Role of endothelial cell-derived angptl2 in vascular inflammation leading to endothelial dysfunction and atherosclerosis progression.

OBJECTIVE: Cardiovascular disease (CVD), the most common morbidity resulting from atherosclerosis, remains a frequent cause of death. Efforts to develop effective therapeutic strategies have focused on vascular inflammation as a critical pathology driving atherosclerosis progression. Nonetheless, molecular mechanisms underlying this activity remain unclear. Here, we ask whether angiopoietin-like protein 2 (Angptl2), a proinflammatory protein, contributes to vascular inflammation that promotes atherosclerosis progression. APPROACH AND RESULTS: Histological analysis revealed abundant Angptl2 expression in endothelial cells and macrophages infiltrating atheromatous plaques in patients with cardiovascular disease. Angptl2 knockout in apolipoprotein E-deficient mice (ApoE(-/-)/Angptl2(-/-)) attenuated atherosclerosis progression by decreasing the number of macrophages infiltrating atheromatous plaques, reducing vascular inflammation. Bone marrow transplantation experiments showed that Angptl2 deficiency in endothelial cells attenuated atherosclerosis development. Conversely, ApoE(-/-) mice crossed with transgenic mice expressing Angptl2 driven by the Tie2 promoter (ApoE(-/-)/Tie2-Angptl2 Tg), which drives Angptl2 expression in endothelial cells but not monocytes/macrophages, showed accelerated plaque formation and vascular inflammation because of increased numbers of infiltrated macrophages in atheromatous plaques. Tie2-Angptl2 Tg mice alone did not develop plaques but exhibited endothelium-dependent vasodilatory dysfunction, likely because of decreased production of endothelial cell-derived nitric oxide. Conversely, Angptl2(-/-) mice exhibited less severe endothelial dysfunction than did wild-type mice when fed a high-fat diet. In vitro, Angptl2 activated proinflammatory nuclear factor-κB signaling in endothelial cells and increased monocyte/macrophage chemotaxis. CONCLUSIONS: Endothelial cell-derived Angptl2 accelerates vascular inflammation by activating proinflammatory signaling in endothelial cells and increasing macrophage infiltration, leading to endothelial dysfunction and atherosclerosis progression.

White-coat and masked hypertension are associated with carotid atherosclerosis in a general population: the Hisayama study.

BACKGROUND AND PURPOSE: On the basis of combined measurements of clinic blood pressure (CBP) and home blood pressure (HBP), blood pressure status can be divided into normotension, white-coat hypertension (WCHT), masked hypertension (MHT), and sustained hypertension (SHT). Despite the clear impact of MHT and SHT on clinical and subclinical arterial disease, uncertainty about the influence of WCHT remains. The objective of this study was to investigate the associations of WCHT, MHT, and SHT with carotid atherosclerosis in a general population. METHODS: This is a cross-sectional survey of 2915 community-dwelling Japanese aged ≥ 40 years. Normotension was defined as CBP<140/90 and HBP<135/85 mm Hg; WCHT, CBP ≥ 140/90 and HBP<135/85 mm Hg; MHT, CBP<140/90 and HBP ≥ 135/85 mm Hg; and SHT, CBP ≥ 140/90 and HBP ≥ 135/85 mm Hg. Mean intima-media thickness of carotid arteries was measured using a computer-automated system, and carotid stenosis was defined as diameter stenosis ≥ 30%. RESULTS: There were 1374 subjects (47.1%) with normotension, 200 (6.9%) with WCHT, 639 (21.9%) with MHT, and 702 (24.1%) with SHT. The geometric average of mean intima-media thickness was significantly higher among subjects with WCHT (0.73 mm), MHT (0.77 mm), and SHT (0.77 mm) than those with normotension (0.67 mm; all P<0.001 versus normotension). Compared with normotension, all types of hypertension were also associated with increased likelihood of carotid stenosis (age- and sex-adjusted odds ratio, 2.36 [95% confidence interval, 1.27-4.37] for WCHT, 1.95 [1.25-3.03] for MHT, and 3.02 [2.01-4.54] for SHT). These associations remained significant even after adjustment for other cardiovascular risk factors. CONCLUSIONS: WCHT, as well as MHT, and SHT were associated with carotid atherosclerosis in a general Japanese population.

