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Purpose: Hypertension (HT), dyslipidemia (DL), and diabetes mellitus (DM) are major risk factors for cardiovascular diseases. Despite the wide availability of medications to reduce this risk, poor adherence to medications remains an issue. The aim of this study is to evaluate medication adherence of prevalent users in these disease medications (HT, DL, DM) using claims data. Factors associated with non-adherence were also examined., Methods: Of 7538 participants of the Tsuruoka Metabolomics Cohort Study, 3693 (HT: 2702, DL: 2112, DM: 661) were identified as prevalent users of these disease medications. Information on lifestyle was collected through a questionnaire. Adherence was assessed by a proportion of days covered (PDC) and participants with PDC ≥0.8 were defined as adherent. Predictors of non-adherence were determined by performing multivariable logistic regression., Results: Medication adherence differed by treatment status. Among those without comorbidities, those with HT-only showed the highest adherence (90.2%), followed by those with DM-only (81.2%) and those with DL-only (80.8%). Factors associated with non-adherence in each medication group were skipping breakfast and poor understanding of medications among those with HT medications, females, having comorbidities, having a history of heart disease, and drinking habit among those with DL medications, and good sleep quality and skipping breakfast among those with DM medications., Conclusion: While participants showed high medication adherence, differences were observed across medication groups. The identified predictors of non-adherence could help target those in need of adherence support., (© 2024 The Author(s). Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Background: Although self-reported questionnaires are widely employed in epidemiologic studies, their validity has not been sufficiently assessed. The aim of this study was to evaluate the validity of a self-reported questionnaire on medication use by comparison with health insurance claims and to identify individual determinants of discordance in the Tsuruoka Metabolomics Cohort Study., Methods: Participants were 2,472 community-dwellers aged 37 to 78 years from the Tsuruoka Metabolomics Cohort Study. Information on lifestyle and medications was collected through a questionnaire. Sensitivity and specificity were determined using health insurance claims from November 2014 to March 2016, which were used as a standard. Potential determinants of discordance were assessed using multivariable logistic regression., Results: The self-reported questionnaire on medication use showed high validity. Sensitivity and specificity were 0.95 (95% CI, 0.93-0.96) and 0.97 (95% CI, 0.96-0.98) for antihypertensive medications, 0.94 (95% CI, 0.91-0.97) and 0.98 (95% CI, 0.98-0.99) for diabetes medications, and 0.84 (95% CI, 0.82-0.87) and 0.98 (95% CI, 0.97-0.99) for dyslipidemia medications, respectively. Males without high education and those who currently smoke cigarettes were found to be associated with discordant reporting which affected sensitivity, especially those with medication use for dyslipidemia., Conclusions: In this population-based cohort study, we found that the self-reported questionnaire on medication use was a valid measure to capture regular medication users. Sensitivity for dyslipidemia medications was lower than those for the other medications. Type of medication, sex, education years, and smoking status influenced discordance, which affected sensitivity in self-reporting.

Aim: Prediabetes defined by HbA1c 5.7-6.4 has been shown to be associated with left ventricular (LV) hypertrophy and diastolic dysfunction in hypertensive patients. We hypothesized HbA1c prediabetes may be related to the alterations of LA contractility or volume in nondiabetic hypertension., Methods: Nondiabetic individuals on sinus rhythm were enrolled; 107 patients with never-treated hypertension, 134 patients with treated hypertension, and 71 normotensive subjects. Participants were classified as normal glucose tolerance (NGT, HbA1c<5.7), prediabetes (HbA1c 5.7-6.4) according to the ADA criteria. They underwent echocardiography to measure left atrial (LA) phasic volumes and functions, as well as mitral E/e' and mitral e'., Results: In nondiabetic patients with never-treated hypertension, prediabetes saw lower LA total emptying fraction (53.7 ± 8.2 vs. 48.3 ± 9.9*) and mitral e' (7.38 ± 2.18 vs. 6.17 ± 1.50*) than NGT, implicating that the association of prediabetes with reduced LA contractility and LV stiffness. On the other hand, in nondiabetic patients with treated hypertension, prediabetes saw higher maximum LA volume/BSA (29.7 ± 7.1 vs. 32.9 ± 6.2* ml/mm 2 ) and mitral E/e' (10.72 ± 3.08 vs. 12.37 ± 3.35*) than NGT, suggesting the relationship of prediabetes with increased LA preload., Conclusion: Prediabetes may be involved in the progression of LA structural and functional alterations in nondiabetic hypertensive patients., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Inter-arm differences of SBP ≧5 mmHg have been associated with all-cause and cardiovascular mortalities in hypertensive subjects. Inter-arm differences of SBP appears to be mediated by arterial stiffness. We hypothesized inter-arm differences of SBP ≧5 mmHg may be related to higher pulse pressure/stroke volume index, a surrogate marker of arterial stiffness., Materials and Methods: To obtain inter-arm differences of SBP (the absolute difference of right and left arm) and ankle-brachial index, bilateral blood pressures were measured simultaneously at the four limbs using an automated oscillometric device in patients with treated hypertension (n = 234) and in normotensive subjects (n = 40). Pulse pressure was calculated as SBP-DBP. Stroke volume was obtained by time-velocity integral method using echocardiography. Left ventricular mass and relative wall thickness were calculated by the conventional methods., Results: All hypertensive patients were medically treated and had average blood pressure levels of 135/85 mmHg. Inter-arm differences of SBP ≧5 mmHg was detected in 26.5% of hypertensive patients. Hypertensive patients with inter-arm differences of SBP ≧5 mmHg had higher pulse pressure/stroke volume index, lower ankle-brachial index, higher BMI, and higher relative wall thickness, higher prevalence of female than those with inter-arm differences of SBP <5 mmHg. Multiple linear regression analysis confirmed inter-arm differences of SBP ≧5 mmHg was associated with higher pulse pressure/stroke volume index, higher relative wall thickness, and lower ankle-brachial index., Conclusion: Inter-arm difference of SBP measured by automated double-cuff device was related to large artery stiffness in patients with hypertension.

