Excess body weight and risk of first eve

European Journal of Neurology 2007, 14: 762–769

doi:10.1111/j.1468-1331.2007.01849.x

Excess body weight and risk of first-ever acute ischaemic non-embolic
stroke in elderly subjects
H. J. Milionisa, T. D. Filippatosa, C. S. Derdemezisa, K. J. Kalantzia, J. Goudevenosa,
K. Seferiadisb, D. P. Mikhailidisc and M. S. Elisafa
a

Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece; bLaboratory of Biochemistry, University
Hospital of Ioannina, Ioannina, Greece; and cDepartment of Clinical Biochemistry, Royal Free Hospital, London, UK

Keywords:

BMI, HDL, metabolic
syndrome, obesity, stroke,
waist circumference
Received 18 January 2007
Accepted 23 April 2007

In a population-based case–control study we assessed the association between obesity
and acute ischaemic/non-embolic stroke. A total of 163 patients aged older than
70 years (88 men and 75 women) admitted due to a first-ever-in-a-lifetime acute
ischaemic/non-embolic stroke and 166 volunteers (87 men and 79 women) without a
history of cardiovascular disease were included. The association of stroke with body
mass index (BMI) or waist circumference (WC) was determined by multivariate
logistic regression modelling after adjusting for potential confounding factors. Overweight and obesity were more prevalent amongst stroke patients compared to
controls. Subjects with a BMI ‡30 kg/m2 had 2.5-times higher odds to suffer an acute
ischaemic/non-embolic stroke compared to subjects within the lowest BMI category of
18.5–20.9 kg/m2. Analysis of interaction showed that in the presence of overweight
and/or obesity (classified as a BMI ‡25 kg/m2 and/or a WC >102 cm in men and
>88 cm in women) the inverse relationship between HDL cholesterol and ischaemic/
non-embolic stroke was negated. Excess weight is associated with an increased risk of
acute ischaemic/non-embolic stroke in elderly individuals independently of concurrent
metabolic derangements. Moreover, in the presence of obesity, HDL cholesterol loses
its protective effect against ischaemic stroke.

Introduction
Obesity is becoming increasingly common and is
recognized as a major public health problem worldwide

[1]. It is a chronic condition that is associated with
premature death and significant healthcare costs as it
constitutes an independent risk factor for a variety of
diseases, including type 2 diabetes mellitus, the metabolic syndrome (MetS), cardiovascular disease,
gallbladder disease and some types of cancer [1].
Stroke is a major cause of mortality in the industrialized countries leading to serious long-term physical
and mental disabilities amongst survivors, especially
amongst the elderly [2]. Excess weight is associated with
an increased prevalence of several factors that may lead
to stroke [3]. However, data on the overall association
of obesity and stroke are limited and inconclusive.
Several studies have suggested that a high body mass
index (BMI) may increase the risk of stroke [4,5]. In the
Framingham Heart Study, an association between
weight and atherothrombotic stroke was found in
women but not in men [4]. The Honolulu Heart Program reported that BMI was associated with increased
Correspondence: Moses S. Elisaf, MD, FRSH, FASA, Department of
Internal Medicine, School of Medicine, University of Ioannina, 45 110
Ioannina, Greece (tel.: +30 2651 0 97509; fax: +30 2651 0 97016;
e-mail: egepi@cc.uoi.gr).

762

risk of thromboembolic stroke amongst non-smoking
men in older middle age [6]. In contrast, the NursesÕ
Health Study showed that women with increased BMI
had an increased risk of ischaemic stroke, but not after
adjustment for hypertension, diabetes mellitus and high
cholesterol [7]. Other studies have also failed to find an
independent relationship between obesity (measured by
BMI) and increased risk of stroke [8–12].
Evidence from studies investigating the association
between abdominal obesity and stroke in middle-aged
individuals indicates that the distribution of body fat
predicts better stroke risk than total body fat [8,11,13].
Body fat tends to be redistributed with ageing [14].
There is limited information with regard to the association of the overall and abdominal obesity with stroke
in the elderly, who comprise the fastest growing proportion of the population.
In a population-based case–control study, we evaluated potentially modifiable risk factors for acute ischaemic/non-embolic stroke, including overweight and
obesity [assessed by BMI or waist circumference (WC)

measurements], amongst the elderly [15,16]. This study
was conducted in the prefecture of Ioannina, Epirus
(north-western Greece), a non-industrialized part of the
country with 170 000 inhabitants, with those older than
70 years of age representing 18–20% of the total
population [15,16].

