(Stroke. 1999;30:328-337.)
© 1999 American Heart Association, Inc.
Original Contributions |
Leptin Is a Risk Marker for First-Ever Hemorrhagic Stroke in a Population-Based Cohort
From the Department of Medicine (S.S., B.S., O.J., P.-G.W., T.O.), Department of Epidemiology and Public Health (L.W.), and Department of Nutritional Research (G.H.), Umeå University, Umeå, Sweden, and the Department of Medicine (B.A.), Lund University, Malmö, Sweden.
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Abstract |
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Background and Purpose—Leptin, important for body weight regulation, may be involved in the pathogenesis of the insulin resistance syndrome, associated with cardiovascular disease. We tested to determine whether leptin is a risk marker for first-ever stroke in a nested case-referent study.
Methods—We identified 113 patients with first-ever stroke (94 with ischemic and 19 with hemorrhagic stroke) who, before the stroke, had participated in population-based health surveys in northern Sweden. Referents were matched for sex, age, date and type of health survey, and geographic region. Blood pressure (BP), body mass index (BMI), and presence of smoking, diabetes, and hypertension were recorded. Total cholesterol, insulin, and leptin were analyzed in stored samples. Risk markers for first-ever stroke were analyzed by conditional logistic regression analysis.
Results—Patients with hemorrhagic stroke had higher levels
of BMI and systolic and diastolic BPs. Leptin
levels were 72% and 59% higher in males and females, respectively,
with hemorrhagic stroke versus referents. Patients with
ischemic stroke more often had hypertension, diabetes mellitus,
and higher fasting glucose and insulin levels. A diagnosis of
hypertension and elevated systolic and diastolic
BPs were significant risk markers for first-ever hemorrhagic stroke in
univariate analysis. High leptin (OR=20.55; 95%
CI, 1.12 to 376.7) levels together with hypertension (OR=16.28; 95%
CI, 1.49 to 177.3) remained as significant risk markers in a
multivariate model. The combination of high leptin and
high systolic or diastolic BP were associated with
a profoundly increased risk for hemorrhagic stroke (OR=22.11; 95% CI,
1.57 to 310.9). Diabetes, hypertension, and obesity (BMI 
27),
together with high levels of insulin, glucose, systolic and
diastolic BP, were significant risk markers for first-ever
ischemic stroke in univariate analysis.
Hypertension (OR=2.10; 95% CI, 1.14 to 3.86) remained as an
independent risk marker in a multivariate model.
Conclusions—Plasma leptin is strongly associated with an increased risk for first-ever hemorrhagic stroke, independent of other risk markers for cardiovascular disease. Leptin may be an important link in the development of cardiovascular disease in obesity.
Key Words: leptin • risk factors • stroke, hemorrhagic • stroke, ischemic
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Introduction |
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Well-established risk factors for stroke include hypertension, cigarette smoking, atrial fibrillation, diabetes mellitus, and alcohol abuse.1 The risk factors for ischemic and hemorrhagic stroke differ to some extent. A consistent finding, however, has been the association between hypertension and the risk of ischemic and hemorrhagic stroke2 and the protective effect of antihypertensive treatment.3 4
The cluster of risk factors named the insulin resistance syndrome, or syndrome X,5 6 has attracted considerable interest as a major contributing cause for coronary heart disease. Key features of this syndrome include hyperinsulinemia, hypertension, dyslipidemia, and dysfibrinolysis.7 Much less attention has been paid to the contribution of some of these factors to cerebrovascular disease. Notably, it has recently been suggested that insulin resistance with compensatory hyperinsulinemia may be an important pathogenetic factor of atherothrombotic brain infarction.8
The newly discovered protein product of the ob gene leptin may be an important link between obesity, the insulin resistance syndrome, and an increased risk for vascular disease.9 10 Leptin reduces food intake and increases energy expenditure when administered to mice11 12 but has recently been suggested to have adverse effects in an "overflow" situation, including effects on blood pressure (BP) regulation.10 13
The aim of this nested case-referent study was to examine to what extent leptin may be an independent risk marker for first-ever stroke.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Study Populations
The two northernmost counties in Sweden (Västerbotten and Norrbotten), with a total population of 510 000, have constituted since 1985 one of 39 collaborating centers in the WHO MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) study.14 Population-based surveys were performed in 1986, 1990, and 1994. For each survey, a total of 2000 individuals (250 men and 250 women, randomly selected from each of the following age groups: 25 to 34, 35 to 44, 45 to 54, and 55 to 64 years) were invited. In total, 4725 men and women in the age group 25 to 64 years participated in the MONICA surveys.
