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American Journal of Epidemiology
Copyright © 2004 by the Johns Hopkins Bloomberg School of Public Health
All rights reserved
Vol. 160, No. 2
Printed in U.S.A.
DOI: 10.1093/aje/kwh177
High Density Lipoprotein Cholesterol and the Risk of Stroke in Elderly Men
The Honolulu Heart Program
J. David Curb1,2,3, Robert D. Abbott1,3,4, Beatriz L. Rodriguez1,2,3, Kamal H. Masaki1,2,3, Randi
Chen1, Jordan S. Popper3, Helen Petrovitch1,2,3, G. Webster Ross1,2,3, Irwin J. Schatz2, Gina C.
Belleau1, and Katsuhiko Yano1
1
Pacific Health Research Institute, Honolulu, HI.
Departments of Geriatric Medicine and Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI.
3 Honolulu Heart Program, Kuakini Medical Center, Honolulu, HI.
4 Division of Biostatistics and Epidemiology, University of Virginia School of Medicine, Charlottesville, VA.
2
Received for publication November 20, 2003; accepted for publication January 29, 2004.
High density lipoprotein (HDL) cholesterol has been inversely associated with coronary heart disease.
Associations with stroke are less clear, particularly among the elderly. In this study, the authors examined the
relation between HDL cholesterol levels and the risk of stroke in elderly men. Levels of HDL cholesterol were
measured in 2,444 Honolulu Heart Program men aged 71–93 years at the 1991–1993 examinations. The
participants, who were free of prevalent stroke, coronary heart disease, and cancer at baseline, were followed to
the end of 1998 for thromboembolic and hemorrhagic stroke. While HDL cholesterol was unrelated to
hemorrhagic events, incidence of thromboembolic stroke declined consistently with increasing HDL cholesterol
level (p = 0.003). There was a nearly threefold excess of thromboembolic stroke in men with low HDL cholesterol
levels (<1.0 mmol/liter (<40 mg/dl)) compared with men with high levels (≥1.6 mmol/liter (≥60 mg/dl)) (10.6/1,000
person-years vs. 3.6/1,000 person-years; p = 0.001). Adjustment for other risk factors had little effect on these
findings, although associations appeared strongest in elderly men with “desirable” total cholesterol levels,
hypertension, or diabetes mellitus. These findings suggest that HDL cholesterol level is inversely related to the
risk of thromboembolic stroke in elderly men. Whether HDL cholesterol alters the effect of other factors on stroke
risk in elderly men warrants further study.
aged; cerebrovascular accident; lipoproteins, HDL cholesterol; men
Abbreviation: HDL, high density lipoprotein.
High density lipoprotein (HDL) cholesterol has been
inversely associated with the incidence of coronary heart
disease in population-based studies (1–9). Associations with
stroke, however, have not been clearly identified, particularly in the elderly (10–13). To our knowledge, no studies
have prospectively examined the relation between HDL
cholesterol and risk of stroke in older persons without prevalent disease, while also having the capacity to examine
effects within risk factor strata. Such studies in the elderly
are especially important in light of increasing evidence that
relations between traditional risk factors and cardiovascular
disease appear to change with advancing age. In the study
described here, we examined the association between HDL
cholesterol and risk of thromboembolic and hemorrhagic
stroke in elderly men without clinical cardiovascular disease
or cancer.
MATERIALS AND METHODS
Background and study sample
From 1965 to 1968, the Honolulu Heart Program began
following 8,006 men of Japanese ancestry living on the island
of Oahu, Hawaii, for the development of coronary heart
Reprint requests to Dr. J. David Curb, Pacific Health Research Institute, 846 South Hotel Street, Suite 301, Honolulu, HI 96817 (e-mail:
[email protected]).
150
Am J Epidemiol 2004;160:150–157
HDL Cholesterol and Stroke 151
disease and stroke (14, 15). Participants received complete
physical examinations at the time of study enrollment, when
they were aged 45–68 years. Since that time, subjects have
undergone repeat examinations, with comprehensive followup regarding all hospital discharges, death certificates, and
autopsy records for morbidity and mortality due to coronary
heart disease, cancer, and stroke. Procedures used have been
in accordance with institutional guidelines and approved by an
institutional review committee. Informed consent has been
obtained from the study participants.
