Unrecognized myocardial infarction detected on cardiac magnetic resonance imaging: Association with coronary artery calcium score and cardiovascular risk prediction scores in asymptomatic Asian cohort
Unrecognized myocardial infarction detected on cardiac magnetic resonance imaging: Association with coronary artery calcium score and cardiovascular risk prediction scores in asymptomatic Asian cohort
Min Jae Cha 0 1 2
Sung Mok Kim 0 1 2
Yiseul Kim 0 1 2
Hyun Su Kim 0 1 2
Soo Jin Cho 0 2
Jidong Sung 0 2
Yeon Hyeon Choe 0 1 2
0 Current address: Department of Radiology, Chung-Ang University Hospital, Chung-Ang University College of Medicine , Dongjak-gu, Seoul , Republic of Korea
1 Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine , Gangnam-gu, Seoul , Republic of Korea, 2 Cardiovascular Imaging Center, Heart Vascular and Stroke Institute, Samsung Medical Center , Gangnam-gu, Seoul , Republic of Korea, 3 Center for Health Promotion, Samsung Medical Center , Gangnam-gu, Seoul , Republic of Korea, 4 Division of Cardiology, Department of Medicine, Sungkyunkwan University School of Medicine, Prevention & Rehabilitation Center, Heart Vascular & Stroke Institute, Samsung Medical Center , Seoul , Republic of Korea
2 Editor: Vincenzo Lionetti, Scuola Superiore Sant'Anna , ITALY
Data Availability Statement: All relevant data are
within the paper.
Funding: The authors received no specific funding
for this work.
Competing interests: The authors have declared
that no competing interests exist.
To investigate the association between unrecognized myocardial infarction (UMI) assessed
with cardiac magnetic resonance (CMR) and coronary artery calcium (CAC) and
cardiovascular risk prediction scores in asymptomatic Asian subjects.
Materials and methods
Total 872 asymptomatic subjects without prior cardiovascular event (male:female, 817:55;
age, 53.88 ± 5.91) who underwent both CMR and CAC scoring CT were included. UMI were
accessed and framingham risk score (FRS) and ASCVD (atherosclerotic cardiovascular
disease) risk score by ACC/AHA were calculated.
Late gadolinium enhancement indicating UMI was noted in 23 of 872 subjects (2.64%), but
only three of them showed ECG abnormality (13.04%). Subjects with UMI showed higher
CAC scores, FRS, and ASCVD scores than those without UMI (p < .001, p = .011 and p =
.024, respectively). The prevalence of UMI differed significantly according to the CAC
scores as follows: 1% in CAC = 0 (4/403), 1% in 1
CAC <100 (2/293), 6.1% in 100
< 400 (7/114) and 14.5% in CAC
400 (9/62), respectively (p < .001). Receiver operating
characteristics (ROC) analysis by using CAC score demonstrated an area under the curve
(AUC) of 0.816 (95% confidence interval (CI), 0.780±0.848; p < .0001) for predicting UMI,
which is superior to FRS [AUC, 0.712; 95% CI, 0.671±0.751; p = .009] and ASCVD risk
score [AUC, 0.689; 95% CI, 0.648±0.729; p = .036].
The prevalence of UMI increases with increasing burden of CAC and FRS. CAC score is a
good discriminator for UMI, superior to FRS and ASCVD score, in asymptomatic population.
Introduction of late gadolinium enhancement (LGE) images on cardiac magnetic resonance
(CMR) allows accurate detection of myocardial infarctions (MIs) and other myocardial scars.
With advances of LGE imaging technique, the detection rate of clinically unrecognized MIs
(UMIs) has increased. Earlier studies demonstrated that CMR depicts significantly larger
number of UMIs than has previously been estimated by electrocardiography (ECG).[1±3]
Until now, many researchers have sought for the clinical implication of UMIs detected on
the CMR. Various population studies have been performed in Sweden, Iceland, Scotland and
US to document the prevalence and clinical impact of myocardial scars and UMIs.[1,3±6]
Studies including patients with coronary artery disease (CAD) stated that the presence of UMI
is an independent predictor of major adverse cardiac events (MACE) and cardiac mortality.
