Susumu Ohmori

Incidence and risk factors of vascular dementia and Alzheimer's disease in a defined elderly Japanese population The Hisayama Study

Article abstract—We followed 828 nondemented residents of Hisayama Town, Kyushu, Japan, aged 65 years or older (88.3% of the elderly population) for 7 years starting in 1985 in order to determine the type-specific incidence of dementia and its risk factors in the general Japanese population. Only two subjects were lost to the follow-up, during which period 103 subjects developed dementia. Morphologic examination of the brains of 89 subjects (86.4%) was made by autopsy or CT. We made the initial diagnosis of dementia based on the DSM-111-R criteria, with the diagnoses of vascular dementia (VD) being based on the NINDS-AIREN criteria and Alzheimers disease (AD) on the NINCDS-ADRDA criteria. The incidence of VD and AD increased with age for both sexes. The age-adjusted total incidence (per 1,000 person-years) of dementia was 19.3 for men and 20.9 for women. The corresponding rates for VD were 12.2 for men and 9.0 for women, and for AD, 5.1 for men and 10.9 for women. Among the VD subjects whose brain morphology we examined, the most frequent type of stroke was multiple lacunar infarcts (42%), but half these subjects lacked a stroke episode in their histories. Multivariate analysis showed that age, prior stroke episodes, systolic blood pressure, and alcohol consumption were significant independent risk factors for the occurrence of VD. In contrast, age and a low score on Hasegawas dementia scale were significant risk factors for AD, and physical activity was a significant preventive factor for AD. Our findings suggest that asymptomatic stroke is an important factor in the development of VD, with age, prior stroke episodes, systolic blood pressure, and alcohol consumption being independent risk factors for its occurrence. Age and a low scare on Hasegawas dementia scale are significant risk factors for AD, with moderate physical activity having a statistically significant preventive effect.

Decreased endothelium-dependent hyperpolarization to acetylcholine in smooth muscle of the mesenteric artery of spontaneously hypertensive rats.

The endothelium-dependent vascular relaxation to acetylcholine (ACh) in spontaneously hypertensive rats (SHR) may be impaired because of an imbalance of endothelium-derived relaxing factor and contracting factor. However, the role of the endothelium-dependent hyperpolarization remains undetermined. We examined the ACh-induced hyperpolarization and its contribution to relaxation in arteries of SHR. Membrane potentials were recorded from the mesenteric artery trunk of 6-8-month-old male SHR and also Wistar-Kyoto (WKY) rats. Endothelium-dependent hyperpolarization to ACh was unaffected by NG-nitro-L-arginine, indomethacin, or glibenclamide; was reduced by tetraethylammonium or high K+ solution; and was enhanced by low K+ solution or methylene blue, thereby indicating that hyperpolarization is not mediated by nitric oxide (endothelium-derived relaxing factor) but is presumably mediated by a hyperpolarizing factor and is due to an opening of K+ channels that probably differ from the ATP-sensitive ones. Hyperpolarizations to ACh were markedly reduced in SHR compared with findings in WKY rats (maximum, 8 +/- 1 versus 17 +/- 1 mV). In addition, under conditions of depolarization with norepinephrine (10(-5) M), the ACh-induced hyperpolarization was even less and transient in SHR, while it was large and sustained in WKY rats (6 +/- 1 versus 29 +/- 2 mV). Endothelium-dependent relaxations to ACh in arterial rings precontracted with 10(-5) M norepinephrine were far less in SHR than in WKY rats, even in the presence of indomethacin. Furthermore, high K+ solution showed smaller inhibitory effects on the relaxations in SHR than in WKY rats. Endothelium-independent hyperpolarizations and relaxations to cromakalim, a K+ channel opener, were similar between SHR and WKY rats. It would thus appear that the endothelium-dependent hyperpolarization to ACh is reduced in SHR and this would, in part, account for the impaired relaxation to ACh in SHR mesenteric arteries.

