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Gender Differences in Risk Factors for Intracranial Cerebral Atherosclerosis Among Asymptomatic Subjects
GENDER MEDICINE/VOL. 8, NO. 1, 2011
Gender Differences in Risk Factors for Intracranial Cerebral Atherosclerosis Among Asymptomatic Subjects Young-Suk Kim, OMD, PhD1; Jin-Woo Hong, OMD, PhD2; Woo-Sang Jung, OMD, PhD1; Seong-Uk Park, OMD, PhD1; Jung-Mi Park, OMD, PhD1; Sung-Il Cho, MD, PhD3; Young-min Bu, OMD, PhD4; and Sang-Kwan Moon, OMD, PhD1 1
Department of Cardiovascular and Neurologic Disease, College of Oriental Medicine, Kyung Hee University, Seoul, Korea; 2Department of Internal Medicine, School of Korean Medicine, Pusan University, Pusan, Korea; 3Department of Epidemiology, School of Public Health, Seoul National University, Seoul, Korea; and 4Department of Herbal Pharmacology, College of Oriental Medicine, Kyung Hee University, Seoul, Korea
ABSTRACT Background: Gender is known to be one of the factors linked to differences in cardiovascular morbidity and mortality. However, little information is available regarding gender differences in the risk factors for intracranial cerebral atherosclerosis (ICAS). Objective: This study investigated the risk factors for ICAS separately by gender in an asymptomatic population. Methods: We collected data from a consecutive series of 935 subjects who had no history of stroke and who had undergone transcranial Doppler ultrasonography (TCD). For each subject, their medical history was documented and tests for biochemical markers were performed. Multiple logistic regression analyses were separately conducted to assess the risk factors associated with ICAS by gender. Results: The risk factors for asymptomatic ICAS were determined for every 10-year increase in age (odds ratio [OR] ⫽ 1.74, 95% confidence interval [CI] ⫽ 1.23–2.46), diabetes mellitus (DM) (OR ⫽ 3.45, 95% CI ⫽ 1.49 –7.95), smoking (OR ⫽ 2.09, 95% CI ⫽ 1.01– 4.32), and hypercholesterolemia (OR ⫽ 3.31, 95% CI ⫽ 1.15–9.50) for male subjects; risk factors female subjects included hypertension (OR ⫽ 2.10, 95% CI ⫽ 1.40 – 3.15) and DM (OR ⫽ 2.45, 95% CI ⫽ 1.11–5.44). An additional stratified analysis indicated that there was no significant risk factor for male subjects aged ⬍50 years, whereas hypertension (OR ⫽ 2.90, 95% CI ⫽ 1.57–5.37) was the significant risk factor for female subjects aged ⬍50 years. For male subjects aged ⱖ50 years, DM (OR ⫽ 6.00, 95% CI ⫽ 1.87–19.20), hypercholesterolemia (OR ⫽ 4.72, 95% CI ⫽ 1.05–21.19), and every 10-year increase in age (OR ⫽ 4.33, 95% CI ⫽ 2.02–9.28) were significant risk factors for asymptomatic ICAS, whereas DM (OR ⫽ 2.93, 95% CI ⫽ 1.14 –7.48) was significant for female subjects aged ⱖ50 years. Conclusions: The findings suggest that the risk factors for asymptomatic ICAS differ between sexes, indicating a possible role of sex hormones in the development of ICAS. (Gend Med. 2011;8:14 –22) © 2011 Elsevier HS Journals, Inc. All rights reserved. Key words: gender differences, intracranial atherosclerosis, intracranial arterial disease, risk factors, transcranial Doppler. Accepted for publication January 26, 2011. © 2011 Elsevier HS Journals, Inc. All rights reserved.
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doi:10.1016/j.genm.2011.01.001 1550-8579/$ - see front matter
Y.-S. Kim et al.
INTRODUCTION Intracranial cerebral atherosclerosis (ICAS) is attracting considerable attention because it has been recognized as an important cause of ischemic stroke.1–3 The main risk factor for ICAS is hypertension, whereas extracranial carotid atherosclerosis is primarily caused by hyperlipidemia.4,5 This knowledge, however, was based on studies in symptomatic subjects where differentiating atherosclerosis from emboli was difficult. To avoid these pitfalls, recent studies have investigated the risk factors for ICAS among asymptomatic subjects. A study in Hong Kong reported that old age, hypertension, diabetes mellitus (DM), and hyperlipidemia were significant risk factors for ICAS in asymptomatic populations.6 In contrast, a Korean study found that the independent risk factors for asymptomatic ICAS included old age, DM, and hypertension, but not hyperlipidemia.7 A Japanese study suggested that the risk factors for ICAS in stroke-free subjects were age and hypertension.8 The discrepancy in the results from previous studies, especially the role of hyperlipidemia in ICAS, may be related to differences in the study populations, but the exact cause is not known. Gender is known to be one of the factors linked to differences in cardiovascular morbidity and mortality because premenopausal women are at a lower risk of cardiovascular disease (CVD) than both men of a comparable age and postmenopausal women.9,10 Estrogen is considered a key factor in gender-related differences in not only CVD incidence but also endothelium-dependent maintenance of vascular tone.10 A number of reports have shown that this hormone may enhance nitric oxide (NO)-mediated relaxation and may exert direct antioxidant effects on vascular cells.10 –12 Oxidative stress, which can occur when the generation of reactive oxygen species (ROS) is enhanced and/or their metabolism by antioxidant systems is impaired, is believed to play an important role in the initiation and progression of atherosclerosis induced by DM, hyperlipidemia, and hypertension.12–16 Therefore, the role of estrogen in the development of atherosclerosis is probably responsible for the sex-related differences in the risk factors for ICAS and for the discrepancies in ICAS risk
factors in previous studies. To our knowledge, however, no study has investigated the differences in the classic risk factors for asymptomatic ICAS between genders. In this study, we examined the role of the classic risk factors for asymptomatic ICAS, as assessed using transcranial Doppler (TCD) ultrasonography, between genders.
PATIENTS AND METHODS Patients Demographic and clinical data and TCD findings for 2940 consecutive patients who had visited a stroke prevention clinic at Kyung Hee Oriental Medicine Hospital in Seoul, Korea, between January 2001 and December 2003, were collected prospectively. The patients usually visited the clinic just for screening or because they were worried about stroke occurrence due to a family history of stroke, the presence of well-known stroke risk factors, or the development of symptoms that were believed in general to be associated with stroke, such as headache or dizziness. In this study, the following inclusion criteria were used: (1) ⱖ30 years of age; (2) no history of stroke or transient ischemic attack, and (3) the absence of neurologic deficits consistent with stroke. The exclusion criteria were as follows: (1) the presence of migraine, thyroid disease, anemia, congestive heart failure, or other systemic illnesses that could affect TCD results; (2) a poor acoustic temporal window; and (3) ambiguous findings on the TCD (flow velocity in any artery lower than the Korean reference value17 minus 2 SDs). The study was approved by the institutional review board of Kyung Hee Oriental Medicine Hospital.
TCD Evaluation TCD examinations were performed by one experienced technician with a Pioneer 2020 TCD instrument (EME, Uberlingen, Germany). Using a standardized protocol based on a previously described principle,18 the large intracranial arteries were examined through the temporal and occipital windows. In brief, the following arteries were examined (both right and left): the middle cerebral artery (MCA), the anterior cerebral artery (ACA),
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the posterior cerebral artery (PCA), and the vertebrobasilar artery. Atherosclerotic stenosis was diagnosed at the following peak systolic flow velocities: ⱖ140 cm/s for the MCA, ⱖ120 cm/s for the ACA, and ⱖ100 cm/s for the PCA and the vertebrobasilar artery.18 The subjects were classified as having ICAS if at least 1 of the arteries studied showed evidence of atherosclerotic stenosis. Apart from the above-mentioned velocity criteria, we took into account the age of each patient, the presence of turbulence, and whether the abnormal velocity was segmental.
