Plasma Adiponectin Levels and Five-Year Survival After
First-Ever Ischemic Stroke
Stamatis P. Efstathiou, MD; Dimitrios I. Tsioulos, MD; Aphrodite G. Tsiakou, MD;
Yannis E. Gratsias, MSc, BSc; Angelos V. Pefanis, MD; Theodore D. Mountokalakis, MD
Downloaded from http://stroke.ahajournals.org/ by guest on June 15, 2017
Background and Purpose—This study aimed to investigate the association between plasma adiponectin levels and 5-year
survival after first-ever ischemic stroke.
Methods—Plasma adiponectin measured within 24 hours after first-ever ischemic stroke was related to 5-year outcome.
The Kaplan–Meier technique was applied in survival analysis, and the Cox proportional hazards model was used to
evaluate the relationship between risk factors and prognosis.
Results—The probabilities of death were 92.8%, 52.5%, and 10.5% (P⬍0.001) for patients stratified according to tertiles
of adiponectin (⬍4 ␮g/mL, 4 to 7 ␮g/mL, and ⬎7 ␮g/mL, respectively). The relative risk of death was 8.1 (95% CI,
3.1, 24.5; P⬍0.001) for individuals with adiponectin levels in the lowest tertile compared with the upper tertile.
Adiponectin ⬍4 ␮g/mL (hazard ratio [HR], 5.2; 95% CI, 2.1, 18.4; P⬍0.001), score ⬎15 in the National Institutes of
Health Stroke Scale (HR, 3.6; 95% CI, 1.7, 15.9; P⬍0.001), and coronary heart disease (HR, 2.9; 95% CI, 1.5, 12.3;
P⬍0.001) were independently associated with mortality.
Conclusions—Low plasma adiponectin is related to an increased risk of 5-year mortality after first-ever ischemic stroke,
independently of other adverse predictors. (Stroke. 2005;36:1915-1920.)
Key Words: prognosis 䡲 stroke, ischemic 䡲 survival
A
diponectin (ADPN) is a recently discovered adipocytokine, structurally homologous with collagen VIII
and X as well as with complement factor C1q.1 It is
predominantly secreted by adipocytes and accounts for
⬇0.05% of total serum proteins.1 This novel molecule is
found in higher levels among women than men1,2 and has
been implicated in the development of atherosclerotic
cardiovascular (CV) disease.1,2
The levels of the ADPN are reduced in patients with
obesity,3–7 insulin resistance,6 type 2 diabetes,6,8 hypertension,9 –11 and coronary artery disease.12–14 Moreover, low
plasma ADPN concentrations have been associated with
greater risk of type 2 diabetes,15 of myocardial infarction in
men,16 as well as of CV events in patients with end-stage
renal disease.17 In addition, data from animal and human
studies suggest that this adipocytokine has insulin-sensitizing,
antiatherogenic, and antiinflammatory properties.1,2
Inflammatory processes play a fundamental role in atherosclerotic cerebrovascular disease and stroke, which is the
second leading cause of death worldwide and a major cause
of long-term disability.18 Only scant information exists so far
on the relationship between ADPN and future stroke,19
whereas data on the prognostic significance of this protein in
patients who already had a stroke are lacking. The aim of the
See Editorial Comment, pg 1919
present study was to investigate the association between
ADPN levels and 5-year survival after first-ever ischemic
stroke.
Materials and Methods
Baseline Assessment and Follow-Up
All subjects admitted between May 1998 and December 1999 with a
presumable diagnosis of first-ever ischemic stroke were prospectively evaluated for inclusion in the study. Informed consent was
obtained from all subjects or their legal representatives, and the study
protocol was approved by our institutional committee. Cerebral
infarction was defined as a focal neurological deficit of sudden onset
that persisted for ⬎24 hours in surviving patients, documented by
brain computed tomography (CT) performed within the first 72
hours. Excluded were patients with concurrent renal or hepatic
insufficiency, malignancy and recent infection, surgery, or major
trauma. Initial stroke severity was assessed by the National Institutes
of Health Stroke Scale (NIHSS).20 The largest diameter (A) of the
infarct and its largest perpendicular diameter (B) were measured
with a caliper, whereas the third, vertical diameter (C) was determined by summing the thicknesses of the CT slices in which the
lesion was visible. Infarct volume was calculated according to the
formula 0.5⫻A⫻B⫻C, as described previously.21 CV death included (1) sudden death; (2) death from myocardial infarction,
congestive heart failure, new fatal stroke, systemic or pulmonary
Received February 5, 2005; final revision received April 13, 2005; accepted April 21, 2005.
