Risk factors for first ever acute ischem

International Journal of Cardiology 99 (2005) 269 – 275
www.elsevier.com/locate/ijcard

Risk factors for first-ever acute ischemic non-embolic
stroke in elderly individuals
Haralampos J. Milionis a, Evangelos Liberopoulos a, John Goudevenos a,
Eleni T. Bairaktari b, Konstantinos Seferiadis b, Moses S. Elisaf a,*
a

Department of Internal Medicine, Medical School, University of Ioannina, 451 10 Ioannina, Greece
b
Laboratory of Biochemistry, University Hospital of Ioannina, Ioannina, Greece

Received 25 September 2003; received in revised form 31 December 2003; accepted 8 January 2004
Available online 2 April 2004

Abstract
Background: Stroke is a leading cause of mortality and subsequent serious long-term physical and mental disability among survivors. In
the elderly, ischemic stroke accounts for more than 80% of all strokes. Objectives: To identify major risk factors for a first-ever acute
ischemic/non-embolic stroke in individuals older than 70 years. Methods: A population-based case-control study of patients admitted to the
University Hospital of Ioannina, Epirus, Greece, due to first-ever ischemic/non-embolic stroke from March 1997 to January 2002. All

patients were subjected to brain CT and had their serum lipids and biochemical metabolic parameters determined within 24 h from the onset
of symptoms. Results: A total of 163 (aged > 70 years) consecutive stroke patients and 166 apparently healthy volunteers were studied. An
atherogenic lipid profile and metabolic disturbances were more prevalent in the patient group than in stroke-free controls. Multivariate
logistic regression analysis identified diabetes mellitus (odds ratio (OR), 1.92; 95% CI, 1.02 – 3.63), triglycerides (TG) (OR, 1.16; 95% CI,
1.09 – 1.22), HDL-cholesterol (OR, 0.57; 95% CI, 0.43 – 0.76), apo A – I (OR, 0.80; 95% CI, 0.70 – 0.92), lipoprotein(a) [LP(a)] (OR, 1.51;
95% CI, 1.25 – 1.79), uric acid (OR, 1.30; 95% CI, 1.06 – 1.59) albumin (OR, 0.38; 95% CI, 0.20 – 0.70) fibrinogen (OR, 1.10; 95% CI, 1.05 –
1.13) and the metabolic syndrome (OR 2.48, 95% CI, 1.16 – 5.29) as significantly associated with ischemic/non-embolic stroke. Conclusion:
Ischemic non-embolic stroke in the elderly is associated with dyslipidemia and several predictor metabolic factors, which could be
substantially modified by lifestyle changes and therapeutic intervention.
D 2004 Elsevier Ireland Ltd. All rights reserved.
Keywords: First-ever acute ischemic non-embolic stroke; Elderly individuals; Dyslipidemia

1. Introduction
Throughout the industrialized world, a remarkable increase in the proportion of the ‘‘elderly’’ population, however
this term is defined, has taken place [1]. Therefore, it is
becoming increasingly important for societies to quantify the
burden of illness in their ageing populations [2]. Stroke is one
of the leading causes of mortality in the developed countries
leading to serious long-term physical and mental disabilities
among survivors [3]. In the elderly, more than 80% of all

strokes have an ischemic etiology. There is some debate as to
whether hyperlipidemia is causally associated with stroke [4].
Although, there is limited evidence of proven benefit from
* Corresponding author. Tel.: +30-26510-97509; fax: +30-2651097016.
E-mail address: hmilioni@cc.uoi.gr (M.S. Elisaf).
0167-5273/$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ijcard.2004.01.013

correcting the ‘‘deranged variables’’, it would be clinically
useful to identify, monitor and appropriately manage any
modifiable risk factors for stroke in elderly populations [5].
The aim of our study was to identify major risk factors
for a first-ever acute ischemic/non-embolic stroke in individuals older than 70 years of age.

2. Subjects and methods
We conducted a population-based case-control study in
the prefecture of Ioannina, Epirus, a region of Northwestern
Greece with about 170,000 inhabitants. A total of 163
elderly patients (88 men and 75 women) who were consecutively hospitalized over a 5-year period for first-ever acute
ischemic/non-embolic stroke were studied (March 1997 to

January 2002). Enrollment criteria were as follows: (i)

270

H.J. Milionis et al. / International Journal of Cardiology 99 (2005) 269–275

patients diagnosed to suffer a first-ever episode of acute
cerebral ischemia (fatal/non-fatal cerebral infarctions, and
transient ischemic attacks), (ii) subjects older than 70 years
of age, (iii), subjects residing in the prefecture of Ioannina,
and (iv) patients reaching the Emergency Department of the
University Hospital of Ioannina within 12 h from the onset
of symptoms. Diagnosis of acute ischemic stroke was
established by clinical evaluation and confirmed by computed tomography [6].
One hundred and sixty-six apparently healthy volunteers (87 men and 79 women) annually evaluated in the
primary care setting (Public Primary Care Health Center
facilities) in the prefecture of Ioannina comprised the
control group. About 2000 individuals routinely receive
health care (in terms of check up, lab tests and drug
prescribing) in these facilities every year. The control