] Several studies of elderly population also showed that the presence of UMI entailed a
risk for MACE.[
] In addition, there were studies on the clinical significance of UMI based
on highly selected patients such as those with diabetes mellitus or aortic stenosis.[11±13]
The prevalence of UMIs has been described varying 7.8~25%.[1±3,8,9] However, previous
studies might have inflated the prevalence of UMIs in general population, because they were
performed in elderly populations or included those with known CAD and specific
cardiovascular risk factors. The prevalence of UMIs in asymptomatic general population without prior
cardiovascular event has not been thoroughly studied, especially in Asian population. In
addition, there is little information on the association between UMI depicted on CMR and known
risk stratification methods such as Framingham risk score (FRS) and ASCVD (atherosclerotic
cardiovascular disease) risk score proposed by American College of Cardiology/American
Heart Association (ACC/AHA) and coronary artery calcium (CAC) score. Thus, the aim of
this study is to investigate the association between UMIs and CAC score and cardiovascular
risk prediction scores to identify diagnostic accuracy for UMI prevalence in asymptomatic
The institutional review board of Samsung medical center approved the study
(IRB-2018-05187), and informed consent was waived for the use of patients' medical and imaging data.
We identified 1270 asymptomatic subjects over 40 years of age who underwent both CMR and
coronary artery calcium scoring CT for a health checkup at the Health Promotion Center of
Samsung Medical Center between September 2009 and October 2016. Among them, 465
patients were excluded for the following reasons: 1) history of percutaneous transluminal
coronary angioplasty due to obstructive CAD (n = 5), 2) nonischemic cardiomyopathy such as
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Fig 1. Composition of the study subjects.
hypertrophic cardiomyopathy confirmed on CMR (n = 8), and 3) Interval between acquisition
of CMR and CAC scoring CT longer than a year (n = 452). Through medical chart review, we
confirmed that none of the study population had visited hospital or medicated for chest pain
or chest discomfort in the past. In addition, none had previous history of cardiac operation or
diagnosed with congenital heart disease or other nonischemic cardiomyopathy. Sixty-seven
patients whose CAC score was 0, which was obtained more than a year after CMR acquisition,
were additionally included, under the assumption that their CAC score was 0 at the time of
CMR acquisition. Finally, a total of 872 self-referred asymptomatic subjects (male:female,
817:55; age, 53.88 ± 5.91) were included in our study (Fig 1).
The clinical information and laboratory results were obtained from chart review.
Cardiovascular risk scores were calculated in 519 of 872 subjects, as full medication history of 353
subjects was not available due to insufficient medical records. Ten-year risk of cardiovascular
event was calculated based on FRS, and subjects were classified into low risk (10% or less risk
at 10 years), intermediate risk (10±20%) and high risk (20% or more).[
] ASCVD risk scores
were also assessed based on the ACC/AHA guideline published on 2013.[
] ECG abnormality
was defined as presence of pathologic Q-wave, ischemic ST-segment or T-wave changes, or
complete left bundle branch block (LBBB) on a resting 12-lead ECG obtained on the day of
All subjects underwent CMR in a 1.5-T scanner (Magnetom Avanto, Syngo MR B17 version;
Siemens Medical Solutions, Erlangen, Germany) with a 32-channel phased-array receiver coil.