Left atrial (LA) phasic volumes consist of reservoir, conduit and booster pump volumes. Arterial stiffness is linked to lower systemic arterial compliance (SAC) contributing to cardiac afterload. Arterial stiffness may be a modulator of LA phasic volumes. Echocardiography was performed in 161 hypertensive patients and in 50 normotensive subjects in order to assess biplane LA volumes (maximum, before atrial contraction, minimum), early and late diastolic mitral annular velocity (e' and a'), and LV stroke volume. LA emptying volumes (total, passive, active) were calculated from these LA volumes. Blood pressures were measured using an automated oscillometric device simultaneously at the four limbs for evaluating pulse pressure (PP) and ankle-brachial index (ABI). SAC was estimated by the ratio of LV stroke volume indexed by body surface area (BSA) divided by PP. All three LA volumes, LA total volume and LA active emptying volume were greater in hypertensive patients than in normotensive subjects. A multiple linear regression analysis indicated that LA passive emptying volume (reservoir=early diastole)/BSA correlated positively with ABI after being adjusted for age, gender, BSA, LV mass, max LA volume, e' and SAC in hypertensive patients. LA active emptying volume (booster=late diastole)/BSA correlated positively with SAC after being adjusted for age, gender, BSA, LV mass, LA volume before atrial contraction, a' and ABI. LA reservoir volume was associated with ABI, and LA booster volume was related to systemic arterial stiffness in hypertensive patients, suggesting the LA-arterial coupling in this clinical setting.

Aim: Urinary type IV collagen is an early biomarker of diabetic nephropathy. Concomitant prediabetes (the early stage of diabetes) was associated with left ventricular (LV) diastolic dysfunction and increased brain natriuretic peptide (BNP) in hypertensive patients. We hypothesized that urinary type IV collagen may be related to these cardiac dysfunctions., Methods: We studied hypertensive patients with early prediabetes (HbA1c <5.7% and fasting glucose >110, n=18), those with prediabetes (HbA1c 5.7-6.4, n=98), and those with diabetes (HbA1c>6.5 or on diabetes medications, n=92). The participants underwent echocardiography to assess left atrial volume/body surface area (BSA) and the ratio of early mitral flow velocity to mitral annular velocity (E/e'). Left ventricular diastolic dysfunction (LVDD) was defined if patients had E/e'≥15, or E/e'=9-14 accompanied by left atrial volume/BSA≥32ml/mm(2). Urinary samples were collected for type IV collagen and albumin, and blood samples were taken for BNP and HbA1c., Results: Urinary type IV collagen and albumin increased in parallel with the deterioration of glycemic status. In hypertensive patients with prediabetes, subjects with LVDD had higher levels of BNP and urinary type IV collagen than those without LVDD. In contrast, in hypertensive patients with diabetes, subjects with LVDD had higher urinary albumin and BNP than those without LVDD. Urinary type IV collagen correlated positively with BNP in hypertensive patients with prediabetes, whereas it correlated with HbA1c in those with diabetes., Conclusions: In hypertensive patients with prediabetes, urinary type IV collagen was associated with LV diastolic dysfunction and BNP., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Cystatin C, a cathepsin inhibitor, is involved in the remodeling of human aortic valve and left ventricle (LV)., Objective: Cystatin C may be related to the severity of aortic regurgitation (AR)., Methods: We measured cystatin C and CRP in hypertensive patients with mild-to-moderate AR (n=120) and in those without AR (n=128). Echocardiography was performed to assess the vena contracta width (the narrowest region of regurgitant jet, VCW) as a marker of the severity of AR, relative wall thickness as a marker of LV concentric remodeling, and the ratio of early peak mitral flow to early diastolic mitral annular velocity (E/e') as an index of LV diastolic function. Glomerular filtration rate (GFR) was estimated using the MDRD methods., Results: Cystatin C levels were greater in hypertensive patients with AR than in those without AR. A multiple linear regression analysis indicated cystatin C levels correlated with the VCW independent of GFR, body mass index, CRP, relative wall thickness, and E/e' in hypertensive patients with AR., Conclusions: Cystatin C was associated with the severity of regurgitation independent of renal function body composition chronic inflammation LV remodeling and diastolic function in hypertensive patients with mild-to-moderate AR., (© 2013 Elsevier B.V. All rights reserved.)

Many studies have demonstrated that increased carotid intima-media thickness (IMT) is related to future cardiovascular events and is influenced by cardiovascular risk factors such as sex, hypertension, diabetes, and hypercholesterolemia. Although aging is a well-known risk factor for an increase in carotid IMT, few studies have investigated which factors influence carotid IMT in the very elderly. In the present study, we investigated the relationship of pulse pressure (PP), blood pressure (BP), and its variability (six consecutive visits) with carotid IMT among 240 high-risk elderly in whom risk factors were managed clinically (average age was 79 ± 5 years). In the simple correlation, mean systolic BP (SBP) had a positive correlation with IMT and max IMT (P = .012 and P = .045), as did PP (P = .018 and P = .004), but did not diastolic BP or standard deviation of BP and coefficient of variation of BP. In multiple regression analyses, mean SBP and mean PP were each determinants of both IMT and max IMT, when each parameter was added separately to the regression model. We concluded that high SBP and wide PP still have an influence on increased carotid IMT in the very elderly Japanese patients.

Objective: Clinical uncertainty remains whether the blood pressure classification and risk stratifications recommended by the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2009) are useful in predicting the risks of stroke and its subtypes in the general Japanese population., Methods: A total of 1621 stroke-free residents of a Japanese community aged at least 40 years were followed up for 32 years. Outcomes were total and cause-specific stroke (lacunar infarction, atherothrombotic infarction, cardioembolic infarction, cerebral haemorrhage and subarachnoid haemorrhage). Incidence was calculated by the pooling of repeated observations method., Results: The age-adjusted incidence of total stroke rose progressively with higher blood pressure levels in both sexes (both P for trend <0.0001). A similar pattern was observed for lacunar infarction in both sexes and for cerebral haemorrhage in men: the differences were significant between optimal blood pressure and grades 1-3 hypertension (all P < 0.05). The age-adjusted incidence of atherothrombotic infarction in either sex and that of cardioembolic infarction and subarachnoid haemorrhage in women significantly increased in grade 3 hypertension (all P < 0.05). These associations remained substantially unchanged even after adjustment for other risk factors. In regard to risk stratification, the age-adjusted incidence of stroke significantly increased with the level of risk in both sexes., Conclusion: Our findings suggest that the blood pressure classification and risk stratifications recommended by the JSH 2009 guidelines are useful in predicting the risk of stroke in a general Japanese population, but the magnitude and patterns of the impact of blood pressure categories are different among stroke subtypes.

