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Elevated plasma YKL-40 levels and ischemic stroke in the general population.

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ORIGINAL ARTICLE
Elevated Plasma YKL-40 Levels and
Ischemic Stroke in the General Population
Alisa D. Kjaergaard, MD,1 Stig E. Bojesen, MD, PhD, DMSc,1,2
Julia S. Johansen, MD, DMSc,3 and Børge G. Nordestgaard, MD, DMSc1,2
Objective: We hypothesized that elevated plasma YKL-40 levels are associated with increased risk of ischemic
cardiovascular disease in the general population. In contrast to C-reactive protein (CRP) produced in the liver in
response to inflammation, YKL-40 is produced by lipid-laden macrophages inside the vessel wall.
Methods: We measured plasma YKL-40 in 8,899 21- to 93-year-old participants of the Copenhagen City Heart Study
1991–1994 examination, and followed them for up to 18 years. Endpoints were ischemic stroke, ischemic
cerebrovascular disease, myocardial infarction, and ischemic heart disease. Hazard ratios were calculated for plasma
YKL-40 levels in 10-year age percentile categories of 34 to 66%, 67 to 90%, and 91 to 100% versus 0 to 33%.
Results: Multifactorially and CRP-adjusted hazard ratios for ischemic stroke were 1.2 (95% confidence interval,
0.9–1.6) for 33 to 66%, 1.8 (1.3–2.4) for 67 to 90%, and 2.3 (1.5–3.3) for 91 to 100% versus the 0 to 33% percentile
category (p-trend < 0.001). Corresponding hazard ratios for ischemic cerebrovascular disease were 1.2 (0.9–1.5), 1.6
(1.2–2.0), and 2.2 (1.6–3.2) (p-trend < 0.001). Hazard ratios for myocardial infarction were not significant, whereas
corresponding hazard ratios for ischemic heart disease were 1.0 (0.8–1.2), 1.2 (1.0–1.5), and 1.3 (1.0–1.6) (p-trend ¼
0.01). Stratifying for CRP or other risk factors gave similar results. A doubling in plasma YKL-40 was associated with
multifactorially and CRP-adjusted increased risk of 20% (95% confidence interval, 11%–30%) for ischemic stroke, 16%
(8%–24%) for ischemic cerebrovascular disease, 3% (-5%–11%) for myocardial infarction, and 7% (1%–12%) for
ischemic heart disease.
Interpretation: In the general population, elevated plasma YKL-40 levels are associated with increased risk of
ischemic stroke and ischemic cerebrovascular disease, independent of plasma CRP levels.
ANN NEUROL 2010;68:672–680
A
therosclerosis is caused by lipoprotein infiltration
into the intima, and is considered to be an inflammatory disease in which the initial process involves infiltration of monocytes into the vessel wall and their subsequent differentiation into lipid-laden macrophages.1
YKL-40, also named chitinase-3-like-1 (CHI3L1) and
human cartilage glycoprotein 39 (HC-gp39), is a novel
inflammatory biomarker secreted by these cells.2,3 The
abbreviation YKL-40 is based on the 1-letter code for the
first 3 N-terminal amino acids: tyrosine (Y), lysine (K),
and leucine (L), and its molecular weight of 40kDa.
YKL-40 is produced by inflammatory cells and cancer
cells, and has a role in inflammation, cell proliferation,
differentiation, protection against apoptosis, angiogenesis,
and tissue remodelling.2
In contrast to C-reactive protein (CRP) that is
produced in the liver by hepatocytes in response to
systemic inflammation represented by cytokine production in inflamed tissues, YKL-40 is produced locally in
inflamed tissues by local lipid-laden macrophages at
the vessel wall. Whether baseline elevated plasma YKL40 levels associate with later development of cardiovascular disease in the general population is presently
unknown.