A community intervention program concerning cardiovascular disease and diabetes prevention, the Västerbotten Intervention Program (VIP), was performed in 1 of the 2 counties. This program, started in 1985, combines a population- and an individual-oriented strategy.15 Men and women in Västerbotten county were asked to participate in a health survey (the same design as the MONICA population surveys) at their primary health care center the year they became 30, 40, 50, and 60 years of age. The total population in Västerbotten is 260 000 people. Between January 1, 1985, and August 31, 1996, approximately 40 000 individuals took part in the VIP health surveys.
Participants in both the MONICA and the VIP surveys were requested to donate a fasting blood sample to be stored at the Northern Sweden Medical Research Bank for future research.
Case Findings
All cases with acute stroke (age group 25 to 74 years) and acute
myocardial infarction (AMI; age group 25 to 64 years) from the MONICA
area have since 1985 been included in the Northern Sweden MONICA
registries. Every case has been strictly validated according to MONICA
criteria before registration.16 17 An acute stroke case
was defined as "rapidly developing clinical signs of focal (or
global) disturbance of cerebral function lasting more than 24
hours (unless interrupted by surgery or death) with no apparent cause
other than a vascular origin."14 Global clinical signs
were accepted only in patients with deep coma or subarachnoid
hemorrhage. This definition excluded transient ischemic
attacks, subdural hemorrhage, traumatic
intracerebral hemorrhage, and lesions caused by
brain tumor.
Case-finding was based on clinical presentation, and cases detected by brain imaging but not presenting with any acute symptoms of stroke were excluded.
The subtypes of acute stroke, according to the MONICA manual, were based on the following findings (International Classification of Diseases, Revision 9[ICD-9] codes are in parentheses). Subarachnoid hemorrhage (430): bloodstained cerebrospinal fluid and an aneurysm or an arteriovenous malformation found on angiography, or positive finding on CT scan or necropsy. Subarachnoid hemorrhages were excluded in this study. Hemorrhagic stroke (431): positive finding on CT scan or at autopsy. In cases of a hemorrhagic stroke, autopsy (alone or in combination with CT scan) was performed in 14.6% of the cases and CT scan alone in the remaining 85.4%. The proportion of hemorrhagic stroke events in the MONICA registry was 11.0% and 10.8% for men and for women, respectively. Ischemic stroke (434): no signs of hemorrhage on CT scan or at autopsy. Unspecified stroke (436): none of the investigations (CT scan or autopsy) were performed. In this study, 3 of 113 had a diagnosis of unspecified stroke, and these were categorized as "ischemic stroke" in the analysis.
This study used a nested case-referent design in which the incident cases were definite first-ever stroke events, classified according to MONICA criteria and identified during the period January 1, 1985, through August 31, 1996. We identified 166 individuals who, after participation in either the MONICA or VIP health survey, suffered from a first-ever ischemic or hemorrhagic stroke before the age of 74. For this study, 113 cases (94 ischemic stroke [10 from MONICA and 84 from VIP] and 19 hemorrhagic stroke [2 from MONICA and 17 from VIP]; 71 men and 42 women) remained, after exclusion of individuals with a previous AMI (n=15), stroke (n=9), or cancer diagnosis according to the Regional Cancer registry (n=13), or those for whom the amount of blood in the sample taken was inadequate for analysis (n=16).
Potential referents for each case were randomly selected among participants in the MONICA or the VIP survey. They were matched for sex, age (±2 years), type (MONICA or VIP) and date (±1 year) of health survey, and geographical region.
Individuals were excluded if they had died or had moved away from the Northern MONICA region on or before August 31, 1996. Referents were also excluded if they were known from the Northern Sweden MONICA incidence registry to have had an AMI or stroke before the health survey. An additional questionnaire was sent to all referents to further ensure absence of stroke and/or AMI in their history. Finally, 2 referents for each case were selected.
The study was approved by the Research Ethics Committee of Umeå University and the data handling procedures by the National Computer Data Inspection Board.