group was made up of individuals consecutively evaluated
during the study period; subjects eligible for the control
group were older than 70 years of age, resided in the
prefecture of Ioannina, and had no previous history of
cardiovascular disease. All subjects gave informed consent
to use information concerning their hospitalization and the
study protocol was approved by the Institutional Ethics
Committee.
Subjects with a history of a previous stroke, coronary
events (angina or myocardial infarction), active infections,
neoplasia, renal or liver disease, thyroid dysfunction, chronic obstructive pulmonary disease, chronic inflammatory
bowel disease, and a history of excessive alcohol consumption were excluded from the study. Stroke patients and
controls with an identifiable embolic source (i.e. atrial
fibrillation, heart valve disease, patients receiving anticoagulant treatment) were also excluded [7]. Subjects were
included in the study on the basis of complete laboratory
analyses.
According to their medical records, 77 stroke patients
and 60 controls were on antihypertensive treatment, including diuretics, beta-blockers, ACE inhibitors and calcium
antagonists; 41 patients and 29 controls were treated for
diabetes mellitus with oral hypoglycemic agents (biguanide

or sulfornylurea) F insulin, while 12 subjects in the patient
group and 15 subjects in the control group were taking
aspirin. None of the participants was receiving lipid-lowering treatment, such as statins and fibrates during the study
period.
Hypertensive patients were recorded according to medical history and relevant drug treatment. Diabetes mellitus
was coded as present if a subject was treated for diabetes as
well as by fasting blood glucose measurements (>126 mg/
dl). The diagnosis of metabolic syndrome was made when
three or more of the following risk determinants were
present: abdominal obesity (waist circumference >102 cm
for men and >88 cm for women), triglycerides z 150 mg/dl,
low HDL-cholesterol (i.e. < 40 mg/dl for men and < 50 mg/
dl for women), blood pressure z 130/ z 85 mm Hg, and
fasting glucose z 110 mg/dl (8).

3. Laboratory investigations
Upon admission blood samples were drawn for complete
blood count, plasma fibrinogen, serum creatinine, urea and
electrolytes, iron, ferritin, uric acid, albumin, total bilirubin,
thyroid stimulating hormone (TSH), total T3, and free

thyroxine (free T4) determinations [9].
Blood samples for glucose and lipid determination were
drawn after overnight fasting.
All biochemical analyses were performed by commercially available standardized methods within 24 h after
stroke onset.
Plasma fibrinogen levels were measured by the Clauss
method as previously described [10].
The laboratory determinations were carried out by automated chemical analysis in our laboratory using Olympus
AU 560 analyzer. Specifically, serum samples were analyzed by using ion-sensitive electrodes for sodium, potassium and chloride, for calcium, and photometric assays for
phosphorus and magnesium. The glutamate dehydrogenase
(GLDH) method was used for the determination of urea
levels, and a modification of the Jaffe´-method for creatinine.
Serum total protein concentrations were measured by the
Biuret method, and serum albumin by the bromocresol
green (BCG) method. Glucose was measured by the hexokinase method, and serum iron levels were measured by the
TPTZ (2,4,6-Tri [2 pyridyl]-5-tiazine) method. Total bilirubin, was measured by the diazonium tetrafluoroborate
(DPD) method. A chemiluminescent microparticle immunoassay (CMIA) was used for the determination of serum
ferritin (Architect Ferritin assay, Abbot Laboratories, Abbott
Park, IL, USA).
Total T3 (reference range 0.6 – 1.7 ng/ml), free T4

(reference range 0.7 –2.7 ng/dl) and TSH (reference range
0.2 – 4.8 mU/l) were measured by immunoassay on an
AxSYM analyzer (Abbot Laboratory). The sensitivities of
the assays were calculated to be 0.3 ng/ml, 0.4 ng/dl and
0.03 mU/l, respectively.
Levels of total cholesterol (TC) and triglycerides (TG)
were determined by an enzymatic colorimetric assay using a
RA-1000 analyzer (Technicon Instruments, Terrytown, NY,
USA). HDL cholesterol (HDL-C) was determined enzymatically from the supernatant after precipitation of other lipoproteins with dextran sulfate magnesium. Levels of LDL
cholesterol (LDL-C) were calculated using the Friedewald
formula. Serum levels of apolipoproteins (apo) A –I and B
were measured by immunonephelometry using a Beckman
array analyzer (Beckman Instruments, Fullerton, CA, USA).
Lipoprotein (a) [Lp(a)] levels were measured using a monoclonal antilipoprotein (a) antibody technique and enzymelinked immunoassay (Terumo Medical Corporation Diagnostic Division, Elkron, MD, USA) [11]. The lower limit of
detectability was 0.8 mg/dl. In cases of Lp(a) levels less than
0.8 mg/dl, the value of 0.8 mg/dl was used for statistical
analysis. The intra-assay and interassay coefficients of variation were less than 6% and 10.3%, respectively.