Clinical Assessments The potential vascular risk factors for each subject were determined from their medical records. Hypertension was defined as the presence of a history of hypertension, a systolic blood pressure ⬎140 mmHg, or a diastolic pressure ⬎90 mmHg. DM was diagnosed if the subject was currently undergoing treatment with insulin or oral hypoglycemic agents, or if his/her fasting blood glucose level was ⬎140 mg/dL. Hyperlipidemia was categorized into high, borderline, and normal depending on the total cholesterol levels (reference values ⱖ240, 200 –239, and ⬍200 mg/dL, respectively). Subjects taking lipid-lowering drugs were included in the high category. A smoking habit was defined as a self-reported current or past smoking. Alcohol use was defined as a self-reported current or past drinking of alcohol. Body mass index (BMI) was calculated as the weight in kilograms divided by the square of the patient’s height in meters. The BMI values were divided into 2 categories (normal weight, ⬍25; high, ⱖ25).
Statistical Analysis The characteristics of the patients with and without ICAS were compared using the Pearson 2 test or Fisher exact test. Group means were compared using an independent-sample t test. The Mantel-Haenszel 2 test was used to examine the dose-response relationship between the categorization of blood lipid levels and the presence of ICAS. Multiple logistic regression analyses were performed using the presence of ICAS as a dependent variable; independent variables included age,
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sex, hypertension, DM, categorization of total cholesterol levels, smoking, and categorization of BMI values. When there was evidence of interaction between gender and each risk factor, separate analyses by gender were also conducted. Crude and adjusted odds ratios (OR) with 95% confidence intervals were calculated using SPSS for Windows version 12.0 (Chicago, Illinois). A P value ⬍0.05 was considered significant.
RESULTS A total of 935 subjects were included in the final analyses. ICAS was found in 184 (19.7%) of these subjects. The clinical characteristics and biochemical results of the subjects with or without ICAS are summarized in Table I. The gender, age distribution, prevalence of hypertension, and prevalence of DM were significantly different in subjects with ICAS compared with those without ICAS. Table II reports the comparison between the subjects with and without ICAS after stratifying by gender. In the male stratum, the subjects with ICAS were significantly older and had a significantly higher proportion of DM, a higher level of total cholesterol, and a lower level of BMI than those without ICAS. In the female stratum, the subjects with ICAS had a significantly higher prevalence of hypertension and DM than those without ICAS. As depicted in Table II, the role of the level of total cholesterol in the development of ICAS seemed to differ between genders, which was proven by a statistical result that an interaction term between gender and cholesterol categorization was significant (P ⫽ 0.029; Figure 1). Therefore, additional analyses were done separately for each gender stratum. In the male stratum, multiple logistic regression analysis revealed that each 10-year increase in age, DM, smoking, and hypercholesterolemia were significantly associated with the presence of ICAS. In the female stratum, hypertension and DM were the independent risk factors for ICAS (Table III). To investigate the role of sex hormones in the differences between genders, we further stratified the subjects into those aged ⬍50 and ⱖ50 years. In male subjects aged ⬍50 years, there was
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Table I. Comparisons of clinical characteristics between subjects with and without ICAS*
Male sex Mean age, y Age, y ⬍40 40⫺49 50⫺59 60⫺69 ⱖ70 Hypertension Diabetes mellitus Smoking Alcohol drinking Total cholesterol, mg/dL LDL cholesterol, mg/dL Triglycerides, mg/dL Body mass index, kg/m2
With ICAS (n ⫽ 184)
Without ICAS (n ⫽ 751)
44 (23.9) 52.1 (11.7)
264 (35.2) 50.7 (10.2)
25 (13.6) 55 (29.9) 46 (25.0) 48 (26.1) 10 (5.4)
109 (14.5) 242 (32.2) 248 (33.0) 128 (17.0) 24 (3.2)
P† 0.004 0.15 0.04
98 (53.3) 26 (14.1) 36 (19.6) 47 (25.5) 200.7 (37.1) 126.3 (33.3) 140.4 (103.9) 23.5 (2.7)
287 (38.2) 39 (5.2) 138 (18.4) 227 (30.2) 199.6 (34.9) 122.8 (32.1) 138.0 (96.0) 23.9 (3.0)
⬍0.001 ⬍0.001 0.71 0.21 0.72 0.19 0.77 0.12
ICAS ⫽ intracranial cerebral atherosclerosis; LDL ⫽ low-denisty lipoprotein. *Figures are means (SD) or numbers of subjects with percentages in parentheses. † P values were calculated by the Pearson 2 test or independent-sample t test when appropriate.
no significant risk factor after adjusting other factors, whereas hypertension was significantly associated with the presence of ICAS in female subjects aged ⬍50 years (Table IV). In male subjects aged ⱖ50 years, multivariate analysis showed that DM, hypercholesterolemia, and each 10-year increase in age were significantly associated with the presence of ICAS. In contrast, in female subjects aged ⱖ50 years, DM was a significant risk factor for ICAS after adjusting for other associated factors (Table V).
DISCUSSION In this study, we first found that the independent risk factors for asymptomatic ICAS were different between genders, mainly . The role of hypercholesterolemia in the development of ICAS, especially, seemed to be converse according to gender. The differences in risk factors for ICAS between genders were probably due to the influence of sex hormones. DM was found to be an independent risk factor for ICAS in previous studies where asymptomatic subjects from China, Hong Kong, and Korea were assessed.6,7,19 These studies were similar to the
present study in terms of the TCD assessment of ICAS. The results of this study are also consistent with those of the above-mentioned studies. Especially, DM was found to be the most important risk factor for ICAS among other factors because it was significantly associated with ICAS in both. An additional analysis demonstrated that DM was a significant risk factor for ICAS in both male and female subjects aged ⱖ50 years, although it was not in those aged ⬍50 years. These findings suggested that the increased role of DM in the development of ICAS after ⱖ50 years, which corresponds to the postmenopausal period in Korea,20,21 might be associated with the reduced levels of sex hormones in both men and women. In addition, the adjusted OR in male subjects aged ⱖ50 years was 6.0, almost twice more than that for female subjects, which suggested that the effect of diminishing sex hormone levels on DM in the development of atherosclerosis might differ between genders. A few studies have reported a positive correlation between serum cholesterol levels and asymptomatic ICAS.6 However, the association between serum cholesterol levels and ICAS has been some-
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Table II. Comparisons of clinical characteristics between subjects with and without ICAS after stratifying by gender* ICAS in Male Subjects
Mean age, y Age, y ⬍40 40–49 50–59 60–69 ⱖ70 Hypertension DM Smoking Alcohol drinking Total cholesterol, mg/dL Total cholesterol ⬍200 mg/dL 200⫺239 mg/dL ⱖ240 mg/dL LDL cholesterol, mg/dL Triglycerides, mg/dL BMI, kg/m2 BMI ⬍25 kg/m2 ⱖ25 kg/m2
Yes (n ⫽ 44)
No (n ⫽ 264)
56.7 (13.1)
50.2 (10.8)
5 (11.4) 9 (20.5) 7 (15.9) 16 (36.4) 7 (15.9)
45 (17.0) 83 (31.4) 78 (29.5) 50 (18.9) 8 (3.0)
26 (59.1) 14 (31.8) 25 (56.8) 28 (63.6) 205.4 (34.4)
121 (45.8) 23 (8.7) 113 (42.8) 157 (59.5) 194.5 (33.8)
18 (40.9) 18 (40.9) 8 (18.2)
156 (59.1) 83 (31.4) 25 (9.5)
ICAS in Female Subjects P† ⬍0.001
Yes (n ⫽ 140)
No (n ⫽ 487)
50.6 (10.8)
51.0 (9.8)
P† 0.70
⬍0.001
0.10 ⬍0.001 0.08 0.60 0.05
0.83 20 (14.3) 46 (32.9) 39 (27.9) 32 (22.9) 3 (2.1)
64 (13.1) 159 (32.6) 170 (34.9) 78 (16.0) 16 (3.3)
72 (51.4) 12 (8.6) 11 (7.9) 19 (13.6) 199.2 (37.9)
166 (34.1) 16 (3.3) 25 (5.1) 70 (14.4) 202.4 (35.2)
76 (54.3) 42 (30.0) 22 (15.7)
239 (49.1) 169 (34.7) 79 (16.2)
126.5 (35.4) 126.6 (73.4) 23.5 (2.8)
125.5 (32.6) 125.9 (86.8) 23.5 (3.0)
99 (70.7) 41 (29.3)
350 (71.9) 137 (28.1)
⬍0.001 0.008 0.22 0.81 0.35
0.02
125.9 (25.9) 184.4 (161.0) 23.8 (2.3)
118.0 (30.6) 160.3 (107.6) 24.7 (2.8)
0.11 0.20 0.04
0.42
0.04 30 (68.2) 14 (31.8)
135 (51.1) 129 (48.9)
0.75 0.94 0.94 0.79
BMI ⫽ body mass index; DM ⫽ diabetes mellitus; LDL ⫽ low-density lipoprotein; ICAS ⫽ intracranial cerebral atherosclerosis. *Data are mean (SD) or number (%) of subjects. † P values were calculated by independent-sample t test or the Pearson 2 test or Mantel-Haenszel 2 test when appropriate.