From the Center for the Prevention of Cardiovascular Disease (S.P.E., Y.E.G., T.D.M.), “Hygieias Melathron,” Athens, Greece; Internal Medicine
Department (D.I.T.), Metropolitan Hospital, Pireus, Greece; and Third University Department of Medicine (A.G.T., A.V.P.), Medical School, Sotiria
General Hospital, Athens, Greece.
Correspondence to Stamatis P. Efstathiou, MD, 19 Fidiou St, Athens 15562, Greece. E-mail [email protected]
© 2005 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
DOI: 10.1161/01.STR.0000177874.29849.f0
1915
1916
Stroke
September 2005
embolism, or peripheral arterial disease; and (3) death as consequence of the qualifying stroke in the absence of other intervening
causes. Participants were prospectively assessed at 3, 6, and 12
months and subsequently every year until death or completion of 5
years after index stroke. Follow-up data were also obtained from
physicians in private practice, hospital records, death certificates,
and autopsy reports.
Measurements
Within 24 hours from stroke onset, fasting plasma samples were
obtained and were stored at ⫺80°C for subsequent assay. The plasma
concentration of ADPN was evaluated by a commercially available
sandwich ELISA (human ADPN ELISA; BioVendor Laboratory
Medicine, Inc.) with a detection limit of 0.2 ␮g/mL and intra-assay
and interassay coefficients of variation 6.4% and 7.3%, respectively.
C-reactive protein (CRP) was also determined by sandwich ELISA
(Abazyme LLC) in a subgroup of patients.
Statistical Analysis
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Analysis was performed using the Statistical Package for the Social
Sciences software (SPSS Inc; release 10.0). The normality of data
distribution was assessed by the KolmogorovorSmirnov test. Comparisons were made by using (1) ␹2 test with Yates’ correction or
Fischer exact test for categorical data, (2) unpaired Student t test or
1-way ANOVA for continuous normally distributed variables, and
(3) the Mann–Whitney test or Kruskal–Wallis test as appropriate for
continuous non-normally distributed variables. The ␬ statistic was
used to assess the level of agreement in the classification of subjects
according to ADPN levels during the acute stroke phase and 1 year
after stroke. The Kaplan–Meier technique was applied to survival
analysis, and the log-rank test was used to compare rates of death.
Significant univariate correlates were assessed in a multivariate Cox
TABLE 1.
proportional hazards model. Ninety-five percent CIs were calculated
for each comparison. All tests of significance were 2-tailed, and a P
value ⬍0.05 was used to indicate statistical significance.
Results
Among 164 patients diagnosed with first-ever ischemic
stroke and fulfilling the inclusion criteria, adequate data on
admission and follow-up were available for 160 individuals
(97.6%) who were finally included in the analysis. Table 1
summarizes baseline demographic data, CV risk factors, and
stroke characteristics of study participants. Patients were
stratified into 3 groups according to intertertile cutoff points
(4 and 7 ␮g/mL) of the distribution of ADPN concentrations
in the total study population.
Although no difference was detected in the percent of
individual risks, there was a marginally significant negative
correlation between ADPN levels and the number of stroke
risk factors a patient had in this study (median 4 [range 2 to
7] factors; r⫽⫺0.32; P⫽0.037), whereas all patients dying
after the first year had ⱖ2 risk factors (median 3 [range 2 to
5] factors). The application of age-adjusted partial correlation
coefficients yielded a marginally significant inverse correlation between ADPN and body mass index (BMI; r⫽⫺0.31;
P⫽0.033), hypertension (r⫽⫺0.28; P⫽0.038), and diabetes
mellitus (r⫽⫺0.25; P⫽0.041), whereas there was no significant association with hypercholesterolemia (r⫽⫺0.13; P⫽
0.177), coronary heart disease (r⫽⫺0.11; P⫽0.196), and
peripheral arterial disease (r⫽⫺0.08; P⫽0.224). NIHSS