 2007 EFNS

Obesity and ischaemic stroke

Subjects and methods
A total of 163 elderly patients (88 men, 75 women) who
were consecutively hospitalized over a 5-year period for
first-ever-in-a-lifetime acute ischaemic stroke and 166
volunteers (87 men, 79 women) consecutively evaluated
in the primary care setting were included in the study
[15,16]. The study was based on all the available eligible
consecutive patients that we could assemble over a
period of 5 years.

Criteria for inclusion in the study were: (i) subjects
aged older than 70 years, (ii) residing in the prefecture
of Ioannina, (iii) known to attend the Public Primary
Care Health Centre facilities regularly for the last
5 years prior to enrolment and (iv) patients reaching the
Emergency Department of the University Hospital of
Ioannina (the referral centre for patients with cerebrovascular disease over 65 years old in the region) within
12 h from the onset of symptoms. The diagnosis of firstin-a-lifetime acute ischaemic/non-embolic stroke was
based upon history (clinical course, associated symptoms), physical examination (including neurological
and cardiac assessment) and radiological study [initial
non-contrast brain computed tomography (CT) scan].
Further confirmation involved full cardiac evaluation
(history and physical, electrocardiogram, and a transthoracic echocardiogram) and carotid Doppler ultrasound to exclude a cardiac and/or carotid artery source
of emboli, and a new brain CT scan where appropriate
[15,16].
Subjects with a history of vascular disease [previous
stroke (including those with old infarcts on imaging),
angina, myocardial infarction, revascularizations, peripheral artery disease], active infections, neoplasia, renal or liver disease, thyroid dysfunction, chronic
obstructive pulmonary disease, chronic inflammatory
bowel disease and excessive alcohol consumption were

excluded. Stroke patients and controls with a known or
possible cardiac source of emboli (atrial fibrillation,
heart valve disease, patients receiving anticoagulant
treatment) were also excluded. None of the participants
was receiving specific lipid lowering treatment (i.e. a
statin or a fibrate). All subjects gave informed consent
and the study protocol was approved by the Institutional Ethics Committee.
BMI and WC assessments

Body weight was measured using a digital scale (Seca
Personal Floor Scale 861; Seca, Marsden, UK) with an
accuracy of ±100 g. Subjects were weighed without
shoes, in the minimum clothing possible. Standing
height was measured without shoes to the nearest
0.1 cm with the Portable Leister height measure (Seca)

 2007 EFNS European Journal of Neurology 14, 762–769

763

with the shoulders in relaxed position and arms
hanging freely. BMI was calculated by dividing weight
(kg) by height squared (m2). We evaluated BMI on the
basis of the World Health Organization (WHO) categories of 88 cm for women],
triglycerides ‡1.7 mmol/l, low HDL cholesterol (i.e.
88 cm in women or
less), lipid variables were expressed as continuous variables, whilst MetS was expressed as a binary variable.
All statistical analyses were carried out using the
SPSS software version 12.0 (SPSS Inc., Chicago, IL,
USA) package for personal computers. In all analyses,
P < 0.05 was used to indicate statistical significance.

Results
The clinical and laboratory characteristics of the study
population with regard to weight status are shown in
Table 1. No subjects with a BMI lower than 18.5 kg/m2
were identified in either group. BMI was highly

Table 1 Clinical and laboratory characteristics of the study population according to weight status
Stroke patients

Age (years)
Sex
Men
Women
Body mass index (kg/m2)
Men
Women
Waist circumference (cm)
Men
Women
Current smokers
Diabetes mellitus
Arterial hypertension
Metabolic syndrome
Total cholesterol (mmol/l)
LDL cholesterol (mmol/l)
HDL cholesterol (mmol/l)
Triglycerides (mmol/l)
Apolipoprotein A-I (mg/dl)

Apolipoprotein B (mg/dl)
Lipoprotein (a) (mg/dl)
Fibrinogen (g/l)
Uric acid (lmol/l)

Control population

Normal
(n ¼ 55)

Overweight
(n ¼ 92)

Obese
(n ¼ 16)

Normal
(n ¼ 72)

Overweight

(n ¼ 73)

Obese
(n ¼ 11)