Biomedical Factors and Biochemical Analyses
Smokers were defined as those who reported smoking cigarettes
(n=57), cigars (n=1), or a pipe (n=10) daily. Ex-smokers or
"occasional smokers" were classified as nonsmokers. The presence or
absence of diabetes was based on self-reported data and/or fasting
glucose >7.7 mmol/L and/or postload glucose levels>11.0
mmol/l. BP was recorded after 5 minutes' rest with a mercury
sphygmomanometer. With the subject in the sitting position,
Korotkoff's 5th phase was used as the diastolic pressure.
For subjects whose BP was measured only in a recumbent position, an
adjustment was made for sitting posture based on comparisons between
sitting and recumbent positions in 1850 subjects from the VIP health
survey.18 Systolic BP was divided into 3 groups:
<130, 130 to 160, and >160 mm Hg. Diastolic BP was
grouped into <85, 85 to 95, and >95 mm Hg. Hypertension was
defined as systolic BP 160 mm Hg and/or
diastolic BP 95 mm Hg and/or antihypertensive
medication therapy. Weight was measured without shoes in light indoor
clothing and recorded to the nearest 0.2 kilogram; height was
measured to the nearest centimeter, without shoes. Body mass index
(BMI) was calculated as total body weight in kilograms divided by
height in meters squared. BMI was divided into 3 groups: <27, 27 to
30, and >30 kg/m2, according to the
classification by Bray.19
Most subjects were screened in the morning after an overnight fast, even if the requested minimum fasting period was only 4 hours, for practical reasons. This period was extended to 8 hours from 1992 on. In the majority of subjects, an abbreviated oral glucose tolerance test was performed according to the standard of WHO, with a 75-g glucose load.20 Fasting and postload glucose (2 hours) were measured. Total serum cholesterol was measured with a benchtop analyzer (Reflotron, Boehringer Mannheim GmbH Diagnostica) at each health survey center at the time of the health survey or by an enzymatic method (Boehringer Mannheim GmbH Diagnostica) at a central laboratory. The results from the benchtop analysis have been evaluated earlier21 and show a high correlation to those obtained by the enzymatic method at a central laboratory. For total cholesterol, 3 groups were considered clinically relevant: <6.5, 6.5 to 7.8, and >7.8 mmol/L.
Plasma samples for the following analyses were obtained after patients fasted for a minimum of 4 hours; the samples were stored in a deep-freeze blood bank at -80°C. Insulin was measured with a double-antibody radioimmunoassay technique. Guinea pig anti-human insulin antibodies, human insulin standard, and mono-125I-Tyr-human insulin (Linco Research, Inc) were used. This assay had a cross-reaction under 0.2% with intact and des(31,32) proinsulin, according to the manufacturer. The detection limit was 10 pmol/L and the CV (both interassay and intraassay) was <3%. The leptin analysis was performed by use of a double antibody radioimmunoassay with rabbit anti-human leptin antibodies, 125I-labeled human leptin as tracer and human leptin as standard. Interassay CV was 1.9% at low levels (<5 ng/mL) and 3.2% at high levels (10 to 15 ng/mL) (Linco Research, Inc).
Statistical Analysis
Missing values for categorical variables were treated as a
separate category (omitted from tables) in the analysis, while
missing continuous values in the logistic regression analysis
were replaced by the mean value representing the referents,
thus ensuring a conservative result. (Median value for leptin and
insulin due to positive skew). The presence of outliers were checked by
visual inspection of scatterplots and a male referent to a hemorrhagic
stroke were omitted from the analysis due to very high BP
(205/150 mm Hg). Means and SDs are presented. The
significance of any difference in means between cases and referents was
tested using unpaired Student's t test or the Mann-Whitney
U test when appropriate. Possible interactions between study
variables were explored with bivariate and partial (adjusted for
BMI) correlation analysis with ln-transformed values of leptin
and insulin. Two-tailed tests were used, with a value of
P<0.05 considered significant. The influence of studied
variables on first-ever stroke (stratified for type of stroke) was
tested by univariate and multivariate
logistic regression analysis by use of the conditional maximum
likelihood routine designed for matched analysis to estimate
ORs and 95% CIs. (The effect of gender was tested with ordinary
logistic regression because of the matched design). To test the
relationship between increasing levels of risk markers and the risk of
stroke, we categorized the continuous variables into tertiles by
the distribution of the referent values, men and women separately.