Characteristics of the Study Population Consisting of Patients With First-Ever Ischemic Stroke
Characteristics, No. (%)
Overall
(n⫽160)
Adiponectin ⬍4 ␮g/mL
(n⫽42; 26.3%)
Adiponectin 4 –7 ␮g/mL
(n⫽80; 50%)
Adiponectin ⬎7 ␮g/mL
(n⫽38; 23.7%)
70.2⫾11.3
Demographic/anthropometric data
Age, y
70.9⫾14.7
69.5⫾14.1
70.6⫾12.3
88 (55)
23 (54.8)
43 (53.8)
22 (57.9)
27.8⫾5.1
28.1⫾5.3
27.9⫾3.9
27.6⫾3.9
117 (73.1)
29 (69.1)
59 (73.8)
29 (76.3)
69 (43.1)
18 (42.9)
33 (41.3)
18 (47.4)
Diabetes mellitus
57 (35.6)
13 (31)
29 (36.3)
15 (39.5)
Coronary heart disease
61 (38.1)
15 (35.7)
30 (37.5)
16 (42.1)
Atrial fibrillation
54 (33.8)
14 (33.4)
28 (35)
12 (31.6)
Peripheral arterial disease
16 (10)
Males (%)
2
BMI, kg/m
Cardiovascular risk factors/disease
Hypertension
Hypercholesterolemia
Smoking (%)
3 (7.2)
9 (11.3)
4 (10.5)
54 (33.8)
15 (35.7)
25 (31.3)
14 (36.8)
25.5⫾20.3
24.5⫾20.1
25.9⫾19.4
24.8⫾21.6
6.1⫾3.1
2.2⫾1.6
5.8⫾1.4
9.5⫾2.4
NIHSS score, median (range)
14 (1–37)
14 (1–32)
14 (1–33)
15 (2–37)
Atherothrombotic
72 (45)
19 (45.2)
37 (46.3)
16 (42.1)
Cardioembolic
64 (40)
18 (42.9)
31 (38.8)
15 (39.5)
Lacunar
24 (15)
6 (14.3)
11 (13.8)
7 (18.4)
Aspirin
88 (55)
22 (52.4)
46 (57.5)
20 (52.6)
Clopidogrel/ticlopidine
40 (25)
10 (23.8)
19 (23.8)
11 (28.9)
Warfarin
32 (20)
10 (23.8)
15 (18.8)
7 (18.4)
Alcohol consumption, g/day of ethanol
Adiponectin levels, ␮g/mL
Stroke severity/types
Treatment during hospitalization
All differences between subgroups stratified according to adiponectin tertiles are nonsignificant.
Efstathiou et al
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Five-year survival of stroke patients in terms of tertiles of ADPN
levels.
score on admission and ADPN values had an inverse association (r⫽⫺0.20; P⫽0.066), which also reached statistical
significance only after adjustment for age (r⫽⫺0.29; P⫽
0.035). Initial infarct volume was precisely measured in 102
subjects (median 39.0 cm3 [interquartile range 9.0 to 93.0
cm3]) and was also found to have a consistent reciprocal
correlation to ADPN levels with (r⫽⫺0.51; P⫽0.002) and
without adjustment for age (r⫽⫺0.41; P⫽0.021). The value
of CRP in the first 24 hours after stoke onset, which was
available for 87 of the study participants (median 14 [range 2
to 41] mg/L), showed a significant negative correlation with
ADPN as well (r⫽⫺0.48; P⫽0.004).
Eighty-five patients (53.1%) died within 5 years after index
stroke (66 [77.6%] because of CV events). About one third
(29 of 85; 34.1%) and half (47 of 85; 55.3%) of total deaths
occurred within the first 30 days and the first year after
stroke, respectively. The overall 30-day and 1-year case
fatality rates were 18.1% (29 of 160) and 29.4% (47 of 160),
respectively, whereas after the first year, ⬇10% of survivors
continued to die each year (8.9%, 8.7%, 10.6%, and 10.7%
from second to fifth year). Subjects who died during the
5-year follow-up period had lower mean ADPN (4.1⫾2.1
␮g/mL) than survivors (7.3⫾2.2 ␮g/mL; P⬍0.001). Nonfatal
CV events were observed in 27 of 160 participants during the
5 years (16.9%; 13 events within the first year), being as well
more common in subjects with ADPN ⬍4 ␮g/mL (13 of 42;
31%) than 4 to 7 ␮g/mL (12 of 80; 15%) or ⬎7 ␮g/mL (2 of
38; 5.3%; P⬍0.001).
TABLE 2.
Adiponectin and Ischemic Stroke
A greater probability of CV (80.9%) and all-cause 5-year
mortality (92.8%) was found in patients with ADPN in the
lowest tertile compared with the middle (37.5% and 52.5%,
respectively) and the upper tertile (5.2% and 10.5%, respectively; P⬍0.001) (Figure). Similar associations existed with
regard to the 30-day and the 1-year probability of death, both
being greater in patients with ADPN concentrations ⬍4
␮g/mL (P⬍0.05 and P⬍0.01, respectively). Compared with
individuals with ADPN in the highest tertile, the relative risk
of death within 5 years was 8.1 (95% CI, 3.1, 24.5; P⬍0.001)
for subjects with ADPN in the lowest tertile and 4.3 (95% CI,
1.5, 14.6; P⬍0.01) for those with ADPN in the middle tertile.