Temporal trends in sudden unexpected death in a general population: the Hisayama study.

BACKGROUND: Studies addressing the temporal trends in the prevalence of sudden unexpected death (SUD) and its underlying causes in the general population are limited. METHODS: Among a total of 1934 residents aged ≥20 years of the town of Hisayama, Japan, who died of endogenous causes of death and underwent autopsy examination (autopsy rate 78.5%) from 1962 to 2009, 204 were determined to be cases of SUD within 24 hours. RESULTS: The trend in the age- and sex-adjusted prevalence of SUD among all autopsy subjects was stable over four 12-year periods (13.1% in 1962-1973, 13.4% in 1974-1985, 15.0% in 1986-1997, and 14.6% in 1998-2009; P for trend = .80). Regarding causes of death, the prevalence of SUD from stroke significantly declined with time (8.0%, 5.0%, 2.3%, and 2.1%, respectively; P for trend < .001), whereas significant increments were observed in the prevalence of SUD from heart disease (4.0%, 6.2%, 8.6%, and 9.7%; P for trend = .02) and from aortic aneurysm and dissection (0.2%, 1.2%, 2.9%, and 2.8%; P for trend = .01). In particular, the prevalence of ischemic heart disease increased 3-fold from 2.1% in 1962-1973 to 6.6% in 1998-2009 (P = .04). Reflecting the increment of ischemic heart disease, SUD within 1 hour increased significantly from 2.5% to 7.6% during this period (P = .01). CONCLUSIONS: The trend in the prevalence of SUD was stable across a half century in a general Japanese population. Despite the decrement in the prevalence of SUD from stroke, that from heart disease, especially ischemic heart disease, increased significantly with time.

Haemoglobin A1c even within non-diabetic level is a predictor of cardiovascular disease in a general Japanese population: the Hisayama Study.

BACKGROUND: There is little information about predictive ability of haemoglobin A1c (HbA1c) for cardiovascular disease (CVD) in Asians. To investigate the discriminatory ability of HbA1c to identify subjects who are at greater risk of developing CVD in a prospective study of a defined community-dwelling Japanese population. METHODS: A total of 2,851 subjects aged 40-79 years were stratified into five groups (HbA1c levels with ≤ 5.0, 5.1-5.4, 5.5-6.4, and ≥ 6.5% and a group with antidiabetic medication) and followed up prospectively for 7 years (2002-2009). RESULTS: During the follow-up, 119 subjects developed CVD. The multivariable-adjusted risk of CVD was significantly increased in subjects with HbA1c levels of 5.5-6.4 and ≥ 6.5% and diabetic medication compared to HbA1c level with ≤ 5.0% (hazard ratio, 2.26 [95% confidence interval, 1.29-3.95] for the 5.5-6.4%; 4.43 [2.09-9.37] for the ≥ 6.5%; and 5.15 [2.65-10.0] for the antidiabetic medication group). With regard to CVD subtype, the positive associations between HbA1c levels and the risk of coronary heart disease (CHD) and ischaemic stroke were also significant, but no such associations were seen for haemorrhagic stroke. The C statistic for developing CVD was significantly increased by adding HbA1c values to the model including other risk factors (0.789 vs. 0762, p = 0.006), and the net reclassification improvement was 0.105 (p = 0.004). CONCLUSIONS: Our findings suggest that elevated HbA1c levels are an independent risk factor for CVD, especially CHD and ischaemic stroke, and that the addition of HbA1c to the model with traditional risk factors significantly improves the predictive ability of CVD.

Angiopoietin-like protein 2 is associated with chronic kidney disease in a general Japanese population: the Hisayama Study.