271

H.J. Milionis et al. / International Journal of Cardiology 99 (2005) 269–275

4. Statistical analysis

Table 2
Laboratory parameters in the study population

Values were expressed as mean F S.D., except for age,
Lp(a), and fibrinogen which were expressed in terms of
median and range. A comparison of continuous variables
was performed by an unpaired two-tailed Student’s test,
while v2-tests were used for categorical variables. Because
of the highly skewed distribution of Lp(a), the non-parametric Mann – Whitney U test was applied to discriminate
differences in Lp(a) levels between patients and controls.
The strength of associations between serum parameters
(lipid and non-lipid) and acute ischemic/non-embolic stroke
were assessed by means of logistic regression analysis
(backward stepwise likelihood ratio) comparing stroke and
control subjects. Two models were used for analysis: a first
model which included age, gender, BMI, the presence of

hypertension, diabetes mellitus, metabolic syndrome, smoking, and lipidemic parameters [TC, TG, HDL, apo A –I, apo
B, Lp(a)] and a second model which, in addition, included
fibrinogen and other metabolic parameters, such as uric
acid, albumin, total bilirubin and ferritin.
Significance levels were set at p < 0.05 in all cases. SPSS
10.0 for Windows (SPSS, 1989 – 1999), and Statistica
(1998, Statsoft, Tulsa, OK, USA) were used to perform
statistical analysis.

Parameters*

Stroke patients
(n = 163)

Control population
(n = 166)

p

TC (mg/dl)

LDL-C (mg/dl)
HDL-C (mg/dl)
TG (mg/dl)
TC/HDL-C
Apo A – I (mg/dl)
Apo B (mg/dl)
Lp(a) (mg/dl)
Fibrinogen (mg/dl)
Uric acid (mg/dl)
Albumin (g/dl)
Total Bilirubin (mg/dl)
Iron (Ag/dl)
Ferritin (ng/ml)
TSH (AU/ml)
Free T4 (ng/dl)
T3 (ng/ml)
Creatinine (mg/dl)
Urea (mg/dl)
Potassium (mmol/l)
Sodium (mmol/l)

Calcium (mg/dl)
Magnesium (mEq/l)
Phosphorus (mg/dl)

207 F 49
132 F 42
40 F 11
175 F 74
5.5 F 1.8
130 F 24
132 F 24
15.7(0.8 – 65.3)
432(132 – 633)
5.6 F 1.7
3.8 F 0.5
0.7 F 0.3
64.4 F 29.4
42.9 F 18.9
1.8 F 1.1
1.3 F 0.4
1.1 F 0.2
1.1 F 0.6
41.8 F 14.9
4.3 F 0.5
138.5 F 3.5
8.4 F 0.9
1.5 F 0.2
3.2 F 0.8

208 F 43
132 F 45
51 F 11
125 F 80
4.2 F 1.2
150 F 22
127 F 26
7.1(0.8 – 48)
302(114 – 608)
4.8 F 1.4
4.1 F 0.6
0.8 F 0.3
63.9 F 27.1
41.6 F 17.3
1.7 F 1.2
1.3 F 0.3
1.1 F 0.2
1.0 F 0.6
38.4 F 14.2
4.3 F 0.5
138.9 F 3.0
8.5 F 1.0
1.5 F 0.2
3.4 F 0.7

NS
NS
< 0.001
< 0.001
< 0.001
< 0.001
NS
< 0.001
< 0.001
< 0.001
< 0.001
< 0.02
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS

5. Results
The clinical characteristics of the study population are
shown in Table 1. Body weight and smoking habits were
similar among patients and controls. The prevalence of
hypertension and diabetes mellitus was greater in stroke
patients compared to the control group. However, there were
no statistically significant differences among groups (Table
1). Metabolic syndrome was more frequent among patients
suffering first-ever acute ischemic stroke than in the control
group (46.0% vs. 15.7%, p < 0.001; Table 1). Among
patients with the metabolic syndrome, 52 (69.4%) had three

Table 1
Clinical characteristics of the study population
Stroke patients Control population p
(n = 163)
(n = 166)
Gender
Male
Female
Age (years)
Body mass index (kg/m2)
Current smokers
Male
Female
Hypertension
Diabetes mellitus
Metabolic syndromea

NS
88
75
78 (70 – 90)
26.1 F 3.1

87
79
77 (70 – 92)
25.5 F 2.6

38
5
77 (47.2%)
46 (28.2%)
75 (46.0%)

42
3
61 (36.7%)
34 (20.5%)
26 (15.7)

NS
NS
NS

0.07
0.1
< 0.001

Age is expressed as median (range), and body mass index as means F S.D.
a
Metabolic syndrome is defined in the text.

TC: total cholesterol, TG: triglycerides, Apo: apolipoprotein, Lp(a):
lipoprotein(a). Values represent means F S.D., except for Lp(a) and
fibrinogen where median and ranges are shown.
*To convert data from mg/dl to mmol/l divide TC, LDL-C, and HDL-C by
38.7 and TG by 88.6. To convert data from mg/dl to g/l divide fibrinogen
by 100. To convert data from g/dl to g/l, multiply albumin by 10. To convert
mg/dl to Amol/l, multiply uric acid by 59.5, creatinine by 88.4, and total
bilirubin by 17.10. To convert Ag/dl to Amol/l, multiply iron by 0.18. To
convert data from AU/ml to mU/l, multiply TSH by 1.0. To convert data
from ng/dl to pmol/l, multiply free T4 by 12.9. To convert data from ng/ml
to nmol/l, multiply T3 by 0.0154. To convert mg/dl to mmol/l, multiply
urea by 0.17, calcium by 0.25 and phosphorus by 0.32. To convert data
from mEq/l to mmol/l, multiply magnesium by 0.5.