Categories and tertiles were combined to get 1 "exposed" (usually
the highest category/tertile) and 1 "unexposed" (the remaining
categories/tertiles) group. This strategy was adopted because of the
limited number of cases in some cells and guided by the results in the
univariate analysis. For assessment of the
influence of separate biomedical risk factors, we controlled for BMI,
hypertension, smoking, diabetes (or fasting glucose),
cholesterol, insulin, and leptin in various models.
Possible interactions between leptin on one hand and BP,
cholesterol, and insulin on the other were studied by
visual inspection of scatterplots and construction of combination
terms, including high and low levels (below and over the median value
for referents, stratified for type of stroke and sex) of the studied
variables. The confounding effect of gender and type of stroke was
evaluated by stratification. Furthermore, the presence of other
possible confounders and the stability of multivariate
models were tested in multiple steps of adding/deleting all possible
combinations of variables (both as continuous and as categorical
variables when appropriate). All calculations were made with the
statistical programs SPSS (version 6.1; SPSS, Inc,) and Stata (version
5.0; Stata Corp) on a Macintosh computer (Apple Computer, Inc).
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Results |
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One hundred thirteen patients with a first-ever stroke were included in the study. Ninety-four patients (55 men and 39 women) had had an ischemic stroke and 19 (16 men and 3 women) a hemorrhagic stroke. The stroke event occurred on average 30 months after the health survey.
Basal characteristics are presented in Table 1
. Patients with ischemic stroke
were more often hypertensive and had higher systolic and
diastolic BPs at the time of investigation than their
matched referents. Furthermore, they more often had diabetes, and they
had higher fasting glucose and insulin levels. The same pattern of
differences was seen after stratification for sex, even if some
parameters did not reach statistical significance (data not
shown).
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Patients with hemorrhagic stroke had higher diastolic and systolic BPs and BMI than their referents, a pattern also seen among men (data not shown; a separate analysis of women with hemorrhagic stroke was not meaningful because of few cases). Compared with the referents, the leptin levels were 72% higher in male and 59% higher in female patients with hemorrhagic stroke, a difference not seen between ischemic cases and their referents. Cholesterol levels and the number of smokers did not differ between cases and referents, irrespective of type of stroke and sex.
Significant correlations between study variables were found (Table 2). In men, high levels of leptin were
associated with high BMI, high diastolic and
systolic BPs, and high levels of cholesterol,
fasting glucose, and insulin. Significant associations remained between
leptin on one hand and glucose, insulin, and cholesterol on
the other, after adjustment for BMI. Furthermore, high leptin levels
correlated to high BMI and elevated insulin levels (after adjustment
for BMI as well) in women.
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Univariate logistic regression revealed that a diagnosis of
diabetes mellitus as well as high fasting glucose and insulin levels,
together with known hypertension and high
diastolic/systolic BP levels, were significant risk
markers for first-ever ischemic stroke (Table 3). A high BMI was associated with
ischemic stroke (27) and hemorrhagic stroke (continuous). In
addition, first-ever hemorrhagic stroke was associated with known
hypertension and high systolic and diastolic BPs at
the time of investigation (Table 4). High
levels of leptin (the upper two tertiles) were associated with elevated
risk for first-ever hemorrhagic stroke, although not significant
(OR=8.58; 95% CI, 0.98 to 74.9). Neither daily smoking nor high levels
of cholesterol were associated with stroke of any kind.
Variables associated with increased risk for future stroke in the
univariate analysis retained their predictive power
after stratification for sex, although not always significantly,
because of the limited number of cases in some cells.
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Hypertension was significantly associated with ischemic stroke
in a multivariate model (Table 3
). Furthermore,
diabetes mellitus and high BP (diastolic BP 85
mm Hg or systolic BP 130 mm Hg) became significant
risk markers for first-ever ischemic stroke if BP was
analyzed categorized as diastolic or
systolic BP instead of hypertension (data not shown). Leptin
was not associated with ischemic stroke in any of these
models.