BACKGROUND: Angiopoietin-like protein 2 (Angptl2) is an adipokine that promotes inflammation and endothelial dysfunction of the vessels. The aim of this study was to investigate the relationship between serum Angptl2 level and chronic kidney disease (CKD). METHODS AND RESULTS: A total of 3,169 community-dwelling subjects aged ≥40 years were divided into quintiles by Angptl2 level. CKD was defined as the presence of albuminuria (urine albumin-creatinine ratio ≥30.0mg/g) or decreased estimated glomerular filtration rate (eGFR <60ml·min(-1)·1.73m(-2)). The odds ratio (OR) for the presence of CKD was calculated using a logistic regression model. The overall prevalence of CKD was 37.5%. The age- and sex-adjusted ORs for the presence of CKD increased with higher serum Angptl2 level. This trend remained significant after adjusting for known cardiovascular risk factors (<2.01ng/ml: OR, 1.00 (reference); 2.01-2.48ng/ml: OR, 1.67, 95% confidence interval [CI]: 1.24-2.24; 2.49-2.99ng/ml: OR, 1.70, 95% CI: 1.27-2.28; 3.00-3.65ng/ml: OR, 1.78, 95% CI: 1.32-2.39; ≥3.66ng/ml: OR, 1.79, 95% CI: 1.32-2.43; P-value for trend=0.001). Multivariate-adjusted ORs for the presence of albuminuria increased significantly with elevated serum Angptl2 (P-value for trend=0.004), while there was no evidence of a significant relationship between serum Angptl2 level and decreased eGFR (P-value for trend=0.08). CONCLUSIONS: Elevated serum Angptl2 is associated with the likelihood of CKD in the general population.

Elevated depressive symptoms in metabolic syndrome in a general population of Japanese men: a cross-sectional study.

BACKGROUND: Uncertainty still surrounds the association between metabolic syndrome (MetS) and depression. We aimed to evaluate the association between MetS and elevated depressive symptoms in a general Japanese population. METHODS: This is a cross-sectional survey of 3,113 community-dwelling individuals aged 40 years or over. MetS was defined according to the joint interim statement. MetS was diagnosed when a subject had three or more of the following components: 1) central obesity (waist circumference ≥ 90 cm for men, ≥ 80 cm in for women); 2) elevated blood pressure (≥ 130/85 mmHg or current use of antihypertensive medication); 3) hypertriglyceridemia (≥ 1.7 mmol/L); 4) low HDL cholesterol (< 1.0 mmol/L for men, < 1.3 mmol/L for women); and 5) elevated fasting plasma glucose (≥ 5.55 mmol/L or current use of antidiabetic medication). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). The age- and multivariable-adjusted odds ratio (OR) and 95% confidence interval (CI) were estimated using a logistic regression model. RESULTS: Elevated depressive symptoms were observed in 4.3% of male and 6.3% of female participants. In men, the age-adjusted prevalence of elevated depressive symptoms was significantly higher in subjects with MetS than in those without (7.1% versus 3.6%, p = 0.04). The prevalence of elevated depressive symptoms rose progressively as the number of MetS components increased (3.5%, 3.6%, 5.8%, and 9.2% in male subjects with 0-1, 2, 3, and ≥ 4 components, respectively; p = 0.02 for trend). This association remained significant even after adjustment for age, marital status, history of cardiovascular disease, smoking habit, alcohol intake, and regular exercise. In women, on the other hand, there was no clear association between MetS and depressive symptoms. CONCLUSIONS: MetS was associated with elevated depressive symptoms in a general population of Japanese men.

White blood cell count and risk of gastric cancer incidence in a general Japanese population: the Hisayama study.

The authors examined the association between white blood cell (WBC) count and the development of gastric cancer in a 19-year follow-up study of 2,558 Japanese subjects aged ≥40 years (1988-2007). The subjects were stratified into 4 groups according to baseline WBC quartile (≤4.4, 4.5-5.2, 5.3-6.3, or ≥6.4 × 10(3) cells/µL). During follow-up, 128 subjects developed gastric cancer. The age- and sex-adjusted incidence of gastric cancer increased linearly with higher WBC level: 1.7, 2.6, 3.9, and 5.4 per 1,000 person-years, respectively, for the 4 quartile groups (P for trend < 0.01). The risk of gastric cancer was 2.22-fold (95% confidence interval: 1.19, 4.14) higher in the highest WBC quartile group than in the lowest group after adjustment for confounding factors. With respect to Helicobacter pylori infection status, H. pylori-seropositive subjects in the highest WBC quartile group showed a significantly greater risk of gastric cancer than those in the lower 3 quartile groups, whereas such an association was not observed in H. pylori-seronegative subjects. There was no evidence of heterogeneity in the association (P for heterogeneity = 0.65). The study findings suggest that higher WBC levels are a risk factor for gastric cancer, especially in subjects with H. pylori infection.