CMR scans consisted of localizing images (axial, coronal, and sagittal), cine scans (2-chamber
view, 3-chamber view, 4-chamber view, and short-axis view), and LGE scans. LGE imaging
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was acquired using a phase-sensitive inversion recovery (PSIR) technique 15 min after
injection of 0.2 mmol/kg gadobutrol (Gadovist; Bayer Healthcare, Berlin, Germany) at an injection
rate of 3 ml/sec, followed by a 30-ml saline flush. Contiguous short-axis image acquisition of
10±12 slices at 6 mm thickness and a 4-mm interslice gap was used. Inversion delay times were
typically 280±360 msec. Detailed CMR protocol has been described elsewhere.[
CAC score acquisition
All CT scans were performed using a 64-slice scanner system (Lightspeed, GE Healthcare,
Waukesha, WI, USA) and a 40-slice scanner system (Brilliance 40, Philips, Hamburg,
Germany). Tube voltage was 120 kVp and tube current was 125 mA. Step and shoot mode was
used with prospectively ECG triggered to 75% of the R-R interval in subjects with a heart rate
(HR) at most 65 beats per minute (bpm) and 45% of the R-R interval in subjects with a HR
faster than 65 bpm. Imaging was reconstructed into a 2.5-mm slice thickness with a 512 X 512
matrix and a 25-cm field-of-view. No premedication with nitrate or beta-blocker was
administered. CAC score analysis was performed using dedicated software (Terarecon Aquarius
Workstation, San Mateo, California, USA) and CAC scores were subsequently calculated
using the methods described by Agatston et al..[
] Then, subjects were classified into four
groups according to CAC score as follows: 0, 1±99, 100±399 and 400.[
CMR data were analyzed using a commercially available dedicated software tool (Dynamic
Signal Analysis, Argus, Siemens Medical Solutions) by an experienced MR technician (Y.K.,
with 6 year experience), who was blinded to the clinical information of the participants.
Parameters such as left ventricular (LV) end-diastolic volume, LV end-systolic volume, LV
ejection fraction, LV mass, and stroke volume (SV) were obtained by drawing LV contours at
the end of diastole and systole. Papillary muscles and trabeculation were included in the LV
cavity for volume and mass measurements. Cardiac output was calculated as the product of SV
and HR. The LV mass index (LVMI) and cardiac index were calculated as LV mass and cardiac
output divided by the body surface area, respectively.
Analysis of the LGE sequences was performed by use of picture archiving and
communication system (Centricity 3.0; GE Healthcare, Mt. Prospect, IL, USA). The presence of LGE was
interpreted by the consensus of two observers (M.J.C., with 4-year experience and S.M.K.,
with 7-year experience in cardiovascular imaging) blinded to patient history. High
signalintensity lesion with subendocardial or transmural involvement, located in territories
consistent of specific epicardial coronary arteries, on LGE images were considered to represent
UMIs (Fig 2). The location and extent of UMI was evaluated using the American Heart
Association (AHA) 17 segment model.
Continuous data were expressed as mean and standard deviation, and all categorical data were
presented as proportions. Student's t-test and one-way ANOVA were used to test for
differences in normally distributed continuous variables, and the Wilcoxon rank sum test,
Mannwhitney test, and Kruskal-Wallis test were used for comparison involving variables that were
not normally distributed. The Jonckheere-Terpstra test was used to report the association of
variables according to the groups classified with CAC score and FRS. Categorical variables
were compared with the chi-square test or Fisher's exact test, as appropriate. A two-tailed p
values less than 0.05 were considered statistically significant. The confidence level and cutoff
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Fig 2. Unrecognized myocardial infarction as detected with cardiac magnetic resonance imaging in a 58-year-old
male. Late gadolinium enhancement image demonstrated subendocardial hyperenhancement at anterior wall of left
ventricular base level. His coronary artery calcium score was 462.
value of each variable was analyzed with use of the receiver operating characteristic (ROC)
method. Statistical analysis was executed using SAS version 9.4 (SAS Institute, Cary, NC).
Among 872 subjects, LGE indicating UMI was noted in 23 patients (2.64%). In terms of elderly
population, the prevalence of UMI was elevated to 3.74% (4/107) for subjects older than 60
and 4.55% (2/44) for those older than 65. Only three of 23 patients showed ECG abnormality
(Q-wave, ischemic ST-segment changes or complete LBBB), with a sensitivity of 13.04% for
detecting MI. Among 23 patients with UMI, 15 showed focal MI involving only one segment,
whereas remaining eight patients showed MI involving multiple segments, ranging from three
to 10 segments. In terms of three patients who showed ECG abnormality, the infarcted
myocardial territory was significantly larger than those without ECG abnormality (8.67 ± 1.53
segments vs. 1.95 ± 1.88 segments; p = .006), and all three of them showed transmural extent of
infarction of over 75%. The coronary territories of UMIs were as follows: 11 patients with left
anterior descending artery (LAD)-territory, two patients with left circumflex coronary artery
(LCX)-territory, five patients with right coronary artery (RCA)-territory, one patient with
LAD+LCX-territories, two patients with LAD+RCA-territories, and two patients with LAD
In 12 of 872 (1.38%), atypical pattern LGE, not typical for MI, showing nonspecific
epicardial or mid-wall LGE without relation to a coronary territory on CMR was noted (Fig 3). The
most common feature of these atypical LGE was linear mid-wall enhancement (9 of 12
subjects), followed by focal myocardial enhancement at RV insertion point (4 of 12 subjects).