Diabetes and cardiovascular disease in a prospective population survey in Japan : The Hisayama study

To elucidate the effect of glucose intolerance on cardiovascular disease in the current Japanese population, we performed a 75-g oral glucose tolerance test in 2,427 Hisayama residents aged 40–79 years in 1988, who were free from a previous history of stroke or myocardial infarction, and followed them prospectively for 5 years. The prevalence of diabetes (NIDDM) among men was 13% and that of impaired glucose tolerance (IGT) was 20%; the corresponding values for women were 9 and 19%, respectively. The age- and sex-adjusted incidence of cerebral infarction (6.5 per 1,000 person-years, P 0.01) and coronary heart disease (5.0 per 1,000 person-years, P 0.05) was significantly higher in subjects with NIDDM than in those with normal glucose tolerance (1.9 and 1.6 per 1,000 person-years, respectively). In addition, subjects with IGT and NIDDM had a higher risk of cardiovascular disease including stroke and coronary heart disease than did those with normal glucose tolerance after adjustment for age and sex, namely the relative risk for IGT was 1.9 (95% CI 1.2–3.2), and the relative risk for NIDDM was 3.0 (95% CI 1.8–5.2). These associations remained significant even after controlling for six other risk factors including hypertension in multivariate analysis. Our data suggest that NIDDM is a significant risk factor for both cerebral infarction and coronary heart disease and also that IGT itself is a risk factor for cardiovascular disease in the general Japanese population today.

Prevalence of Type 2 (non-insulin-dependent) diabetes mellitus and impaired glucose tolerance in the Japanese general population: the Hisayama study

SummaryWe determined the population-based prevalence of diabetes mellitus in members of the Japanese community, Hisayama aged 40–79 years old by a 75-g oral glucose tolerance test. The basic population used to calculate diabetic prevalence was 1,077 men (72.8% of the whole population in the same age range) and 1,413 women (80.8%) including ten diabetic patients on insulin therapy. In addition, we compared the prevalence of history of diabetes which was acquired by interview or questionnaire, between participants and non-participants in the 75-g oral glucose tolerance test, but they were not statistically different. The age-adjusted prevalence of diabetes to world population was 12.7% for men and 8.4% for women, and that of impaired glucose tolerance was 19.6% for men and 18.4% for women. These figures were much higher than those previously reported from several Japanese communities. The results obtained from the present study could reveal true prevalence of diabetes among the Japanese population. In addition, the reasons for the increasing prevalence of diabetes among the recent Japanese population are also discussed.

Hyperinsulinemia and Left Ventricular Geometry in a Work-Site Population in Japan

The present study was designed to test whether hyperglycemia or hyperinsulinemia influences left ventricular mass and geometry. An echocardiogram and 75-g oral glucose tolerance test were performed in 210 normotensive and 180 mildly to moderately hypertensive male workers in a bus company who were free from cardiac diseases and were not taking medication for hypertension and diabetes mellitus. When we divided subjects into four groups according to the left ventricular geometric pattern using left ventricular mass index of 110 g/m2 and relative wall thickness (ratio of 2 x posterior wall thickness to end-diastolic left ventricular diameter) of 0.44, body mass index and systolic blood pressure were higher in those with concentric hypertrophy and eccentric hypertrophy. In addition, hemoglobin A(Ic) level and the sum of fasting and 2-hour postload serum glucose levels were higher in subjects with concentric hypertrophy. In subjects without diabetes mellitus (n=336), 2-hour postload serum insulin level and the sum of fasting and 2-hour postload serum insulin levels tended to be higher in those with concentric hypertrophy and concentric remodeling. In multiple regression analysis, the sum of glucose levels (or hemoglobin A(Ic) level) in all subjects and the sum of insulin (or 2-hour postload insulin) levels in subjects without diabetes mellitus significantly correlated with relative wall thickness, independent of age, systolic blood pressure, and body mass index. Neither glucose nor insulin levels correlated with left ventricular mass index. Our results suggest that hyperglycemia and hyperinsulinemia may promote concentric changes in the left ventricle in normotensive and mildly to moderately hypertensive men.

