Cardiovascular Biomarkers during Acute Periods of Ischemic Stroke due to Non-Valvular Atrial Fibrillation

Abstract

Background A subanalysis study of the ENGAGE AF-TIMI 48 trial showed that cardiac troponin I, N-terminal proB-type natriuretic peptide, and D-dimer, were powerful predictors of cerebrovascular adverse events. We aimed to evaluate D-dimer and cardiac troponin I levels during the acute period of ischemic stroke in anticoagulation-naïve patients with non-valvular atrial fibrillation (NVAF) and also studied the association between these biomarkers and stroke severity. Methods Consecutive anticoagulation-naïve patients with acute ischemic stroke due to NVAF were enrolled within two days after each stroke event, and all patients were stratified into either moderate-to-severe or mild neurologic deficit groups using the National Institutes of Health Stroke Scale (NIHSS) at admission. Results A total of 98 patients were enrolled in this study. The median value for the D-dimer was above the upper limit of the normal reference range, but the troponin I value was within the normal range for all patients. After adjusting for CHA2DS2-VASc risk factors, the log-transformed values for D-dimer were positively correlated with an increasing NIHSS score (r=0.233; P=0.051). In the multivariate logistic analysis, the log-transformed D-dimer was positively associated with more severe strokes (odds ratio, 30.1; 95% confidence interval [CI], 1.9-486.2 and 29.7; 95% CI, 2.0-430.8 in the upper two quartiles respectively). The log-transformed values for troponin I did not correlate with the NIHSS score. Conclusion D-dimer levels were higher and an independent risk factor for severe stroke in anticoagulation-naïve patients with NVAF related stroke. In contrast, troponin I levels were normal and were not associated with stroke severity.

Full text

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Cardiovascular Biomarkers during Acute Periods of Ischemic
Stroke due to Non-Valvular Atrial Fibrillation
Taewon Kim, MD, PhD1, Jaseong Koo, MD, PhD2, In-Uk Song, MD, PhD1, Si-Ryung Han, MD, PhD3, Sung-Woo Chung, MD, PhD1,
Seong-hoon Kim, MD4, Kwang-Soo Lee, MD, PhD2
1Department of Neurology, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon; 2Department of Neurology, Seoul St. Mar y’s
Hospit al, College of Medicine, The Catholic University of Korea, Seoul; 3Department of Neurology, Vincent’s Hospital, College of Medicine, The Catholic Universit y of
Korea, Suwon; 4Department of Neurology, Uijeongbu St. Mar y’s Hospit al, College of Medicine, The Catholic University of Korea, Uijeongbu, Korea
Background: A subanalysis study of the ENGAGE AF-TIMI 48 trial showed that cardiac
troponin I, N-terminal proB-type natriuretic peptide, and D-dimer, were powerful predictors
of cerebrovascular adverse events. We aimed to evaluate D-dimer and cardiac troponin I
levels during the acute period of ischemic stroke in anticoagulation-naïve patients with non-
valvular atrial fibrillation (NVAF) and also studied the association between these biomarkers
and stroke severity.
Methods: Consecutive anticoagulation-naïve patients with acute ischemic stroke due to NVAF
were enrolled within two days after each stroke event, and all patients were stratified into
either moderate-to-severe or mild neurologic deficit groups using the National Institutes of
Health Stroke Scale (NIHSS) at admission.
Results: A total of 98 patients were enrolled in this study. The median value for the D-dimer
was above the upper limit of the normal reference range, but the troponin I value was within
the normal range for all patients. After adjusting for CHA2DS2-VASc risk factors, the log-
transformed values for D-dimer were positively correlated with an increasing NIHSS score
(r=0.233;
P
=0.051). In the multivariate logistic analysis, the log-transformed D-dimer was
positively associated with more severe strokes (odds ratio, 30.1; 95% confidence interval [CI],
1.9-486.2 and 29.7; 95% CI, 2.0-430.8 in the upper two quartiles respectively). The log-
transformed values for troponin I did not correlate with the NIHSS score.
Conclusion: D-dimer levels were higher and an independent risk factor for severe stroke in
anticoagulation-naïve patients with NVAF related stroke. In contrast, troponin I levels were
normal and were not associated with stroke severity.
J Neurocrit Care 2018;11(1):23-31
Key words: Biomarkers; Stroke; Atrial fibrillation
Received December 19, 2017
Revised April 17, 2018
Accepted May 30, 2018
Corresponding Author:
In-Uk Song, MD, PhD
Department of Neurology, Incheon St.
Mary’s Hospital, College of Medicine,
The Catholic University of Korea, 56
Dongsu-ro, Bupyeong-gu, Incheon
21431, Korea
Tel: +82-32-280-5013
Fax: +82-32-280-5244
E-mail: siuy@catholic.ac.kr
J Neurocrit Care 2018;11(1):23-31
https://doi.org/10.18700/jnc.170036
eISSN 2508-1349
대한신경집중치료학회
Original article
Copyright © 2018 The Korean Neurocritical
Care Society
cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-
nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
INTRODUCTION
The most common risk stratification method used to
predict embolic events in non-valvular atrial fibrillation
(NVAF) is the CHA2DS2-VASc risk score, which is based on
congestive heart failure, hypertension, age, diabetes melli-