Background: Resistin, secreted from adipocytes, causes insulin resistance in mice. The relationship between resistin and coronary artery disease is highly controversial, and the information regarding resistin and ischemic stroke is limited. In the present study, the association between serum resistin concentration and cardiovascular disease (CVD) was investigated in a general Japanese population., Methods: A total of 3,201 community-dwelling individuals aged 40 years or older (1,382 men and 1,819 women) were divided into quintiles of serum resistin, and the association between resistin and CVD was examined cross-sectionally. The combined effect of either diabetes or hypertension and high serum resistin was also assessed. Serum resistin was measured using ELISA., Results: Compared to those without CVD, age- and sex-adjusted mean serum resistin concentrations were greater in subjects with CVD (p = 0.002) or ischemic stroke (p < 0.001), especially in those with lacunar and atherothrombotic infarction, but not elevated in subjects with hemorrhagic stroke or coronary heart disease. When analyzed by quintile of serum resistin concentration, the age- and sex-adjusted odds ratio (OR) for having CVD and ischemic stroke increased with quintile of serum resistin (p for trends, 0.02 for CVD, < 0.001 for ischemic stroke), while such associations were not observed for hemorrhagic stroke or coronary heart disease. Compared to the first quintile, the age- and sex-adjusted OR of ischemic stroke was greater in the third (OR = 3.54; 95% confidence interval [CI], 1.17-10.67; p = 0.02), fourth (OR = 4.48; 95% CI, 1.53-13.09; p = 0.006), and fifth quintiles (OR = 4.70; 95% CI, 1.62-13.61; p = 0.004). These associations remained substantially unchanged even after adjustment for other confounding factors including high-sensitivity C-reactive protein. In the stratified analysis, the combination of high serum resistin and either diabetes or hypertension markedly increased the risk of ischemic stroke., Conclusion: Elevated serum resistin concentration appears to be an independent risk factor for ischemic stroke, especially lacunar and atherothrombotic infarction in the general Japanese population. The combination of high resistin and the presence of either diabetes or hypertension increased the risk of ischemic stroke.

Hypertension is one of the greatest risk factors for cardiovascular disease, but its contribution to cardiovascular mortality weakens with aging. We have previously demonstrated that at the age of 80, higher systolic blood pressure (SBP) is not correlated with increased mortality in Japan. However, we did not examine in detail whether diastolic blood pressure (DBP) independently affects mortality. In the present study, 639 participants, who were 80 years old in 1997, were enrolled. The subjects were divided by their DBP [below 70 mmHg (group 1, n = 136), from 70 mmHg to 80 mmHg (group 2, n = 200), from 80 mmHg to 90 mmHg (group 3, n = 194), over 90 mmHg (group 4, n = 109)]. During the 4-year follow-up period, 90 individuals died. Cox multivariate regression analysis revealed that group 1 showed a significantly higher mortality rate than group 4 [relative risk (RR) 2.47, confidence interval (CI) 1.07-5.70, p = 0.03)]. The relative risks of deaths from cardiovascular diseases, pneumonia, and cancer tended to be higher in group 1 than in group 4, but the difference did not reach statistical significance. These results suggest that decreased DBP is associated with higher mortality in the Japanese elderly.

Many guidelines recommended strict blood pressure (BP) control to prevent cardiovascular events. However, BP control in a substantial majority of hypertensives remains to be insufficient. We have determined the trends of BP control of the same patients during 15 years in a hypertension clinic. One hundred three patients (age 32-91, mean 68 +/- 11 years in 2006), who were followed at our hypertension clinic between 1991-2006, were retrospectively investigated. We compared the clinical characteristics of the patients in 2006 to those in 1991, 1996, and 2001, using the averaged BP determined at two occasions of each year for our analysis. The average BP decreased from 144 +/- 17/87 +/- 10 mmHg to 132 +/- 12/75 +/- 10 mmHg (p < 0.01) during the 15 years between 1991 and 2006. When good BP control was defined as < 140/90 mmHg, the rate of patients with good BP control increased from 35% in 1991 to 45% in 1996, to 54% in 2001 (p < 0.01 vs. 1991), and to 72% in 2006 (p < 0.01 vs. 1991). The number of anti-hypertensive drugs used in 2006 significantly increased compared to those in 1991, 1996, and 2001. More specifically, the use of diuretics and alpha-blockers increased significantly during this period. Results suggest that BP control improved in the 15 years studied, and the increased use of the anti-hypertensive drugs, as well as the increased awareness of the importance of strict BP control, seems to have contributed to improve the BP control.

Aortic valve sclerosis (AVS) may predispose to a prothrombotic state, as AVS is predictor of cardiovascular events in hypertensive populations. Thrombin exerts non-thrombotic effects such as vessel tone regulation, progression of atherosclerosis and stimulation of atrial natriuretic peptide (ANP) secretion. We hypothesized that hypertensive patients with AVS may have a persistently activated thrombin generation. We studied 234 asymptomatic never-treated hypertensive patients (73 of them with AVS). Prothrombin F1+2 (F1+2), as a marker of thrombin generation and fibrin D-dimer, as a marker of thrombus formation, ANP and brain natriuretic peptide (BNP) were measured. Presence of AVS, aortic jet velocity and left ventricular diameter at diastole were determined by echocardiography. Glomerular filtration rate was estimated using the Modification of Diet in Renal Disease formula. F1+2 (median and interquartile range (IQR) = 1.05, 0.87-1.38 nM vs. 0.93, 0.72-1.16) and ANP (22, 14-37 pg ml(-1) vs. 17, 11-25) levels were greater, and glomerular filtration rate values (65+/-9 ml min(-1)/1.73 m2 vs. 68+/-11) were lower in hypertensive patients with AVS than in those without AVS. F1+2 (odds ratio, 95% CI = 2.94, 1.07-8.6) was independently associated with AVS after being adjusted for age, gender and the variables of cardiorenal functions measured. After 6 months of treatment using valsartan, F1+2 levels remained elevated in hypertensive patients with AVS (1.14, 0.83-1.42 nM vs. 1.07, 0.84-1.5, n=19), but decreased in those without AVS (1.01, 0.85-1.31 vs. 0.8, 0.84-1.78, n=27). Thrombin generation was associated with AVS in untreated hypertensive patients, and this association was persistent after blood-pressure-lowering treatment using valsartan.

Plasma levels of von Willebrand factor (vWF), a marker of endothelial dysfunction/damage, are elevated in high-risk hypertensive patients and in patients with severe aortic regurgitation (AR). Patients with mild-to-moderate AR, frequently detected in hypertensive elderly, have additional left ventricular morphological and functional dysfunctions. We hypothesized that hypertensive patients with mild-to-moderate AR may have enhanced endothelial and/or left ventricular dysfunctions that may lead to a deteriorated prognosis. We measured vWF, prothrombin F1+2 (F 1+2) as a marker of thrombin generation, brain natriuretic peptide (BNP) in 104 hypertensive patients with mild-to-moderate AR and 66 hypertensive patients without AR. The left ventricular diameter at systole (LVDs) and left ventricular posterior wall thickness (LVWT) were determined by echocardiography and indexed by body surface area (LVDs/BSA and LVWT/BSA). VWF (median, interquartile range (IQR) 154, 120-196%) and BNP (34.7 pg ml(-1), 15-65%) levels were greater in patients with AR than in those without AR (135, 98-175% and 20, 10.3-49 pg ml(-1)). All patients were prospectively followed up for cardiac events during the period of median 43 months (IQR 31-81). Patients with AR had an increased risk of cardiac events (regression ratio (RR) 1.87, 95% confidence interval 1.28-2.87) when compared to those without AR. A multivariate Cox hazard analysis indicated that log vWF (RR 4.93) and log BNP (RR 1.9) were independent predictors in patients with AR. VWF was an independent predictor of clinical outcome in hypertensive patients with mild-to-moderate AR.