what controversial because, in previous studies, no significant correlation was observed between asymptomatic ICAS and hyperlipidemia.7,8,19 The current study indicated that hypercholesterolemia was an independent risk factor for ICAS in male subjects,
but not in female subjects; this was proved by a statistical result that showed significant interaction between and cholesterol categorization. Further separate analyses among subjects aged ⱖ50 years showed that hypercholesterolemia was a sig-
Figure 1. The role of the level of total cholesterol in the development of ICAS differed between genders, which was proved by a statistical result that an interaction term between gender and total cholesterol categorization was significant (P ⫽ 0.029) in subjects of all ages (left). After additional stratification of the subjects into those aged ⬍50 and ⱖ50 years, there was no interaction between gender and cholesterol categorization in subjects aged ⬍50 years (middle). However, interaction term between gender and cholesterol categorization reached almost significance (P ⫽ 0.050) in the subjects aged ⱖ50 years (right).
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Table III. Crude and adjusted odd ratios (OR) for the presence of ICAS in male and female subjects of all ages Presence of ICAS in Male Subjects (n ⫽ 308)
Presence of ICAS in Female Subjects (n ⫽ 627)
Crude OR (95% CI)
Adjusted OR (95% CI)
Crude OR (95% CI)
Adjusted OR (95% CI)
Age, 10 y Hypertension DM Smoking
1.71* (1.26⫺2.30) 1.71 (0.89⫺3.26) 4.89* (2.28⫺10.51) 1.76 (0.92⫺3.35)
1.74* (1.23⫺2.46) 1.46 (0.71⫺2.99) 3.45* (1.49⫺7.95) 2.09* (1.01⫺4.32)
1.02 (0.85⫺1.23) 2.05* (1.40⫺3.00) 2.76* (1.27⫺5.98) 1.58 (0.76⫺3.29)
0.95 (0.78⫺1.17) 2.10* (1.40⫺3.15) 2.45* (1.11⫺5.44) 1.68 (0.79⫺3.57)
Total cholesterol ⬍200 mg/dL 200⫺239 mg/dL ⱖ240 mg/dL
1.00 1.88 (0.93⫺3.81) 2.77* (1.09⫺7.06)
1.00 1.98 (0.92⫺4.26) 3.31* (1.15⫺9.50)
1.00 0.78 (0.51⫺1.20) 0.88 (0.51⫺1.50)
1.00 0.77 (0.49⫺1.20) 0.78 (0.44⫺1.38)
High BMI
0.49* (0.25⫺0.96)
0.52 (0.24⫺1.10)
1.06 (0.70⫺1.60)
0.95 (0.62⫺1.47)
BMI ⫽ body mass index; CI ⫽ confidence interval; DM ⫽ diabetes mellitus; ICAS ⫽ intracranial cerebral atherosclerosis; OR ⫽ odds ratio. Adjusted OR: adjusted for all the other variables shown in this table. *P ⬍ 0.05.
nificant risk factor in male subjects, but not in female subjects, As discussed above, the interaction term between and cholesterol categorization almost reached significance (P ⫽ 0.050). These findings suggested that the role of hypercholesterolemia in the development of ICAS might be influenced more by diminishing androgen levels in males than by reduced female sex hormone levels. In subjects aged ⬍50 years, although hypercholesterolemia was not a significantly associated factor
for ICAS in either gender, there seemed to be remarkable differences of adjusted ORs between genders. Taken together, there might be interaction or effect modification between hypercholesterolemia and gender. This effect may explain the inconsistencies among previous studies where gender was not considered as an effect modifier about the role of hyperlipidemia in ICAS development. Hypertension is an independent risk factor for asymptomatic ICAS.6 – 8,19 However, this study
Table IV. Crude and adjusted odds ratios (OR) for the presence of ICAS in male and female subjects aged ⬍50 years Presence of ICAS in Male Subjects (n ⫽ 142)
Presence of ICAS in Female Subjects (n ⫽ 289)
Crude OR (95% CI)
Adjusted OR† (95% CI)
Crude OR (95% CI)
Adjusted OR† (95% CI)
Age, 10 y Hypertension DM Smoking
0.98 (0.31⫺3.09) 0.81 (0.26⫺2.56) 3.61 (0.85⫺15.30) 3.34 (0.89⫺12.53)
0.99 (0.26⫺3.73) 0.88 (0.25⫺3.15) 3.34 (0.61⫺18.42) 3.11 (0.78⫺12.37)
0.93 (0.51⫺1.69) 2.69* (1.50⫺4.81) 2.08 (0.48⫺8.93) 1.67 (0.69⫺4.07)
0.80 (0.42⫺1.53) 2.90* (1.57⫺5.37) 1.89 (0.39⫺9.12) 1.94 (0.76⫺4.98)
Total cholesterol ⬍200 mg/dL 200⫺239 mg/dL ⱖ240 mg/dL
1.00 0.91 (0.25⫺3.29) 2.14 (0.49⫺9.31)
1.00 0.66 (0.16⫺2.66) 2.12 (0.41⫺11.00)
1.00 0.68 (0.34⫺1.38) 0.81 (0.29⫺2.27)
1.00 0.60 (0.29⫺1.26) 0.59 (0.19⫺1.81)
High BMI
0.60 (0.20⫺1.84)
0.60 (0.18⫺2.05)
1.09 (0.54⫺2.18)
0.95 (0.46⫺1.97)
BMI ⫽ body mass index; CI ⫽ confidence interval; DM ⫽ diabetes mellitus; ICAS ⫽ intracranial cerebral atherosclerosis. *P ⬍ 0.05. † Adjusted for all the other variables shown in this table.