For this report, follow-up for stroke began at the examination given to 3,741 participants in the Honolulu Heart
Program between 1991 and 1993 (approximately 80 percent
of the surviving cohort members). Follow-up for morbidity
and mortality due to stroke was complete through the end of
1998. After the exclusion of 1,192 men with prevalent
stroke, coronary heart disease (including angina pectoris and
coronary insufficiency), or cancer at the time of the baseline
examination (1991–1993) and 105 men with missing data on
HDL cholesterol, 2,444 men remained available for followup to the end of 1998. The average age at which follow-up
began was 78 years (range, 71–93 years).
Diagnosis of stroke
A diagnosis of stroke was made when a neurologic deficit
was accompanied by blood in the cerebrospinal fluid or by
evidence of an infarct or hemorrhage based on confirmation
from neuroimaging (conducted in more than 90 percent of
stroke victims). Probable strokes included neurologic deficits that persisted for at least 2 weeks or until death but were
not accompanied by blood in the cerebrospinal fluid or by
findings based on available neuroimaging data. All diagnoses were reviewed and confirmed by a study neurologist
and the Honolulu Heart Program Morbidity and Mortality
Review Committee. Possible strokes (neurologic deficits
lasting for at least 24 hours but less than 2 weeks or of
unknown duration) were not included among the stroke
events because of a lack of diagnostic certainty. A stroke was
considered thromboembolic if the focal neurologic deficit
usually occurred without prolonged unconsciousness, nuchal
rigidity, fever, pronounced leukocytosis, or blood in the
spinal fluid. Identification of hemorrhagic stroke was based
on a focal neurologic deficit accompanied by a loss of
consciousness, headache, and the presence of blood in the
spinal fluid (determined by atraumatic lumbar puncture,
computerized tomography, or surgical findings). Subjects
who experienced focal neurologic episodes attributed to
other conditions such as blood dyscrasia, neoplastic disease,
head injury, surgical accident, meningoencephalitis, fat
embolism, epilepsy, or cardiac arrest were not included
among the stroke victims. Further details on the diagnosis of
stroke are provided elsewhere (15).
HDL cholesterol levels and risk factors
Procedures for preparing collected blood specimens for
laboratory analysis adhered to the guidelines of the Lipid
Standardization Laboratory of the Centers for Disease
Control and Prevention. Blood specimens were collected
Am J Epidemiol 2004;160:150–157
after an overnight fast of at least 12 hours. Plasma was later
separated in a refrigerated centrifuge at 4°C and frozen at
–70°C for up to 2 months. Samples were then shipped on dry
ice to the University of Vermont for determination of total
cholesterol and HDL cholesterol levels. HDL cholesterol
was separated by precipitation with dextran sulfate and
magnesium chloride (16).
Other risk factors assessed or measured at the time blood
was drawn included age; hypertension; diabetes mellitus;
ankle-brachial index, a marker of peripheral vascular
disease; electrocardiographic evidence of atrial fibrillation;
body mass index (weight (kg)/height (m)2); alcohol intake
(ounces/day); and an index of physical activity. A diagnosis
of hypertension was made when either systolic blood pressure was ≥160 mmHg or diastolic blood pressure was ≥95
mmHg or the subject was taking medication for high blood
pressure. Diabetes was defined on the basis of medical
history or the use of insulin or oral hypoglycemic agents.
Diabetes was also considered present when fasting glucose
concentrations exceeded 6.9 mmol/liter (125 mg/dl) or when
glucose levels were at least 11.1 mmol/liter (200 mg/dl) 2
hours after ingestion of a 75-g glucose load. Peripheral
vascular disease was defined as an ankle-brachial index (the
ratio of a systolic blood pressure measurement in the ankle to
a systolic measurement in the arm) less than 0.9 (17).