Information regarding the association between prehypertension BP level and renal arteriosclerosis is limited. In 652 consecutive population-based autopsy samples without hypertension treatment before death, the relationship between the severity of renal arteriosclerosis and BP levels classified according to the criteria of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure was examined. The age- and gender-adjusted frequencies of renal arteriosclerosis linearly increased with elevating BP levels; both hypertensive and prehypertensive subjects had significantly higher frequencies of renal arteriosclerosis than subjects with normal BP (normal 11.9%; prehypertension 28.5%; stage 1 hypertension 32.9%; stage 2 hypertension 58.2%; all P < 0.01 versus normal). In a logistic regression model, prehypertension was significantly associated with renal arteriosclerosis after adjustment for other cardiovascular risk factors (prehypertension multivariate-adjusted odds ratio [mOR] 5.99 [95% confidence interval (CI) 2.20 to 15.97]; stage 1 hypertension mOR 6.99 [95% CI 2.61 to 18.72]; stage 2 hypertension mOR 22.21 [95% CI 8.35 to 59.08]). This significant association was observed for all renal arterial sizes. The similar association was also observed for arteriolar hyalinosis. When the subjects were divided into those with and those without target organ damage, the impact of prehypertension on renal arteriosclerosis was similar for both groups (subjects without target organ damage mOR 5.04 [95% CI 1.36 to 18.62]; subjects with target organ damage mOR 6.42 [95% CI 1.29 to 32.04]). These findings suggest that both hypertension and prehypertension are associated significantly with the severity of renal arteriosclerosis, regardless of the presence or absence of target organ damage.

Heart-type fatty acid-binding protein (H-FABP), a marker of acute myocardial infarction and a soluble cytosolic protein, may be released following left ventricular remodelling in cardiac overloaded hearts caused by hypertension, aortic regurgitation (AR) or aortic stenosis (AS). Our aim was to investigate if H-FABP levels are associated with left ventricular remodelling and clinical outcome in hypertensive patients with AR or AS. H-FABP and brain natriuretic peptide (BNP) were measured, glomerular filtration rate (GFR) was estimated using the modification of diet in renal disease (MDRD) equation, and left ventricular dimension at systole corrected for body surface area (LVDs/BSA) and relative wall thickness (RWT) were determined by echocardiography in hypertensive patients with mild-to-moderate AR (n=78), those with mild-to-moderate AS (n=73) and those without valvular heart diseases (HT) (n=50). H-FABP levels were significantly higher in AR (4.9+/-3 ng/ml) and in AS (4.5+/-3) than in HT (3.4+/-1) and BNP (65+/-73 pg/ml, 76+/-75, 35+/-22). H-FABP correlated with LVDs/BSA in AR (beta=0.23, P<0.05), and RWT in AS (beta=0.18, P<0.05) after adjustment for age, gender and all the other variables. AS and AR patients were prospectively followed up for cardiac events during 34+/-19 months. A multivariate Cox hazard analysis indicated H-FABP was an independent predictor of outcome both in AR (relative risk (RR)=7.61, 95% CI=2.39-25.3) and AS (RR=13.6, 95% CI=3.27-66.9). H-FABP, associated with left ventricular remodelling, is useful in predicting clinical outcome in hypertensive patients with mild-to-moderate aortic valve diseases.

Accumulation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) in DNA is associated with mutagenesis and cell death. Little attention has been given to the biological significance of 8-oxo-dG accumulation in cardiovascular tissues during the different stage of hypertension and its prevention. We thus investigated the levels and localization of both 8-oxo-dG accumulation and expression of MTH1, which hydrolyzes 8-oxo-dGTP to prevent its incorporation into DNA, in the thoracic aorta prepared from stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched Wister-Kyoto rats (WKY), aged 5-32 weeks. HPLC-MS/MS analysis revealed that the levels of nuclear 8-oxo-dG in the aorta increased significantly in SHRSP, but not WKY, with aging. Immunohistochemical study revealed that both TUNEL reactivity and 8-oxo-dG immunoreactivity were increased in smooth muscle cells (SMC) and endothelial cells (EC) of the aorta with aging, and they exhibited similar distributions in serial sections. The number of 8-oxo-dG and TUNEL positive cells in EC, but not in SMC, was significantly higher in SHRSP than WKY at 32 weeks of age. In contrast, the expression levels of Mth1mRNA and MTH1 protein in the aorta were similarly decreased both in SHRSP and WKY with aging. However, the number of MTH1 expressing EC was remarkably increased in the older SHRSP compared to the younger ones or age-matched WKY. Hypertension significantly increased not only 8-oxo-dG accumulation but also the expression of MTH1 in EC of the aorta during aging. While accumulation of 8-oxo-dG in SMC of the aorta was slightly increased, the expression of MTH1 protein in SMC was rather decreased by hypertension. We thus suggest that MTH1 may protect EC in the aorta from the oxidative damage increased by hypertension.

For hypertensive patients with renal diseases (RD), strict blood pressure (BP) control has been recommended in recent hypertension guidelines, such as JNC VI, JNC 7, WHO/ISH 1999 and ESH-ESC 2003. We assessed the current status of BP control and the changes of BP control before and after the publication of these guidelines in 489 hypertensive patients with or without RD (age, 19-89 years, mean 59+/-13 years) who visited the hypertension and kidney outpatient clinic at Kyushu University Hospital. The clinical characteristics of RD and non-RD patients were assessed (RD patients: age, 20-89 years, mean 60+/-13 years, n=311; non-RD patients: age, 19-86 years, mean 58+/-13 years, n=178). In addition, we compared the BP control status in 2003 to that in 1996. In 2003, the BP in RD patients was 134+/-16/78+/-10 mmHg and that in non-RD patients was 138+/-12/83+/-9 mmHg. When strict BP control was defined as <130/80 mmHg, the frequency of strict BP control in RD patients was 28.9% in 2003. In addition, the BP levels of RD patients in 2003 were significantly lower than those in 1996 (134+/-16/78+/-10 mmHg vs. 141+/-17/85+/-10 mmHg, p<0.05 for both systolic blood pressure [SBP] and diastolic blood pressure [DBP]), and the frequency of strict BP control in RD patients was higher in 2003 than in 1996 (28.9% vs. 11.8%, p<0.01). The BP levels of non-RD patients in 2003 tended to be lower than those in 1996 (138+/-12/83+/-9 mmHg vs. 141+/-13/85+/-9 mmHg, n.s.). In 2003, angiotensin II receptor blockers (ARBs) were more frequently prescribed to RD patients than to non-RD patients. Furthermore, the use of ARBs was markedly increased in 2003 compared with 1996. In conclusion, in our outpatient clinic, BP levels in hypertensive patients with RD have improved in recent years, and were lower than those in hypertensive patients without RD, which may in part reflect the physicians' awareness of the importance of strict BP control in RD patients, as suggested by several recent hypertension guidelines.