We tested the hypothesis that elevated plasma YKL40 levels are associated with increased risk of ischemic
stroke, ischemic cerebrovascular disease, myocardial infarction, and ischemic heart disease during up to 18 years
of follow-up. For this purpose, we included 8,899 participants from the Danish general population.
View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.22220
Received Jun 15, 2010, and in revised form Jul 23, 2010. Accepted for publication Aug 6, 2010.
Address correspondence to Dr Nordestgaard, Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75,
DK-2730 Herlev, Denmark. E-mail: brno@heh.regionh.dk
From the 1Department of Clinical Biochemistry, Herlev Hospital; 2Copenhagen City Heart Study, Bispebjerg Hospital; and 3Department of Medicine and
Oncology, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
Additional Supporting Information can be found in the online version of this article.
C 2010 American Neurological Association
672 V
Kjaergaard et al: YKL-40 and Ischemic Stroke
Subjects and Methods
Participants
We used a population-based prospective study of the Danish
general population, the 1991 to 1994 examination of the Copenhagen City Heart Study; this Study was initiated in 1976 to
1978 with follow-up examinations in 1981 to 1983, 1991 to
1994, and 2001 to 2003. Participants aged 20 years were
selected randomly after sex and age stratification into 5-year
groups among residents of Copenhagen. Of the 17,180 subjects
invited, 10,135 participated, and plasma was available for YKL40 determination in 8,899 participants. Roughly 99% were
whites of Danish descent.
The study was approved by Herlev Hospital and a Danish scientific ethical committee (No. 100.2039/91 and 01-144/
01), and conducted according to the Declaration of Helsinki.
Participants gave written informed consent.
Participants were followed using their unique national
Danish Civil Registration number from baseline at the 1991 to
1994 examination until the 9th of May 2009 for ischemic cardiovascular disease diagnosis and death. Follow-up was 100%
complete; that is, we did not lose track of even a single participant. Information on death was obtained from the national
Danish Civil Registration System. Diagnoses of ischemic cardiovascular disease were obtained from the national Danish
Patient Registry and the national Danish Causes of Death
Registry, and were validated as described previously.4–7
Diagnoses of ischemic stroke, ischemic cerebrovascular
disease, myocardial infarction, and ischemic heart disease were
based on World Health Organization, International Classification of Diseases 8th revision (ICD-8) codes 432-434, 432-435,
410, and 410-414 until the end of 1993, and thereafter based
on the 10th revision (ICD-10) codes I63, I63-I64 and G45,
I21-I22, and I20-I25, respectively. For each person with ischemic cerebrovascular disease (ICD-8 432-435 and ICD-10 I63I64 and G45), hospital records were requested. To also include
nonfatal nonhospitalized ischemic stroke patients, the participants were asked at the 4 study examinations whether they had
had a stroke. If a person answered ‘‘yes,’’ further information
was obtained from that person’s general practitioner. An experienced neurologist reviewed all potential cases.8 To distinguish
among infarction, intracerebral hemorrhages, and subarachnoidal hemorrhages, either computed tomography or magnetic resonance imaging (MRI) scan, autopsy, spinal fluid examination,
or surgical description was necessary. If the scan did not visualize an infarction or hemorrhage, but the person had symptoms
that met the criteria of the stroke definition, then the event was
diagnosed as ischemic infarction.9 The diagnosis of stroke was
not applied in cases where a scan revealed signs of prior cerebrovascular disease, but without history of any symptoms. The
diagnostic criteria for diagnosis of ischemic stroke was focal
neurological symptoms lasting >24 hours. Ischemic cerebrovascular disease was determined on the basis of sudden onset of
focal neurological symptoms (ischemic stroke, transient ischemic attack, or amaurosis fugax). Hemorrhagic stroke and subarachnoidal hemorrhage were excluded from the ischemic stroke
November, 2010
and ischemic cerebrovascular disease groups. The diagnosis of
myocardial infarction required the presence of characteristic
chest pain, elevated cardiac enzymes, and/or electrocardiographic changes indicative of myocardial infarction, and was
>99% correct.10 Ischemic heart disease was defined as myocardial infarction and/or characteristic symptoms of angina
pectoris.