Association between glucose tolerance level and cancer death in a general Japanese population: the Hisayama Study.

The authors examined the associations of glucose tolerance status and fasting and 2-hour postload glucose levels with the risk of cancer death in a 19-year follow-up study of 2,438 Japanese subjects aged 40-79 years who underwent a 75-g oral glucose tolerance test (1988-2007). During follow-up, 229 subjects died of cancer. The risk of cancer death was significantly higher in subjects with fasting plasma glucose levels of ≥5.6 mmol/L or 2-hour postload glucose levels of ≥11.1 mmol/L than in those with the lowest fasting or 2-hour postload glucose levels, after adjustment for potentially confounding factors. According to glucose tolerance status, not only diabetes but also impaired fasting glycemia and impaired glucose tolerance were significant risk factors for cancer death (for impaired fasting glycemia, multivariable-adjusted hazard ratio (HR) = 1.49 (95% confidence interval (CI): 1.05, 2.11); for impaired glucose tolerance, HR = 1.52 (95% CI: 1.05, 2.22); and for diabetes, HR = 2.10 (95% CI: 1.41, 3.12)). With regard to site-specific cancers, elevated fasting or 2-hour postload glucose levels were associated with the risks of death from stomach, liver, and lung cancer. These findings suggest that both prediabetic hyperglycemia and diabetes are significant risk factors for cancer death in the general Japanese population.

Functional SNP of ARHGEF10 confers risk of atherothrombotic stroke.

Although stroke is a common cause of death and a major cause of disability all over the world, genetic components of common forms of ischemic stroke are largely unknown. To identify susceptibility genes of atherothrombotic stroke, we performed a large case-control association study and a replication study in a total of 2775 cases with atherothrombotic stroke and 2839 controls. Through the analysis in 860 cases and 860 age- and sex-matched controls, we found that a single-nucleotide polymorphism (SNP), rs2280887, in the ARHGEF10 gene was significantly associated with atherothrombotic stroke even after the adjustment of multiple testing by a permutation test [unadjusted P = 1.2 x 10(-6), odds ratio = 1.80, 95% confidence interval (CI) = 1.42-2.28]. This association was replicated in independent 1915 cases and 1979 controls. Subsequent fine mapping found another three SNPs which showed similar association due to strong linkage disequilibrium to rs2280887 (r(2) > 0.95). In the functional analyses of these four highly associated SNPs, using luciferase assay and electrophoretic mobility shift assay we found that rs4376531 affected ARHGEF10 transcriptional activity due to the different Sp1-binding affinity. In small GTPase activity assay, we found that a gene product of ARHGEF10 specifically activated RhoA. A population-based cohort study revealed the subjects with rs4376531 CC or CG to increase the incidence of ischemic stroke (P = 0.033, hazard ratio = 1.79, 95% CI = 1.05-3.04). Our data suggest that the functional SNP of ARHGEF10 confers the susceptibility to atherothrombotic stroke.

N-terminal pro-brain natriuretic peptide and risk of cardiovascular events in a Japanese community: the Hisayama study.

OBJECTIVE: Few studies have examined the association between natriuretic peptides and the incidence of cardiovascular disease (CVD) in Asian populations. METHODS AND RESULTS: A total of 3104 community-dwelling Japanese individuals aged ≥40 years without history of CVD were followed up for 5 years. A total of 127 CVD events were identified. The age- and sex-adjusted incidence of CVD increased with increasing N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (<55, 55-124, 125-399, and ≥400 pg/mL) at baseline and was significantly higher even in subjects with a modest increase. This association remained robust even after adjustment for other potential risk factors (55-124 pg/mL: multivariate-adjusted hazard ratio=1.85 [95% CI 1.07-3.18], P=0.03; 125-399 pg/mL: 2.98 [95% CI 1.65-5.39], P<0.001; ≥400 pg/mL: 4.54 [95% CI 2.22-9.29], P<0.001). The multivariate-adjusted hazard ratios for the development of total CVD and its subtypes, coronary heart disease and stroke, were significantly increased by a 1 SD increment of the log NT-proBNP concentrations and were nearly equal among CVD subtypes. Similar findings were observed for stroke subtypes of ischemic stroke and intracerebral hemorrhage but not subarachnoid hemorrhage. The effects of the 1 SD increment in log NT-proBNP values were comparable in subjects with and without other cardiovascular risk factors, except for sex. The area under the receiver operating characteristic curve was significantly (P=0.006) increased by adding NT-proBNP values to the model including other potential risk factors. CONCLUSIONS: Elevated NT-proBNP levels were shown to be a significant risk factor for the development of CVD and its subtypes in a general Japanese population, independently of other cardiovascular risk factors.