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tus, stroke, transient ischemic attack or thromboembolism,
vascular disease, and female gender.1 Because this method
was developed based on demographic and epidemiological
data, it lacked the pathophysiologic variables associated
with NVAF thrombogenic mechanisms, such as atrial tissue
damage, hypercoagulable state, and blood stasis.2 There-
fore, various biomarkers resulting from left atrial enlarge-
ment, inflammation, coagulation activity, hemodynamic
stress, myocardial injury, and renal dysfunction have been
included in clinical assessments and have been shown to
be associated with an increased risk of adverse events for
patients with AF.2,3
Recently, several large phase 3 trials and one subanaly-
sis study of the Safety and Effectiveness of Edoxaban (DU-
176b) vs. Standard Practice of Dosing With Warfarin in
Patients With Atrial Fibrillation (ENGAGE AF-TIMI 48) trial
showed that cardiovascular biomarkers, in particular, car-
diac troponin I, N-terminal proB-type natriuretic peptide,
and D-dimer, were powerful predictors of cerebrovascular
adverse events, and even higher predictors of deaths which
were not reflected in CHA2DS2-VASc risk score.4
In this study, we evaluated the troponin I and D-dimer
levels during the acute stage of ischemic stroke in anticoag-
ulation-naïve patients with NVAF to verify the implications
of these biomarkers on cerebrovascular events, as shown in
the above-mentioned subanalysis study. The fact that bio-
markers are dynamic and change with time suggests the
need to evaluate cardiovascular biomarkers just prior to or
immediately after embolic events.
We also studied the association between these biomark-
ers and initial stroke severity. Hypothetically, an increase
in biomarkers associated with higher blood stasis and
hypercoagulability will predict larger thrombus formation
and more severe neurologic deficits. Additionally, if there
is a significant association between these biomarkers, they
could be useful for predicting not only a simple embolic
event, but also stroke severity, which is the most important
prognostic factor for long-term functional outcomes.
METHODS
Patients
This study was approved by the ethics committee of
Seoul St. Mary’s Hospital (No. KC14RISI0138). We used a
prospectively collected stroke registry of all stroke patients
admitted to the Seoul St. Mary’s Hospital Stroke database.
Eligible patients were consecutive patients with acute
ischemic stroke due to NVAF who were anticoagulation-
naïve from September 2010 to September 2013. The char-
acteristics and selection criteria of this study population
were described in our previous study and are summarized
below.2 Patients who met all of the following inclusion
criteria were enrolled: 1) ischemic stroke within 2 days
after stroke onset based on clinical history and neurologi-
cal examination with compatible new lesions on magnetic
resonance (MR) diffusion-weighted images; 2) a medical
history of AF or documentation of AF on continuous elec-
trocardiographic monitoring in an emergency department
or stroke unit and 24-hour Holter monitoring during
admission regardless of AF pattern, such as paroxysmal,
persistent, or permanent episodes; 3) not taking antico-
agulation drugs currently or within the past 3 months
with a normal activated partial thromboplastin time and
prothrombin time international normalized ratio; and (4)
no cardiac valvular disease on echocardiography. Patients
were excluded if they had any of the following: 1) focal ath-
erosclerotic stenosis of the vessels proximal to the ischemic
lesions as a possible cause of artery-to-artery embolism; 2)
any laboratory or clinical findings suggestive of infectious,
inflammatory, vasculitic, demyelinating, or connective tis-
sue diseases; 3) pre-existing significant disability (defined
as a modified Rankin scale ≥2) from any condition; 4) his-
tory of stroke in the past 3 months; or 5) transient, revers-
ible AF caused by hyperthyroidism or perioperative state
(within 2 weeks of surgery).
All patients underwent a detailed clinical evaluation, in-
cluding a neurological examination, laboratory tests, chest
radiography, 12-lead electrocardiography, continuous elec-
trocardiographic monitoring, 24-hour Holter monitoring,
transthoracic and/or transesophageal echocardiography,