YKL-40 Analysis
Plasma levels of YKL-40 were determined in duplicates in sam
ples frozen for 12 to 15 years at 80 C by a commercial 2-site,
sandwich-type enzyme-linked immunosorbent assay (ELISA)
(Quidel Corporation, San Diego, California),11 using streptavidin-coated microplate wells, a biotinylated-Fab monoclonal capture antibody, and an alkaline phosphatase-labeled polyclonal
detection antibody. The recovery of the ELISA was 102%, and
the detection limit was 20lg/l. The intra-assay coefficients of
variations were 5% (at 40lg/l), 4% (at 104lg/l), and 4% (at
155lg/l). The interassay coefficient of variation was <6%.
Covariates
The participants filled out a self-administered questionnaire on
lifestyle, health, and medicine use, which was completed by the
participant and an investigator on the day of attendance. Participants reported on alcohol consumption (grams per week), statin use, immunomodulatory drug use (against asthma, chronic
obstructive pulmonary disease, and arthritis), and smoking habits. We subdivided participants into never and ever smokers
(previous and current smokers). Body mass index was calculated
by measured weight in kilograms divided by measured height
in meters squared. Diabetes mellitus was defined as selfreported disease, current use of insulin or other medication for
treatment of diabetes, and/or a nonfasting plasma glucose
>11mmol/l. Hypertension was defined as use of antihypertensive medication, a systolic blood pressure 140mmHg, and/or
a diastolic blood pressure 90mmHg. Levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were measured with use of standard hospital assays (Boehringer Mannheim, Mannheim, Germany). High-sensitivity CRP
was measured by turbidimetry (Dako, Glostrup, Denmark).
Diagnostic codes for autoimmune diseases are listed in Supplementary Table 1.
Statistical Analysis
We used STATA version 10.1 (Stata Corp, College Station,
TX). Two-sided p < 0.05 was considered significant. Because
YKL-40 levels increase with age, plasma YKL-40 levels were
stratified into categories according to plasma YKL-40 percentiles in 10-year age-groups; the 4 percentile categories were 0 to
33%, 34 to 66%, 67 to 90%, and 91 to 100%.12 The four percentile groups were prespecified, as in a previous examination
of a biomarker in the same study population,13 to evaluate
both tertiles in the lower range and extreme phenotypes in the
upper range. Also, hazard ratios for a doubling of plasma YKL40 on a continuous scale were assessed by calculating hazard
ratios of an increase in 1U of base 2 logarithm of plasma YKL-
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TABLE 1: Characteristics of Participants from the Danish General Population according to Increasing Plasma
YKL-40 Levels
Covariates
p for Trend
Plasma YKL-40 Percentiles
0–33%
34–66%
67–90%
91–100%
Number of participants
2,970
2,917
2,128
884
Age, yr
61 (48–71)
61 (48–71)
61 (48–71)
61 (48–71)
0.08
Women, %
60
58
54
43
<0.0001
Postmenopausal women, %
76
76
78
75
0.72
Diabetes mellitus, %
6.5
7.3
9.6
14.6
<0.0001
Autoimmune disease, %
9.2
10.0
12.1
16.5
<0.0001
Hypertension, %
23.8
26.0
28.1
31.0
<0.0001
Atrial fibrillation, %
9.1
9.8
10.2
12.8
0.004
Statin treatment, %
0.8
1.0
1.1
1.1
0.26
Immunomodulatory drugs, %
11.2
12.2
14.9
15.1
0.0002
Ever smokers, %
73
77
80
84
<0.0001
48 (0–108)
60 (12–132)
84 (24–180)
144 (48–324)
<0.0001
Alcohol consumption, g/wk
25.2 (4.1)
25.6 (4.3)
25.6 (4.4)
25.9 (4.6)
<0.0001
Total cholesterol, mmol/l
6.1 (1.3)
6.3 (1.3)
6.3 (1.3)
6.0 (1.3)
0.72
HDL cholesterol, mmol/l
1.60 (0.48)
1.56 (0.49)
1.57 (0.50)
1.58 (0.58)
0.005
Triglycerides, mmol/l
1.4 (1.0–2.0)