Background: The potent vasodilators nicardipine and prostaglandin E1 (PGE1) are useful for the treatment of systemic hypertension or pulmonary hypertension during aortic surgery., Methods: We measured cerebral pial arteriolar diameters, using a rabbit closed cranial window preparation: before (baseline) and 15 min after the start of an IV infusion (preclamp) (0.9% saline [control group], nicardipine [at 0.1, 1.0, or 10 microg x kg(-1) x min(-1)], or PGE1 [at 0.1 or 1.0 microg x kg(-1) x min(-1)]), just after aortic clamping, 20 min after clamping, and at 0-60 min after unclamping., Results: In the control group, a significant decrease in diameter persisted for at least 60 min after unclamping (maximum [at 60 min], -16% for large [> or =75 microm], and -27% for small [<75 microm] arterioles versus baseline). Although the aortic unclamping-induced vasoconstriction was unaffected under the smallest dose of nicardipine, it was significantly attenuated under larger doses in both large and small arterioles (residual vasoconstriction, -10% and -6% for large and -18% and -10% for small arterioles; at 60 min). The pial arteriolar constriction observed at 5 min or more after unclamping in the control group was not altered by PGE1 in either large or small arterioles., Conclusions: The larger doses of nicardipine, but neither dose of PGE1, attenuated aortic unclamping-induced sustained cerebral pial arteriolar constriction.

Although vascular cells express multiple members of the Nox family of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase, including gp91phox, Nox1, and Nox4, the reasons for the different expressions and specific roles of these members in vascular injury in chronic hypertension have remained unclear. Thus, we quantified the mRNA expressions of these NAD(P)H oxidase components by real-time polymerase chain reaction and evaluated superoxide production and morphological changes in the aortas of 32-week-old stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched Wistar Kyoto rats (WKY). The aortic media of SHRSP had an approximately 2.5-fold greater level of Nox4 mRNA and an approximately 10-fold greater level of Nox1 mRNA than WKY. The mRNA expressions of gp91phox and p22phox in SHRSP and WKY were comparable. SHRSP were treated from 24 weeks of age for 8 weeks with either high or low doses of candesartan (4 mg/kg/day or 0.2 mg/kg/day), or a combination of hydralazine (30 mg/kg/day) and hydrochlorothiazide (4.5 mg/kg/day). The high-dose candesartan or the hydralazine plus hydrochlorothiazide decreased the blood pressure of SHRSP to that of WKY, whereas the low-dose candesartan exerted no significant antihypertensive action. Media thickening and fibrosis, as well as the increased production of superoxide in SHRSP, were nearly normalized with high-dose candesartan and partially corrected with low-dose candesartan or hydralazine plus hydrochlorothiazide. These changes by antihypertensive treatment paralleled the decrease in mRNA expression of Nox4 and Nox1. These results suggest that blood pressure and angiotensin II type 1 receptor activation are involved in the up-regulation of Nox1 and Nox4 expression, which could contribute to vascular injury during chronic hypertension.

Background: The aim of the present study was to determine whether sex differences contribute to the association of serum uric acid and left ventricular hypertrophy in individuals with hypertension., Methods and Results: Seventy participants with essential hypertension (34 men, 36 women; 54.4 +/- 1.6 years old) were enrolled to undergo echocardiography to calculate the left ventricular mass index (LVMI). Twenty-four-hour ambulatory blood pressure monitoring was done to assess blood pressure level precisely. The LVMI was significantly correlated with serum uric acid (r = 0.295, p = 0.013) in all participants. After controlling for factors such as age, sex, mean 24-h systolic blood pressure, creatinine clearance, and duration of hypertension, serum uric acid was still found to be significantly and independently associated with LVMI. Because serum uric acid was significantly higher in men than in women (6.8 +/- 0.3 and 5.1 +/- 0.2 mg/dl, respectively), subsequent analysis was performed by gender. Multiple regression analysis revealed that the LVMI was significantly and independently associated with serum uric acid in women, but not in men., Conclusions: The potential effect of uric acid on LV hypertrophy is more pronounced in female than in males with essential hypertension.

Background: Aldosterone induces cardiac fibrosis in experimental animal models, but only limited information is available on the association between aldosterone and left ventricular (LV) hypertrophy in human beings. The aim of the present study was to determine the role of aldosterone in LV geometry and to investigate other types of target organ damage in hypertensive patients., Methods: A total of 25 patients with primary aldosteronism caused by Conn's adenoma, 29 patients with renovascular hypertension, and 29 patients with essential hypertension (EHT) were included in the present study. Echocardiographic examinations and 24-h ambulatory blood pressure (BP) monitoring were conducted in all subjects., Results: The mean 24-h systolic and diastolic BP in primary aldosteronism and renovascular hypertension were found to be comparable to those in EHT. However, LV mass index adjusted by age, sex, mean 24-h systolic BP, mean 24-h pulse rate, body mass index, and duration of hypertension was significantly increased in the patients with primary aldosteronism and renovascular hypertension compared with values in patients with EHT (150.2 +/- 7.7, 142.3 +/- 7.2, and 115.2 +/- 7.2 g/m(2), respectively). Hypertensive organ damages, such as proteinuria and hypertensive retinopathy, were more pronounced in the patients with renovascular hypertension; however, LV hypertrophy was especially exaggerated in patients with primary aldosteronism., Conclusions: These results indicate that aldosterone may induce LV hypertrophy in human beings as well as in experimental animals, and that angiotensin II and aldosterone may differentially participate in causing hypertensive target organ damage.