of its features, 16 (21.3%) had four, and 7 (9.3%) had all
five features; in the control group, 19 (73.1%) subjects had
three, 6 (23.1%) had four and 1 (3.8%) had all five features
of the metabolic syndrome.
Stroke patients exhibited a more atherogenic lipid profile
compared to controls (Table 2). Specifically, both groups
had similar serum TC levels LDL-C and apo B levels.
Nevertheless, stroke patients had higher values of the
atherogenic risk ratio (TC/HDL-C, 5.5 F 1.8 vs. 4.2 F 1.2,
p < 0.001), TG [175 F 74 mg/dl (2.0 F 0.8 mmol/l) vs.
125 F 80 mg/dl (1.4 F 0.9 mmol/l), p < 0.001], and Lp(a)
(median value, 15.7 vs. 7.1 mg/dl, p < 0.001), whereas they
displayed lower concentrations of HDL-C [40 F 11 mg/dl
(1.0 F 0.3 mmol/l) vs. 51 F 11 mg/dl (1.3 F 0.3 mmol/l),
p < 0.001], and apo A –I (130 F 24 vs. 150 F 22 mg/dl,
p < 0.001) (Table 2).
Stroke patients had increased serum uric acid [5.6 F 1.7
mg/dl (333.1 F 101.1 Amol/l) vs. 4.8 F 1.4 mg/dl
(285.5 F 83.3 Amol/l), p < 0.001] and plasma fibrinogen

272

H.J. Milionis et al. / International Journal of Cardiology 99 (2005) 269–275

levels [median value 432 mg/dl (4.3 g/l) vs. 302 mg/dl (3.0
g/l), p < 0.001] compared to controls (Table 2). There were
no statistically significant differences in fibrinogen levels
between men and women either in the patients’ group
[median value 444 mg/dl (4.4 g/l) in men vs. 412 mg/dl
(4.1 g/l) in women] or in the control group [median value
311 mg/dl (3.1 g/l) in men vs. 293 mg/dl (2.9 g/l) in
women]. In contrast, serum albumin and total bilirubin
levels were lower in the patients’ group [3.8 F 0.5 g/dl
(38 F 5 g/l) vs. 4.1 F 0.6 g/dl (41 F 6 g/l), p < 0.001 for
albumin; 0.7 F 0.3 mg/dl (12.0 F 4.8 Amol/l) vs. 0.8 F 0.3
mg/dl (13.2 F 4.4 Amol/l), p < 0.02 for bilirubin]. No significant differences were shown for serum creatinine, urea
and electrolytes, iron and ferritin levels (Table 2).
In logistic regression analysis model 1, TG, HDL-C, apo
A – I, and Lp(a) levels were the major lipidemic parameters
to be strongly associated with stroke among elderly subjects
(Table 3). The presence of diabetes mellitus was associated
with a two-fold stroke risk (odds ratio (OR), 1.92; 95%
confidence interval, 1.02 – 3.63). In the second model
(which also included fibrinogen and serum metabolic
parameters, such as uric acid, albumin, total bilirubin, and
ferritin) strong associations were evident between ischemic
stroke and TG, HDL-C, Lp(a), fibrinogen, uric acid and
albumin, but not for total bilirubin (Table 3). It is of
importance that in this model, metabolic syndrome (which
represents a cluster of metabolic disturbances, including
impaired glucose tolerance, dyslipidemia, insulin resistance,
hypertension, and upper body obesity) was identified as
significantly associated with ischemic/non-embolic stroke
(odds ratio, 2.48; 95% confidence interval, 1.16 – 5.29).

Table 3
Multivariate comparison of cases and controls by logistic regression
analysis (backward stepwise likelihood ratio)
Parameters

Odds ratio (95% CI)a

p

Model 1
Diabetes mellitus
TG (mg/dl)
HDL-C (mg/dl)
Apo A – I (mg/dl)
Lp(a) (mg/dl)

1.92
1.16
0.57
0.80
1.51

(1.02 – 3.63)
(1.09 – 1.22)
(0.43 – 0.76)
(0.70 – 0.92)
(1.25 – 1.79)

0.04
< 0.001
< 0.001
0.002
< 0.001

Model 2
Metabolic syndrome
TG (mg/dl)
HDL-C (mg/dl)
Lp(a) (mg/dl)
Uric acid (mg/dl)
Albumin (g/dl)
Fibrinogen (mg/dl)

2.48
1.13
0.63
1.37
1.30
0.38
1.10

(1.16 – 5.29)
(1.06 – 1.21)
(0.46 – 0.86)
(1.12 – 1.67)
(1.06 – 1.59)
(0.20 – 0.70)
(1.05 – 1.13)

0.02
< 0.001
0.004
0.002
0.01
0.002
< 0.001

First model included age, gender, BMI, the presence hypertension, diabetes,
metabolic syndrome and smoking as well as lipidemic parameters [TC, TG,
HDL, apo A – I, apo B, Lp(a)]. Second model, in addition, included
fibrinogen, uric acid, albumin, total bilirubin and ferritin.
a
Values represent odds ratios per 10 mg/dl changes in TG, HDL-C,
Apo A – I, Lp(a) and fibrinogen levels, whereas values for uric acid and
albumin represent odd ratios per mg/dl and g/dl changes, respectively.