Optimal cutoff value of the serum pepsinogen level for prediction of gastric cancer incidence: the Hisayama Study.

BACKGROUND: Serum pepsinogen (sPG) levels have been established as a good marker of chronic atrophic gastritis and the sequential occurrence of gastric cancer. However, there have been few prospective investigations which investigated the predictive performance of sPG for future gastric cancer incidence. SUBJECTS AND METHODS: We prospectively followed-up a total of 2446 community-dwelling Japanese aged ≥ 40 years for 10 years and used the Youden's index to determine the cutoff values of the pepsinogen I level and pepsinogen I/II ratio to accurately discriminate gastric cancer events. Predictive performance of sPG was assessed by ROC curve. RESULTS: During the follow-up, 69 subjects developed gastric cancer. The most predictive sPG test criteria were determined to be a pepsinogen I level ≤ 59 ng/ml and pepsinogen I/II ratio ≤ 3.9. The sensitivity and specificity of these criteria to discriminate the actual occurrence of gastric cancer were 71.0% and 69.2%, respectively. The area under the ROC curve for gastric cancer occurrence increased significantly by adding the sPG test to the model that included the status of Helicobater pylori infection and other potential risk factors (from 0.742 to 0.809; p for difference in the area < 0.001). CONCLUSIONS: This study determined the optimal sPG test criteria for predicting gastric cancer occurrence over 10 years in a general Japanese population. These criteria would be effective to screen for individuals at high risk of this disease.

Prospective study on waist circumference and risk of all-cause and cardiovascular mortality: pooled analysis of Japanese community-based studies.

BACKGROUND: The aim of the present study was to clarify the association between waist circumference and all-cause and cardiovascular disease (CVD) mortality risk in relatively lean Japanese subjects. METHODS AND RESULTS: A total of 3,554 men and 4,472 women who had no history of CVD were examined and their waist circumference measured at baseline. The subjects were aged ≥40 years and were obtained from 3 prospective cohort studies during 1988-1996. Hazard ratios for all-cause and CVD mortality were analyzed over a follow-up period of 14.7 years using a Cox proportional hazards model and penalized spline method, after adjustment for study cohort, age, smoking, alcohol drinking, hypertension, dyslipidemia, and diabetes. Compared with the lowest quintile, the highest quintile of waist circumference in men was associated with a linear reduction in all-cause mortality risk (multivariate-adjusted hazard ratio, 0.73; 95% confidence interval: 0.60-0.89; P for trend=0.001). CVD mortality risk was increased in men aged ≤65 years with a higher waist circumference. This relationship was U-shaped. Waist circumference was not associated with all-cause or CVD mortality risk in women. CONCLUSIONS: Waist circumference was associated inversely with increased risk of all-cause death in men, but not in women. Middle-aged men with a greater waist circumference potentially have an increased risk of CVD mortality.

Dietary vitamin A intake and incidence of gastric cancer in a general Japanese population: the Hisayama Study.