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brain magnetic resonance imaging, and contrast-enhanced
MR angiography or computed tomography angiography.
Stroke severity assessment
Stroke severity was assessed at the time of admission us-
ing the National Institutes of Health Stroke Scale (NIHSS;
scores range from 0 to 42, with higher scores indicating
greater deficits).5 Ischemic stroke severity was dichoto-
mized into either mild or moderate-to-severe neurologic
deficit using an NIHSS score cutoff of 10 based on previous
studies.6,7
Biomarker assessment
Blood samples for measuring troponin I and serum D-
dimer levels were obtained immediately after admission to
the emergency department before any intravenous fluids
or medications were administered. Cardiac troponin I was
measured (ethylene-diamine-tetraacetic-acid plasma)
using a commercially available sensitive assay (TnI-Ultra;
Siemens Healthcare Diagnostics, Erlangen, Germany) with
a lower detection limit of 0.006 ng/mL and an established
99th percentile reference limit of 0.04 ng/mL, with a coeffi-
cient of variation of 10% at a concentration of 0.03 ng/mL.8
D-dimer was measured using an immunoturbidimetric
assay (InnovanceTM D-dimer; Sysmex Coagulation Analyzer,
Erlangen, Germany) with an upper reference range limit of
0.5 pg/mL.
Statistical analyses
Statistical analyses were performed using SPSS for Win-
dows version 17.0 (SPSS Inc., Chicago, IL, USA). Pearson’s
χ2 test, an independent sample
t
-test, and Fisher’s exact
test were appropriately used. Because D-dimer and tropo-
nin I value distributions were markedly right- skewed (Fig.
1), data transformations using a natural logarithm were
performed to reduce right skewness, and log-transformed
values were used for further analysis. Correlations between
the log-transformed values for troponin I/D-dimer and
NIHSS score were determined using a partial correlation
coefficient adjusted for CHA2DS2-VASc risk factors.
The log-transformed values for troponin I and D-dimer
were divided by quartile (Q1, Q2, Q3, and Q4), and odds
ratios were calculated for moderate-to-severe neurological
deficits (defined as NIHSS ≥10), using logistic multivariate
regression analysis adjusted for CHA2DS2-VASc risk factors.
The area of the Receiver Operation Characteristic Curve
(ROC) and the cutoff value of the serum D-dimer level for
the severe neurologic deficit (NIHSS ≥10) were also deter-
mined.
RESULTS
Baseline characteristics
A total of 98 consecutive anticoagulation-naïve patients
A B
Figure 1. Box plots for D-dimer (A) and troponin I (B) levels. The horizontal line inside each box indicates the median, the top and bot-
tom of the box indicate the interquartile range, the I bars indicate the 5th and 95th percentiles, and circles indicate outliers.

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with acute infarction due to NVAF were enrolled in this
subanalysis of the ENGAGE-AF TIMI 48 trial (Fig. 2). The
study population included 64 (65.3%) men and the mean
age at baseline examination was 72.2±9.1 years (range,
46-92). Hypertension (n=63, 64.3%) was the most fre-
quent vascular risk factor, followed by smoking (n=37,
37.8%), diabetes mellitus (n=25, 25.5%), dyslipidemia
(n=20, 20.4%), ischemic heart disease (n=19, 19.4%),
previous stroke (n=12, 12.2%), and peripheral vascular
disease (n=2, 2%). The median body mass index was
23.8±3.5 kg/m2 (range, 16-36). Table 1 shows the clinical
and demographic characteristics for the mild neurologic
deficit group, moderate-to-severe neurologic deficit group,
and entire study population. Among the total number of
98 ischemic stroke patients, 61 patients were identified
as having a mild neurologic deficit, and 37 patients were
identified as having moderate-to-severe neurologic defi-
cits.
A comparison of the percentages of right hemispheric
lesions between the mild and moderate-to-severe neuro-
logic deficit groups (48.6% vs. 52.5%) showed no signifi-
cant differences. Although the proportion of patients with
posterior circulation infarction (infarction in the vertebral,
basilar, or posterior cerebral artery territories) was larger
in the mild neurologic deficit group than in the moderate-
to-severe neurologic deficit group (21.3% vs. 8.1%), the
difference did not achieve statistical significance (
P
=0.100
by Fisher’s exact test).
Distribution of serum D-dimer and troponin I levels
The median values for serum D-dimer levels were 0.94,
0.60, and 2.34 mg/L for all enrolled patients i.e., the mild
neurologic deficit group, and the moderate-to-severe
neurologic deficit group, respectively, and all these median
values were above the upper limit of the normal reference
range (Table 1). Mean D-dimer levels were significantly
higher in the moderate-to-severe neurologic deficit group
compared to the mild group (4.38±7.01 vs. 1.57±2.59;
P
=0.042). The interquartile range (IQR, 0.42-2.72 mg/L)
and box plots are shown in Fig. 1A. The distribution of se-
rum D-dimer levels was markedly right skewed as shown in
Fig. 1B.
The median values for troponin I levels were 0.026,
0.017, and 0.05 pg/mL, respectively, for all study subjects
and subgroups i.e., the mild neurologic deficit group, and
the moderate-to-severe neurologic deficit group, respec-
tively. Although the median values of troponin I among
all enrolled patients and the mild neurologic deficit group
were within the normal reference range, this value was
above the upper limit for the normal reference range (0.04
Figure 2. Flow diagram for recruitment. AF, atrial fibrillation; NVAF, non-valvular atrial fibrillation.