1.6 (1.1–2.3)
1.6 (1.2–2.4)
1.9 (1.2–3.0)
<0.0001
C-reactive protein, mg/l
1.5 (1.2–2.3)
1.7 (1.3–2.8)
2.1 (1.4–4.1)
2.3 (1.4–4.9)
<0.0001
Body mass index, kg/m
2
Values are baseline values collected at the 1991 to 1994 examination of the Copenhagen City Heart Study, or ever diagnosed diabetes mellitus, autoimmune disease, or atrial fibrillation, and expressed as number of participants, frequencies, mean (standard
deviation) for the normally distributed variables (body mass index, total cholesterol, and HDL cholesterol) or medians (interquartile ranges) for the rest of the continuous variables, because triglycerides and C-reactive protein are skewed with a tail toward
higher levels, and neither age nor alcohol consumption are normally distributed. Statistical comparisons between the 4 YKL-40
percentile categories were calculated by Cuzick test for trend (YKL-40 categories were coded 0, 1, 2, and 3 for increasing percentile categories).
HDL ¼ high-density lipoprotein.
40. Plasma YKL-40 was chosen a priori to test the hypothesis
of association with vascular outcomes, and thus we performed
no correction for multiple comparisons.
Cumulative incidences of events were plotted using KaplanMeier curves, and differences across plasma YKL-40 percentile categories were examined using log-rank trend tests. Hazard ratios
and 95% confidence intervals (CIs) were calculated using Cox
regression analysis with age as the time scale and delayed entry at
blood sampling. Hazard ratios were adjusted for the following factors at baseline and with changing covariates during follow-up:
age, sex, postmenopausal status (women only), hypertension, statin use, immunomodulatory drug use, smoking status, alcohol
consumption, body mass index, total cholesterol, HDL cholesterol, triglycerides, CRP, and having ever been diagnosed with diabetes mellitus, autoimmune disease, or atrial fibrillation (only for
ischemic stroke and ischemic cerebrovascular disease); information
on these covariates was >99% complete, and missing data were
included in the statistical analysis as categorical or imputed values
674
(for body mass index, total cholesterol, HDL cholesterol, and triglycerides) without losing participants. However, we did not
impute CRP, and thus we lost 23 participants in the analyses
including CRP. For trend test, increasing plasma YKL-40 categories labeled 0, 1, 2, and 3 were used as a continuous variable in the
Cox regression. Proportionality of hazards over time was assessed
by plotting ln(ln[survival]) versus ln(analysis time). Suspicion
of nonparallel lines was further explored using a test employing
Schoenfeld residuals. No major violations of the proportional hazard assumption were detected. Follow-up began at blood sampling
and ended at event, death or May 9, 2009, whichever came first.
Participants with events prior to blood sampling were excluded
from the specific analysis. When specific events (eg, ischemic
stroke) were considered as outcome, then other events (eg, myocardial infarction or transient ischemic attack) were not considered
in the analysis. Recurrent events were not considered.
In stratified analyses, hazard ratios were adjusted for all
the covariates except the 1 they were stratified for. Covariates
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Kjaergaard et al: YKL-40 and Ischemic Stroke
were categorized into 2 categories for these analyses by sex,
presence/absence (of diabetes mellitus, hypertension, atrial fibrillation, and ever smoking), and above/below median (of age,
alcohol consumption, body mass index, total cholesterol, HDL
cholesterol, triglycerides, and CRP).