BACKGROUND: The results of prospective studies examining the association between dietary vitamin A intake and the risk of gastric cancer have often been conflicting. The objective of this study was to investigate this issue in a general Japanese population. METHODS: A total of 2,467 community-dwelling Japanese subjects aged 40 years or older were followed up prospectively for 14 years. Dietary vitamin A intake was estimated using a semiquantitative food frequency method. RESULTS: During the follow-up period, gastric cancer developed in 93 subjects. The age- and sex-adjusted incidence of gastric cancer rose progressively with increasing levels of dietary vitamin A intake: at 2.2, 3.0, 3.8, and 4.5 per 1,000 person-years for quartile groups defined by dietary vitamin A intake levels of <639, 639-837, 838-1,061, and >1,061 µg retinol equivalents (RE)/day, respectively (P for trend <0.01). The risk of gastric cancer was significantly higher in the fourth quartile than in the first one even after multivariate adjustment [hazard ratio (HR) = 1.47, 95% confidence interval (CI) = 0.70-3.09, P = 0.30 for the second quartile; HR = 1.85, 95% CI = 0.82-4.18, P = 0.14 for the third quartile; HR = 2.96, 95% CI = 1.12-7.80, P = 0.03 for the fourth quartile]. Comparable effects of vitamin A intake were observed irrespective of the location or histological type of gastric cancer. The HR for gastric cancer increased significantly only in subjects with a combination of high vitamin A intake (>1,061 µg RE/day) and Helicobacter pylori infection. CONCLUSIONS: Our findings suggest that dietary vitamin A intake is clearly associated with the risk of gastric cancer in the general Japanese population.

Prevalence and causes of functional disability in an elderly general population of Japanese: the Hisayama study.

BACKGROUND: There are limited data on the prevalence and causes of disability in the elderly general population in Japan. METHODS: In a population-based cross-sectional study of 1550 Japanese aged 65 years or older, we examined the prevalence of functional disability (defined as a Barthel Index score of ≤95) and its causes. RESULTS: A total of 311 of the participants had a disability (prevalence 20.1%). The prevalence of disability increased with age and doubled with every 5-year increment in age. Prevalence was higher in women than in men, especially among those aged 85 years or older. With respect to the cause of functional disability, dementia accounted for 23.5%, stroke for 24.7%, orthopedic disease for 12.9%, and other disease for 38.9% of cases in men; in women, the respective values were 35.8%, 9.3%, 31.0%, and 23.9%. Regarding age, dementia was the most frequent cause of disability in subjects aged 75 years or older, whereas stroke was most common in subjects aged 65 to 74 years. Approximately two-thirds of cases of total dependence were attributed to dementia in both sexes, whereas the main cause of slight or moderate/severe dependence was stroke in men and orthopedic disease in women. Among participants with total dependence, 94.8% resided in a hospital or health care facility. CONCLUSIONS: Our findings indicate that functional disability is common among Japanese elderly adults and that its major cause is stroke in men and dementia in women.

Smoking cessation improves mortality in Japanese men: the Hisayama study.

BACKGROUND: Although the smoking rate among Japanese men has been the highest in developed countries, the epidemiological evidence about whether smoking cessation can extend their lifespan is not well established. METHODS: A total of 1083 Japanese men aged ≥40 years were classified by their smoking status and followed up prospectively for 18 years (1988-2006). RESULTS: Current smoking was a significant risk factor for all-cause death: the multivariate-adjusted HRs of all-cause death for current smokers of 1-19, 20-39 and ≥40 cigarettes per day were 1.61 (95% CI 1.16 to 2.22), 1.56 (95% CI 1.08 to 2.23) and 3.15 (95% CI 1.59 to 6.24), respectively. Former smokers did not have an increased risk of all-cause death compared with never smokers. The excess risk of all-cause death for current smokers tended to decrease within 5 years after smoking cessation, eventually reaching a level almost equivalent to that of never smokers. The risk of cancer death decreased by 53% in subjects who had quit smoking for ≥10 years, while the risk of cardiovascular death decreased by 56% in subjects with the cessation period of <10 years. CONCLUSIONS: Our findings suggest that even a modest smoking habit significantly increases the risk of death among Japanese men, and the risk of death diminishes soon after cessation of smoking. These results imply the importance of smoking cessation to extend life in Japanese men.

High serum bilirubin levels and diabetic retinopathy: the Hisayama Study.