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Table V. Crude and adjusted odds ratios (OR) for the presence of intracranial cerebral atherosclerosis (ICAS) in male and female subjects aged ⱖ50 years Presence of ICAS in Male Subjects (n ⫽ 166)
Presence of ICAS in Female Subjects (n ⫽ 338)
Crude OR (95% CI)
Adjusted OR† (95% CI)
Crude OR (95% CI)
Adjusted OR† (95% CI)
Age, 10 y Hypertension DM Smoking
3.19* (1.72–5.91) 2.27 (0.97–5.30) 5.05* (2.00–12.74) 1.72 (0.77–3.81)
4.33* (2.02–9.28) 2.37 (0.87–6.46) 6.00* (1.87–19.20) 1.61 (0.61–4.27)
1.30 (0.86–1.96) 1.82* (1.08–3.06) 3.19* (1.27–8.01) 1.35 (0.35–5.23)
1.22 (0.79–1.88) 1.68 (0.98–2.88) 2.93* (1.14–7.48) 1.37 (0.34–5.58)
Total cholesterol ⬍200 mg/dL 200–239 mg/dL ⱖ240 mg/dL
1.00 2.81* (1.17–6.74) 3.55* (1.04–12.15)
1.00 4.34* (1.49–12.61) 4.72* (1.05–21.19)
1.00 0.86 (0.48–1.55) 0.93 (0.47–1.86)
1.00 0.97 (0.53–1.79) 0.97 (0.48–1.95)
0.49 (0.20–1.18)
0.46 (0.16–1.37)
1.07 (0.63–1.81)
1.00 (0.58–1.73)
High BMI
BMI ⫽ body mass index; DM ⫽ diabetes mellitus. *P ⬍ 0.05. † Adjusted for all the other variables shown in this table.
found that hypertension was not an independent risk factor for ICAS in male subjects of all ages and in female subjects aged ⱖ50 years. It was only a risk factor for female subjects aged ⬍50 years. Hypertension induces atherosclerosis via circumferential wall tension (CWT) and the implication of ROS. In particular, blood pressure-induced arterial wall stress and the accompanying stretch have been reported to be primary factors contributing to the localization of atherosclerotic lesions.22 Wall stress, specifically CWT, is proportional to blood pressure and internal diameter.22,23 In this study, the weak influence of hypertension on ICAS suggests that blood pressure-induced arterial CWT may decrease in the intracranial space owing to the anatomic characteristics of arteries with high vessel curvature. In contrast, during the premenopausal period, estrogen may enhance NO-mediated relaxation in the intracranial arteries.10 In this situation, the increase in internal diameter probably makes the blood pressure-induced arterial CWT in premenopausal women much higher than that in men of a comparable age and in postmenopausal women. This effect consequently can reinforce the OR for hypertension. This study also suggests that the role of ROS in ICAS development in the presence of hypertension may be minimally, if at all, present, because if hypertension had caused
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ICAS mainly via ROS involvement, the OR for hypertension would conversely have reduced in the female subjects aged ⬍50 years. This postulation was also supported by the previous study indicating that the pathophysiologic role of oxidative stress in hypertension was less conclusive when considered from a clinical viewpoint.14 Studies on asymptomatic ICAS have reported that old age is an independent risk factor.6 – 8,19 In this study, old age was an independent risk factor for ICAS in male subjects, especially in those aged ⱖ50 years. These findings partly support the hypothesis that a reduction in androgen was independently associated with cardiovascular disease risk including atherosclerosis.24 However, old age was not significantly associated with ICAS in female subjects; interestingly, this might be indicative of the effects of diminishing sex hormone levels in the development of atherosclerosis differing between genders. Another possible explanation for this observation may come from the detection of the TCD signal through the temporal bone, which is more difficult to observe in older women than in men of the same age.25 Thus, the higher exclusion rate is probable in female subjects with ICAS aged ⱖ70 years than in corresponding male subjects. These factors may lead to underestimate the role of old
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age in the development of ICAS in female subjects. This study is, nevertheless, subject to certain limitations. First, the study design is cross-sectional and provides only a snapshot of the subject’s health status, because we did not know if the risk factors were present before or after the development of ICAS. Moreover, the study population was hospital based rather than community based; hence, any generalization may be limited. Second, TCD was the only diagnostic tool used in this study and its findings were not confirmed using angiography. However, TCD is particularly well suited for screening a large number of subjects in a clinic setting, which was the basis for this study; this is because TCD is a noninvasive, safe, and reliable method for the diagnosis of intracranial arterial stenosis.6,7,19,26 Other limitations of this study are the lack of data on several potential risk factors such as carotid disease, inflammatory markers, physical activity, emotional factors, dietary habits, and family medical history.
REFERENCES 1. Qureshi AI, Feldmann E, Gomez CR, et al. Intracranial atherosclerotic disease: An update. Ann Neurol. 2009;66:730 –738. 2. Suri MFK, Johnston SC. Epidemiology of intracranial stenosis. J Neuroimaging. 2009;19:11S– 16S. 3. Qureshi AI, Feldmann E, Gomez CR, et al. Consensus conference on intracranial atherosclerotic disease: Rationale, methodology, and results. J Neuroimaging 2009;19:1S–10S. 4. Caplan LR, Gorelick PB, Hier DB. Race, sex and occlusive cerebrovascular disease: A review. Stroke. 1986;17:648 – 655. 5. Kuller L, Reisler DM. An explanation for variations in distribution of stroke and arteriosclerotic heart disease among populations and racial groups. Am J Epidemiol. 1971;93:1–9. 6. Wong KS, Ng PW, Tang A, et al. Prevalence of asymptomatic intracranial atherosclerosis in highrisk patients. Neurology. 2007;68:2035–2038. 7. Bae HJ, Lee J, Park JM, et al. Risk factors of intra-
CONCLUSIONS The independent risk factors for ICAS in asymptomatic subjects differed between genders: age, DM, hyperlipidemia, and smoking in the male gender; and hypertension and DM in the female gender. These differences may be attributable to the role of sex hormones in the development of ICAS. Our results may help develop a gender-based strategy for the prevention of vascular events after ICAS.
cranial cerebral atherosclerosis among asymptomatics. Cerebrovasc Dis. 2007;24:355–360. 8. Uehara T, Tabuchi M, Mori E. Frequency and clinical correlates of occlusive lesions of cerebral arteries in japanese patients without stroke: Evaluation by MR angiography. Cerebrovasc Dis. 1998;8: 267–272. 9. Kleijn MJJ, Schouw YT, Verbeek AL, et al. Endogenous estrogen exposure and cardiovascular mortality risk in postmenopausal women. Am J Epidemiol. 2002;155:339 –345.
ACKNOWLEDGMENTS This work was supported by grant number KHU20080593 (2008) from Kyung Hee University, Seoul, Korea. Drs. Kim and Moon developed the research question and study design, performed the data collection and analysis, and drafted and finalized the manuscript. Drs. Hong, Jung, Park, Park, Cho, and Bu contributed to the study design and data collection, provided consultation for data analysis, assisted with manuscript revisions, and approved the final manuscript. The authors have indicated that they have no conflicts of interest regarding the content of this article.