It has been shown that the pressor responses to microinjection of L-glutamate in the rostral ventrolateral medulla (RVLM) are augmented in spontaneously hypertensive rats (SHR), and that these augmented responses are not altered by chronic conventional antihypertensive treatment. The aim of the present study was to determine the effect of chronic oral treatment with a new angiotensin II type 1 (AT(1)) receptor antagonist, RNH-6270 (the active form of olmesartan medoxomil), on cardiovascular responses to excitatory amino acids in the RVLM of SHR. SHR (12 weeks old) were treated with RNH-6270 (30 mg/kg/day) or vehicle for 4 weeks. At 16 weeks of age, L-glutamate (2 nmol), N-methyl-D-aspartate (NMDA; an ionotropic glutamate receptor agonist (20 pmol)), or (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD; a metabotropic glutamate receptor agonist (1 nmol)) was microinjected into the RVLM of rats. The pressor responses to microinjection of L-glutamate or NMDA in the RNH-6270-treated SHR (+28.3 +/- 1.0 and +48.3 +/- 2.5 mm Hg, respectively) were significantly smaller than those in untreated SHR (+45.7 +/- 2.2 and +69.4 +/- 7.0 mm Hg, respectively, P < 0.05 each); however, they were still greater than those in the Wistar-Kyoto rats (+21.7 +/- 1.0 and +28.6 +/- 3.3 mm Hg, respectively, P < 0.05 each). In contrast, the augmented pressor responses to microinjection of (1S,3R)-ACPD in SHR were not affected by the RNH-6270 treatment. These results demonstrated that chronic oral treatment with RNH-6270, an AT(1) receptor antagonist, partly normalizes the pressor responses to L-glutamate or NMDA, but not (1S,3R)-ACPD, in the RVLM of SHR, suggesting that endogenous angiotensin II may be involved in the exaggerated pressor response to l-glutamate, probably through its ionotropic glutamate receptors.

1. Endothelial function is impaired in hypertension and ageing and this may be associated with an increase in cardiovascular disease. Several clinical studies have shown that blocking the renin-angiotensin system (RAS) improves endothelial function not only in hypertensive patients, but also in normotensive patients with cardiovascular disease. 2. The aim of the present study was to test whether endothelium-derived hyperpolarizing factor (EDHF)-mediated smooth muscle hyperpolarization and relaxation are altered in hypertension and ageing and, if so, whether chronic treatment with RAS inhibitors (the angiotensin-converting enzyme inhibitor enalapril and the angiotensin AT1 receptor antagonist candesartan) would correct such changes. 3. Endothelium-derived hyperpolarizing factor-mediated responses were examined in mesenteric arteries from 12-month-old spontaneously hypertensive rats (SHR) and 3-, 6-, 12- and 24-month-old normotensive Wistar-Kyoto (WKY) rats. Furthermore, both strains were treated for 3 months with either RAS blockers or a conventional therapy with hydralazine and hydrochlorothiazide from 9 to 12 months of age. 4. In arteries of 12-month-old SHR, EDHF-mediated responses were impaired compared with age-matched WKY rats. In SHR, all antihypertensive treatments improved the impairment of EDHF-mediated responses; however, RAS inhibitors tended to improve these responses to a greater extent compared with conventional therapy with hydralazine and hydrochlorothiazide. 5. In arteries of WKY rats, EDHF-mediated responses were impaired at the age of 12 and 24 months compared with 3- and 6-month-old rats, with the response tending to be impaired to a greater extent in 24-month-old rats. 6. Three months of treatment of WKY rats, until 12 months of age, with RAS inhibitors, but not with conventional therapy with hydralazine and hydrochlorothiazide, improved the age-related impairment of EDHF-mediated responses, despite a similar reduction in blood pressure by both treatments. 7. These findings suggest that: (i) EDHF-mediated hyperpolarization and relaxation decline with hypertension and ageing in rat mesenteric arteries; (ii) antihypertensive treatment restores the impaired EDHF-mediated responses in hypertension; (iii) RAS inhibitors may be more efficacious in improving endothelial dysfunction associated with hypertension; and (iv) chronic treatment with RAS inhibitors improves the age-related impairment of EDHF-mediated responses, presumably through the blockade of RAS but not blood pressure lowering alone.

Blockade of the renin-angiotensin system improves the impaired endothelium-dependent relaxations associated with hypertension and aging, partly through amelioration of endothelium-derived hyperpolarizing factor (EDHF)-mediated responses. Although the nature of EDHF is still controversial, recent studies have suggested the involvement of gap junctions in EDHF-mediated responses. Gap junctions consist of connexins (Cx), and we therefore tested whether the expression of Cx in vascular endothelial cells would be altered by hypertension and antihypertensive treatment. Spontaneously hypertensive rats (SHR) were treated with either the angiotensin II type 1 receptor antagonist candesartan or the combination of hydralazine and hydrochlorothiazide for 3 mo from 5 to 8 mo of age. Confocal laser scanning microscopy after immunofluorescent labeling with antibodies against Cx37, Cx40, and Cx43 revealed that the expression of Cx37 and Cx40 in endothelial cells of the mesenteric artery was significantly lower in SHR than in WKY. Treatment with candesartan, but not the combination of hydralazine and hydrochlorothiazide, significantly increased the expression of Cx37 and Cx40, although blood pressure decreased similarly. On the other hand, the expression of Cx43, though scarce and heterogeneous, was increased in SHR compared with WKY, and candesartan treatment lowered the expression of Cx43. These findings suggest that renin-angiotensin system blockade corrects the decreased expression of Cx37 and Cx40 in arterial endothelial cells of hypertensive rats, partly independently of blood pressure, whereas the expression of Cx43 changed in the opposite direction. It remains to be clarified whether these changes in Cx37 and Cx40 are related to endothelial function, particularly that attributable to EDHF.

A 37-year-old man with juvenile and refractory hypertension was admitted to our hospital for progressive left hearing loss, vertigo, and dizziness. Neurological examination revealed left hearing loss and exaggerated deep tendon reflexes and vestibular dysfunction. MRI and cerebral angiography disclosed megadolichobasilar artery (MDBA). Moreover, modified MR cisternography at the medulla disclosed marked compression and deformity of the left rostral ventrolateral medulla (RVLM) by the dolichoectatic right vertebral artery. In the literatures, bulbovascular compression has been reported in 4 among 9 patients with MDBA (including the present patient), for whom MRI of the medulla was presented. All 4 patients suffered from hypertension, and at least 3 of them showed juvenile and refractory hypertension. Ipsilateral pyramidal tract disturbance (Opalski syndrome) was observed in 3 patients. Considering the recent concept that the cardiovascular center can be localized at the RVLM, juvenile and refractory hypertension, and possibly Opalski syndrome in the present patient can be attributed to bulbovascular compression by MDBA. In the patients with MDBA and hypertension or Opalski syndrome, MR cisternography of the medulla is warranted to evaluate compression by MDBA.