78.0 ± 4.7

77.2 ± 4.7

78.2 ± 6.0

77.8 ± 5.2

77.6 ± 4.7

78.1 ± 5.9

27
28
23.1 ± 1.3a,b

23.4 ± 1.2a,b
22.7 ± 1.4a,b
77.9 ± 8.5a,b
83.4 ± 6.8a,b
71.7 ± 5.4a,b
15 (27.2%)
13 (23.6%)
27 (49.1%)
18 (32.7%)a,b
5.3 ± 1.3
3.4 ± 1.1
1.0 ± 0.3
2.0 ± 0.9
127.8 ± 23.8
132.5 ± 40.4
15.7 (0.8–65.3)
4.0 (1.3–6.3)
315.2 ± 95.2

53
39
27.1 ± 1.3a
27.0 ± 1.2a
27.3 ± 1.4a
92.9 ± 9.4a
96.9 ± 8.8a
87.3 ± 7.0a
25 (27.2%)
28 (30.4%)
43 (46.7%)
48 (52.2%)a
5.4 ± 1.1
3.4 ± 0.9
1.0 ± 0.3
1.9 ± 0.8
132.0 ± 24.1
131.1 ± 30.7
15.5 (0.8–62.0)
4.4 (1.8–5.6)
349.1 ± 102.3

8
8
33.4 ± 3.1b
34.4 ± 5.6b
33.0 ± 2.0b
103.1 ± 8.2b
113.7 ± 7.2b
99.1 ± 3.9b
3 (18.7%)
5 (31.2%)
7 (43.7%)
9 (56.2%)b
5.4 ± 2.1
3.7 ± 1.9
0.9 ± 0.3
1.8 ± 0.8
124.2 ± 28.5
131.1 ± 33.8
10.6 (1.8–50.0)
3.5 (2.1–5.3)
306.9 ± 74.9

40
42
22.8 ± 1.2c,d
22.8 ± 1.1c,d
22.9 ± 1.3c,d
77.2 ± 6.8c,d
81.9 ± 3.7c,d
71.2 ± 4.7c,d
24 (33.3%)
15 (20.8%)
18 (25.0%)
5(6.9%)
5.5 ± 1.1
3.5 ± 1.0
1.3 ± 0.3
1.4 ± 0.5
150.9 ± 23.7
129.2 ± 22.9
5.4 (0.8–48.0)
2.9 (1.1–6.1)
274.2 ± 77.3

41
32
27.0 ± 1.2c
27.1 ± 1.2c
26.8 ± 1.1c
92.3 ± 10.2c
99.3 ± 8.5c
85.3 ± 6.1c
19 (26%)
16 (21.9%)
39 (53.4%)
17 (23.3%)
5.3 ± 1.1
3.3 ± 1.2
1.3 ± 0.3
1.3 ± 0.5
150.0 ± 21.3
124.6 ± 25.1
7.7 (0.8–48.0)
3.1 (1.5–5.6)
292.6 ± 84.5

6
5
31.4 ± 1.0d
31.8 ± 1.1d
31.0 ± 0.8d
107.3 ± 8.2d
113.6 ± 1.4d
98.8 ± 3.0d
2 (18.2%)
3 (27.3%)
4 (36.4%)
4 (36.4%)
5.7 ± 1.2
3.7 ± 1.0
1.3 ± 0.2
1.4 ± 0.6
144.3 ± 16.9
134.7 ± 48.6
11.8(3.5–25.0)
2.4 (1.5–2.9)
304.0 ± 95.2

Data are reported as mean ± SD, except for Lp(a) and fibrinogen where median (range) is shown. Classification according to WHO guidelines:
normal: BMI £25 kg/m2; overweight: BMI 25–29.9 kg/m2; obese: BMI ‡30 kg/m2. Statistical significance of the between-group differences derived
by post hoc multiple comparisons: aP < 0.01, overweight versus normal stroke patients; bP < 0.01, obese versus normal stroke patients;
c
P < 0.01, overweight versus normal controls; dP < 0.01, obese versus normal controls.

 2007 EFNS European Journal of Neurology 14, 762–769

Obesity and ischaemic stroke

Table 2 Prevalence of overweight and obesity in the study population
and frequency of subjects across body mass index (BMI) categories
Stroke patients
(%) (n ¼ 163)

Controls (%)
(n ¼ 166)

P

(a) WHO classification
Normal (BMI 102 cm for men; >88 cm for women) was
similar in cases and controls [56 (34%; 21 women) vs.
53 (32%; 19 women) respectively; P ¼ NS].