Assessment of physical activity was based on the physical
activity index, a common measure that is used to quantify
overall metabolic output in a typical 24-hour period and is
known to be inversely associated with the risk of cardiovascular disease (18). Cigarette smoking was not included
among the risk factors, since only 170 of the 2,444 men
continued to smoke cigarettes in this age group. Control of
past and current smoking also had no effect on the reported
findings.
Statistical methods
For this report, HDL cholesterol categories were created
on the basis of the current recommendations of the National
Cholesterol Education Program (19). The categories
included levels that were low (<1.0 mmol/liter (<40 mg/dl))
and high (≥1.6 mmol/liter (≥60 mg/dl)). Intermediate levels
were defined as those that ranged from 1.0 mmol/liter to 1.5
mmol/liter (40–59 mg/dl). Strata for total cholesterol also
adhered to National Cholesterol Education Program guidelines. The categories included levels that were “desirable”
(<5.2 mmol/liter (<200 mg/dl)), “borderline-high” (5.2–6.1
mmol/liter (200–239 mg/dl)), and “high” (≥6.2 mmol/liter
(≥240 mg/dl)).
Within the ranges of HDL cholesterol values, crude and
age-adjusted incidences of stroke per 1,000 person-years
were estimated on the basis of follow-up from the baseline
examination (1991–1993) to the end of 1998 (20). Ageadjusted levels of risk factors across the HDL cholesterol
ranges were also derived. To test for an independent effect of
HDL cholesterol on the risk of stroke, we used proportional
hazards regression (21). Adjustments were made for age and
the other risk factors. While HDL cholesterol was modeled
as a continuous variable, relative risks of stroke (and 95
percent confidence intervals) were also estimated,
152 Curb et al.
TABLE 1. Percentage distributions of high density lipoprotein cholesterol level and incidence of
thromboembolic stroke according to age at the beginning of study follow-up (1991–1993),
Honolulu Heart Program, 1991–1998
High density lipoprotein cholesterol level*
Age
(years)
Incidence of stroke†
Sample
size
Low: <1.0
mmol/liter
(<40 mg/dl)
Intermediate: 1.0–1.5
mmol/liter
(40–59 mg/dl)
High: ≥1.6
mmol/liter
(≥60 mg/dl)
71–74
758
18.1 (137)‡
60.4 (458)
21.5 (163)
2.9
15
75–79
1,003
18.3 (184)
58.1 (583)
23.5 (236)
5.9
37
80–84
425
16.2 (69)
55.5 (236)
28.2 (120)
7.7
20
85–93
258
17.4 (45)
58.9 (152)
23.6 (61)
13.1
17
17.8 (435)
58.5 (1,429)
23.7 (580)
5.8
89
Total
2,444
Rate/1,000 No. of stroke
person-years
events
* The percentage of men within each category of high density lipoprotein cholesterol did not change
significantly with age.
† The incidence of thromboembolic stroke increased significantly with age (p < 0.001).
‡ Numbers in parentheses, number of men.
comparing the risk of stroke in men with low and intermediate levels of HDL cholesterol with the risk in men whose
concentrations were high. All reported p values were based
on two-sided tests of significance.
RESULTS
Among the 2,444 men who were followed for incident
stroke, the average HDL cholesterol concentration was 1.3
mmol/liter (51 mg/dl) (range, 0.5–3.3 mmol/liter (20–129
mg/dl)). Table 1 shows the percentages of men with low
(<1.0 mmol/liter (<40 mg/dl)), intermediate (1.0–1.5 mmol/
liter (40–59 mg/dl)), and high (≥1.6 mmol/liter (≥60 mg/dl))
concentrations of HDL cholesterol according to age at which
the HDL cholesterol determinations were made (1991–
1993). Overall, the percentages of men with low, intermediate, and high HDL cholesterol levels were 17.8, 58.5, and
23.7, respectively. Between age groups, the distribution of
men across HDL cholesterol strata was similar. Age had no
association with HDL cholesterol concentrations in this
elderly sample.