Additional measurements of ADPN and CRP were performed 1 year after index stroke in 71 of the 113 1-year
survivors who were considered as lacking other conditions
that could influence the levels of the latter proteins. Using
data only from the ⬎71 patients with acute phase and 1-year
values, ADPN 1 year after stroke (mean⫾SD; 7.8⫾2.5
␮g/mL) did not differ significantly from the initial average
value (7.3⫾1.6 ␮g/mL; P⫽0.102), whereas the 2 measurements were highly correlated (r⫽0.84; P⬍0.001), the above
associations persisting after adjustments for BMI. Not only
the 1-year follow-up ADPN levels were similar to the initial
ones, but also the majority of the above patients (66 of 71;
93%) tended to be in the same ADPN tertile groups as
initially stratified (␬⫽0.89; P⬍0.001). CRP of the ⬎71
subjects declined significantly within 1 year (median 1-year
value 6 [range 1 to 13] mg/L compared with 9 [range 1 to 21]
mg/L in the acute stroke phase; P⫽0.019) but still remained
higher than the upper normal limit of 5 mg/L. Nevertheless,
CRP at 1 year after the event showed a significant positive
correlation with its baseline values (r⫽0.45; P⫽0.011) as
well as a negative correlation with ADPN at 1 year
(r⫽⫺0.41; P⫽0.017).
Univariate correlates of mortality within 5 years were
initial NIHSS score (odds ratio [OR], 4.9; 95% CI, 2.1, 11.2;
P⬍0.001), ADPN levels (OR, 3.8; 95% CI, 1.6, 9.1;
P⬍0.001), coronary heart disease (OR, 3.3; 95% CI, 1.5,
8.4; P⬍0.01), age ⬎70 years (OR, 3.1; 95% CI, 1.4, 7.7;
P⬍0.05), and peripheral arterial disease (OR, 2.7; 95% CI,
1.2, 6.5; P⬍0.05). In the multivariate Cox model, the risk of
death was significantly associated with an ADPN level in the
lowest tertile, stroke severity on NIHSS, and coronary heart
disease (Table 2).
Discussion
The present study suggests that low ADPN levels appear to
be associated with poor outcome after first-ever ischemic
stroke independently of other adverse predictors. Further, the
Independent Predictors of Mortality in the Total Study Population
Subjects With the Variable
(% of the overall
population)
Deaths Within 5 y (% of
subjects with the variable)
P Value
HR
95% CI
Adiponectin ⬍4 ␮g/mL
42 (26.3)
39 (92.8)
⬍0.001
5.2
2.1, 18.4
NIHSS score ⬎15
76 (47.5)
57 (75)
⬍0.001
3.6
1.7, 15.9
Coronary heart disease
61 (38.1)
43 (70.5)
⬍0.001
2.9
1.5, 12.3
Variables
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1918
Stroke
September 2005
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reciprocal relationship between initial infarct volume and
ADPN in a subgroup of our stroke population outlines the
potential role of the latter protein as a biomarker inversely
reflecting the extent of brain injury. These results are consistent with previous reports indicating that an excessive inflammatory response in coronary and cerebral arteries may be
related to scantiness of this adipocytokine, which could be
considered an endogenous biological modulator of vascular
remodeling.
The intriguing finding of no inverse relationship between
CV risk factors and ADPN in our study (Table 1) might be
attributed to several reasons. First, an acute phase reaction
could blur the above association, inasmuch as our investigation is the first to assess ADPN in the first day after the onset
of a CV event. In this respect, ADPN was shown to have a
significant negative correlation with CRP in a subgroup of the
present study participants. Second, a confounding influence
of age on the results could not be excluded because we
evaluated an older population than most of the previous
studies. Although the elderly could be anticipated to have
lower ADPN levels given the increased prevalence of CV risk
factors, a positive correlation between ADPN and age has
repeatedly been demonstrated.11,22,23 It has been suggested
that aging and advanced stages of CV disease may trigger a
counter-regulatory response that raises plasma ADPN, thus
inverting to some extent its original association with CV risk
factors.22,23 In line with the latter hypothesis is the marginally
significant reciprocal association of ADPN with BMI, hypertension, and diabetes mellitus, which was revealed in the
present study after adjustment for age. Third, the possibility
of a type 2 statistical error could not be ruled out, taking into
account the relatively limited sample size of 2 of the 3 groups
stratified according to ADPN levels.