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Fig 3. Atypical pattern of late gadolinium enhancement detected with cardiac magnetic resonance imaging in a
50-year-old male. Linear mid-myocardial wall enhancement is noted in mid to basal interventricular septum. His
coronary artery calcium score was 0.
In terms of CMR parameters such as LV function, reduced LVEF below 55%
(asymptomatic mild LV dysfunction) was observed in 20 of 872 (2.3%) subjects, with a range from 45.7%
to 54.8%. However, only one of them had UMI and none of them showed atypical LGE.
Comparison of cohort characteristics and risk stratification scores
according to the presence of UMI
The baseline characteristics and CMR parameters of the patients with and without UMI are
summarized in Table 1. Subjects with UMI showed higher serum NT-proBNP and glucose
level than those without UMI (p < .001 and p = .030, respectively). In addition, CAC score was
significantly higher in subjects with UMI (p < .001). In terms of LV parameters on CMR,
however, LV function and myocardial mass did not differ significantly between the two groups.
In the comparison between one-segment (n = 15) and multi-segment UMI (n = 8), CAC
score was significantly higher in multi-segment UMI group [median (interquartile), 1043.5
(447.5±2346.3) vs. 154 (10±387), p = .011]. However, there was no significant difference in
CMR parameters such as LV function and LV mass. When we compared transmural (n = 4)
and non-transmural (n = 19) infractions among UMI patients, LVEF was significantly reduced
in those with transmural UMI [median (interquartile), 59.9 (55.7±62.1) vs. 67.8(61.3±70.7),
p = .032]. When we compared CAC scores of each coronary artery according to the presence
or absence of UMI, significant difference in LAD calcium score was noted between those with
(n = 16) and without (n = 7) LAD-territorial infarction. LAD calcium score of patients with
LAD-territorial infarction was significantly higher than those without it [median
(interquartile), 160.5 (25.5±515.5) vs. 7.0 (0.0±18.0), p = .034]. In terms of those with UMI of LCX and
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RCA territories, however, no significant difference in CAC scores of LCX [median
(interquartile), 110 (14.5±544.0) vs. 12.5 (0.0±112.3), p = .290] and RCA [median (interquartile), 201.0
(51.5±268.5) vs. 61.0 (2.3±385.5), p = .507] was observed.
Comparison between those with atypical pattern LGE (n = 12) and without LGE (n = 838)
demonstrated no significant difference in baseline characteristics and CMR parameters
between two groups.
Among 519 subjects whose risk stratification scores were available, UMI was noted in 12
patients (2.3%). In the comparison between those with and without UMI, subjects with UMI
showed higher prevalence of diabetes mellitus (p = .041) and higher risk assessment scores
such as FRS and ASCVD score compared with those without UMI (p = .011 and p = .024,
respectively). In addition, CAC score was also significantly higher in subjects with UMI (p <
.001) (Table 2).
Comparison of UMI prevalence and cohort characteristics according to
NT-proBNP, plasma glucose level, and LVMI on CMR with increasing amount of coronary
artery calcium among CAC groups (p < .001, p = .022, p = .009, p < .001, and p < .001,
respectively). On the other hand, serum cholesterol level and LDL showed negative correlation with
significant difference (all p = .001), according to CAC groups, which is presumed to be a result
of increasing use of statins in those with heavy coronary calcium (p = .003).