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mg/L) in the moderate-to-severe neurologic deficit group
(Table 1).8 Mean troponin I values were not significantly
different between the mild and moderate-to-severe neuro-
logic deficit groups. The IQR of troponin I was 0.007-0.100
pg/mL. The distribution of troponin I levels also showed
severe right skewness, as seen in Fig. 1B.
Correlation between biomarkers and stroke severity
The partial correlation coefficient analysis adjusted for
CHA2DS2-VASc risk factors showed the log-transformed
values of D-dimer were positively correlated with increas-
ing NIHSS score (r=0.233;
P
=0.051) (Fig. 3A). The log-
transformed values for troponin I did not correlate with the
Table 1. Demographic and clinical characteristics of mild neurologic deficit (NIHSS <10) versus moderate to severe (defined as NIHSS
≥10) groups in patients with ischemic stroke and non-valvular AF
Total (n=98) Mild neurologic decit
group (n=61)
Moderate to severe
neurologic decit group
(n=37)
P value
Age (years) 72 .2± 9.1 70.3±9.5 75.2±7.6 0.009*
Male 64 (65.3) 40 (65.6) 24 (64.9) 1.000
Initial NIHSS score 8.4 ± 7.5 3.6±2.6 16.4±6.0 <0.0 01*
Location of stroke in left hemisphere 48 (49.0) 29 (47.5) 19 ( 51.4) 0.668
Posterior circulation infarction†16 (16.3) 13 (21.3) 3 ( 8 .1) 0.100
Hypertension 63 (6 4.3) 34 (55.7) 29 (78.4) 0.030‡
Diabetes mellitus 25 (25.5) 16 (26.2) 9 (24.3) 1.000
Smoking 37 (37.8) 26 (42.6) 11 ( 2 9.7 ) 0.283
Previous stroke 12 (12.2) 4 (6.6) 8 (21.6) 0.052
Ischemic heart disease 19 (19. 4) 9 (14.8) 10 (27.0) 0.1 88
Peripheral vascular disease 2 (2.0) 1 (1.6) 1 (2.7) 1.000
CHA2DS2-VASc scores 3. 0±1.8 2.6 ±1.7 3.6 ±1. 9 0.010 ‡
Body mass index 23.8±3.5 23.7±3.6 23.8±3.3 0.880
History of taking antiplatelet agents 50 (51.0) 32 (53.3) 18 (48.6) 0.681
Statin use 20 (20.4) 8 (13.6) 12 (3 2. 4) 0.038‡
Diagnosed as AF previously 45 (45.9) 23 (37.7) 22 (59.5) 0.040‡
PT INR 1.1± 0 .1 1.1± 0 .1 1.1±0.1 0.200
Serum D-dimer (mg/L) 0.94 (0.08-35.20) 0.6 (0.08-15.54) 2.34 (0.27-35.20)
25% 0.42 0.36 0 .74
75% 2.72 1.33 4.31
Mean 1.57±2.59 4.38±7. 01 0.042‡
Troponin I (pg/mL) 0.026 (0.006-0.558) 0.017 (0.006-0.371) 0.05 (0.006-0.558)
25% 0.007 0.007 0.014
75% 0.10 0 0.10 0 0 .10 0
Mean 0.059±0.081 0.073±0.100 0.482
MDRD-eGFR (mL/min/1.73 m2)79.1±28.4 76.6±23.5 8 3.1± 34. 9 0.325
Left ventricular ejection fraction (%) 58.0±10.6 58.6±11.2 57.0±9.4 0.548
NIHSS, National Institutes of Health Stroke Scale; AF, atrial brillation; PT INR, prothrombin time international normalized ratio; MDRD-
eGFR, estimated glomerular ltration rate using modication of diet in renal disease.
Values are presented as mean±standard deviation, number (%), or median (range).
Analyses were performed by the independent sample t-test, Fisher’s exact test or χ
2
test.
*P<0.01.
†
Posterior circulation infarction includes infarction in the vertebral, basilar, and posterior cerebral arter y territories.
‡
P<0.05.