10. Kublickiene K, Luksha L. Gender and the endothelium. Pharmacological Reports. 2008;60:49 – 60. 11. Miller AA, Drummond GR, Mast AE, et al. Effect of gender on NADPH-oxidase activity, expression, and function in the cerebral circulation - Role of estrogen. Stroke. 2007;38:2142–2149. 12. Miller AA, Silva TM, Jackman KA, Sobey CG. Effect of gender and sex hormones on vascular oxidative stress. Clin Exper Pharmacol Physiol. 2007;34:1037– 1043. 13. Kaneto H, Katakami N, Matsuhisa M, Matsuoka T. Role of reactive oxygen species in the pro-
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gression of type 2 diabetes and atherosclerosis. Mediators Inflamm. 2010;2010:453892. 14. Paravicini TM, Touyz RM. NADPH oxidases, reactive oxygen species, and hypertension - clinical implications and therapeutic possibilities. Diabe-
20. Lee MS, Kim JH, Park MS, et al. Factors influencing
tes Care. 2008;31(Suppl 2):S170 –S180. 15. Poli G, Sottero B, Gargiulo S, Leonarduzzi G. Cholesterol oxidation products in the vascular remodeling due to atherosclerosis. Mol Aspects Med. 2009;30:180 –189. 16. Sottero B, Gamba P, Gargiulo S, et al. Cholesterol oxidation products and disease: An emerging topic of interest in medicinal chemistry. Curr Med Chem. 2009;16:685–705. 17. Ahn GB, Chi CS, Chung CS. Recording of cerebral blood flow velocity using transcranial Doppler ultrasound in normal subjects. J Korean Neurol Assoc.
and related factors in Korean women. J Korean
1991;9:277–285. 18. Wong KS, Li H, Chan YL, et al. Use of transcranial Doppler ultrasound to predict outcome in patients with intracranial large-artery occlusive disease. Stroke. 2000;31:2641–2647. 19. Huang HW, Guo MH, Lin RJ, et al. Prevalence and risk factors of middle cerebral artery stenosis in asymptomatic residents in Rongqi county, Guangdong. Cerebrovasc Dis, 2007;24:111–115.
the severity of menopause symptoms in Korean post-menopausal women. J Korean Med Sci. 2010; 25:758 –765. 21. Park YJ, Kim HS, Kang HC. The age at menopause Acad Nurs. 2002;32:1024 –1031. 22. Prado CM, Rossi MA. Circumferential wall tension due to hypertension plays a pivotal role in aorta remodelling. Int J Exp Path. 2006;87:425– 436. 23. Hayashia K, Naikia T. Adaptation and remodeling of vascular wall; biomechanical response to hypertension. J Mech Behavior Biomed Mat. 2009;2:3–19. 24. Yeap BB. Androgens and cardiovascular disease. Curr Opin Endocrinol Diabetes Obes. 2010;17:269 – 276. 25. Itoh T, Matsumoto M, Handa N, et al. Rate of successful recording of blood flow signals in the middle cerebral artery using transcranial Doppler sonography. Stroke. 1993;24:1192–1195. 26. Sloan MA, Alexandrov AV, Tegeler CH, et al. Assessment: Transcranial Doppler ultrasonography – Report of the therapeutics and technology assessment subcommittee of the American academy of neurogy. Neurology. 2004;62:1468 –1481.
Address correspondence to: Sang-kwan Moon, MD, PhD, Department of Cardiovascular and Neurologic Diseases, College of Oriental Medicine, Kyung Hee University, #1, Hoegi-dong, Dongdaemun-gu, Seoul # 130-702, Korea (Republic of). E-mail: [email protected]
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Gender Differences in Risk Factors for Intracranial Cerebral Atherosclerosis Among Asymptomatic Subjects Young-Suk Kim, OMD, PhD1; Jin-Woo Hong, OMD, PhD2; Woo-Sang Jung, OMD, PhD1; Seong-Uk Park, OMD, PhD1; Jung-Mi Park, OMD, PhD1; Sung-Il Cho, MD, PhD3; Young-min Bu, OMD, PhD4; and Sang-Kwan Moon, OMD, PhD1 1
Department of Cardiovascular and Neurologic Disease, College of Oriental Medicine, Kyung Hee University, Seoul, Korea; 2Department of Internal Medicine, School of Korean Medicine, Pusan University, Pusan, Korea; 3Department of Epidemiology, School of Public Health, Seoul National University, Seoul, Korea; and 4Department of Herbal Pharmacology, College of Oriental Medicine, Kyung Hee University, Seoul, Korea
ABSTRACT Background: Gender is known to be one of the factors linked to differences in cardiovascular morbidity and mortality. However, little information is available regarding gender differences in the risk factors for intracranial cerebral atherosclerosis (ICAS). Objective: This study investigated the risk factors for ICAS separately by gender in an asymptomatic population. Methods: We collected data from a consecutive series of 935 subjects who had no history of stroke and who had undergone transcranial Doppler ultrasonography (TCD). For each subject, their medical history was documented and tests for biochemical markers were performed. Multiple logistic regression analyses were separately conducted to assess the risk factors associated with ICAS by gender. Results: The risk factors for asymptomatic ICAS were determined for every 10-year increase in age (odds ratio [OR] ⫽ 1.74, 95% confidence interval [CI] ⫽ 1.23–2.46), diabetes mellitus (DM) (OR ⫽ 3.45, 95% CI ⫽ 1.49 –7.95), smoking (OR ⫽ 2.09, 95% CI ⫽ 1.01– 4.32), and hypercholesterolemia (OR ⫽ 3.31, 95% CI ⫽ 1.15–9.50) for male subjects; risk factors female subjects included hypertension (OR ⫽ 2.10, 95% CI ⫽ 1.40 – 3.15) and DM (OR ⫽ 2.45, 95% CI ⫽ 1.11–5.44). An additional stratified analysis indicated that there was no significant risk factor for male subjects aged ⬍50 years, whereas hypertension (OR ⫽ 2.90, 95% CI ⫽ 1.57–5.37) was the significant risk factor for female subjects aged ⬍50 years. For male subjects aged ⱖ50 years, DM (OR ⫽ 6.00, 95% CI ⫽ 1.87–19.20), hypercholesterolemia (OR ⫽ 4.72, 95% CI ⫽ 1.05–21.19), and every 10-year increase in age (OR ⫽ 4.33, 95% CI ⫽ 2.02–9.28) were significant risk factors for asymptomatic ICAS, whereas DM (OR ⫽ 2.93, 95% CI ⫽ 1.14 –7.48) was significant for female subjects aged ⱖ50 years. Conclusions: The findings suggest that the risk factors for asymptomatic ICAS differ between sexes, indicating a possible role of sex hormones in the development of ICAS. (Gend Med. 2011;8:14 –22) © 2011 Elsevier HS Journals, Inc. All rights reserved. Key words: gender differences, intracranial atherosclerosis, intracranial arterial disease, risk factors, transcranial Doppler. Accepted for publication January 26, 2011. © 2011 Elsevier HS Journals, Inc. All rights reserved.
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doi:10.1016/j.genm.2011.01.001 1550-8579/$ - see front matter
Y.-S. Kim et al.
INTRODUCTION Intracranial cerebral atherosclerosis (ICAS) is attracting considerable attention because it has been recognized as an important cause of ischemic stroke.1–3 The main risk factor for ICAS is hypertension, whereas extracranial carotid atherosclerosis is primarily caused by hyperlipidemia.4,5 This knowledge, however, was based on studies in symptomatic subjects where differentiating atherosclerosis from emboli was difficult. To avoid these pitfalls, recent studies have investigated the risk factors for ICAS among asymptomatic subjects. A study in Hong Kong reported that old age, hypertension, diabetes mellitus (DM), and hyperlipidemia were significant risk factors for ICAS in asymptomatic populations.6 In contrast, a Korean study found that the independent risk factors for asymptomatic ICAS included old age, DM, and hypertension, but not hyperlipidemia.7 A Japanese study suggested that the risk factors for ICAS in stroke-free subjects were age and hypertension.8 The discrepancy in the results from previous studies, especially the role of hyperlipidemia in ICAS, may be related to differences in the study populations, but the exact cause is not known. Gender is known to be one of the factors linked to differences in cardiovascular morbidity and mortality because premenopausal women are at a lower risk of cardiovascular disease (CVD) than both men of a comparable age and postmenopausal women.9,10 Estrogen is considered a key factor in gender-related differences in not only CVD incidence but also endothelium-dependent maintenance of vascular tone.10 A number of reports have shown that this hormone may enhance nitric oxide (NO)-mediated relaxation and may exert direct antioxidant effects on vascular cells.10 –12 Oxidative stress, which can occur when the generation of reactive oxygen species (ROS) is enhanced and/or their metabolism by antioxidant systems is impaired, is believed to play an important role in the initiation and progression of atherosclerosis induced by DM, hyperlipidemia, and hypertension.12–16 Therefore, the role of estrogen in the development of atherosclerosis is probably responsible for the sex-related differences in the risk factors for ICAS and for the discrepancies in ICAS risk
factors in previous studies. To our knowledge, however, no study has investigated the differences in the classic risk factors for asymptomatic ICAS between genders. In this study, we examined the role of the classic risk factors for asymptomatic ICAS, as assessed using transcranial Doppler (TCD) ultrasonography, between genders.