6. Discussion
It has been reported that in Japan and China, the age
standardized annual death rate from stroke is greater than
that of coronary heart disease (CHD), whereas in Northern
Europe and the USA the CHD associated mortality is three
to four times greater than the stroke related deaths [12]. In
contrast, in Mediterranean countries, deaths as a result of
both CHD and stroke display an approximate 1:1 ratio
[12,13]. Serum lipid values, smoking, alcohol intake, and
traditional diets may account for these differences [14]. Our
study was held in the prefecture of Ioannina, Epirus (Northwestern Greece), a non-industrialized region of the country
where at least the elderly (which comprise about 17% of the
population) lead their lives in a more traditional way. In this
area, eating habits in the elderly population remained
unchanged for years (Mediterranean diet, including olive
oil and minimal saturated fat consumption, close to NCEP
step I diet), while smoking is strictly considered as a ‘‘male
privilege’’ [12,13,15]. This is in contrast to a more westernized way of living followed by urban younger population
residing in the city of Ioannina. Surprisingly, smoking was
not identified as a significant risk factor for ischemic stroke.
This could be explained by the small number of smokers
among study participants, especially women.
Hypertension and diabetes rates were relatively high in
the study population. It is well documented that the prevalence of hypertension rises with advancing age. For example in the Framingham cohort, in those aged 70 to 79,
almost 50% had borderline hypertension [16]. Moreover, the
institution of the novel criteria introduced by the American
Diabetes Association for the diagnosis of diabetes mellitus
leads to an increased number of subjects at risk [17]. The
presence of diabetes mellitus was associated with a two-fold
stroke risk in our study. All things considered, a gradual
decline in the physiologic reserve of all organ systems,
vulnerability to degenerative diseases and polypharmacy are
common problems associated with old age [5].
In the present study, stroke patients exhibited a more
atherogenic lipid profile compared to CHD-free controls.
Whether lipid abnormalities are causally associated with a
higher incidence of stroke remains controversial [18,19].
Early studies did not suggest that raised serum TC levels
consistently predict stroke-related mortality [20,21]. Furthermore, in some studies, TC levels are strongly but
inversely related to stroke death [22]. Nevertheless, the
presence of a link between hyperlipidemia and stroke is
supported by the growing evidence that lipid-lowering
treatment (especially statins) can significantly reduce the
risk of stroke [23 – 27]. In the recently published Heart
Protection Study (HPS), in which large numbers of older
individuals (men and women) were included, simvastatin
treatment produced a favorable effect on blood lipids and on
vascular disease outcomes [28]. There was a definite and
substantial reduction in ischemic stroke, including transient
ischemic attacks, whereas lipid-lowering therapy was not

H.J. Milionis et al. / International Journal of Cardiology 99 (2005) 269–275

associated with a decrease in the risk of hemorrhagic stroke
[28]. Very low TC levels have been associated with an
increased risk for hemorrhagic strokes [23]. However,
evidence from recent statin trials, in which patients reached
very low LDL-C levels, showed a decrease in strokes
[29,30].
Total-C, LDL-C and apoB levels were similar among
stroke patients and controls. It was the TG, HDL and apoA
levels, which significantly differed between the two groups.
It has been shown that postprandial hypertriglyceridemia is
associated with carotid artery atherosclerosis [31]. However,
there is a controversy regarding the association between
serum TG levels and stroke [32]. Nonetheless, in the
Copenhagen City Heart Study, a log linear association
between serum TG levels and non-hemorrhagic stroke was
found, which was independent of age and gender [33]. In
general, in the majority of studies, an inverse association
between HDL-C and stroke risk has been documented [32].
In the Northern Manhattan Stroke Study, increased levels of
HDL-C are associated with reduced risk of ischemic stroke
in the elderly and among different racial or ethnic groups
[34]. These findings are in concordance with evidence
relating these lipid parameters to stroke and strongly support
HDL-C and TG as important modifiable stroke risk factors
[35].
Stroke patients had remarkably higher Lp(a) levels as
compared to controls. Elevated LDL and Lp(a) levels have
been associated with an increased risk of non-hemorrhagic
stroke [36,37]. Lp(a), a predictor of atherosclerotic disease,
has been proposed as a link between lipids and hemostasis
[38]. The accumulation of Lp(a) molecules has been demonstrated in the arterial walls of both human coronary and
cerebral vessels. However, the evidence that Lp(a) is a
strong predictor for ischemic stroke is contradictory
[37,39]. Methodological problems in the determination of
Lp(a) levels might contribute to the existing confusion in
attributing risk to Lp(a) [11,38,39]. It has also been suggested that the coexistence of other risk factors (such as
dyslipidemia or raised homocysteine values) reinforces the
atherosclerotic potential of Lp(a) [37,38].
Stroke patients had significantly higher fibrinogen levels
compared to controls. This finding is in agreement with
evidence suggesting that fibrinogen is a powerful predictor
of vascular events in healthy populations as well as and
patients with cardiovascular disease [40]. Plasma fibrinogen
levels are associated with an increased stroke risk and are
considered of significant prognostic influence in stroke
patients [41,42]. However, measurement of fibrinogen levels is subjected to certain methodological limitations
[10,40]. In the present study, we followed the recommendations most authorities advocate that fibrinogen levels
should be measured within 24 h from the onset of symptoms
[10,40,42,43]. Although high fibrinogen levels have been
reported to be accounted for by environmental and genetic
influence, its expression is regulated by interleukin-6 and
impaired by transforming growth factor-h similar to other