Note. Median (interquartile range), CAC = coronary artery calcium, UMI = unrecognized myocardial infarction, BMI = body mass index, LVEF = left ventricular
ejection fraction, LVSV = left ventricular stroke volume, LVMI = left ventricular mass index
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Comparison of UMI prevalence and cohort characteristics according to
Diagnostic accuracy for predicting UMI in asymptomatic subjects
The ROC curve by using CAC score in 872 subjects demonstrated an area under the ROC
curve (AUC) of 0.795 (95% confidence interval (CI), 0.766±0.821; p < .0001) with a cutoff
value of 79, showing a sensitivity of 78.3% and a specificity of 78.5%. For 519 patients, the
AUCs for CAC score, FRS and ASCVD risk score were 0.816 [95% CI, 0.780±0.848; p < .001]
with a cutoff value of 79, 0.712 [95% CI, 0.671±0.751; p = .009] with a cutoff value of 15.8 and
0.689 [95% CI, 0.648±0.729; p = .036] with a cutoff value of 17.2, respectively.
As CAC scoring CT is generally indicated for intermediate-risk subjects according to the
2010 guideline for the appropriate use of cardiac CT , we additionally performed subgroup
ROC analysis for 204 patients of intermediate-risk group. The rate of UMI in
intermediaterisk group was 2.9% (6 of 204). The AUCs of FRS and ASCVD risk score were as low as 0.552
Note. Median (interquartile range), UMI = unrecognized myocardial infarction, BMI = body mass index, CVD = cardiovascular disease, ASCVD = atherosclerotic
cardiovascular disease, CAC = coronary artery calcium, LVEF = left ventricular ejection fraction, LVSV = left ventricular stroke volume, LVMI = left ventricular mass
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(95% CI, 0.481±0.622; p = .723) and 0.526 (95% CI, 0.455±0.596; p = .856) without statistical
significance for predicting UMI. However, the AUC for CAC score was 0.780 (95% CI, 0.717±
0.835; p = .020) with a cutoff value of 77, showing a sensitivity of 83.3% and a specificity of
In this study, we have demonstrated that CAC score is a good discriminator for UMI, superior
to FRS and ASCVD risk scores, in asymptomatic Asian cohort. Furthermore, our ROC
analyses suggest a potential role of CAC score as a predictor of UMI in those with intermediate risk
of cardiovascular disease, as indicated in the 2010 guideline by ACCF/SCCT/ACR/AHA/ASE/
ASNC/NASCI/SCAI/SCMR. We also demonstrated that the prevalence of UMI is
significantly higher with increasing burden of coronary artery calcium and increasing risk of 10-year
cardiovascular disease based on FRS in subgroup analyses. These results are consistent with
previous reports which have suggested that CAC score is a sensitive, accurate, and
reproducible parameter, reflecting coronary atherosclerosis.[
] In addition, prior study has shown
that CAC score predicts cardiac death, nonfatal MI, and the need for coronary
revascularization in asymptomatic patients. It may be hard to generalize our result due to relatively low
event rate of UMI, however, our study has clinical implication that it shows a potential of CAC
score as a predictor of UMI in asymptomatic general population as well as for those indicated
according to the guideline.
One of unique result of our study is that subjects with UMI did not show any functional
degradation, such as LVEF and cardiac index, compared with those without UMI. Many of prior
studies, on the contrary, have stated a prognostic implication of UMI, demonstrating impaired LV
function and increased myocardial mass in those with UMI compared with normal groups.
] One of the reasons for this conflicting result can be a younger age of our study
population (53.88 ± 5.91), compared with prior studies with a mean age of 69 years and 65.4 years,
] J.R.Weir-McCall et al. had reported that UMIs had significant functional
implications in relatively young age group with a mean age of 54 years, however, the incidence of UMI
was extremely low (0.2%; 3/1529), making it hard to generalize the results. Our study may
explain the reason why these MIs were remained ªsilentº and ªunrecognizedº. Considering 15 of
23 UMIs were focal infarction involving only one segment and 19 of 23 UMIs were
non-tranmural (subendocardial) infarctions, the lesions might not be critical enough to result in chest pain
and might be easily compensated without cardiac dysfunction, unlike recognized MI. Though we
did not deal with MACE and cardiac mortality as a final outcome due to relatively short follow up
period, UMI may not always be a decisive factor for poor prognosis. Long-term study based on
multi-ethnic group with large population is required to determine the real clinical consequences
of UMI, in terms of cardiac function and prognosis.