PATIENTS AND METHODS Patients Demographic and clinical data and TCD findings for 2940 consecutive patients who had visited a stroke prevention clinic at Kyung Hee Oriental Medicine Hospital in Seoul, Korea, between January 2001 and December 2003, were collected prospectively. The patients usually visited the clinic just for screening or because they were worried about stroke occurrence due to a family history of stroke, the presence of well-known stroke risk factors, or the development of symptoms that were believed in general to be associated with stroke, such as headache or dizziness. In this study, the following inclusion criteria were used: (1) ⱖ30 years of age; (2) no history of stroke or transient ischemic attack, and (3) the absence of neurologic deficits consistent with stroke. The exclusion criteria were as follows: (1) the presence of migraine, thyroid disease, anemia, congestive heart failure, or other systemic illnesses that could affect TCD results; (2) a poor acoustic temporal window; and (3) ambiguous findings on the TCD (flow velocity in any artery lower than the Korean reference value17 minus 2 SDs). The study was approved by the institutional review board of Kyung Hee Oriental Medicine Hospital.
TCD Evaluation TCD examinations were performed by one experienced technician with a Pioneer 2020 TCD instrument (EME, Uberlingen, Germany). Using a standardized protocol based on a previously described principle,18 the large intracranial arteries were examined through the temporal and occipital windows. In brief, the following arteries were examined (both right and left): the middle cerebral artery (MCA), the anterior cerebral artery (ACA),
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the posterior cerebral artery (PCA), and the vertebrobasilar artery. Atherosclerotic stenosis was diagnosed at the following peak systolic flow velocities: ⱖ140 cm/s for the MCA, ⱖ120 cm/s for the ACA, and ⱖ100 cm/s for the PCA and the vertebrobasilar artery.18 The subjects were classified as having ICAS if at least 1 of the arteries studied showed evidence of atherosclerotic stenosis. Apart from the above-mentioned velocity criteria, we took into account the age of each patient, the presence of turbulence, and whether the abnormal velocity was segmental.
Clinical Assessments The potential vascular risk factors for each subject were determined from their medical records. Hypertension was defined as the presence of a history of hypertension, a systolic blood pressure ⬎140 mmHg, or a diastolic pressure ⬎90 mmHg. DM was diagnosed if the subject was currently undergoing treatment with insulin or oral hypoglycemic agents, or if his/her fasting blood glucose level was ⬎140 mg/dL. Hyperlipidemia was categorized into high, borderline, and normal depending on the total cholesterol levels (reference values ⱖ240, 200 –239, and ⬍200 mg/dL, respectively). Subjects taking lipid-lowering drugs were included in the high category. A smoking habit was defined as a self-reported current or past smoking. Alcohol use was defined as a self-reported current or past drinking of alcohol. Body mass index (BMI) was calculated as the weight in kilograms divided by the square of the patient’s height in meters. The BMI values were divided into 2 categories (normal weight, ⬍25; high, ⱖ25).
Statistical Analysis The characteristics of the patients with and without ICAS were compared using the Pearson 2 test or Fisher exact test. Group means were compared using an independent-sample t test. The Mantel-Haenszel 2 test was used to examine the dose-response relationship between the categorization of blood lipid levels and the presence of ICAS. Multiple logistic regression analyses were performed using the presence of ICAS as a dependent variable; independent variables included age,
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sex, hypertension, DM, categorization of total cholesterol levels, smoking, and categorization of BMI values. When there was evidence of interaction between gender and each risk factor, separate analyses by gender were also conducted. Crude and adjusted odds ratios (OR) with 95% confidence intervals were calculated using SPSS for Windows version 12.0 (Chicago, Illinois). A P value ⬍0.05 was considered significant.
RESULTS A total of 935 subjects were included in the final analyses. ICAS was found in 184 (19.7%) of these subjects. The clinical characteristics and biochemical results of the subjects with or without ICAS are summarized in Table I. The gender, age distribution, prevalence of hypertension, and prevalence of DM were significantly different in subjects with ICAS compared with those without ICAS. Table II reports the comparison between the subjects with and without ICAS after stratifying by gender. In the male stratum, the subjects with ICAS were significantly older and had a significantly higher proportion of DM, a higher level of total cholesterol, and a lower level of BMI than those without ICAS. In the female stratum, the subjects with ICAS had a significantly higher prevalence of hypertension and DM than those without ICAS. As depicted in Table II, the role of the level of total cholesterol in the development of ICAS seemed to differ between genders, which was proven by a statistical result that an interaction term between gender and cholesterol categorization was significant (P ⫽ 0.029; Figure 1). Therefore, additional analyses were done separately for each gender stratum. In the male stratum, multiple logistic regression analysis revealed that each 10-year increase in age, DM, smoking, and hypercholesterolemia were significantly associated with the presence of ICAS. In the female stratum, hypertension and DM were the independent risk factors for ICAS (Table III). To investigate the role of sex hormones in the differences between genders, we further stratified the subjects into those aged ⬍50 and ⱖ50 years. In male subjects aged ⬍50 years, there was
Y.-S. Kim et al.
Table I. Comparisons of clinical characteristics between subjects with and without ICAS*
Male sex Mean age, y Age, y ⬍40 40⫺49 50⫺59 60⫺69 ⱖ70 Hypertension Diabetes mellitus Smoking Alcohol drinking Total cholesterol, mg/dL LDL cholesterol, mg/dL Triglycerides, mg/dL Body mass index, kg/m2
With ICAS (n ⫽ 184)
Without ICAS (n ⫽ 751)
44 (23.9) 52.1 (11.7)
264 (35.2) 50.7 (10.2)
25 (13.6) 55 (29.9) 46 (25.0) 48 (26.1) 10 (5.4)
109 (14.5) 242 (32.2) 248 (33.0) 128 (17.0) 24 (3.2)
P† 0.004 0.15 0.04
98 (53.3) 26 (14.1) 36 (19.6) 47 (25.5) 200.7 (37.1) 126.3 (33.3) 140.4 (103.9) 23.5 (2.7)
287 (38.2) 39 (5.2) 138 (18.4) 227 (30.2) 199.6 (34.9) 122.8 (32.1) 138.0 (96.0) 23.9 (3.0)
⬍0.001 ⬍0.001 0.71 0.21 0.72 0.19 0.77 0.12
ICAS ⫽ intracranial cerebral atherosclerosis; LDL ⫽ low-denisty lipoprotein. *Figures are means (SD) or numbers of subjects with percentages in parentheses. † P values were calculated by the Pearson 2 test or independent-sample t test when appropriate.
no significant risk factor after adjusting other factors, whereas hypertension was significantly associated with the presence of ICAS in female subjects aged ⬍50 years (Table IV). In male subjects aged ⱖ50 years, multivariate analysis showed that DM, hypercholesterolemia, and each 10-year increase in age were significantly associated with the presence of ICAS. In contrast, in female subjects aged ⱖ50 years, DM was a significant risk factor for ICAS after adjusting for other associated factors (Table V).