PURPOSE: To assess the association between serum total bilirubin levels and diabetic retinopathy prevalence in participants of the Hisayama Study who had diabetes and impaired glucose metabolism. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: Of 3119 participants of the Hisayama Study Eye Examinations in 2007, Japan, 1672 aged ≥40 years with either diabetes or impaired glucose metabolism (defined by a 75-g oral glucose tolerance test) were enrolled in the present study. METHODS: Diabetic retinopathy was assessed via ophthalmic examination after pupil dilatation. The presence and the severity of diabetic retinopathy were determined by grading of color fundus photographs using the modified Airlie House classification system. Association of diabetic retinopathy with serum bilirubin quartiles was assessed using logistic regression model adjusting for age and known risk factors for diabetic retinopathy. MAIN OUTCOME MEASURES: Prevalent diabetic retinopathy. RESULTS: Diabetic retinopathy was present in 70 of 1672 (4.2%) participants. The prevalence of diabetic retinopathy in persons with the highest bilirubin quartile (≥0.9 mg/dL) was 2.7%, compared with the prevalence of 3.4%, 5.1%, and 5.1% in those with the first (<0.6 mg/dL), second (0.6-0.69 mg/dL), and third quartiles (0.7-0.89 mg/dL). After adjusting for factors known to be associated with diabetic retinopathy, the prevalence was significantly lower among persons with the highest bilirubin quartile compared with those with the lowest quartile (odds ratio [OR], 0.25; 95% confidence interval [CI], 0.09-0.72) or compared with those in the 3 lower quartiles (OR, 0.25; 95% CI, 0.11-0.58). CONCLUSIONS: Elevated serum bilirubin levels may be protective against diabetic retinopathy among persons with either diabetes or impaired glucose metabolism, independent of known risk factors for diabetic retinopathy.

Combined effects of smoking and hypercholesterolemia on the risk of stroke and coronary heart disease in Japanese: the Hisayama study.

BACKGROUND: Cigarette smoking is an established risk factor for stroke and coronary heart disease (CHD) in Western countries. However, it is uncertain whether or not smoking raises the risk of stroke in Japanese. We examined the influence of smoking on the development of stroke and CHD and the effects of interactions between smoking and hypercholesterolemia on these outcomes in a general Japanese population. METHODS: A total of 2,421 community-dwelling Japanese individuals, aged 40-79 years, with no history of cardiovascular disease, were followed up for 14 years. RESULTS: During the follow-up, 194 total stroke and 112 CHD events occurred. Compared with never smokers, the multivariate-adjusted hazard ratios for the occurrence of total stroke were 1.53 (95% confidence interval = 0.90-2.61) in former smokers, 1.90 (1.18-3.06) in current light smokers (<20 cigarettes/day) and 2.01 (1.11-3.65) in current heavy smokers (≥ 20 cigarettes/day). The multivariate-adjusted hazard ratios for the development of CHD were 1.10 (0.56-2.15), 1.88 (1.02-3.47) and 2.31 (1.17-4.57), respectively. In regard to stroke subtypes, current smoking was an independently significant risk factor for ischemic stroke and subarachnoid hemorrhage. Furthermore, the combination of smoking and hypercholesterolemia synergistically increased the risks of total stroke and CHD (all p for interaction <0.05). CONCLUSION: Our findings suggest that smoking raises the risks of ischemic stroke, subarachnoid hemorrhage and CHD occurrence in the Japanese population, and that this effect is strengthened by hypercholesterolemia.

Impact of glucose tolerance status on development of ischemic stroke and coronary heart disease in a general Japanese population: the Hisayama study.

BACKGROUND AND PURPOSE: Few studies have shown the association between glucose tolerance status defined by a 75-g oral glucose tolerance test and the development of different types of cardiovascular disease. METHODS: A total of 2421 community-dwelling Japanese subjects aged 40 to 79 years who underwent the oral glucose tolerance test were followed up for 14 years. RESULTS: In multivariable analysis, the risks of ischemic stroke in both sexes and coronary heart disease (CHD) in women were significantly higher in subjects with diabetes determined by the World Health Organization criteria than in those with normal glucose tolerance even after adjustment for other confounding factors, but such association was not seen for CHD in men (ischemic stroke: adjusted hazard ratio [HR]=2.54, P=0.002 in men; adjusted HR=2.02, P=0.03 in women; CHD: adjusted HR=1.26, P=0.47 in men; adjusted HR=3.46, P=0.002 in women). Similar associations were observed for fasting plasma glucose levels of >or=7.0 mmol/L (ischemic stroke: adjusted HR=2.15, P=0.03 in men; adjusted HR=2.10, P=0.045 in women; CHD: adjusted HR=1.29, P=0.47 in men; adjusted HR=3.83, P=0.003 in women) and for 2-hour postload glucose levels of >or=11.1 mmol/L (ischemic stroke: adjusted HR=2.71, P=0.003 in men; adjusted HR=2.19, P=0.03 in women; CHD: adjusted HR=1.58, P=0.16 in men; adjusted HR=4.44, P<0.001 in women). The age-adjusted incidences of ischemic stroke and CHD did not significantly increase in subjects with impaired fasting glycemia or impaired glucose tolerance in either sex. CONCLUSIONS: Our findings suggest that diabetes is an independent risk factor for ischemic stroke in both sexes and CHD in women in the Japanese population.

