Fumie Ikeda

Secular Trends in Cardiovascular Disease and Its Risk Factors in Japanese Half-Century Data From the Hisayama Study (1961–2009)

Background— Changes in lifestyle and advances in medical technology during the past half century are likely to have affected the incidence and mortality of cardiovascular disease and the prevalence of its risk factors in Japan. Methods and Results— We established 5 cohorts consisting of residents aged ≥40 years in a Japanese community, in 1961 (n=1618), 1974 (n=2038), 1983 (n=2459), 1993 (n=1983), and 2002 (n=3108), and followed up each cohort for 7 years. The age-adjusted incidence of stroke decreased greatly, by 51% in men and by 43% in women, from the 1960s to the 1970s, but this decreasing trend slowed from the 1970s to the 2000s. Among the stroke subtypes, ischemic stroke in both sexes and intracerebral hemorrhage in men showed a similar pattern. Stroke mortality decreased as a result of the decline in incidence and a significant improvement in survival rate. Although the incidence of acute myocardial infarction did not change in either sex, disease mortality declined slightly in women. From the 1960s to the 2000s, blood pressure control among hypertensive individuals improved significantly and the smoking rate decreased, but the prevalence of glucose intolerance, hypercholesterolemia, and obesity increased steeply. Conclusions— Our findings suggest that in Japanese, the decreasing trends in the incidence of ischemic stroke have recently slowed down, and there has been no clear change in the incidence of acute myocardial infarction, probably because the benefits of hypertension control and smoking cessation have been negated by increasing metabolic risk factors. # Clinical Perspective {#article-title-30}Background— Changes in lifestyle and advances in medical technology during the past half century are likely to have affected the incidence and mortality of cardiovascular disease and the prevalence of its risk factors in Japan. Methods and Results— We established 5 cohorts consisting of residents aged ≥40 years in a Japanese community, in 1961 (n=1618), 1974 (n=2038), 1983 (n=2459), 1993 (n=1983), and 2002 (n=3108), and followed up each cohort for 7 years. The age-adjusted incidence of stroke decreased greatly, by 51% in men and by 43% in women, from the 1960s to the 1970s, but this decreasing trend slowed from the 1970s to the 2000s. Among the stroke subtypes, ischemic stroke in both sexes and intracerebral hemorrhage in men showed a similar pattern. Stroke mortality decreased as a result of the decline in incidence and a significant improvement in survival rate. Although the incidence of acute myocardial infarction did not change in either sex, disease mortality declined slightly in women. From the 1960s to the 2000s, blood pressure control among hypertensive individuals improved significantly and the smoking rate decreased, but the prevalence of glucose intolerance, hypercholesterolemia, and obesity increased steeply. Conclusions— Our findings suggest that in Japanese, the decreasing trends in the incidence of ischemic stroke have recently slowed down, and there has been no clear change in the incidence of acute myocardial infarction, probably because the benefits of hypertension control and smoking cessation have been negated by increasing metabolic risk factors.

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=4.9%, 5.0%-5.9%, 6.0%-6.9%, and >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=4.9% group (3.6 per 1000 person-years). This association remained substantially unchanged even after adjusting for the confounding factors including Helicobacter pylori seropositivity, (multivariate-adjusted hazard ratio [HR], 2.13; 95% confidence interval [CI]: 1.30-3.47 for the 6.0%-6.9% group and HR, 2.69; 95% CI: 1.24-5.85 for 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.

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.

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.

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.

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. Conclusion—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.

Body mass index and stroke incidence in a Japanese community: the Hisayama study

Although obesity is one of the major risk factors for coronary heart disease, its role in the development of stroke remains controversial. A total of 2421 residents, aged 40–79 years of a Japanese community were followed up prospectively for 12 years. The subjects were divided into four groups according to body mass index (BMI) levels (<21.0, 21.0–22.9, 23.0–24.9 and ⩾25.0 kg m−2). During the follow-up, 107 ischemic and 51 hemorrhagic strokes occurred. The age-adjusted incidence of ischemic stroke for men significantly increased with increasing BMI levels (P for trend=0.005). This association remained substantially unchanged even after adjustment for other risk factors: namely, systolic blood pressure, electrocardiogram abnormalities, diabetes, total cholesterol, high-density lipoprotein-cholesterol, triglycerides, smoking habits, alcohol intake and regular exercise (P for trend<0.001). Compared with that of the BMI levels of <21.0 kg m−2, the multivariate-adjusted risk of ischemic stroke was significant even in the BMI levels of 23.0–24.9 kg m−2 (multivariate-adjusted hazard ratio (HR)=3.12; 95% confidence interval (CI), 1.24–7.87; P=0.02) as well as in the BMI levels of ⩾25 kg m−2 (multivariate-adjusted HR=5.59; 95% CI, 2.09–14.91; P<0.001). In stratified analyses, the risk of ischemic stroke for men synergistically increased in subjects having both obesity and diabetes or a smoking habit. We found no significant associations between BMI levels and ischemic stroke in women and between BMI levels and hemorrhagic stroke in either sex. In conclusion, our findings suggest that overweight and obesity are independent risk factors for ischemic stroke in Japanese men.

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

Abstract 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 Youdens 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.

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.

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.