DISCUSSION In this study, we first found that the independent risk factors for asymptomatic ICAS were different between genders, mainly . The role of hypercholesterolemia in the development of ICAS, especially, seemed to be converse according to gender. The differences in risk factors for ICAS between genders were probably due to the influence of sex hormones. DM was found to be an independent risk factor for ICAS in previous studies where asymptomatic subjects from China, Hong Kong, and Korea were assessed.6,7,19 These studies were similar to the
present study in terms of the TCD assessment of ICAS. The results of this study are also consistent with those of the above-mentioned studies. Especially, DM was found to be the most important risk factor for ICAS among other factors because it was significantly associated with ICAS in both. An additional analysis demonstrated that DM was a significant risk factor for ICAS in both male and female subjects aged ⱖ50 years, although it was not in those aged ⬍50 years. These findings suggested that the increased role of DM in the development of ICAS after ⱖ50 years, which corresponds to the postmenopausal period in Korea,20,21 might be associated with the reduced levels of sex hormones in both men and women. In addition, the adjusted OR in male subjects aged ⱖ50 years was 6.0, almost twice more than that for female subjects, which suggested that the effect of diminishing sex hormone levels on DM in the development of atherosclerosis might differ between genders. A few studies have reported a positive correlation between serum cholesterol levels and asymptomatic ICAS.6 However, the association between serum cholesterol levels and ICAS has been some-
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Table II. Comparisons of clinical characteristics between subjects with and without ICAS after stratifying by gender* ICAS in Male Subjects
Mean age, y Age, y ⬍40 40–49 50–59 60–69 ⱖ70 Hypertension DM Smoking Alcohol drinking Total cholesterol, mg/dL Total cholesterol ⬍200 mg/dL 200⫺239 mg/dL ⱖ240 mg/dL LDL cholesterol, mg/dL Triglycerides, mg/dL BMI, kg/m2 BMI ⬍25 kg/m2 ⱖ25 kg/m2
Yes (n ⫽ 44)
No (n ⫽ 264)
56.7 (13.1)
50.2 (10.8)
5 (11.4) 9 (20.5) 7 (15.9) 16 (36.4) 7 (15.9)
45 (17.0) 83 (31.4) 78 (29.5) 50 (18.9) 8 (3.0)
26 (59.1) 14 (31.8) 25 (56.8) 28 (63.6) 205.4 (34.4)
121 (45.8) 23 (8.7) 113 (42.8) 157 (59.5) 194.5 (33.8)
18 (40.9) 18 (40.9) 8 (18.2)
156 (59.1) 83 (31.4) 25 (9.5)
ICAS in Female Subjects P† ⬍0.001
Yes (n ⫽ 140)
No (n ⫽ 487)
50.6 (10.8)
51.0 (9.8)
P† 0.70
⬍0.001
0.10 ⬍0.001 0.08 0.60 0.05
0.83 20 (14.3) 46 (32.9) 39 (27.9) 32 (22.9) 3 (2.1)
64 (13.1) 159 (32.6) 170 (34.9) 78 (16.0) 16 (3.3)
72 (51.4) 12 (8.6) 11 (7.9) 19 (13.6) 199.2 (37.9)
166 (34.1) 16 (3.3) 25 (5.1) 70 (14.4) 202.4 (35.2)
76 (54.3) 42 (30.0) 22 (15.7)
239 (49.1) 169 (34.7) 79 (16.2)
126.5 (35.4) 126.6 (73.4) 23.5 (2.8)
125.5 (32.6) 125.9 (86.8) 23.5 (3.0)
99 (70.7) 41 (29.3)
350 (71.9) 137 (28.1)
⬍0.001 0.008 0.22 0.81 0.35
0.02
125.9 (25.9) 184.4 (161.0) 23.8 (2.3)
118.0 (30.6) 160.3 (107.6) 24.7 (2.8)
0.11 0.20 0.04
0.42
0.04 30 (68.2) 14 (31.8)
135 (51.1) 129 (48.9)
0.75 0.94 0.94 0.79
BMI ⫽ body mass index; DM ⫽ diabetes mellitus; LDL ⫽ low-density lipoprotein; ICAS ⫽ intracranial cerebral atherosclerosis. *Data are mean (SD) or number (%) of subjects. † P values were calculated by independent-sample t test or the Pearson 2 test or Mantel-Haenszel 2 test when appropriate.
what controversial because, in previous studies, no significant correlation was observed between asymptomatic ICAS and hyperlipidemia.7,8,19 The current study indicated that hypercholesterolemia was an independent risk factor for ICAS in male subjects,
but not in female subjects; this was proved by a statistical result that showed significant interaction between and cholesterol categorization. Further separate analyses among subjects aged ⱖ50 years showed that hypercholesterolemia was a sig-
Figure 1. The role of the level of total cholesterol in the development of ICAS differed between genders, which was proved by a statistical result that an interaction term between gender and total cholesterol categorization was significant (P ⫽ 0.029) in subjects of all ages (left). After additional stratification of the subjects into those aged ⬍50 and ⱖ50 years, there was no interaction between gender and cholesterol categorization in subjects aged ⬍50 years (middle). However, interaction term between gender and cholesterol categorization reached almost significance (P ⫽ 0.050) in the subjects aged ⱖ50 years (right).
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Table III. Crude and adjusted odd ratios (OR) for the presence of ICAS in male and female subjects of all ages Presence of ICAS in Male Subjects (n ⫽ 308)
Presence of ICAS in Female Subjects (n ⫽ 627)
Crude OR (95% CI)
Adjusted OR (95% CI)
Crude OR (95% CI)
Adjusted OR (95% CI)
Age, 10 y Hypertension DM Smoking
1.71* (1.26⫺2.30) 1.71 (0.89⫺3.26) 4.89* (2.28⫺10.51) 1.76 (0.92⫺3.35)
1.74* (1.23⫺2.46) 1.46 (0.71⫺2.99) 3.45* (1.49⫺7.95) 2.09* (1.01⫺4.32)
1.02 (0.85⫺1.23) 2.05* (1.40⫺3.00) 2.76* (1.27⫺5.98) 1.58 (0.76⫺3.29)
0.95 (0.78⫺1.17) 2.10* (1.40⫺3.15) 2.45* (1.11⫺5.44) 1.68 (0.79⫺3.57)
Total cholesterol ⬍200 mg/dL 200⫺239 mg/dL ⱖ240 mg/dL
1.00 1.88 (0.93⫺3.81) 2.77* (1.09⫺7.06)
1.00 1.98 (0.92⫺4.26) 3.31* (1.15⫺9.50)
1.00 0.78 (0.51⫺1.20) 0.88 (0.51⫺1.50)
1.00 0.77 (0.49⫺1.20) 0.78 (0.44⫺1.38)
High BMI
0.49* (0.25⫺0.96)
0.52 (0.24⫺1.10)
1.06 (0.70⫺1.60)
0.95 (0.62⫺1.47)
BMI ⫽ body mass index; CI ⫽ confidence interval; DM ⫽ diabetes mellitus; ICAS ⫽ intracranial cerebral atherosclerosis; OR ⫽ odds ratio. Adjusted OR: adjusted for all the other variables shown in this table. *P ⬍ 0.05.
