(Stroke. 2002;33:2177.)
© 2002 American Heart Association, Inc.
Original Contributions |
From the Third Department of Internal Medicine and Cardiovascular Research Institute, Kurume University School of Medicine, Kurume, Japan.
Correspondence to Hisashi Adachi, MD, PhD, Third Department of Internal Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan. E-mail hadac{at}med.kurume-u.ac.jp
| Abstract |
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Methods In 1111 cases (452 men, 659 women) aged 63±10 years old (range, 40 to 94 years) recruited from a population-based survey performed in 1999, we measured fasting plasma total homocysteine levels and performed bilateral carotid B-mode ultrasound. The participants underwent measurements of other blood chemistries (total cholesterol, HDL cholesterol, glycosylated hemoglobin A1c, and creatinine).
Results For the total population, the mean total homocysteine level was 10.9 µmol/L. Total homocysteine levels were higher in men than in women and increased with aging. With multiple linear regression analysis after adjustments for age and sex, the most powerful determinant of total homocysteine levels was serum creatinine (P<0.001). With multiple stepwise regression analysis after adjustments for age, sex, and other confounding factors, total homocysteine was significantly (P<0.05) related to IMT. Furthermore, when mean values of IMT adjusted for age, sex, and other related factors were analyzed across total homocysteine quartiles, IMT (P<0.05) showed a significant trend as total homocysteine level increased.
Conclusions Plasma total homocysteine levels in Japan are similar to those reported in western countries. Mild hyperhomocysteinemia is an independent risk factor for increased carotid artery wall thickness in Japan as well.
Key Words: atherosclerosis epidemiology homocysteine intima-media thickness
| Introduction |
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| Subjects and Methods |
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Data Collection
The subjects medical history, use of alcohol, and smoking were ascertained by questionnaire. Alcohol intake and smoking were classified as current habitual use or not. Height and weight were measured, and body mass index (kilograms per meter squared) was calculated as an index of obesity. Blood pressure was measured twice with the subjects in the supine position. The second BP after 5 deep breaths with the fifth phase diastolic pressure was used for analysis. Hypertensive subjects were defined as those with BP
140 and/or 90 mm Hg or those receiving antihypertensive medication.
Blood was drawn from the antecubital vein for determination of lipids (total cholesterol and HDL cholesterol), glycosylated hemoglobin A1c (HbA1c), creatinine, and total homocysteine levels in the morning after 12-hour fast. Fasting blood samples were centrifuged within 1 hour after collection. Plasma total homocysteine was measured by high-pressure liquid chromatography.12 Other chemistries, such as serum total cholesterol, HDL cholesterol (enzymatic assay method), HbA1c (ion-exchange high-performance liquid chromatography), and creatinine (enzymatic assay method) were measured at a commercially available laboratory (Kyodo Igaku Laboratory, Fukuoka, Japan).
Carotid intimal-medial wall thickness (IMT) of the common carotid artery was determined with the use of duplex ultrasonography (SSA-380A, Toshiba) with a 10-MHz transducer, with the subject in the sitting position with the head upright. Longitudinal B-mode images at the diastolic phase of the cardiac cycle were recorded by a single trained technician who was blinded as to the subjects background. The images were magnified and printed with a high-resolution line recorder (LSR-100A, Toshiba). Measurements of IMT were made by the same technician using fine slide calipers at 3 levels of the lateral and medial walls 1 to 3 cm proximal to the carotid bifurcation. These 6 combined near- and far-wall measurements were averaged. Interobserver and intraobserver variations were 3.8% and 4.2%, respectively.13
This study was approved by the Ukiha branch of the Japan Medical Association, by the mayor, and by the welfare section of Tanushimaru district. All participants gave informed consent.