Whereas the value of plasma ADPN shows a wide
variation in humans (1 to 30 ␮g/mL), apparently healthy
individuals usually have ADPN ranging from 6 to 20
␮g/mL, the latter thresholds suggested as defining “normal” ADPN levels.1–17 Thus, the mean ADPN value (6.1
␮g/mL) in our population of patients in the poststroke acute
phase could be classified at the low cutoff of “normal”
interval. Nevertheless, few data exist on the expected prestroke ADPN levels in subjects with risk factors, derived
solely from a nested case-referent study that showed no
predictive value of this adipocytokine for future stroke.19 In
the latter study, the mean ADPN concentration of 276
subjects who subsequently developed stroke (11.5 ␮g/mL in
men and 18.2 ␮g/mL in women) did not differ from that
observed in the corresponding referents. Furthermore, albeit a
single assessment of ADPN may be susceptible to short-term
variation that would be a possible source of misclassification,
the strong correlation of ADPN concentrations measured 1
year after stroke with the initial values in a subgroup of the
present population corroborates the results of a previous
study showing intraindividual ADPN levels to be stable over
time.24 The above observation implies that low poststroke
ADPN may not be linked only to an immediate, acute process
related to stroke but also to a persistent inflammatory response in stroke survivors as suggested previously.25
Our results may boost the scientific rationale for considerable therapeutic implications. Weight reduction by surgery or
by lifestyle modifications,1,2 as well as treatment with thiazolidinediones,1,2 angiotensin-converting enzyme inhibitors,
or angiotensin II receptor blockers26 have been reported to
increase plasma ADPN. Nevertheless, conflicting data exist
so far on the impact of administration of statins on ADPN
levels because treatment with atorvastatin did not alter ADPN
in a trial on subjects who had diabetes or were at high risk for
developing diabetes,27 whereas the combination of simvastatin with losartan increased ADPN in a very recent study on
hypercholesterolemic hypertensive patients.28
The present study provides additional support to the view
that there is an adipovascular axis with ADPN representing a
direct link between insulin resistance, obesity, and atherosclerosis. Therefore, it is a challenge for interventional trials to
target this protein as a surrogate end point to investigate
whether increasing ADPN levels by weight reduction or drug
administration may prolong survival of stroke patients.
References
1. Diez JJ, Iglesias P. The role of the novel adipocyte-derived hormone
adiponectin in human disease. Eur J Endocrinol. 2003;148:293–300.
2. Goldstein BJ, Scalia R. Adiponectin: a novel adipokine linking adipocytes and vascular function. J Clin Endocrinol Metab. 2004;89:
2563–2568.
3. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta
K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M,
Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y,
Funahashi T, Matsuzawa Y. Paradoxical decrease of an adipose-specific
protein, adiponectin, in obesity. Biochem Biophys Res Commun. 1999;
257:79 – 83.
4. Matsubara M, Maruoka S, Katayose S. Inverse relationship between
plasma adiponectin and leptin concentrations in normal-weight and obese
women. Eur J Endocrinol. 2002;147:173–180.
5. Yang WS, Lee WJ, Funahashi T, Tanaka S, Matsuzawa Y, Chao CL,
Chen CL, Tai TY, Chuang LM. Plasma adiponectin levels in overweight
and obese Asians. Obes Res. 2002;10:1104 –1110.
6. Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE,
Tataranni PA. Hypoadiponectinemia in obesity and type 2 diabetes: close
association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab. 2001;86:1930 –1935.
7. Gavrila A, Chan JL, Yiannakouris N, Kontogianni M, Miller LC, Orlova
C, Mantzoros CS. Serum adiponectin levels are inversely associated with
overall and central fat distribution but are not directly regulated by acute
fasting or leptin administration in humans: cross-sectional and interventional studies. J Clin Endocrinol Metab. 2003;88:4823– 4831.
8. Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y,
Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai
N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T,
Yamashita S, Hanafusa T, Matsuzawa Y. Plasma concentrations of a
novel, adipose-specific protein, adiponectin, in type 2 diabetic patients.
Arterioscler Thromb Vasc Biol. 2000;20:1595–1599.
9. Mallamaci F, Zoccali C, Cuzzola F, Tripepi G, Cutrupi S, Parlongo S,
Tanaka S, Ouchi N, Kihara S, Funahashi T, Matsuzawa Y. Adiponectin
in essential hypertension. J Nephrol. 2002;15:507–511.