273

acute-phase proteins [40]. This raises the question whether
raised plasma fibrinogen is the epiphenomenon of the
severity of the vascular injury taking place in the brain.
Therefore, although relevant from a therapeutic point of
view (i.e. measure fibrinogen levels to identify high risk
subjects), the prognostic value of fibrinogen is still of little
clinical relevance [40 –43].
Increased uric acid levels have been reported to be a
predictor of stroke [44,45]. This is in agreement with our
findings. Although an independent association between
elevated uric acid serum levels and increased atherosclerotic
disease or mortality is evident in some studies, others
suggest that this association is due to concurrent risk factors
related to the polymetabolic syndrome (i.e. hypertension,
diuretic use, insulin resistance, hyperlipidemia, obesity)
[46,47]. It has been proposed that uric acid may increase
platelet adhesiveness and urate crystals may induce platelet
lysis, thus accelerating thrombogenesis [48]. Uric acid may
also play a role in the formation of free radicals and
oxidative stress [49,50].
Interestingly, serum albumin and total bilirubin levels
were lower in stroke patients compared to controls. This
inverse relationship between serum albumin and stroke risk
may reflect the nutritional status and well-being, which are
important factors for the development and prognosis of a
cerebrovascular event [51,52]. There is also evidence that
higher levels of total serum bilirubin are associated with a
lower risk for cardiovascular disease [53]. This was limited
to men in the Framingham study [54]. Bilirubin is a wellknown antioxidant and may protect LDL from oxidation
[55]. Furthermore, bilirubin appears to be cytoprotective to
rat hepatocytes, human erythrocytes and human monocytes
when these cells are exposed to oxyradicals [55]. It has also
been reported that higher levels of bilirubin are inversely
associated with the presence of atheromatous plaques in the
carotid arteries [56]. Thus, higher bilirubin levels seem to
protect against stroke in the elderly.
Iron stores, as measured by serum ferritin levels, were
considered as a risk factor for CHD. However, recent
evidence does not support this hypothesis [57]. According
to our findings, there were no significant differences in
serum ferritin concentrations between stroke patients and
controls.
Metabolic syndrome represents a ‘‘constellation’’ of lipid
and no-lipid risk factors and is closely linked to a generalized metabolic disorder refer to as insulin resistance [8,58].
It is of import that stroke patients in our study were more
frequently diagnosed as suffering from metabolic syndrome
than CHD-free controls and its presence was associated with
a three-fold stroke risk. Since the metabolic syndrome is
considered a potential secondary target of lipid-lowering
treatment, its recognition in the elderly merits management
of its underlying causes.
In conclusion, ischemic non-embolic stroke in the elderly
is associated with dyslipidemia and several predictor metabolic factors. Currently, most authorities suggest that clin-

274

H.J. Milionis et al. / International Journal of Cardiology 99 (2005) 269–275

ical problems and/or metabolic disturbances in the elderly
patient should be considered as the result of a disease
process rather than the result of ‘‘just getting old’’. Therefore, identification of high-risk subjects warrants management with lifestyle changes and appropriate treatment.