Leptin and hypertension were the only remaining risk markers for
hemorrhagic stroke in a multivariate model, including
leptin, BMI, smoking, hypertension, glucose, and insulin (Table 4). The outcome was similar after controlling for
cholesterol as well but at the expense of less precise
estimates (wider confidence intervals). A second
multivariate model including only leptin, hypertension,
and cholesterol is thus presented (Table 4).
Sex did not predict stroke of any type in either univariate analysis or as an interaction term with leptin (data not shown).
The combination of high BP (systolic or diastolic)
and high leptin levels was associated with a pronounced increased risk
of hemorrhagic stroke (Figure 1 and 2), a pattern not seen in patients with
ischemic stroke. The combination of high leptin levels and high
BP (systolic or diastolic) was a significant risk
marker for hemorrhagic stroke both in univariate (OR=12.71;
95% CI, 1.25 to 129.8) and multivariate (OR=20.11;
95% CI, 1.57 to 310.9) models compared with the combination of low
leptin levels and low BP (systolic and diastolic).
In contrast, high BP (systolic or diastolic) alone
predicted ischemic stroke (OR=4.79; 95% CI, 1.80 to 12.76) in
a multivariate model, not in combination with high
leptin levels.
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) and their referents (
). The upper
scatterplot shows cases versus one set of referents and the lower shows
cases versus the other set of randomly chosen referents. The median
values for leptin and diastolic BP in the reference group
are indicated as reference lines. (A separate scatterplot of women with
hemorrhagic stroke was not meaningful because of the small number of
cases.) Note the aggregation of cases in the quadrant corresponding to
high leptin and high diastolic BP.
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Discussion |
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This study examined leptin as a possible independent risk marker for first-ever stroke in a strict population-based, nested case-referent study.22
The nested case-referent design unites the prospective dimension of the cohort study with the efficiency of the case-referent study. Recall and selection bias are minimized, because blood sampling and data collection are carried out before the event. All events in the population, including those not treated in the hospital, are included in the study. The identification and definition of cases is crucial, and it should be stressed that all stroke events in this study were strictly classified according to the MONICA criteria16 by the Northern Sweden MONICA stroke registry. Extensive quality assessments of the registry have been performed.17 This is, therefore, a genuine population-based study, and there are no major differences in risk-factor profiles between participants and nonparticipants in the VIP and MONICA surveys.21 23 The excess of men with hemorrhagic stroke (16 of 19 cases) was unexpected, and there are no obvious reason for this, other than chance, because of the small number of cases; this issue can be solved only by larger studies with more men and women.
The etiology of stroke is multifactorial. In the present study, circulating levels of leptin were found to be significantly associated with other risk markers, including elevated BP, BMI, glucose, insulin, and cholesterol levels. In multivariate analyses, high leptin retained its position as a powerful marker for the future risk of hemorrhagic stroke. This was independent of variables related to high leptin levels, such as high BMI24 and hyperinsulinemia.25 In fact, leptin (together with high BP) emerged as the strongest independent risk marker for hemorrhagic stroke. In contrast, hypertension was the only remaining risk factor for ischemic stroke in a multivariate model after adjustment for covariates, including leptin and other known risk markers for ischemic stroke. The absence of association between diabetes mellitus and smoking on one hand and ischemic stroke on the other, in the multivariate analysis, may be related to the limited study sample.
We have recently shown that a high leptin level is a strong risk marker for first-ever AMI in men independent of other known AMI risk factors in a prospective, nested case-referent study.26 The absence of association between ischemic stroke and leptin levels was thus unexpected and may seem puzzling. However, different pathophysiological mechanisms may be present among subgroups of ischemic stroke, including atherothrombotic, lacunar, and cardioembolic infarctions. Further studies of the predictive power of leptin in larger study populations may take this diversity into account.