10. Adamczak M, Wiecek A, Funahashi T, Chudek J, Kokot F, Matsuzawa Y.
Decreased plasma adiponectin concentration in patients with essential
hypertension. Am J Hypertens. 2003;16:72–75.
11. Iwashima Y, Katsuya T, Ishikawa K, Ouchi N, Ohishi M, Sugimoto K, Fu
Y, Motone M, Yamamoto K, Matsuo A, Ohashi K, Kihara S, Funahashi
T, Rakugi H, Matsuzawa Y, Ogihara T. Hypoadiponectinemia is an
independent risk factor for hypertension. Hypertension. 2004;43:
1318 –1323.
12. Kumada M, Kihara S, Sumitsuji S, Kawamoto T, Matsumoto S, Ouchi N,
Arita Y, Okamoto Y, Shimomura I, Hiraoka H, Nakamura T, Funahashi
T, Matsuzawa Y; Osaka CAD Study Group. Coronary artery disease.
Association of hypoadiponectinemia with coronary artery disease in men.
Arterioscler Thromb Vasc Biol. 2003;23:85– 89.
Efstathiou et al
Downloaded from http://stroke.ahajournals.org/ by guest on June 15, 2017
13. Dzielinska Z, Januszewicz A, Wiecek A, Demkow M, MakowieckaCiesla M, Prejbisz A, Kadziela J, Mielniczuk R, Florczak E, Janas J,
Januszewicz M, Ruzyllo W. Decreased plasma concentration of a novel
anti-inflammatory protein–adiponectin–in hypertensive men with
coronary artery disease. Thromb Res. 2003;110:365–369.
14. Ohashi K, Ouchi N, Kihara S, Funahashi T, Nakamura T, Sumitsuji S,
Kawamoto T, Matsumoto S, Nagaretani H, Kumada M, Okamoto Y,
Nishizawa H, Kishida K, Maeda N, Hiraoka H, Iwashima Y, Ishikawa K,
Ohishi M, Katsuya T, Rakugi H, Ogihara T, Matsuzawa Y. Adiponectin
I164T mutation is associated with the metabolic syndrome and coronary
artery disease. J Am Coll Cardiol. 2004;43:1195–1200.
15. Lindsay RS, Funahashi T, Hanson RL, Matsuzawa Y, Tanaka S,
Tataranni PA, Knowler WC, Krakoff J. Adiponectin and development of
type 2 diabetes in the Pima Indian population. Lancet. 2002;360:57–58.
16. Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB.
Plasma adiponectin levels and risk of myocardial infarction in men. J Am
Med Assoc. 2004;291:1730 –1737.
17. Zoccali C, Mallamaci F, Tripepi G, Benedetto FA, Cutrupi S, Parlongo S,
Malatino LS, Bonanno G, Seminara G, Rapisarda F, Fatuzzo P, Buemi M,
Nicocia G, Tanaka S, Ouchi N, Kihara S, Funahashi T, Matsuzawa Y.
Adiponectin, metabolic risk factors, and cardiovascular events among
patients with end-stage renal disease. J Am Soc Nephrol. 2002;13:
134 –141.
18. Chamorro A. Role of inflammation in stroke and atherothrombosis. Cerebrovasc Dis. 2004;17(suppl 3):1–5.
19. Soderberg S, Stegmayr B, Stenlund H, Sjostrom LG, Agren A, Johansson
L, Weinehall L, Olsson T. Leptin, but not adiponectin, predicts stroke in
males. J Intern Med. 2004;256:128 –136.
20. Brott T, Adams HP Jr, Olinger CP, Marler JR, Barsan WG, Biller J,
Spilker J, Holleran R, Eberle R, Hertzberg V. Measurements of acute
21.
22.
23.
24.
25.
26.
27.
28.
Adiponectin and Ischemic Stroke
1919
cerebral infarction: a clinical examination scale. Stroke. 1989;20:864 –
870.
van der Worp HB, Claus SP, Bar PR, Ramos LM, Algra A, van Gijn J,
Kappelle LJ. Reproducibility of measurements of cerebral infarct volume
on CT scans. Stroke. 2001;32:424 – 430.
Cnop M, Havel PJ, Utzschneider KM, Carr DB, Sinha MK, Boyko EJ,
Retzlaff BM, Knopp RH, Brunzell JD, Kahn SE. Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia.
2003;46:459 – 469.
Adamczak M, Rzepka E, Chudek J, Wiecek A. Ageing and plasma
adiponectin concentration in apparently healthy males and females. Clin
Endocrinol (Oxford). 2005;62:114 –118.