CMR is a valuable modality in the detection of UMI. Prior studies have shown that CMR
can detect UMIs with a higher sensitivity, specificity and reproducibility than ECG.[24,25]
Indeed, only three of 23 subjects with UMI in our study demonstrated abnormal ECG, such as
pathologic Q wave or ST-segment changes. Hence, we cannot regard ECG as a stand-alone
screening modality for MI and CMR should be strongly recommended for those with high risk
In this study, the prevalence of UMIs in asymptomatic Asian subjects was 2.3%. This is far
lower rate of UMI compared with Sweden and Iceland cohorts, described a prevalence of 30%
and 16.8%, respectively.[
] Main reason of this discrepancy is that these prior studies had
focused on an older age group with a mean age of 75 years compared with the current study of
54.5 years, showing a strong association between UMI and age. Meanwhile, US cohort and
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Scottish cohort, composed of middle-aged population with an intermediate or low
cardiovascular risk, demonstrated very low rate of UMIs of 0.2%, suggesting that high risk group of
cardiovascular disease is strongly associated with UMIs.[
] Our study population is consisted of
asymptomatic self-referred Asians without prior hospital-reported ischemic heart disease. We
did not set any special requirements such as age or cardiovascular risk factors (i.e.,
hypertension, diabetes mellitus, or hyperlipidemia) in the study enrollment. Although it is hard to
generalize our findings in all of the other groups, we believe that the prevalence of UMIs of our
cohort might be closer to that of general population.
Atypical LGE, not typical MI, was noted in 12 of 872 patients, and the most common
finding was linear mid-wall enhancement. These atypical LGE is known to be seen in infiltrative
myocardial disease or myocarditis, however, there was no significant difference in baseline
characteristics and CMR parameters between those with atypical LGE and normal group in
our study. Although the exact pathophysiology of atypical myocardial scar is still
unknown, there have been prior reports on the atypical LGE, not MI, on CMR.[
] We think
that it should be an another area of investigation whether these atypical myocardial scars are a
distinct disease entity or just a normal variation of LV myocardium.
There are several limitations in our study. First, our study was limited inherently by its
retrospective design. Second, our study was performed at a single health promotion center of
tertiary referral hospital. All of the subjects in our study were self-referred for a routine health
check-up, who were predominantly male, and therefore, selection bias may limit the
generalizability to other populations. Third, cardiovascular risk scores such as FRS and ASCVD score
were available only in 519 of 872 subjects due to lack of medication history of hypertension.
Fourth, the prevalence of UMI was low, resulting in small sample size and limited power for
analysis. However, we tried to identify the incidence of UMI among asymptomatic Asian
population in this study. Fifth, tiny high signal intensity might be missed if placed in between two
consecutive slices of LGE imaging, which can underestimated the prevalence of UMI.
In conclusion, our study demonstrated that the prevalence of UMI increases with
increasing burden of CAC and increasing risk of 10-year cardiovascular disease on FRS. CAC score is
a good discriminator for UMI, superior to FRS and ASCVD risk scores, in asymptomatic
Asian population, especially for those with intermediate risk of cardiovascular disease, as
indicated in 2010 guideline for cardiac CT. Furthermore, subjects with UMI did not show any LV
functional impairment compared with those without UMI in our study, thus, further study to
figure out the final consequences of UMI in general population, regarding cardiac function
and prognosis, can be a next step.
Conceptualization: Min Jae Cha, Sung Mok Kim, Yeon Hyeon Choe.
Data curation: Min Jae Cha, Sung Mok Kim, Yiseul Kim, Soo Jin Cho, Jidong Sung.
Formal analysis: Sung Mok Kim.
Investigation: Sung Mok Kim, Yiseul Kim, Hyun Su Kim, Soo Jin Cho, Jidong Sung.
Methodology: Min Jae Cha, Sung Mok Kim, Hyun Su Kim.
Supervision: Sung Mok Kim, Yeon Hyeon Choe.
Validation: Sung Mok Kim.
Writing ± original draft: Min Jae Cha, Sung Mok Kim.
Writing ± review & editing: Min Jae Cha, Sung Mok Kim, Yeon Hyeon Choe.
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