nificant risk factor in male subjects, but not in female subjects, As discussed above, the interaction term between and cholesterol categorization almost reached significance (P ⫽ 0.050). These findings suggested that the role of hypercholesterolemia in the development of ICAS might be influenced more by diminishing androgen levels in males than by reduced female sex hormone levels. In subjects aged ⬍50 years, although hypercholesterolemia was not a significantly associated factor
for ICAS in either gender, there seemed to be remarkable differences of adjusted ORs between genders. Taken together, there might be interaction or effect modification between hypercholesterolemia and gender. This effect may explain the inconsistencies among previous studies where gender was not considered as an effect modifier about the role of hyperlipidemia in ICAS development. Hypertension is an independent risk factor for asymptomatic ICAS.6 – 8,19 However, this study
Table IV. Crude and adjusted odds ratios (OR) for the presence of ICAS in male and female subjects aged ⬍50 years Presence of ICAS in Male Subjects (n ⫽ 142)
Presence of ICAS in Female Subjects (n ⫽ 289)
Crude OR (95% CI)
Adjusted OR† (95% CI)
Crude OR (95% CI)
Adjusted OR† (95% CI)
Age, 10 y Hypertension DM Smoking
0.98 (0.31⫺3.09) 0.81 (0.26⫺2.56) 3.61 (0.85⫺15.30) 3.34 (0.89⫺12.53)
0.99 (0.26⫺3.73) 0.88 (0.25⫺3.15) 3.34 (0.61⫺18.42) 3.11 (0.78⫺12.37)
0.93 (0.51⫺1.69) 2.69* (1.50⫺4.81) 2.08 (0.48⫺8.93) 1.67 (0.69⫺4.07)
0.80 (0.42⫺1.53) 2.90* (1.57⫺5.37) 1.89 (0.39⫺9.12) 1.94 (0.76⫺4.98)
Total cholesterol ⬍200 mg/dL 200⫺239 mg/dL ⱖ240 mg/dL
1.00 0.91 (0.25⫺3.29) 2.14 (0.49⫺9.31)
1.00 0.66 (0.16⫺2.66) 2.12 (0.41⫺11.00)
1.00 0.68 (0.34⫺1.38) 0.81 (0.29⫺2.27)
1.00 0.60 (0.29⫺1.26) 0.59 (0.19⫺1.81)
High BMI
0.60 (0.20⫺1.84)
0.60 (0.18⫺2.05)
1.09 (0.54⫺2.18)
0.95 (0.46⫺1.97)
BMI ⫽ body mass index; CI ⫽ confidence interval; DM ⫽ diabetes mellitus; ICAS ⫽ intracranial cerebral atherosclerosis. *P ⬍ 0.05. † Adjusted for all the other variables shown in this table.
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Table V. Crude and adjusted odds ratios (OR) for the presence of intracranial cerebral atherosclerosis (ICAS) in male and female subjects aged ⱖ50 years Presence of ICAS in Male Subjects (n ⫽ 166)
Presence of ICAS in Female Subjects (n ⫽ 338)
Crude OR (95% CI)
Adjusted OR† (95% CI)
Crude OR (95% CI)
Adjusted OR† (95% CI)
Age, 10 y Hypertension DM Smoking
3.19* (1.72–5.91) 2.27 (0.97–5.30) 5.05* (2.00–12.74) 1.72 (0.77–3.81)
4.33* (2.02–9.28) 2.37 (0.87–6.46) 6.00* (1.87–19.20) 1.61 (0.61–4.27)
1.30 (0.86–1.96) 1.82* (1.08–3.06) 3.19* (1.27–8.01) 1.35 (0.35–5.23)
1.22 (0.79–1.88) 1.68 (0.98–2.88) 2.93* (1.14–7.48) 1.37 (0.34–5.58)
Total cholesterol ⬍200 mg/dL 200–239 mg/dL ⱖ240 mg/dL
1.00 2.81* (1.17–6.74) 3.55* (1.04–12.15)
1.00 4.34* (1.49–12.61) 4.72* (1.05–21.19)
1.00 0.86 (0.48–1.55) 0.93 (0.47–1.86)
1.00 0.97 (0.53–1.79) 0.97 (0.48–1.95)
0.49 (0.20–1.18)
0.46 (0.16–1.37)
1.07 (0.63–1.81)
1.00 (0.58–1.73)
High BMI
BMI ⫽ body mass index; DM ⫽ diabetes mellitus. *P ⬍ 0.05. † Adjusted for all the other variables shown in this table.
found that hypertension was not an independent risk factor for ICAS in male subjects of all ages and in female subjects aged ⱖ50 years. It was only a risk factor for female subjects aged ⬍50 years. Hypertension induces atherosclerosis via circumferential wall tension (CWT) and the implication of ROS. In particular, blood pressure-induced arterial wall stress and the accompanying stretch have been reported to be primary factors contributing to the localization of atherosclerotic lesions.22 Wall stress, specifically CWT, is proportional to blood pressure and internal diameter.22,23 In this study, the weak influence of hypertension on ICAS suggests that blood pressure-induced arterial CWT may decrease in the intracranial space owing to the anatomic characteristics of arteries with high vessel curvature. In contrast, during the premenopausal period, estrogen may enhance NO-mediated relaxation in the intracranial arteries.10 In this situation, the increase in internal diameter probably makes the blood pressure-induced arterial CWT in premenopausal women much higher than that in men of a comparable age and in postmenopausal women. This effect consequently can reinforce the OR for hypertension. This study also suggests that the role of ROS in ICAS development in the presence of hypertension may be minimally, if at all, present, because if hypertension had caused
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ICAS mainly via ROS involvement, the OR for hypertension would conversely have reduced in the female subjects aged ⬍50 years. This postulation was also supported by the previous study indicating that the pathophysiologic role of oxidative stress in hypertension was less conclusive when considered from a clinical viewpoint.14 Studies on asymptomatic ICAS have reported that old age is an independent risk factor.6 – 8,19 In this study, old age was an independent risk factor for ICAS in male subjects, especially in those aged ⱖ50 years. These findings partly support the hypothesis that a reduction in androgen was independently associated with cardiovascular disease risk including atherosclerosis.24 However, old age was not significantly associated with ICAS in female subjects; interestingly, this might be indicative of the effects of diminishing sex hormone levels in the development of atherosclerosis differing between genders. Another possible explanation for this observation may come from the detection of the TCD signal through the temporal bone, which is more difficult to observe in older women than in men of the same age.25 Thus, the higher exclusion rate is probable in female subjects with ICAS aged ⱖ70 years than in corresponding male subjects. These factors may lead to underestimate the role of old
Y.-S. Kim et al.
age in the development of ICAS in female subjects. This study is, nevertheless, subject to certain limitations. First, the study design is cross-sectional and provides only a snapshot of the subject’s health status, because we did not know if the risk factors were present before or after the development of ICAS. Moreover, the study population was hospital based rather than community based; hence, any generalization may be limited. Second, TCD was the only diagnostic tool used in this study and its findings were not confirmed using angiography. However, TCD is particularly well suited for screening a large number of subjects in a clinic setting, which was the basis for this study; this is because TCD is a noninvasive, safe, and reliable method for the diagnosis of intracranial arterial stenosis.6,7,19,26 Other limitations of this study are the lack of data on several potential risk factors such as carotid disease, inflammatory markers, physical activity, emotional factors, dietary habits, and family medical history.
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CONCLUSIONS The independent risk factors for ICAS in asymptomatic subjects differed between genders: age, DM, hyperlipidemia, and smoking in the male gender; and hypertension and DM in the female gender. These differences may be attributable to the role of sex hormones in the development of ICAS. Our results may help develop a gender-based strategy for the prevention of vascular events after ICAS.
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ACKNOWLEDGMENTS This work was supported by grant number KHU20080593 (2008) from Kyung Hee University, Seoul, Korea. Drs. Kim and Moon developed the research question and study design, performed the data collection and analysis, and drafted and finalized the manuscript. Drs. Hong, Jung, Park, Park, Cho, and Bu contributed to the study design and data collection, provided consultation for data analysis, assisted with manuscript revisions, and approved the final manuscript. The authors have indicated that they have no conflicts of interest regarding the content of this article.
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Address correspondence to: Sang-kwan Moon, MD, PhD, Department of Cardiovascular and Neurologic Diseases, College of Oriental Medicine, Kyung Hee University, #1, Hoegi-dong, Dongdaemun-gu, Seoul # 130-702, Korea (Republic of). E-mail: [email protected]
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