In the course of follow-up to the end of 1998, 137 strokes
could be attributed to either a thromboembolic cause or a
hemorrhagic cause. Among the strokes, 89 were identified as
thromboembolic events, while 48 were identified as having a
hemorrhagic origin. The incidence of thromboembolic
stroke (table 1) increased consistently from 2.9/1,000
person-years in men aged 71–74 years to 13.1/1,000 personyears in men aged 85 years or older (p < 0.001). Data for
hemorrhagic events are not provided, since associations with
age were absent. Here, incidence varied from 3.1/1,000
person-years to 3.2/1,000 person-years across age groups.
Except for atrial fibrillation and peripheral vascular
disease, all of the other risk factors measured at the time of
study enrollment (table 2) were associated with differences
in concentrations of HDL cholesterol. As might be expected,
increases in HDL cholesterol were associated with increases
in total cholesterol (p < 0.001). Increases in HDL cholesterol
were also associated with less frequent hypertension and
diabetes. Body mass index declined with increasing HDL
cholesterol levels as well (p < 0.001). In contrast, alcohol
intake and physical activity were positively associated with
HDL cholesterol concentrations (p < 0.001).
Table 3 provides the crude and age-adjusted incidences of
thromboembolic stroke for men with low, intermediate, and
high concentrations of HDL cholesterol. For hemorrhagic
events, the incidence rates were 2.1/1,000 person-years, 3.5/
1,000 person-years, and 2.8/1,000 person-years across the
increasing ranges of HDL cholesterol, respectively. Additional data for hemorrhagic stroke are not provided here,
since associations with HDL cholesterol were absent.
After adjustment for age, the incidence of thromboembolic
stroke declined consistently as HDL cholesterol concentrations increased (p = 0.003). Across the three strata of HDL
cholesterol, stroke incidence was 10.6/1,000 person-years,
5.2/1,000 person-years, and 3.6/1,000 person-years in men
with low, intermediate, and high levels of HDL cholesterol,
respectively. After further adjustment for other risk factors,
the association between HDL cholesterol and risk of thromboembolic stroke persisted. Men with low concentrations
experienced a 2.7-fold excess risk of a thromboembolic
event in comparison with men with high concentrations (p =
0.013). Although it was not significant, there was a 1.4-fold
excess incidence of stroke among men with intermediate
concentrations of HDL cholesterol versus men whose HDL
cholesterol levels were high. However, when HDL cholesterol was modeled as a continuous variable, findings
suggested that the risk of stroke declines with rising levels of
HDL cholesterol (p = 0.019).
Associations between HDL cholesterol and the risk of
stroke also seemed to strengthen within important risk factor
strata. In particular, as figure 1 shows, the risk of thromAm J Epidemiol 2004;160:150–157
HDL Cholesterol and Stroke 153
TABLE 2. Age-adjusted mean values and percentages for selected risk factors according to
category of high density lipoprotein cholesterol level observed at the beginning of study
follow-up (1991–1993), Honolulu Heart Program, 1991–1998
High density lipoprotein cholesterol level
Low: <1.0
mmol/liter
(<40 mg/dl)
Risk factor
Intermediate:
1.0–1.5 mmol/liter
(40–59 mg/dl)
High: ≥1.6
mmol/liter
(≥60 mg/dl)
Test for
trend
(p value)*
Mean total cholesterol level
mmol/liter
4.7 (0.9)†
5.0 (0.8)
5.1 (0.8)
mg/dl
180 (33)
192 (32)
196 (32)
<0.001
Hypertension (%)
60.8
54.0
45.2
<0.001
Diabetes mellitus (%)
35.4
28.3
20.0
<0.001
Peripheral vascular disease (%)
15.0
10.5
10.0
0.063
Atrial fibrillation (%)
3.5
2.7
1.9
0.134
Mean body mass index‡
24.6 (2.7)
23.7 (3.0)
21.8 (3.0)
<0.001
Mean alcohol intake (ounces§/day)
0.6 (4.8)
0.5 (1.2)
0.9 (1.6)
<0.001
Mean physical activity index¶
30.4 (4.1)
31.2 (4.7)
31.4 (4.6)
<0.001
* Test of the significance of the association between high density lipoprotein cholesterol (when
modeled as a continuous variable) and each risk factor after adjustment for age.