Hazard ratios were corrected for regression dilution bias.
Plasma YKL-40 levels from 929 individuals attending both the
1991 to 1994 baseline examination and the 2001 to 2003 follow-up examination of the Copenhagen City Heart Study were
used; because YKL-40 increases with increasing age,12 we used
the individual residuals of the linear regression of base 2 logarithm of plasma YKL-40 as a function of age at time of blood
sampling to calculate a regression dilution ratio of 0.75.
Results
The study included 8,899 individuals (57% women)
aged 21 to 93 years with up to 18 years of follow-up;
615 individuals developed ischemic stroke, 769 developed ischemic cerebrovascular disease, 673 developed
myocardial infarction, and 1,475 developed ischemic
heart disease. Baseline characteristics by YKL-40 percentile categories are given in Table 1. The cutoff levels for
different percentile categories in different age groups are
presented in Supplementary Table 2. For the entire
cohort, the level of plasma YKL-40 was 17lg/l for the
2.5 percentile and 341lg/l for the 97.5 percentile.
For plasma YKL-40 in age-adjusted percentile categories, cumulative incidences of ischemic stroke, ischemic
cerebrovascular disease, myocardial infarction, and ischemic
heart disease increased with increasing percentile categories
(Fig 1; log-rank trend p < 0.0001, p < 0.0001, p ¼ 0.01,
p < 0.0001, respectively). This corresponds to multifactorially and CRP-adjusted hazard ratios for ischemic stroke of
1.2 (95% CI, 0.9–1.6) for 33 to 66%, 1.8 (1.3–2.4) for 67
to 90%, and 2.3 (1.5–3.3) for 91 to 100% versus the 0 to
33% YKL-40 percentile category (Table 2; p-trend <
0.001). Corresponding hazard ratios for ischemic cerebrovascular disease were 1.2 (0.9–1.5), 1.6 (1.2–2.0), and 2.2
(1.6–3.2) (p-trend < 0.001). Hazard ratios for myocardial
infarction were not significant, whereas corresponding hazard ratios for ischemic heart disease were 1.0 (0.8–1.2), 1.2
(1.0–1.5), and 1.3 (1.0–1.6) (p-trend ¼ 0.01).
Stratifying in groups of low and high CRP gave
similar hazard ratios (Fig 2). Risk of ischemic stroke and
ischemic cerebrovascular disease increased similarly for
increasing YKL-40 percentiles, whereas risk of myocardial
infarction did not increase, and risk of ischemic heart
disease only increased modestly in the high-CRP group.
A doubling in plasma YKL-40 was associated with
multifactorially and CRP-adjusted increased risk of 20%
(95% CI, 11%–30%) for ischemic stroke, 16% (8%–
24%) for ischemic cerebrovascular disease, 3% (-5%–
November, 2010
FIGURE 1: Cumulative incidence of ischemic stroke,
ischemic cerebrovascular disease, myocardial infarction, and
ischemic heart disease as a function of age and plasma YKL40 levels. Values are from participants of the Copenhagen
City Heart Study with up to 18 years of follow-up.