The association of the insulin resistance syndrome with impaired glucose tolerance and NIDDM in the Japanese general population: the Hisayama study

SummaryTo elucidate the risk factors for initiating glucose intolerance, the relevant factors were explored in a cross-sectional survey conducted in a sample population aged 40–79 years old selected from a Japanese community, Hisayama, Japan in 1988. A 75-g oral glucose tolerance test was used to classify 1,073 men (72.5% of the entire population in the same age range) and 1,407 women (80.5%) into normal, impaired glucose tolerance and diabetes mellitus groups. In all age and sex groups with normal glucose tolerance, the sum of fasting and 2-h post-load insulin values varied widely and demonstrated significant positive correlations with triglycerides, body mass index, waist-hip ratio, systolic and diastolic blood pressure, while it negatively correlated to HDL cholesterol (p<0.05). Insulin resistance was presumed to develop in normal glucose tolerance subjects with hyperinsulinaemia. The sum of the insulin concentrations, triglycerides, body mass index, waist-hip ratio and blood pressure levels was significantly associated with impaired glucose tolerance in all age and sex groups after adjustment for age (p<0.05) and was also related to diabetes in either all or some age and sex groups, respectively (p<0.05). It was shown that glucose intolerance in the general population was associated with the factors related to insulin resistance. These cross-sectional data, therefore, support the hypothesis that insulin resistance is the primary defect in the development of glucose intolerance in the Japanese general population. However, a further prospective study is still needed in order to confirm this hypothesis.

Chaos and spectral analyses of heart rate variability during head-up tilting in essential hypertension

To investigate nonlinear and linear components of heart rate variability (HRV) in essential hypertension (EHT), we analyzed HRV by chaos and spectral analyses in patients with EHT (n = 18) and normotensives (n = 10) during head-up tilting. We used the correlation dimension (CD) and Lyapunov exponents as the parameters of chaos. The CD, an index of complexity, was lower at rest in EHT group than in normotensives, and did not change in EHT group in response to head-up tilting, but decreased in normotensives. Head-up tilting did not change the Lyapunov exponents, an index of sensitive dependence on initial condition, a hallmark of chaos, in both groups. In the spectral analysis, the normalized high-frequency component (%HF) was decreased in EHT group at rest, and head-up tilting increased the low- to high-frequency ratio (L/H) and reduced the %HF in both groups. The CD and Lyapunov exponents at rest were correlated with the %HF and L/H. These results suggest that chaos analysis can assess the different aspect of HRV from spectral analysis and that nonlinear components of HRV may be associated with hypertension through an impaired dynamic regulation of HRV.

Hyperinsulinaemia and blood pressure in a general Japanese population : the Hisayama study

Objectives To study the relationship between serum insulin and blood pressure, as well as the prevalence of hypertension according to the insulin level in a general Japanese population. Design In 1988 a cross-sectional community survey was conducted among Hisayama residents aged 40–79 years. Methods A total of 1073 males and 1407 females (72.5 and 80.5% of the total population, respectively) underwent comprehensive investigation, including a 75-g oral glucose-tolerance test. Fasting and 2-h serum insulin levels were measured by radioimmunoassay. Results The sum of the fasting and 2-h postloading insulin levels was significantly correlated with the systolic blood pressure (SBP; r = 0.18 and 0.26 for males and females, respectively) and the diastolic blood pressure (DBP; r = 0.24 and 0.19, respectively) in the subjects not receiving antihypertensive drugs. In multiple regression analysis the correlation with blood pressure remained significant in both sexes even after controlling for age, body mass index, alcohol intake, smoking, a family history of hypertension, serum total cholesterol and fasting plasma glucose. The age- and sex-adjusted prevalence of hypertension (SBP ≥ 160mmHg or DBP ≥ 95mmHg, or both, or receiving drug treatment) increased significantly with an increase in the sum of fasting and 2-h postload insulin levels in both the non-obese subjects (body mass index <25 kg/m2) and the obese subjects (body mass index ≥ 25kg/m2). Multiple logistic regression showed that the sum of fasting and 2-h postload insulin levels was a significant factor with an independent relationship to hypertension, even after taking the other risk factors into account. Conclusion The present study suggests that hyperinsulinaemia is related to hypertension in a general Japanese population.