Endothelial cells release endothelium-derived hyperpolarizing factor (EDHF), as well as nitric oxide (NO). It has recently been suggested that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) improve NO-mediated endothelial function, partially independently of their cholesterol-lowering effects. It is, however, unclear whether statins improve EDHF-mediated responses. Eight-month-old stroke-prone spontaneously hypertensive rats (SHRSP) were treated with fluvastatin (10 mg/kg per day) for 1 month. Age-matched, normotensive Wistar Kyoto (WKY) rats served as controls. Both EDHF- and NO-mediated relaxations were impaired in SHRSP compared with WKY rats. Fluvastatin treatment did not affect blood pressure and serum total cholesterol. The acetylcholine (ACh)-induced, EDHF-mediated hyperpolarization in mesenteric arteries did not significantly differ between fluvastatin-treated SHRSP and untreated SHRSP and the responses in both groups were significantly smaller compared with those of WKY rats. Endothelium-derived hyperpolarizing factor-mediated relaxations, as assessed by the relaxation to ACh in mesenteric arteries contracted with noradrenaline in the presence of N(G)-nitro-l-arginine and indomethacin, were virtually absent and similar in both SHRSP groups. In contrast, NO-mediated relaxation, as assessed by the relaxation in response to ACh in rings contracted with 77 mmol/L KCl, was improved in fluvastatin-treated SHRSP compared with untreated SHRSP (maximum relaxation in control and fluvastatin groups 42.0 +/- 5.2 and 61.2 +/- 3.8%, respectively; P < 0.05). Hyperpolarization and relaxation in response to levcromakalim, an ATP-sensitive K(+) channel opener, were similar between the two SHRSP groups. These findings suggest that fluvastatin improves NO-mediated relaxation, but not EDHF-mediated hyperpolarization and relaxation, in SHRSP. Thus, the beneficial effects of the statin on endothelial function may be mainly ascribed to an improvement in the NO pathway, but not EDHF.

The objective of the study was to assess whether the publication of new guidelines, such as JNC VI 1997 and WHO/ISH 1999, and the development of new antihypertensive drugs have improved blood pressure (BP) control. A total of 150 patients (age 29-88, mean 66+/-11 years in 2001) who were followed at our hypertension clinic during 1991-2001 were retrospectively investigated. We compared the clinical characteristics of the patients in 2001 to those in 1991 and 1996, using the averaged BP determined at two occasions each year for our analysis. The average BP decreased during the 10 years between 1991 and 2001. When good BP control was defined as <140/90 mmHg, the rate of patients with good BP control increased from 31% in 1991 to 43% in 1996, and to 57% in 2001 (P<0.001 vs 1991). Both younger (< or =64 years) and older (> or =65 years) patients showed similar improvement during these 10 years. In 2001, satisfactory BP control (<130/85 mmHg) was achieved in 24% of younger patients, which was significantly higher than the achievement in 1991 (10%, P=0.02). This improvement occurred at the same time as an increase in the prescription of Ca antagonists and angiotensin II antagonist. The patients with improved BP control during these 10 years (n=50) showed lower body mass index (BMI) and serum total cholesterol levels in 2001 compared to persistently uncontrolled patients (n=54). Furthermore, the change in BMI during these 10 years was significantly less in the patients with improved BP control than in the persistently uncontrolled patients. In conclusion, BP control improved in the 10 years studied, and it seems to be attributable to the more frequent use of the newer drugs such as angiotensin II antagonists and Ca antagonists, to lifestyle modification and also to the growth in awareness of the importance of strict BP control.

We have previously reported that urotensin II acts on the central nervous system to increase blood pressure in normotensive rats. In the present study, we have determined the central cardiovascular action of urotensin II in spontaneously hypertensive rats (SHR). Intracerebroventricular (ICV) injection of urotensin II elicited a dose-dependent increase in blood pressure in both SHR and normotensive Wistar-Kyoto rats (WKY). The changes in mean arterial pressure induced by ICV urotensin II at doses of 1 and 10 nmol in the WKY were 8 +/- 2 and 23 +/- 3 mmHg, respectively. ICV administration of urotensin II caused significantly greater increases in blood pressure in SHR (16 +/- 3 mmHg at 1 nmol and 35 +/- 3 mmHg at 10 nmol, respectively) compared with those in WKY. Urotensin II (10 nmol) elicited significant and comparable increases in heart rate in SHR (107 +/- 10 bpm) and WKY (101 +/- 21 bpm). Plasma epinephrine concentrations after ICV administration of 10 nmol urotensin II were 203 +/- 58 pmol/ml in SHR and 227 +/- 47 pmol/ml in WKY, which tended to be higher than those in artificial cerebrospinal fluid-injected rats (73+/- 7 and 87 +/- 28 pmol/ml, respectively, p < 0.1). The immunoreactivity of urotensin II receptor GPR 14 was expressed extensively in the glial cells within the brainstem, hypothalamus, and thalamus. These results suggest that central urotensin II may play a role in the pathogenesis of hypertension in SHR. Since GPR 14 was expressed in the glial cells of the brain, urotensin II may act as a neuromodulator to regulate blood pressure.

Background: It is not known whether the treatment recommendations presented in the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure are applicable to the Japanese elderly population., Methods: We followed up 588 cardiovascular disease-free residents of a Japanese community who were 60 years or older from November 1, 1961, through October 31, 1993. Treated hypertensive patients were excluded from the analysis. During this period, CVD occurred in 179 subjects. The incidences were estimated by the pooling of repeated observations method., Results: The age- and sex-adjusted incidences of cardiovascular disease significantly increased with elevated blood pressure levels. The hazard ratio for stage 3 hypertension was 5.34 (95% confidence interval, 2.66-10.71; P<.001) compared with optimal blood pressure after adjustment for other covariates. Among subjects aged 60 to 79 years, the incidences for stages 1 through 3 hypertension were significantly higher than for those with optimal and normal blood pressure. In comparison, among those 80 years or older, the incidence was significantly higher only in patients with stage 3 hypertension. We further estimated the incidences according to the risk stratification system. In the younger elderly subjects, the incidences increased with rising blood pressure levels in each risk stratum. Similar relationships were not observed among the older elderly subjects., Conclusions: Our findings demonstrate that the recommendations of the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure were potentially applicable to the Japanese elderly subjects 79 years or younger. Based on our findings, however, hypertension might not be a risk factor for cardiovascular disease among very old hypertensive patients with advanced atherosclerosis.