11%) for myocardial infarction, and 7% (1%–12%) for
ischemic heart disease (Fig 3). Stratifying these analyses by
cardiovascular risk factors including CRP gave similar
results. Although we cannot completely exclude interaction between a doubling in plasma YKL-40 levels and
covariates such as diabetes, hypertension, body mass index,
total cholesterol, HDL cholesterol, triglycerides, and CRP
on risk of ischemic cerebrovascular disease, myocardial infarction, and/or ischemic heart disease, these potential
interactions were not observed consistently across the 4
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TABLE 2: Risk of Ischemic Cardiovascular Disease in the General Population by Plasma YKL-40 Levels
Endpoint
Plasma
YKL-40
Percentiles
Participantsa
All
Multib Adjusted
Sex- and
Age-Adjusted
With HR
Events (95% CI)
p for
Trend
HR
(95% CI)
p for
Trend
Multib and
CRP-Adjusted
HR
(95% CI)
p for
Trend
Ischemic stroke
0–33%
2,938 174
1.0
1.0
1.0
34–66%
2,871 190
1.2 (0.9–1.6)
1.2 (0.9–1.6)
1.2 (0.9–1.6)
67–90%
2,084 175
1.9 (1.4–2.5) <0.001 1.8 (1.3–2.4) <0.001 1.8 (1.3–2.4) <0.001
91–100%
860
2.5 (1.8–3.6)
2.3 (1.5–3.3)
2.3 (1.5–3.3)
Total
8,753 615
76
Ischemic cerebrovascular disease
0–33%
2,918 226
1.0
1.0
1.0
34–66%
2,857 244
1.2 (0.9–1.5)
1.2 (0.9–1.5)
1.2 (0.9–1.5)
67–90%
2,069 204
1.6 (1.3–2.1) <0.001 1.6 (1.2–2.0) <0.001 1.6 (1.2–2.0) <0.001
91–100%
848
2.4 (1.7–3.3)
2.3 (1.6–3.2)
2.2 (1.6–3.2)
Total
8,692 769
95
Myocardial infarction
0–33%
2,902 213
1.0
1.0
1.0
34–66%
2,820 218
1.1 (0.8–1.4)
1.0 (0.8–1.3)
1.0 (0.8–1.3)
67–90%
2,057 174
1.3 (1.0–2.0) 0.02
1.2 (1.0–1.6) 0.05
1.2 (0.9–1.5) 0.26
91–100%
851
1.4 (1.0–2.0)
1.3 (0.9–2.0)
1.2 (0.8–1.7)
Total
8,630 673
68
Ischemic heart disease
0–33%
2,859 461
1.0
1.0
1.0
34–66%
2,761 465
1.1 (0.9–1.3)
1.0 (0.9–1.2)
1.0 (0.8–1.2)
67–90%
2,007 392
1.5 (1.2–1.8) <0.001 1.3 (1.1–1.6) <0.001 1.2 (1.0–1.5) 0.01
91–100%
823
1.7 (1.3–2.1)
Total
8,450 1,475
157
1.4 (1.1–1.8)
1.3 (1.0–1.6)
a
The number of participants varies slightly among the 4 endpoints and different adjustments due to missing availability of C-reactive protein measurements in 23 participants and exclusion of individuals with the relevant events prior to the commencement of
the study.
b
Multifactorially adjusted for sex, age, postmenopausal status, diabetes mellitus, autoimmune disease, hypertension, atrial fibrillation, statin use, immunomodulatory drug use, smoking, alcohol consumption, body mass index, total cholesterol, high-density lipoprotein cholesterol, and triglycerides.
HR¼hazard ratio, CI¼confidence interval, CRP¼C-reactive protein.
endpoints. Also, if we correct these tests of interaction for
multiple comparisons (Bonferroni p < 0.05/48 ¼ 0.001),
none of these interactions remains statistically significant.
Discussion
In this study of 8,899 individuals from the Danish general population followed for up to 18 years, we showed
that elevated plasma YKL-40 levels are associated with
676
increased risk of ischemic stroke and ischemic cerebrovascular disease, independent of plasma CRP levels. These
are novel observations.
Mechanistically, the increased risk of ischemic
stroke and ischemic cerebrovascular disease may be
explained either by the fact that preclinical disease causes
elevated plasma YKL-40 levels, that elevated plasma
YKL-40 levels cause the diseases, or that a common
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FIGURE 2: Hazard ratios of ischemic stroke, ischemic cerebrovascular disease, myocardial infarction, and ischemic heart
disease by increasing levels of plasma YKL-40, stratified by C-reactive protein levels. Values are from participants of the
Copenhagen City Heart Study with up to 18 years of follow-up. The number of participants varies slightly among participants
at the 4 endpoints due to missing availability of C-reactive protein measurements in 23 participants and exclusion of
individuals with the relevant events prior to the commencement of the study. CI 5 confidence interval.