† Numbers in parentheses, standard deviation.
‡ Weight (kg)/height (m)2.
§ 1 ounce = 28.4 g.
¶ A measure used to quantify overall metabolic output in a typical 24-hour period. For details, see
Abbott et al. (18).
boembolic stroke declined consistently with increasing
levels of HDL cholesterol for men with desirable total
cholesterol concentrations (<5.2 mmol/liter (<200 mg/dl))
(p = 0.001) and men with hypertension (p = 0.012) or
diabetes (p = 0.007). Data for men with borderline-high and
high total cholesterol levels were combined, since too few
stroke events were observed in the high range of total cholesterol values (six of 89 events). Although the effects of HDL
cholesterol on the risk of stroke appeared to differ between
the total cholesterol strata, the interaction between HDL
cholesterol and total cholesterol was not significant. Presumably, this was due to limited statistical power resulting from
TABLE 3. Age-adjusted incidence of thromboembolic stroke according to category of high density lipoprotein cholesterol level
observed at the beginning of study follow-up (1991–1993), Honolulu Heart Program, 1991–1998
HDL* cholesterol level
No. of
stroke
events
Incidence of stroke
(rate/1,000 person-years)
No. of
subjects at
risk
Unadjusted
Age-adjusted
Adjusted† excess in stroke
incidence compared with men with
high HDL cholesterol levels
Low: <1.0 mmol/liter (<40 mg/dl)
29
435
10.5‡
10.6‡
2.7§ (1.2, 5.8)¶
Intermediate: 1.0–1.5 mmol/liter (40–59 mg/dl)
47
1,429
5.2
5.2
1.4 (0.7, 2.8)
High: ≥1.6 mmol/liter (≥60 mg/dl)
13
580
3.7
3.6
—#
0.005
0.003
0.019
Test for trend (p value)**
* HDL, high density lipoprotein.
† Adjusted for age, total cholesterol level, hypertension, diabetes mellitus, peripheral vascular disease, atrial fibrillation, body mass index,
alcohol intake, and physical activity index.
‡ Significant excess risk of stroke compared with men with high HDL cholesterol levels (p = 0.001).
§ Significant excess risk of stroke compared with men with high HDL cholesterol levels (p = 0.013).
¶ Numbers in parentheses, 95% confidence interval.
# Reference category.
** Test of the significance of the association between HDL cholesterol (when modeled as a continuous variable) and the risk of
thromboembolic stroke.
Am J Epidemiol 2004;160:150–157
154 Curb et al.
FIGURE 1. Age-adjusted incidence of thromboembolic stroke according to category of high density lipoprotein cholesterol (HDL-C) level, within
strata of total cholesterol, hypertension, and diabetes mellitus. Levels of HDL cholesterol and the other factors were measured in 1991–1993
among men enrolled in the Honolulu Heart Program. Study participants were followed to the end of 1998 for a stroke event. The p values shown
are for the significance of the association between HDL cholesterol (when modeled as a continuous variable) and the risk of thromboembolic
stroke within each risk factor stratum. HDL cholesterol levels were defined as follows: low, <1.0 mmol/liter (<40 mg/dl); intermediate, 1.0–1.5
mmol/liter (40–59 mg/dl); high, ≥1.6 mmol/liter (≥60 mg/dl). Total cholesterol levels were defined as follows: desirable, <5.2 mmol/liter (<200 mg/
dl); borderline-high and high, ≥5.2 mmol/liter (≥200 mg/dl). (*Number of events/sample size.)
the low number of cases (n = 89) of thromboembolic stroke.
Interactions between HDL cholesterol and hypertension and
diabetes were less apparent and also not significant.