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NIHSS score (r=0.062;
P
=0.581) (Fig. 3B).
Biomarkers as a prognostic risk factor for severe neurologic
deficit
When compared to patients with the lowest log-transformed
D-dimer (<0.87) after adjustment for CHA2DS2-VASc risk factors,
patients in the upper two quartiles (Q3 and Q4) had higher odds
for more severe strokes (Table 2). Odds ratios were 30.1 (95%
confidence interval [CI], 1.9-486.2,
P
=0.017) and 29.7 (95% CI,
2.0-430.8,
P
=0.013) when the log-transformed D-dimer ranged
from -0.06 to 1.00 and ≥1.00, respectively. The area of the ROC
for the serum D-dimer was 0.76 (
P
<0.001) and when the cutoff
value of serum D-dimer level for the severe neurologic deficit (NI-
HSS ≥10) was determined as 1.64 mg/L, the sensitivity, and the
specificity were 70% and 78%, respectively.
Compared with the lowest quartile of the log-trans-
formed troponin I value (-4.96) adjusted for CHA2DS2-VASc
risk factors, only patients in the second upper quartile (Q3)
had a significantly higher odds ratio for severe stroke (6.5;
95% CI, 1.3-32.1;
P
=0.021), when assessing the impact
of troponin I levels. The first and third (Q4 and Q1) upper
quartiles did not have significant odds of a more severe
stroke.
DISCUSSION
In this study, we evaluated dynamically changing cardio-
vascular biomarkers during the acute period of ischemic
A B
Figure 3. Scatterplot graph with a regression line between the log-transformed values of D-dimer and NIHSS at admission (A), and
between the log-transformed values of troponin I and NIHSS at admission (B). Analyses were performed using partial correlation coef-
ficient analysis adjusted for CHA2DS2-VASc risk factors.
Table 2. Independent associations of the natural logarithm values of serum D-dimer level (mg/L) and troponin I (pg/mL) with moder-
ate to severe neurologic deficit (NIHSS ≥10)
ln D-dimer ln Troponin I
OR (95% CI) P value OR (95% CI) P value
ln D-dimer <-0.87 (Q1) Reference ln Troponin I <-4.96 (Q1) Reference
-0.87≤ ln D-dimer <-0.06 (Q2) 9.7 (0.7-130.0) 0.086 -4.96≤ ln Troponin I <-3.65 (Q2) 2.6 (0.5-13.8) 0.250
-0.06≤ ln D-dimer <1.00 (Q3) 30.1 (1.9-486.2) 0.017* -3.65≤ ln Troponin I <-2.30 (Q3) 6. 5 (1. 3 -3 2.1) 0. 021*
1.00≤ ln D-dimer (Q4) 29.7 (2.0-430.8) 0. 013* -2.30≤ ln Troponin I (Q4) 0.7 (0.0-16.9) 0.849
NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio; CI, condence interval.
Analyses were performed with multiple logistic regression tests, controlling for CHA
2
DS
2
-VASc risk factors (congestive heart failure,
hypertension, age, diabetes, stroke/TIA, vascular disease, and female sex).
*P<0.05.