factor causes both the diseases and elevated plasma YKL40 levels. It seems less likely that preclinical atherosclerosis per se causes both elevated plasma YKL-40 levels and
increased risk of ischemic stroke and ischemic cerebrovascular disease, because myocardial infarction caused by
atherosclerosis was not associated with elevated plasma
YKL-40 levels. This together with the fact that plasma
YKL-40 is a marker of inflammation14 supports the possibility that the underlying inflammation might cause
both elevated plasma YKL-40 levels and ischemic stroke
and ischemic cardiovascular disease. However, we naturally cannot exclude that elevated plasma YKL-40 levels
could directly cause increased risk of ischemic stroke and
ischemic cerebrovascular disease.
November, 2010
A clue to the mechanism could also come from the
fact that whereas ischemic stroke was associated with elevated plasma YKL-40 levels, myocardial infarction was
not. With the exception of common atherosclerosis, a
main pathogenic difference between ischemic stroke and
myocardial infarction is that ischemic stroke is a very
heterogeneous disease often caused by thromboembolism,15 whereas myocardial infarction is almost always
caused by local thrombosis.16 Local thrombosis occurs
when an atherosclerotic lesion in an artery ruptures, activating the clotting cascade, which causes formation of a
thrombus that plugs the artery. In thromboembolism, the
thrombus is detached from the site of thrombosis at a
ruptured atherosclerotic lesion or at valves or chambers
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FIGURE 3: Hazard ratios of ischemic stroke, ischemic cerebrovascular disease, myocardial infarction, and ischemic heart
disease by a doubling in plasma YKL-40 levels. Values are from participants of the Copenhagen City Heart Study with up to 18
years of follow-up. Stratification covariates were categorized into 2 categories by sex, presence/absence (of diabetes mellitus,
hypertension, atrial fibrillation, and smoking), and high/low level (age, alcohol consumption, body mass index, total
cholesterol, high-density lipoprotein cholesterol, triglycerides, and C-reactive protein) and used as such in the adjustment of
hazard ratios. Hazard ratios were adjusted multifactorially for all the covariates listed above except the 1 stratified for. We
imputed all the missing continuous covariates except C-reactive protein levels and excluded participants with missing
categorical covariates and missing C-reactive protein levels from these analyses, thus keeping the number of participants and
events constant throughout the same endpoint. The number of participants varies slightly among the 4 endpoints due to
exclusion of the individuals with events prior to the commencement of the study. CI 5 confidence interval.
of the heart, and is then carried through the bloodstream
until it lodges in a narrowed vessel and blocks the circulation. The role of YKL-40 in atherosclerosis is currently
unknown, but on the basis of the present findings it is
tempting to speculate that YKL-40 could play a role in
the formation of thromboembolisms, rather than affecting development of local thrombosis or atherosclerosis
per se. Another explanation for ischemic stroke being associated and myocardial infarction not being associated with
elevated plasma YKL-40 levels might be that because
plasma YKL-40 levels are elevated in patients with cancer,
YKL-40 could be a marker for participants with cancer,
known or unknown, who in general are more likely to suffer from ischemic stroke than myocardial infarction.
678
Finally, a recent study showed elevated expression of YKL40 in acute brain infarction; the expression appeared more
astrocytic than macrophage based.17 It is therefore also
plausible that YKL-40 could reflect covert vascular disease
of the brain, such as might be identified on MRI with
infarcts and white matter hyperintensities. Such covert
MRI findings in patients without a history of transient ischemic attack or stroke have been associated with an
increased risk of subsequent overt vascular disease of the
brain, namely ischemic stroke.