Statistical Methods
Results are presented as mean±SD. The medications for hypertension, hyperlipidemia, and diabetes were coded as dummy variables. Multiple linear regression analysis was performed for determinants of total homocysteine levels adjusted for age, sex, and confounding factors. Multiple linear regression analysis was also performed for determinants of carotid IMT measurement adjusted for age, sex, and confounding factors. The IMT levels by quartiles of the increasing total homocysteine values were compared by ANCOVA, adjusted for age, sex, and other related covariates. We confirmed that all of the parameters were not skewed distributions. Statistical significance was defined as P<0.05. All statistical analyses were performed with the use of the SAS system.
| Results |
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| Discussion |
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Determinants of Plasma Total Homocysteine Levels
Normal values of fasting plasma total homocysteine levels are between 5 and 15 µmol/L,12 and the mean values of total homocysteine are 13 µmol/L for men and 10 µmol/L for women in western countries.12 Although a population-based study with a small number of cases (n=474) has been reported from Japan,6 our study is the first to report plasma total homocysteine levels of a large number of cases (n=1111) in a general population in Japan. The mean values of our data were 12.6 µmol/L for men and 9.8 µmol/L for women. Thus, the plasma total homocysteine levels in our population are similar to those in western countries despite differences in diet and other genetic and environmental factors. Our report is somewhat contradictory to that which demonstrated a positive association between plasma total homocysteine levels and cardiovascular mortality, in which the plasma total homocysteine level was reported as <8 µmol/L in 20 Japanese men.14
Previous studies indicated that age and sex are major determinants of plasma total homocysteine levels.5,7,12 We also demonstrated similar findings. With the exception of men aged 40 to 49 years, plasma total homocysteine increased with age in both men and women (Figure 2). Several reasons for high total homocysteine levels in those aged 40 to 49 years must be considered. As shown in Table 3, smoking was one of the most powerful determinants of total homocysteine. Accordingly, the most likely reason for high total homocysteine in subjects aged 40 to 49 years is the high prevalence of smokers in this age group compared with the other age groups (53.3% versus 35.5%: P<0.01). Taken together, age and sex are major determinants of plasma total homocysteine levels.
Our study showed that creatinine was the strongest related variable for total homocysteine. It is known that renal function affects plasma total homocysteine levels.15 However, many previous studies did not consider renal function in the analysis of plasma total homocysteine levels.4,10,11 It may be interesting to note that HbA1c was inversely related to total homocysteine. This inverse association may seem puzzling, but it has been demonstrated that the mean plasma level is normal or low in insulin-dependent diabetes mellitus and noninsulin-dependent diabetes mellitus patients.1619 Indeed, Wollesen et al16 showed that renal hyperfiltration is the cause of the lower than normal mean plasma total homocysteine levels in populations of diabetic patients and concluded that glomerular filtration is rate limiting for renal clearance of homocysteine. Although we did not examine glomerular filtration in our study, the inverse relationship may well be explained by the greater glomerular filtration in subjects with higher HbA1c.
As demonstrated in Table 3, smoking was the second major determinant of total homocysteine level; this finding is consistent with those of western countries.20,21 It is not well known how smoking is related to hyperhomocysteinemia. However, it is suggested that smoking may reduce vitamin B6 in the body, which is one of the vitamins involved in the mechanism for homocysteine metabolism.22
Determinants of IMT
By multiple linear regression analysis (Table 4), total homocysteine was significantly related to IMT after adjustments for age and sex. To further examine this relationship, we performed the following 2 analyses. First, we evaluated determinants of IMT using multiple stepwise regression analysis (Table 5). After adjustments for age, sex, and other confounding factors, plasma total homocysteine levels were positively and independently associated with carotid IMT. Second, as shown in Figure 3, IMT showed a significant dose-dependent relationship among quartiles of total homocysteine levels. Taken together, our results indicate that hyperhomocysteinemia is a significant and independent risk factor for IMT. Positive associations were also found between IMT and known risk factors for carotid atherosclerosis such as BP (the strongest for systolic BP) and low HDL cholesterol. Consistent with previous reports,1,2 hypercholesterolemia and smoking status were not risk factors for carotid atherosclerosis in our study.
In conclusion, we found that plasma total homocysteine levels in Japan are similar to those in western countries and that high plasma total homocysteine levels are related to carotid atherosclerosis in Japan.2325
| Acknowledgments |
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Received August 31, 2001; revision received December 18, 2001; accepted February 27, 2002.
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