearly detected by TEE. The current study
shows that DM and the CAM score are predictive of recur-
rent vascular events in our ESUS patients. Physicians should
be aware that the patient history, including age and diabetes
mellitus, and evaluation for distribution of infarct lesions on
diffusion-weighted imaging and aortic arch calcification on
chest radiograph are critical to predict future recurrent vascu-
lar events in ESUS.
Sources of Funding
This study was supported, in part, by a Grant-in-Aid (S1311011) for
scientific research for the Foundation of Strategic Research Projects
in Private Universities from the Ministry of Education, Culture,
Sports, Science, and Technology (MEXT) of Japan.
Disclosures
None.
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 Emerging Risk Factors for Recurrent Vascular Events in Patients With Embolic Stroke of
Undetermined Source
Yuji Ueno, Kazuo Yamashiro, Ryota Tanaka, Takuma Kuroki, Kenichiro Hira, Naohide Kurita,
Takao Urabe and Nobutaka Hattori
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