In contrast to the findings in the present prospective study of the general population, in case-control studies where blood samples were drawn at the time of diagnosis, plasma levels of YKL-40 were elevated in patients
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with acute myocardial infarction compared to healthy
subjects.18,19 This indicates that elevated plasma YKL-40
levels could be caused by acute myocardial infarction,
rather than vice versa. Indeed, plasma YKL-40 is an acute
phase reactant, because its plasma concentration increases
by >25% following an inflammatory stimulus, and it is
therefore plausible that acute inflammation such as an
acute myocardial infarction results in elevated plasma
YKL-40 levels. In contrast, in a study of 4,300 patients
with stable coronary artery disease followed for >2 years,
plasma YKL-40 could not predict myocardial infarction,20 supporting our findings that the association seen
in case-control studies cannot be translated into longterm risk prediction of myocardial infarction in the general population as observed in the present study.
For ischemic heart disease, it is disputed whether
plasma YKL-40 is elevated in patients versus in healthy
controls.18–21 In some of these studies, cases were older
than controls,18,19,21 and because plasma YKL-40 level
increases with increasing age,12 the association observed
previously might be inflated by an association between
increasing age and risk of ischemic heart disease. In the
present study, association between age-adjusted increasing
plasma YKL-40 levels and risk of ischemic heart disease
was if anything minor.
Limitations of this study include that subjects could
only participate in the study if they survived to the time
of recruitment and blood sampling in 1991 to 1994,
thus excluding subjects who died early in the Copenhagen City Heart Study initiated in 1976. Because a fraction of myocardial infarction and ischemic heart disease
are lethal events, we cannot completely exclude that this
survival bias might have reduced our point estimates to
insignificant levels. However, survival bias cannot explain
our positive findings for ischemic stroke and ischemic
cerebrovascular disease. Furthermore, because ischemic
heart disease and myocardial infarction are more frequent
diseases than ischemic stroke and ischemic cerebrovascular disease, but with similar mortality, we would not
expect the true risk of myocardial infarction and ischemic
heart disease by plasma YKL-40 levels to be considerably
higher than the very modest point estimates in the present study. Second, our study was based on samples stored
at 80 C for 12 to 15 years. This might reduce the precision of the plasma YKL-40 measurements compared to
fresh material, but we would expect this to widen the
CIs, and not change the point estimates of the hazard
ratios. Additionally, because we did find an association
with ischemic stroke, and previously have found positive
association with risk of gastrointestinal cancer using the
same YKL-40 measurements in the same individuals,12
we do not believe that YKL-40 measurement in frozen
November, 2010
samples has distorted our analyses to a large degree.
Also, internal controls in our laboratory have demonstrated that plasma YKL-40 is stable for at least 16
years when stored at 80 C. Additionally, although our
validation of ischemic stroke and other endpoints was
thorough, we naturally cannot completely exclude some
misclassification of endpoints in the present study.
Finally, we only studied white subjects, and therefore
our results may not necessarily apply to other ethnic
groups.
In conclusion, in this large prospective study of
subjects from the general population, we found that elevated plasma YKL-40 levels are associated with increased
risk of ischemic stroke and ischemic cerebrovascular disease, independent of plasma CRP levels.
Acknowledgments
The work was supported by the University of Copenhagen (A.D.K.) and by grants from the Chief Physician Johan Boserup and Lise Boserups Foundation;
Toyota-Fonden, Denmark; Research Council at Herlev
Hospital; Danish Heart Foundation (B.G.N.); and Danish
Medical Research Council. Quidel provided the study with
YKL-40 ELISA kits. The University of Copenhagen is
sponsoring partial travel costs to meetings for A.D.K.
We thank N. Dahl Kjersgaard, H. Damm, T. Løve
Hansen, A. Jochumsen, U. Kjærullf-Hansen, A. LundgrenBeck, and D. Nadelmann for excellent technical assistance
and the participants of the Copenhagen City Heart Study
for their willingness to participate.
Potential Conflicts of Interest
Nothing to report.
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