DISCUSSION
In this population-based sample of elderly men, low
concentrations of HDL cholesterol (<1.0 mmol/liter (<40
mg/dl)) were more likely to be associated with a future risk
of thromboembolic stroke than were high concentrations
(≥1.6 mmol/liter (≥60 mg/dl)). Given the consistent decline
in the risk of stroke with increasing levels of HDL cholesterol that was observed in this sample, data further suggest
that stroke risk increases with each unit decline in HDL
cholesterol level. Even after adjustment for other risk
factors, the relation between HDL cholesterol and thromAm J Epidemiol 2004;160:150–157
HDL Cholesterol and Stroke 155
boembolic stroke persists. These findings are especially
important because they are the first to have been observed in
a sample of elderly men who were without stroke, coronary
heart disease, or cancer when HDL cholesterol determinations were made. In addition, follow-up for stroke was
prospective and was based on diagnoses that adhered to a
rigid protocol of case ascertainment.
Findings further suggest that, in elderly men with a low
total cholesterol level, hypertension, or diabetes, the association between HDL cholesterol and stroke may be more
important than in other groups. Conversely, in the presence
of high levels of HDL cholesterol, the effects of cholesterol,
hypertension, and diabetes on the risk of stroke seem modest
(see figure 1). Whether raising HDL cholesterol concentrations in the elderly can reduce the cardiovascular consequences associated with traditional risk factors warrants
consideration. In the presence of low HDL cholesterol
levels, control of hypertension and diabetes may be especially important. The association between HDL cholesterol
and stroke risk observed when total cholesterol level is low
is also consistent with findings from the Framingham Study,
where significant associations occurred between HDL
cholesterol and myocardial infarction among men in the
bottom quartile of total cholesterol but not among men in
quartiles that were higher (2).
While the Honolulu Heart Program has many strengths,
study limitations prevent follow-up on several issues for
which clarification is needed. For example, observations
from the current sample were based on a single measurement
of HDL cholesterol, and it is not known whether effects of
HDL cholesterol on the risk of stroke are modified by
unknown changes in HDL cholesterol levels over time.
Levels of HDL cholesterol could also be reduced by both
obesity and poor health. While simple adjustment for body
mass index may be inadequate, with only 89 thromboembolic events it is difficult to explore the possibility that HDL
cholesterol predicts stroke because it is a marker of poor
health or subclinical frailty. Although there was a small
excess incidence of stroke in men with a body mass index
greater than 25, there was no clear excess incidence of stroke
in men who were lean (body mass index, <22), nor was there
an excess in men with cachexia (men who lost more than 15
percent of their body weight over a 25-year period). The
removal of the leanest men, men with cachexia, and deaths
and strokes that occurred within the first year of follow-up
also failed to alter the reported findings. The exclusion of 32
percent (n = 1,192) of the original sample of 3,741 men
because of prevalent stroke, coronary heart disease, or
cancer may also have resulted in a sample of elderly men in
which the confounding effects of frailty and poor health
could have been minimized. For persons who are overtly
frail, cachexic, or malnourished, the relation between HDL
cholesterol and stroke may be more complex and may
require further study.
In addition to stroke, low levels of HDL cholesterol have
been independently and strongly linked with increased risk
of coronary heart disease in a number of studies comprising
largely middle-aged persons (1–9). To a far lesser extent,
extensions to the elderly have been less clear (10–13).
However, HDL cholesterol was inversely associated with the
Am J Epidemiol 2004;160:150–157
risk of ischemic stroke in an elderly multiethnic community
in the Northern Manhattan Stroke Study (13). Although findings were similar to those described for the Honolulu
sample, HDL cholesterol concentrations were measured
after the stroke event had occurred among the selected cases.
While it is uncertain whether stroke can influence HDL
cholesterol levels, the current report provides some assurance that the findings from this case-control study are real.
Significant associations between HDL cholesterol levels
and stroke were also found in an elderly Australian sample
and in a study of subjects with hypertension who were
enrolled in the Systolic Hypertension in the Elderly Program
(22, 23). While the latter study comprised selected persons
with isolated systolic hypertension, the Australian study was
more focused on general risk factors for stroke, and no
details were provided on stroke incidence by HDL cholesterol stratum or on possible differences in effects between
men and women. In the Australian sample, 22 percent also
had prevalent coronary heart disease and 6 percent had prevalent stroke (22). In addition, effects of sex on the association between HDL cholesterol and stroke risk could be
important. Although design problems might have contributed to group differences, a report from a nested case-control
analysis of four Northern European populations described a
modest inverse association between HDL cholesterol and the
risk of stroke in men, while in women, associations were
positive (11).