Pischon T, Hotamisligil GS, Rimm EB. Adiponectin: stability in plasma
over 36 hours and within-person variation over 1 year. Clin Chem.
2003;49:650 – 652.
Beamer NB, Coull BM, Clark WM, Briley DP, Wynn M, Sexton G.
Persistent inflammatory response in stroke survivors. Neurology. 1998;
50:1722–1728.
Furuhashi M, Ura N, Higashiura K, Murakami H, Tanaka M, Moniwa N,
Yoshida D, Shimamoto K. Blockade of the renin-angiotensin system
increases adiponectin concentrations in patients with essential hypertension. Hypertension. 2003;42:76 – 81.
Shetty GK, Economides PA, Horton ES, Mantzoros CS, Veves A. Circulating adiponectin and resistin levels in relation to metabolic factors,
inflammatory markers, and vascular reactivity in diabetic patients and
subjects at risk for diabetes. Diabetes Care. 2004;27:2450 –2457.
Koh KK, Quon MJ, Han SH, Chung WJ, Ahn JY, Seo YH, Kang MH,
Ahn TH, Choi IS, Shin EK. Additive beneficial effects of losartan
combined with simvastatin in the treatment of hypercholesterolemic,
hypertensive patients. Circulation. 2004;110:3687–3692.
Editorial Comment
Adiponectin
Spectator or Player?
Despite efforts at controlling traditional risk factors, stroke
remains a devastating and all-too-common disease. Identifying new markers for patients at higher risk of stroke would aid
in future risk factor management as well as potentially
offering new venues for preventive therapies. In this issue of
Stroke, Efstathiou et al1 report on a highly significant inverse
relation between adiponectin levels and subsequent 5-year
mortality. Adiponectin, a recently discovered cytokine, has
previously been theorized to be involved in the development
of atherosclerotic disease.2 Adiponectin appears to have both
anti-inflammatory and antiatherogenic properties, and as
such, it was expected that there would be an inverse relation
between the serum level of adiponectin and subsequent
cerebrovascular mortality. In their study, Efstathiou et al
confirm this inverse relation, finding that patients with
adiponectin levels in the lowest tertile had a 92.8% 5-year
mortality compared with a 10.5% mortality in patients with
adiponectin levels in the highest tertile.1 This corresponds to
an 8-fold increase in risk for individuals with low adiponectin
levels compared with those with the highest tertile of adiponectin levels. Similar results with adiponectin have been
seen in cardiovascular disease. In a case-control analysis from
the Health Professionals Follow-up Study, among the 18 225
men without cardiovascular disease at baseline, those in the
highest quintile of adiponectin level had a significantly
reduced risk for myocardial infarction (relative risk [RR],
0.39; 95% confidence interval, 0.23 to 0.64; P for trend
⬍0.001) compared with in the lowest quintile of adiponectin
level.3
The results of this study support the role of cytokines in
stroke4 and are consistent with prior studies suggesting that a
persistent inflammatory response increases the risk of subsequent cerebrovascular disease. The first group to demonstrate
a persistent inflammatory response was Beamer et al, 5 who
found that fibrinogen, C-reactive protein (CRP), and white
blood cell levels at baseline were predictive of recurrent
vascular events at 1 year. They also found that fibrinogen
remained significantly elevated at 1 year and that it continued
to predict an increased risk for recurrent vascular events.
However, the magnitude of the ability of fibrinogen to predict
recurrent events was much less than that seen in the current
apidonectin study. Other markers of the inflammatory response, including interleukin (IL)-6 and CRP, did not independently predict recurrent events in their study.
In addition to fibrinogen, some of the other inflammatory
markers that have been linked to recurrent cardiac or stroke
events include CRP (RR, 4),6 lipoprotein-associated phospholipase A2 (relative risk, 1.5),7 IL-6 (RR, 2),8 and cell adhesion
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molecules such as soluble intercellular adhesion molecule-1
(RR, 3).9 These compare to the 8-fold increased RR seen in
the current study. However, it should be noted that all of these
results were based on studies involving thousands of patients
compared with the 160 studied by Efstathiou et al.
The current study found that apidonectin levels were
low-normal after acute stroke. Prior studies found that the
anti-inflammatory cytokines IL-6 and IL-1RA increase
acutely after stroke,10 implying that there is activation of
anti-inflammatory components. The finding that apidonectin
did not increase acutely suggests that although apidonectin
may be protective, there may be no mechanisms to quickly
upregulate it, at least shortly after stroke.