Table 3 Odds ratios (95% CI) for firstever-in-a-lifetime acute ischaemic
non-embolic stroke across body mass index
(BMI) categories

Compared to subjects with BMI values in the lowest
category, those within the highest category (i.e. BMI
‡30 kg/m2) had 2.5-times higher odds to suffer an acute
ischaemic/non-embolic stroke [adjusted odds ratio
(OR) 2.46; 95% confidence interval (CI), 1.06–8.61;
P ¼ 0.04) (Table 3). Moreover, those ÔoverweightÕ
(according to WHO guidelines) had a 1.5-fold higher
odds (adjusted OR, 1.53; 95% CI, 0.76–3.10; P ¼ 0.23)
and those ÔobeseÕ a 1.3-fold (adjusted OR, 1.27; 95%
CI, 0.79–2.00; P ¼ 0.34) higher odds of having an acute
ischaemic/non-embolic stroke compared to subjects
with ÔnormalÕ BMI. Likewise, an increased WC
(>102 cm for men; >88 cm for women) was associated
with a twofold higher odds of suffering an acute ischaemic stroke (adjusted OR, 1.99; 95% CI 0.94–4.23;
P ¼ 0.07) compared to subjects with a WC £102 cm
(men) and £88 cm (women).
In logistic regression analysis, crude OR for TG was
4.40 per 1 mmol/l increase (95% CI, 2.87–6.85;
P < 0.001) and for HDL-C 0.03 per 1 mmol/l increase
(95% CI, 0.01–0.08; P < 0.001); this association was
evident after adjusting for potential confounders
(Table 4).ÔInteraction analysisÕ between MetS and
either WC or BMI produced additional interesting
results. In the presence of the MetS, abdominal obesity
(manifested as WC >102 cm in men and >88 cm in
women) was associated with an increased risk of stroke
(adjusted OR, 2.74; 95% CI, 1.15–6.50; P ¼ 0.02).
When BMI was used in place of WC, subjects with a
BMI ‡30.0 kg/m2 showed fourfold higher odds to suffer
an acute ischaemic/non-embolic stroke (adjusted OR,
4.10; 95% CI, 1.33–12.65; P ¼ 0.01).
Further analysis of ÔinteractionÕ between obesity
parameters and serum lipids revealed that an increasing
BMI or WC attenuated the Ôprotective effectÕ of HDL-C
levels in the prediction of stroke, whereas the association of stroke with serum triglycerides remained
significant (Table 4). Of note, in the presence of
overweight and/or abdominal obesity (classified as a
BMI ‡25 kg/m2 and/or a WC >102 cm in men and
>88 cm in women) the strong inverse relationship

Multivariatea

Univariate
BMI category
1
2
3
4
5
6

(18.5–20.9 kg/m2)
(21.0–22.9 kg/m2l)
(23.0–24.9 kg/m2)
(25.0–26.9 kg/m2)
(27.0–29.9 kg/m2)
(‡30.0 kg/m2)

765

OR (95% CI)

P

OR (95% CI)

P

1
0.97
0.50
1.57
1.40
2.58

–
0.93
0.12
0.35
0.42
0.03

1
0.84
0.65
1.71
1.69
2.46

–
0.57
0.44
0.20
0.30
0.04

(0.49–1.92)
(0.21–1.21)
(0.61–4.07)
(0.62–3.19)
(1.06–6.92)

(0.46–1.53)
(0.22–1.95)
(0.66–7.15)
(0.63–4.55)
(1.06–8.61)

a
Adjusted for age, sex, smoking, the presence of hypertension and diabetes mellitus, and levels
of TC, TG, LDL-C and HDL-C.

 2007 EFNS European Journal of Neurology 14, 762–769

766

H. J. Milionis et al.

Multivariatea

Univariate

WC (cm)
TC (mol/l)
HDL-C (mmol/l)
TG (mmol/l)
TC · BMI
TC · BMI25
TC · BMI30
TC · WC
TC · ÔincreasedÕ WC
TG · BMI
TG · BMI25
TG · BMI30
TG · WC
TG · ÔincreasedÕ WC
HDL-C · BMI
HDL-C · BMI25
HDL-C · BMI30
HDL-C · WC
HDL-C · ÔincreasedÕ WC

OR (95% CI)

P

OR (95% CI)

P

1.01
0.98
0.03
4.40
1.00
1.03
1.09
1.00
1.02
1.06
1.36
1.70
1.02
1.34
0.90
0.81
1.23
0.97
0.81

0.47
0.90