Although they are limited to subjects with prevalent
disease, clinical studies provide further evidence of an association between HDL cholesterol and stroke risk and support
arguments for biologic mechanisms (24, 25). While one
review reported that treatment with fibrates and niacin (alone
or in combination with other lipid-lowering agents) can raise
levels of HDL cholesterol (24), another suggested that therapeutic changes in HDL cholesterol concentrations induced
by gemfibrozil can reduce rates of ischemic stroke significantly (25). Although the mechanistic relation between HDL
cholesterol and thromboembolic stroke is not clear, it is
possible that effects observed in these studies occurred
through direct benefits from changes in HDL cholesterol,
along with alterations in a number of atherogenic properties
and common pathophysiologic antecedents for thrombosis
and coronary heart disease (26, 27). Reverse cholesterol
transport that is thought to be enhanced by increases in HDL
cholesterol and its capacity to initiate the flux of cholesterol
from peripheral cells to the liver is likely to be one of the
most important factors in this relation. However, other investigators have shown that increases in HDL cholesterol levels
resulting from treatment with benzafibrate are not associated
with a reduced risk of cerebrovascular events (28).
In general, the relation between lipid levels and cardiovascular disease in the elderly is reported to be weak. In the
Framingham Study, carotid stenosis in a sample of men
whose average age was 75 years had a markedly reduced
association with late-life cholesterol levels as compared with
cholesterol levels measured earlier (29). It has also been
noted in the Honolulu Heart Program that one-time assessment of total cholesterol level in late life could result in a
poor measure of the real risk of disease if past cholesterol
levels were high (30).
156 Curb et al.
Associations of HDL cholesterol and other cholesterol
measures with the risk of stroke in younger persons are also
equivocal. The Atherosclerotic Risk in Communities Study
found no relation between HDL cholesterol, low density
lipoprotein cholesterol, or triglyceride levels and transient
ischemic attack and stroke symptoms based on a standardized questionnaire and algorithm (31). The Framingham
Study investigators and other researchers described an
inverse relation between HDL cholesterol and ischemic
stroke, but associations were weak and not significant (32,
33). In contrast, for men enrolled in the Israeli Ischemic
Heart Disease Study, a significant 1.32-fold excess in the
incidence of stroke was observed among persons in the
lowest tertile of HDL cholesterol versus the highest (12).
The transition from a weak relation between HDL cholesterol and stroke in younger persons to one that is more
apparent in the elderly sample in the Honolulu Heart
Program could be due to age-related changes in the relation
between several risk factors and stroke risk with advancing
age (34). The question of whether declines in total cholesterol with advancing age (35, 36) can lead to a suppression of
HDL cholesterol concentrations and important reductions in
reverse cholesterol transport from peripheral cells to the liver
warrants consideration. Other mechanisms that may become
increasingly important in the elderly could include inflammatory properties of HDL cholesterol (37, 38) or the possibility that inflammation reduces the concentration of HDL
cholesterol or inhibits its protective function (39).
While the current study was also based on a sample of
Japanese-American men, results from the Northern
Manhattan Stroke Study suggest that findings could extend
to Caucasians, Hispanics, and African Americans (13). In
general, risk factor associations in the Honolulu sample are
similar to those that have been observed in other populationbased samples (40, 41). In a recent comparison with the
Framingham Study, the effect of risk factors on the incidence
of stroke was shown to be quite similar (41).
In summary, these data indicate that HDL cholesterol is an
important risk factor for thromboembolic stroke in the
elderly. In conjunction with other risk factors, measurement
of HDL cholesterol (commonly available from routine lipid
screening) could become an increasingly useful tool for
identifying elderly persons at high risk of stroke.
ACKNOWEDGMENTS
This study was supported by the National Heart, Lung, and
Blood Institute (contract NO1-HC-05102 and grant U01HL-56274), the National Institute on Aging (contract NO1AG-4-2149), and the American Heart Association of Hawaii
(grant HIGS-16-97).
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