In the current study, apidonectin appears to be both
potentially a marker of the extent of underlying neurologic
injury and a marker of persistent inflammatory response. That
apidonectin is in part a marker for the extent of neurologic
injury is supported by the negative correlation between initial
infarct volume and apidonectin, as well as the inverse relation
between the National Institutes of Health Stroke Scale and
apidonectin levels. However, the authors also provide data
supporting the theory that apidonectin is involved in a chronic
anti-inflammatory response; in the 71 patients tested at 1
year, apidonectin levels remained nearly the same as they had
at baseline. In addition, patients tended to be in the same
apidonectin tertile group to which they were initially stratified. The authors also found a significant negative correlation
with apidonectin and CRP (P⫽0.004); however, they did not
provide information as to whether CRP was as powerful a
predictor of 5-year mortality as the apidonectin level was. In
addition, although CRP remained elevated compared with
normal in the 71 patients assessed at 1 year, it was more likely
to have declined from the initial baseline value compared
with an apidonectin level that had shown very little change
from baseline. This suggests that CRP is relatively more
reflective of an acute-phase reaction, whereas apidonectin is
more representative of the underlying chronic inflammatory
state of the patient.
What this article does not tell us is whether apidonectin is
merely a marker of a persistent inflammatory response or
whether it has anti-inflammatory properties. There are some
limited data that apidonectin may have some direct insulinsensitizing and anti-inflammatory properties.2 The only way
of proving this in cerebrovascular cases would be to design a
therapeutic trial that targets elevating apidonectin levels in
patients at risk for stroke. The first step in designing such a
therapeutic trial would be to discover an agent that reliably
elevates apidonectin levels. In the discussion section, the
authors reviewed several medications that have variable
effects on raising apidonectin levels. It appears that further
work confirming an effective apidonectin-elevating therapy is
indicated.
The results of this study support the theory that inflammation is involved in recurrent stroke and mortality. At the very
least, apidonectin appears to be a robust marker of subsequent
vascular events. However, it could also provide fertile ground
for potential therapeutic trials that target increasing
apidonectin.
Wayne M. Clark, MD
Oregon Stroke Center
Oregon Health Sciences University
Portland, Oregon
References
1. Efstathiou SP, Tsioulos DI, Tsiakou AG, Gratsias YE, Pefanis AV,
Mountokalakis TD. Plasma adiponectin levels and 5-year survival after
first-ever ischemic stroke. Stroke. 2005;36:1915–1919.
2. Goldstein BJ, Scalia R. Adiponectin: a novel adipokine linking adipocytes and vascular functioin. J Clin Endocrinol Metab. 2004;89:
2563–2568.
3. Pischon CJ, Girman GS, Hotamisligil GS. Plasma apidonectin levels and
risk of myocardial infarction in men. JAMA. 2004;291:1730 –1737.
4. Clark WM. Cytokines and reperfusion injury. Neurology. 1997;49(suppl
4):S10 –S14.
5. Beamer NB, Coull BM, Clark WM, Briley DP, Wynn M, Sexton G.
Persistent inflammatory response in stroke survivors. Neurology. 1998;
50:1722–1728.
6. Bassuk SS, Rifai N, Riker PM. High-sensitivity C-reactive protein:
clinical importance. Curr Probl Cardiol. 2004;29:439 – 493.
7. Packard CJ, O’Reilly DS, Caslake MJ. Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease: West of
Scotland Coronary Prevention Study Group. N Engl J Med. 2000;343:
1148 –1155.
8. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration
of interleukin-6 and the risk of future myocardial infarction among
apparently healthy men. Circulation. 2000;101:1767–1772.
9. Ridker PM, Hennekens CH, Roitman-Johnson B, Stamfer MJ, et al.
Plasma concentration of soluble intercellular adhesion molecule 1 and
risks of future myocardial infarction in apparently healthy men. Lancet.
1998;351:88 –92.
10. Beamer NB, Coull BM, Clark WM, Hazel JS, Silberger JR. Interleukin-6
and interleukin-1 receptor antagonist in acute stroke. Ann Neurol.
1995;6:801– 805.
KEY WORDS: inflammation
䡲
risk factors
Plasma Adiponectin Levels and Five-Year Survival After First-Ever Ischemic Stroke
Stamatis P. Efstathiou, Dimitrios I. Tsioulos, Aphrodite G. Tsiakou, Yannis E. Gratsias,
Angelos V. Pefanis and Theodore D. Mountokalakis
Downloaded from http://stroke.ahajournals.org/ by guest on June 15, 2017
Stroke. 2005;36:1915-1919; originally published online August 18, 2005;
doi: 10.1161/01.STR.0000177874.29849.f0
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2005 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628
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