References
[1] Buckley BM. Healthy ageing: ageing safely. Eur Heart J Suppl 2001;
3(Suppl. N):N6 – 10.
[2] Hankey GJ, Warlow CP. Treatment and secondary prevention of
stroke: evidence, costs, and effects on individuals and populations.
Lancet 1999;354:1457 – 63.
[3] Bonita R. Epidemiology of stroke. Lancet 1992;339:342 – 4.
[4] Futterman LG, Lemberg L. Stroke risk, cholesterol and statins. Am J
Crit Care 1999;8:416 – 9.
[5] Avorn J. Unhealthy ageing: functional and socio-economic impact.
Eur Heart J Suppl 2001;3(Suppl. N):N3 – 5.
[6] Moonis M, Fisher M. Imaging of acute stroke. Cerebrovasc Dis 2001;
11:143 – 50.
[7] Brickner ME. Cardioembolic stroke. Am J Med 1996;100:465 – 74.
[8] Executive summary of the third report of the National Cholesterol
Education Program (NCEP) Expert Panel on Detection, Evaluation,
and Treatment of High Blood Cholesterol in Adults (Adult Treatment
Panel III). J Am Med Assoc 2001;285:2486 – 97.
[9] Bruckert E, Giral P, Chadarevian R, Turpin G. Low free-thyroxine
levels are a risk factor for subclinical atherosclerosis in euthyroid
hyperlipidemic patients. J Cardiovasc Risk 1999;6:327 – 31.
[10] Goudevenos JA, Bairaktari ETh, Chatzidimou KG, Milionis HJ,
Mikhailidis DP, Elisaf MS. The effect of atorvastatin on serum lipids,
lipoprotein (a) and plasma fibrinogen levels in primary dyslipidaemia.
A pilot study involving serial sampling. Curr Med Res Opin 2001;6:
269 – 75.
[11] Lippi G, Guidi G. Standardization and clinical management of lipoprotein (a) measurements. Clin Chem Lab Med 1998;36:5 – 16.
[12] World Health Organization. Tobacco or health: a global status report.
Geneva: World Health Organization; 1997.
[13] Chimonas ET. Mortality trends and main causes of death in the Greek
population. Curr Med Res Opin 2001;17:27 – 33.
[14] Reed DM. The paradox of high risk of stroke in populations with low
risk of coronary heart disease. Am J Epidemiol 1990;131:579 – 88.
[15] Summary of the second report of the National Cholesterol Educational Program (NCEP) Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults. J Am Med Assoc
1993;269:3015 – 23.
[16] Seshadri S, Wolf PA, Beiser A, et al. Elevated midlife blood pressure
increases stroke risk in elderly persons: the Framingham Study. Arch
Intern Med 2001;161:2343 – 50.
[17] Expert Committee on the Diagnosis and Classification of Diabetes
Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997;20:1183 – 97.
[18] Demchuk AM, Hess DC, Brass LM, Yatsu FM. Is cholesterol a risk
factor for stroke? Yes. Arch Neurol 1999;56:1518 – 20.
[19] Landau WM. Is cholesterol a risk factor for stroke? No. Arch Neurol
1999;56:1521 – 4.
[20] Rastenyte D, Tuomilehto J, Domarkiene S, Cepaitis Z, Reklaitiene R.
Risk factors for death from stroke in middle-aged Lithuanian men:
results from a 20-year prospective study. Stroke 1996;27:672 – 6.
[21] Palmer A, Bulpitt C, Beevers G, et al. Risk factors for ischaemic
heart disease and stroke mortality in young and old hypertensive
patients. J Hum Hypertens 1995;9:695 – 7.
[22] Menotti A, Blackburn H, Kromhout D, et al. The inverse relation of
average population blood pressure and stroke mortality rates in the
seven countries study: a paradox. Eur J Epidemiol 1997;13:379 – 86.

[23] Papadakis JA, Mikhailidis DP, Winder AF. Lipids and stroke: neglect of a useful preventive measure? Cardiovasc Res 1998;40:
265 – 71.
[24] Blauw GJ, Lagaay AM, Smelt AH, Westendorp RG. Stroke, statins,
and cholesterol. A meta-analysis of randomized, placebo-controlled,
double-blind trials with HMG-CoA reductase inhibitors. Stroke 1997;
28:946 – 50.
[25] Lewis SJ, Moye LA, Sacks FM, et al., for the CARE Investigators.
Effect of pravastatin on cardiovascular events in older patients with
myocardial infarction and cholesterol levels in the average range.
Results of the Cholesterol and Recurrent Events (CARE) Trial. Ann
Intern Med 1998;129:681 – 9.
[26] Pedersen TR, Kjekshus J, Pyorala K, et al. Effect of simvastatin on
ischaemic signs and symptoms in the Scandinavian Simvastatin Survival Study (4S). Am J Cardiol 1998;81:333 – 5.
[27] White HD, Simes RJ, Anderson NE, et al. Pravastatin therapy and the
risk of stroke. N Engl J Med 2000;343:317 – 26.
[28] Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk
individuals: a randomized placebo-controlled trial. Lancet 2002;360:
7 – 22.
[29] Athyros VG, Papageorgiou AA, Mercouris BR, et al. Treatment with
Atorvastatin to the National Cholesterol Educational Program Goal
versus ‘usual’ care in secondary coronary heart disease prevention.
The GREek Atorvastatin and Coronary-heart-disease Evaluation
(GREACE) Study. Curr Med Res Opin 2002;18:220 – 8.
[30] Sever PS, Dahlo¨f B, Poulter NR, et al., for the ASCOT investigators.
Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol
concentrations, in the Anglo-Scandinavian Cardiac Outcomes TrialLipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361:1149 – 58.
[31] Ryu JE, Howard G, Craven TE, Bond MG, Hagaman AP, Crouse 3rd
JR. Postprandial triglyceridemia and carotid atherosclerosis in middleaged subjects. Stroke 1992;23:823 – 8.
[32] Rizos E, Mikhailidis DP. Are high density lipoprotein (HDL) and
triglyceride levels relevant in stroke prevention? Cardiovasc Res
2001;52:199 – 207.
[33] Lindenstrom E, Boysen G, Nyboe J. Influence of total cholesterol,
high-density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease: the Copenhagen City Heart Study. Br Med J
1994;309:11 – 5.
[34] Sacco RL, Benson RT, Kargman DE, et al. High-density lipoprotein
cholesterol and ischemic stroke in the elderly. The Northern Manhattan Stroke Study. J Am Med Assoc 2001;285:2729 – 35.
[35] Tanne D, Koren-Morag N, Graff E, Goldbourt U. Blood lipids and
first-ever ischemic stroke/transient ischemic attack in the Bezafibrate
Infarction Prevention (BIP) Registry: high triglycerides constitute an
independent risk factor. Circulation 2001;104:2892 – 7.
[36] Bostom AG, Cupples LA, Jenner JL, et al. Elevated plasma lipoprotein (a) and premature coronary heart disease in Framingham men: a
prospective study. J Am Med Assoc 1996;276:544 – 8.
[37] Milionis HJ, Winder AF, Mikhailidis DP. Lipoprotein (a) and stroke. J
Clin Pathol 2000;53:487 – 96.
[38] Hobbs HH, White AL. Lipoprotein (a): intrigues and insights. Curr
Opin Lipidol 1999;10:225 – 36.
[39] Luc G, Bard JM, Arveiler D, et al., on behalf of the PRIME Study
Group. Lipoprotein (a) as a predictor of coronary heart disease: the
PRIME Study. Atherosclerosis 2002;163:377 – 84.
[40] Maresca G, Di Blasio A, Marchioli R, Di Minno G. Measuring plasma fibrinogen to predict stroke and myocardial infarction. Arterioscler
Thromb Vasc Biol 1999;19:1368 – 77.
[41] Folsom AR, Rosamond WD, Shahar E, et al., for the Atherosclerosis
Risk in Communities (ARIC) Study Investigators. Prospective study
of markers of hemostatic function with risk of ischemic stroke. Circulation 1999;100:736 – 42.
[42] Di Napoli M, Papa F, Bocola V. Prognostic influence of increased