Hyperglycemia increases risk of gastric cancer posed by Helicobacter pylori infection: a population-based cohort study.

BACKGROUND & AIMS: Although diabetes mellitus and hyperglycemia are considered to be possible risk factors for various types of malignancy, the epidemiologic evidence concerning gastric cancer is scarce. The aim of this study was to evaluate the impact of hemoglobin A1c (HbA1c) levels on gastric cancer occurrence and their interaction with Helicobacter pylori infection. METHODS: A total of 2603 Japanese subjects aged>or=40 years were stratified into 4 groups according to baseline HbA1c levels (or=7.0%) and followed up prospectively for 14 years. RESULTS: During the follow-up, 97 subjects developed gastric cancer. The age- and sex-adjusted incidence of gastric cancer significantly increased in the 6.0%-6.9% (5.1 per 1000 person-years; P<.05) and >or=7.0% groups (5.5 per 1000 person-years; P<.05) compared with the 5.0%-5.9% group (2.5 per 1000 person-years), whereas it was slightly but not significantly high in the or=7.0% group). Among subjects who had both high HbA1c levels (>or=6.0%) and Helicobacter pylori infection, the risk of gastric cancer was dramatically elevated (interaction term, P=.004). CONCLUSIONS: Our findings suggest that casual hyperglycemia is a risk factor for gastric cancer and is a possible cofactor increasing the risk posed by Helicobacter pylori infection.

Association of kidney function with coronary atherosclerosis and calcification in autopsy samples from Japanese elders: the Hisayama study.

BACKGROUND: Chronic kidney disease (CKD) is associated with increased risk of coronary heart disease. However, information regarding the histopathologic characteristics of coronary atherosclerosis in individuals with CKD is scarce. This study investigated the relationship between CKD and severity of coronary atherosclerosis in population-based autopsy samples. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 126 individuals randomly selected from 844 consecutive population-based autopsy samples. PREDICTOR: Estimated glomerular filtration rate (eGFR) calculated using the 6-variable Modification of Diet in Renal Disease (MDRD) Study equation. OUTCOMES: Severity of atherosclerosis in 3 main coronary arteries, including atherosclerotic lesion types defined using the American Heart Association classification; stenosis rates; and coronary calcified lesions. MEASUREMENTS: The relationship between CKD and severity of coronary atherosclerosis was evaluated using generalized estimating equation methods. RESULTS: Frequencies of advanced atherosclerotic lesions increased gradually as eGFR decreased (33.6%, 41.7%, 52.3%, and 52.8% for eGFRs > or = 60, 45-59, 30-44, and <30 mL/min/1.73 m(2), respectively; P for trend = 0.006). This relationship was substantially unchanged even after adjustment for potential confounding factors (ORs, 1.40 [95% CI, 0.76-2.55], 2.02 [95% CI, 0.99-4.15], and 3.02 [95% CI, 1.22-7.49] for eGFRs of 45-59, 30-44, and <30 mL/min/1.73 m(2), respectively). Frequencies of calcified lesions of coronary arteries also increased gradually with lower eGFRs (P for trend = 0.02). Hypertension and diabetes were associated with increased risk of advanced coronary atherosclerosis and calcification of coronary arteries in individuals with decreased eGFR. LIMITATIONS: Cross-sectional study, absence of data for proteinuria, and extremely high proportion of aged people. CONCLUSIONS: The autopsy findings presented here suggest that CKD is associated significantly with severity of coronary atherosclerosis. Patients with CKD should be considered a high-risk population for advanced coronary atherosclerosis.