Association between hyperinsulinemia and intima-media thickness of the carotid artery in normotensive men.

Objectives To determine whether hyperinsulinemia is associated with early atherosclerosis in normotensive men of a work site population. Design and methods Six hundred and seventeen subjects were screened from 8678 male transport workers for the further examination of cardiovascular disease and diabetes. Subjects aged less than 40 years, those with hypertension or diabetes, or both, and those being administered medications for hyperlipidemia were excluded. Finally, 164 normotensive, nondiabetic subjects were enroled. The intima-media thickness (IMT) was measured by B-mode ultrasonography with a 7.5 MHz probe. Electrocardiography, a 75 g oral glucose-tolerance test (OGTT) and blood chemistry measurements were also performed. The sum of insulin values (ΣIRI) and the ratio of the sum of insulin values to blood glucose levels (ΣIRI/ΣBG) in the 75 g OGTT were used as markers of hyperinsulinemia. Results The mean age of the subjects was 52 ± 5 years (mean ± SD). In a univariate analysis, IMT was associated with age, systolic blood pressure, body mass index, ΣIRI, and ΣIRI/ΣBG. Multivariate analysis showed that age, total cholesterol, and SIRI (or ΣIRI/ΣBG) were independent risk factors for IMT. Conclusions These results suggest that, in addition to age and total cholesterol, hyperinsulinemia as assessed by an OGTT is associated with early atherosclerosis in normotensive, nondiabetic men of a work site population.

Role of eicosanoids in alteration of membrane electrical properties in isolated mesenteric arteries of salt-loaded, Dahl salt-sensitive rats.

The role of eicosanoids in altered membrane electrical properties of Dahl salt‐sensitive (DS) rats was investigated, by use of conventional microelectrodes technique, in isolated superior mesenteric arteries of DS rats and Dahl salt‐resistant (DR) rats fed either a high or low salt diet. The membrane was significantly depolarized in salt‐loaded DS rats compared with the other three groups. In addition, the arteries of salt‐loaded DS rats exhibited spontaneous electrical activity. Spontaneous electrical activity in salt‐loaded DS rats was inhibited by the following: indomethacin, a cyclo‐oxygenase inhibitor; ONO‐3708, a prostaglandin H2/thromboxane A2 receptor antagonist; OKY‐046, a thromboxane A2 synthase inhibitor; nicardipine, a Ca2+‐channel antagonist and by Ca2+‐free solution. In addition, spontaneous electrical activity was enhanced by a thromboxane A2 analogue and by prostaglandin H2. Spontaneous electrical activity was unaffected by phentolamine, atropine and tetrodotoxin. Membrane potential in arteries of salt‐loaded DS rats was not affected by either indomethacin or ONO‐3708. Spontaneous contraction, sensitive to indomethacin, was present, and contractile sensitivity to high potassium solution was enhanced in arteries of salt‐loaded DS rats. These findings suggest that eicosanoid action, together with membrane depolarization, may lead to the activation of voltage‐dependent Ca2+‐channels, thereby causing spontaneous electrical activity in mesenteric arteries of salt‐loaded DS rats. In addition, tension data suggest that these changes in membrane properties are related to enhanced contractile activities in salt‐loaded DS rats. Mechanisms of depolarization remain to be determined.