H.J. Milionis et al. / International Journal of Cardiology 99 (2005) 269–275

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

C-reactive protein and fibrinogen levels in ischemic stroke. Stroke
2001;32:133 – 8.
Di Napoli M, Papa F, for the Villi Pini Stroke Data Bank Investigators. Inflammation, hemostatic markers, and antithrombotic agents in
relation to long-term risk of new cardiovascular events in first-ever
ischemic stroke patients. Stroke 2002;33:1763 – 71.
Matias-Guiu J, Alvarez J, Insa R, et al. Ischemic stroke in young
adults: II. Analysis of risk factors in the etiological subgroups. Acta
Neurol Scand 1990;81:314 – 7.
Longo-Mbenza B, Luila EL, Mbete P, Vita EK. Is hyperuricemia a
risk factor of stroke and coronary heart disease among Africans? Int J
Cardiol 1999;71:17 – 22.
Fang J, Alderman MH. Serum uric acid and cardiovascular mortality.
The NHANES I epidemiologic follow-up study, 1971 – 1992. J Am
Med Assoc 2000;283:2404 – 10.
Lee J, Sparrow D, Vokonas PS, Landsberg L, Weiss ST. Uric acid and
coronary heart disease risk: evidence for a role of uric acid in the
obesity-insulin resistance syndrome. The Normative Aging Study.
Am J Epidemiol 1995;142:288 – 94.
Ginsberg MH, Kozin F, O’Malley M, McCarty DJ. Release of platelet
constituents by monosodium urate crystals. J Clin Invest 1977;60:
999 – 1007.
Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides an
antioxidant defense in humans against oxidant- and radical-caused
aging and cancer: a hypothesis. Proc Natl Acad Sci U S A 1981;78:
6858 – 62.
Nieto FJ, Iribarren C, Gross MD, Comstock GW, Cutler RG. Uric

[51]

[52]

[53]

[54]

[55]

[56]

[57]

[58]

275

acid and serum antioxidant capacity: a reaction to atherosclerosis?
Atherosclerosis 2000;148:131 – 9.
Gillum RF. Assessment of serum albumin concentration as a risk
factor for stroke and coronary disease in African Americans and
whites. J Natl Med Assoc 2000;92:3 – 9.
Gariballa SE, Parker SG, Taub N, Castleden CM. Influence of nutritional status on clinical outcome after acute stroke. Am J Clin Nutr
1998;68:275 – 81.
Hunt SC, Kronenberg F, Eckfeldt JH, Hopkins PN, Myers RH, Heiss
G. Association of plasma bilirubin with coronary heart disease and
segregation of bilirubin as a major gene trait: the NHLBI family heart
study. Atherosclerosis 2001;154:747 – 54.
Djousse L, Levy D, Cupples LA, Evans JC, D’Agostino RB, Ellison
RC. Total serum bilirubin and risk of cardiovascular disease in the
Framingham Offspring Study. Am J Cardiol 2001;87:1196 – 200.
Wu TW, Fung KP, Wu J, Yang CC, Weisel RD. Antioxidation of
human low density lipoprotein by unconjugated and conjugated bilirubins. Biochem Pharmacol 1996;51:859 – 62.
Ishizaka N, Ishizaka Y, Takahashi E, Yamakado M, Hashimoto H.
High serum bilirubin level is inversely associated with the presence of
carotid plaque. Stroke 2001;32:581 – 3.
Pilote L, Joseph L, Be´lisle P, Robinson K, van Lente F, Tager IB. Iron
stores and coronary artery disease: a clinical application of a method
to incorporate measurement error of the exposure in a logistic regression model. J Clin Epidemiol 2000;53:809 – 16.
Vega GL. Obesity, the metabolic syndrome, and cardiovascular disease. Am Heart J 2001;142:1108 – 16.