In evolutionary terms, the role of leptin has been suggested to be that of a protector against the effects of starvation.27 However, hyperleptinemia may contribute to the development of cardiovascular disease via its effects on BP regulation, insulin sensitivity, and a number of other hormonal interactions.10 28 29
In experimental studies, leptin increased renal, brown adipose tissue, and adrenal gland sympathetic nerve activity,30 and intravenous as well as intracerebroventricular administration of leptin causes sustained increase of arterial BP in normal rats.31 32 Our data support a close relationship between leptin and BP, as the combination of high levels of leptin and high diastolic or systolic BP was a strong predictor for hemorrhagic stroke. In contrast, the combination of high levels of leptin and BP did not predict ischemic stroke. The prompt reduction of stroke risk after normalization of high BP related to the relatively small benefit on AMI risk suggests interruption of a precipitating factor rather than interference with atherogenesis.2 A leptin-mediated increase in sympathetic activity via central and peripheral effects may thus induce short-term as well as long-term BP changes.10 33
We found a close association between circulating leptin and insulin levels, verifying data from other study groups.25 Impaired insulin sensitivity has been associated with cardiovascular disease. Insulin resistance has been shown to be associated with atherothrombotic stroke (but not with lacunar or cardioembolic strokes) in nonobese Japanese men and women.8 In another study,34 decreased insulin sensitivity was independently associated with increased atherosclerosis of the carotid arteries.
Leptin secretion is probably regulated by insulin in humans,35 36 but it was notable that in a multiple regression model, insulin lost its apparent predictive value for ischemic stroke when adjusted for leptin levels, whereas leptin was a predictor for hemorrhagic stroke that was independent of insulin. This raises the possibility that the reported association between hyperinsulinemia/insulin resistance and an increased risk of cardiovascular disease is mediated by leptin. Interestingly, the insulin resistance syndrome is associated with increased sympathetic activity, which has been suggested to be an important link in the development of hypertension and associated metabolic abnormalities.7 Furthermore, weight loss reduces sympathetic activity, possibly related to a decrease in leptin levels.37
The association between cholesterol levels and stroke risk is not clear-cut. Interestingly, low HDL cholesterol levels, which correlate with extracranial carotid atherosclerosis38 39 and are a key feature of the dyslipidemia associated with insulin resistance and central obesity, are associated with high leptin levels.40
Central obesity may be of importance in determining leptin levels in men,41 and indirect measures of central obesity, such as visceral fat area or waist circumference, are associated with increased leptin levels in men40 42 and postmenopausal women.40 This is of interest, because central obesity, rather the obesity involving hip and thighs, relates to an increased stroke risk.43 44
A final mechanism behind increased leptin, the insulin resistance syndrome, and cardiovascular disease (including stroke) may be dysfibrinolysis.45 46 Indeed, we have recently shown that elevated leptin levels are associated with low levels of tissue plasminogen activator activity and high levels of plasminogen activator inhibitor-1.40
There are some potential drawbacks with this study, including the lack of standardization of glucose measurements and blood sampling time. However, misclassification of exposure status due to these factors would have been random in cases and referents. The effects of high glucose, insulin, and leptin levels may thus be underestimated in this study because of a regression dilution bias. Furthermore, leptin levels show a diurnal variation, but daytime levels are quite stable, with a variation of approximately 20% compared with levels at 8 AM.47 Our results should be interpreted with caution owing to the relatively limited number of hemorrhagic cases. We believe, however, that a major strength of the study is the nested case-referent design with strictly validated case-finding.
In conclusion, elevated plasma leptin level is an independent predictor of first-ever hemorrhagic stroke but not ischemic stroke. The mechanisms behind this association should be further explored but may include effects of leptin directly or indirectly on sympathetic nervous system activation and BP, lipid levels, and the fibrinolytic system.
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Acknowledgments |
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Supported by grants to the Northern Swedish MONICA Project and from the Swedish Medical Research Council (grants 19X-12237 to Dr Olsson, 14X-6834 to Dr Ahrén, 27P-12314 to Dr Stegmayr, and 27X-12689 to Dr Hallmans), the Swedish Public Health Institute, Ernhold Lundström, Albert Påhlsson, Crafoord and Novo Nordic Foundations, Swedish Diabetes Association, the Joint Committee in the North Medical Care Region, and the Faculties of Medicine, Umeå and Lund Universities. We are indebted to the Northern Sweden MONICA Project, the Västerbotten Intervention Program (Åsa Ågren, Gösta Dahlén, Kjell Asplund), and the grants supporting them. The authors are grateful to Lilian Bengtsson and Hans Stenlund for outstanding assistance in technical and statistical matters.
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Footnotes |
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Address reprint requests to Dr Söderberg at the Department of Medicine, Umeå University Hospital, S-901 85 Umeå, Sweden.
Received June 30, 1998; revision received October 13, 1998; accepted November 24, 1998.
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