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stroke due to NVAF in anticoagulation-naïve patients. The
median D-dimer levels in all enrolled patients were higher
than the normal reference range upper limit. An increas-
ing D-dimer level could be independently correlated with
stroke severity and the upper first and second quartiles of
the D-dimer level were associated with significantly higher
odds ratios for severe ischemic stroke (defined as NIHSS
≥10) compared to the lowest quartile.
In contrast, troponin I showed inconsistent results. Al-
though patients with moderate-to-severe ischemic stroke
had troponin I levels that were higher than the upper limit
of the normal reference range, the mild stroke group had
normal troponin I values and the overall troponin I level
in all enrolled patients was within the normal reference
range. The risk for a severe ischemic stroke was only signifi-
cant in the second upper troponin I quartile, while the first
and third upper quartiles were not significantly associated
with severe stroke.
In addition to CHA2DS2-VASc scores, potential areas
of further risk stratification in NVAF exist, using various
biomarkers and imaging techniques.2,4 Because thrombo-
genesis in NVAF is driven in part by inflammation, atrial
tissue damage, hypercoagulable state, and blood stasis, it
is reasonable to hypothesize that there may exist markers
for thrombogenic conditions, possibly prior to the onset of
severe stroke. D-dimer is a byproduct of the degradation
of fibrin and reflects thrombin and fibrin turnover. With
regard to thrombogenesis in patients with AF, the D-dimer
level is one of the surrogate markers for the hypercoagu-
lable state, which is one component of Virchow’s triad.9,10
Use of the D-dimer level as a reflection of the thrombo-
genic condition and thrombus burden in patients with AF,
has been further supported by findings that high serum D-
dimer levels in AF were reduced by anticoagulation and
cardioversion to sinus rhythm.11,12
Our findings in terms of D-dimer are in line with previ-
ous studies and the recent subanalysis study of the ENGAGE
AF-TIMI 48 trial showing that a higher D-dimer value was
associated with increased risk for adverse cerebrovascular
events.4,13-17 Several researchers have also reported the
cross-sectional association between D-dimer levels and
stroke severity in prior studies.18-20 However, most of these
cross-sectional studies included the patients with ischemic
stroke from heterogeneous etiologies and did not focus
only on the cardioembolic stroke. In addition, while those
studies did not measure the troponin I levels, our study
measured troponin I levels, as well as D-dimer levels simul-
taneously, so that it could provide support for the validity
of these biomarkers in predicting adverse embolic events,
as shown in the recent subanalysis study of the ENGAGE
AF-TIMI 48 trial.4 The anticoagulation-naïve status of the
entire study population was also an advantage over other
studies, since anticoagulation reduces biomarker levels,11
but this also led to a small number of enrolled patients, be-
cause anticoagulation-naïve acute ischemic stroke patients
with previously diagnosed AF or newly diagnosed AF were
less common than expected.
With regard to troponin I, the subanalysis study of the
ENGAGE AF-TIMI 48 trial showed a consistently significant
association with the incidence of embolic events.4 How-
ever, the cross-sectional values in an acute period of stroke
in this study were not higher than the normal upper limit
in most patients, and did not show a significant association
with stroke severity in contrast to the D-dimer level. For
the acute period of the ischemic stroke, D-dimer seemed
to be more significantly associated with NVAF-related
ischemic stroke compared to troponin I. Perhaps it could
be one of the plausible explanations for this discrepancy
that D-dimer is the direct byproduct of fibrin, reflecting
the thrombus burden itself; therefore, it has more advan-
tages than troponin I in evaluating the relevant aspects of
thrombus burden, such as stroke severity, while troponin
I is just a cardiac and skeletal muscle protein. We believe
that it is reasonable to hypothesize that these biomarkers
could be used to predict the future cardiovascular adverse
event prospectively.
Cardioembolic infarction is particularly known to be as-
sociated with more severe stroke morbidity and mortality
compared to other stroke etiologies, such as large artery
atherosclerosis. For these reasons, evaluating the risk fac-
tors for more severe ischemic stroke in AF can potentially
help prevent long-term poor functional individual out-

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comes, as well as reduce medical expenses and the burden
of long-term care for poor functional patients. When we
consider individualized treatment for the prevention of
ischemic stroke in patients with AF and high D-dimer
levels, it is possible that the treatment plan could be op-
timized in relation to D-dimer levels. However, one study
showed that, while D-dimer levels were higher in patients
with severe stroke after adjusting for confounding factors,
this was not statistically significant.21 Further large studies
are necessary to address the exact relationship between D-
dimer levels and stroke severity.
CONCLUSION
D-dimer levels were higher in anticoagulation-naïve
patients with acute ischemic stroke due to NVAF and an
increased D-dimer level was significantly associated with
more severe initial neurologic deficits compared to lower
D-dimer levels. In contrast, troponin I was not consistently
associated with stroke severity.
Conflicts of Interest
The authors have no financial conflicts of interest.
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