We examined the effect and safety of combination therapy with low-dose diuretics (hydrochlorothiazide: HCTZ) and angiotensin II receptor antagonist (losartan) in elderly cases of hypertension, using ambulatory blood pressure monitoring (ABPM). Elderly hypertensive patients (mean age 75 +/- 2 years) were treated with either losartan (25-50 mg/day) or HCTZ (12.5 mg/day) for at least 4 weeks, and then 24-hour blood pressure (BP) was measured by ABPM. Combination therapy with addition of other drug was initiated in 14 patients whose 24-hour systolic BP or daytime systolic BP was over 140 mmHg (160 mmHg for the patients of 80 years or older). After 4 weeks of the combination therapy, ABPM was repeated. Blood cell count and blood chemistry were also done before and after initiation of combination therapy. In the losartan-preceding group (n = 9), the combination therapy with HCTZ reduced 24-hour BP by 19.3 +/- 2.3/6.6 +/- 2.3 mmHg. Similarly, daytime and nighttime BP decreased by 21.4 +/- 4/8.4 +/- 2.8 mmHg and 15.2 +/- 4/4.2 +/- 2.4 mmHg, respectively. In the HCTZ-preceding group, the combination with losartan also decreased 24-hour BP by 12.2 +/- 4.8/3.4 +/- 1.4 mmHg. The decreases of daytime and nighttime BP were 13.8 +/- 6.6/4 +/- 1.1 mmHg and 10 +/- 4.7/3 +/- 2.4 mmHg, respectively. Heart rate did not change with combination therapy in the losartan-preceding group, while heart rate during daytime tended to decrease by addition of losartan in the HCTZ-preceding group (3.8 +/- 1.7/min). Serum electrolytes, uric acid, lipids, renal function and body weight did not change during the study period. Thus, combination therapy of losartan/hydrochlorothiazide seems useful in the treatment of elderly hypertension, showing additive BP lowering effect without metabolic adverse effects.

Objective: To examine the relation of anger expression with blood pressure and hypertension among Japanese., Design: A cross-sectional study., Methods: Subjects were 4374 men and women aged 30-74 years from rural and urban communities. Anger expression was estimated using the anger-out and anger-in scores of the Spielberger Anger Expression Scale. Multiple linear regression analyses were performed to estimate the associations of anger expression scores with blood pressure. Proportions of hypertensives among the tertiles of anger expression scores and the relative odds of hypertension for low versus high tertiles of anger expression scales were calculated using logistic regression models., Results: The anger-out score was inversely associated with systolic and diastolic blood pressure levels for men; a four-point (one standard deviation) lower anger-out score was associated with 1.6 mmHg [95% confidence interval (CI), 0.6-2.6] greater systolic blood pressure and 0.6 mmHg (95% CI, -0.03 to 1.2) greater diastolic pressure after adjustment for age, body mass index, alcohol intake, smoking category, and parental history of hypertension. The adjusted relative odds of hypertension for low versus high tertiles of anger-out was 1.60 (95% CI, 1.19-2.15). These inverse associations were more evident among men with low coping behavior than among those with high coping behavior. For women, the anger-out score was not associated with blood pressure. There was no relation between the anger-in score and either blood pressure or hypertension in either men or women., Conclusions: This study suggests that Japanese men who do not express their anger, especially when they have low coping behavior, may have an increased risk of high blood pressure.

Objective: To examine the interaction of sodium intake with genetic variations of the angiotensinogen gene and hypertension., Design: A community-based case-reference study., Setting: Two rural Japanese communities., Participants: Non-overweight and non-drinking Japanese men and women: 229 hypertensives and 229 age-, sex- and community-matched normotensives aged 32 to 83 years., Methods: Polymorphisms of the angiotensinogen gene detected by an allele-specific polymerase chain reaction. A priori hypothesis is individuals with 174M (threonine-to-methionine substitution) or 235T (methionine-to-threonine substitution) allelic variations may have an elevated risk of hypertension when they have a high sodium intake, estimated by 24-h urine collection and a dietary questionnaire., Results: The genotypic frequency of the haplotype including both the 174M and 235T alleles was higher among hypertensives than among normotensives (23 versus 14%, P= 0.02). The frequency of the 174M allele was specifically higher among hypertensives than normotensives (12 versus 7%, P=0.01), and the odds ratio of hypertension associated with the 174M (versus 174T) allele was 1.8 [95% confidence interval (CI) 1.1-3.0, P=0.01]. The frequency of the 235T allele did not vary between the two groups (80 versus 82%, P= 0.40). The relationship between the 174M allele and hypertension was more evident among persons who had higher urinary sodium excretion (> = 166 mmol/day) than those with lower excretion (< 166 mmol/day): odds ratio 2.5 (95% CI, 1.2-5.2), P=0.01 versus 1.5 (95% CI, 0.7-3.1), P= 0.31; P for interaction = 0.04, and this trend was primarily observed for early-onset hypertension (< 55 years at onset). A similar but nonsignificant association was observed when stratified using present and past sodium intake scores derived from questionnaires., Conclusion: Angiotensinogen genotype may affect the development of early-onset hypertension among Japanese, particularly in those who have a high sodium intake.

Background and Purpose: Although randomized clinical trials have demonstrated the benefit of antihypertensive treatment in preventing stroke, the effectiveness of community-based programs is largely unknown. We investigated long-term community-based prevention activities., Methods: In rural northeastern Japan, people aged > or = 30 years numbered 3219 in the full intervention community and 1468 in the minimal intervention community in 1965. Systematic blood pressure screening and health education began in 1963. Stroke was registered through 1987., Results: More than 80% of people aged 40 to 69 years were screened in both communities in the 1960s. One community charged for screening services after 1968, whereas the other community intensified intervention; subsequently, screening rates and the follow-up of hypertensive individuals declined in the minimal intervention community, especially in men. In men, stroke incidence declined more (P < 0.001) in the full intervention (42% in the period 1970 to 1975, 53% in the period 1976 to 1981, and 75% in the period 1982 to 1987) than in the minimal intervention community (5% increase, 20% decrease, and 29% decrease, respectively); in women, the stroke incidence declined about 45% to 65% in both communities. Changes in stroke prevalence paralleled those in stroke incidence. Trends in systolic blood pressure levels tend to explain the differential stroke rates in men., Conclusions: Delivery of hypertension control services through intensive, free, community-wide screening and health education was effective in prevention of stroke for men in a community.

Background: It has been suggested that echocardiographically determined left ventricular mass (LVM) is useful in the prediction of hypertension. To examine the relation between LVM and subsequent blood pressure (BP) change, a 6- to 8-year follow-up was conducted in adult Japanese men., Methods and Results: LVM was determined by M-mode echocardiography using the American Society of Echocardiography formula among 354 normotensive men aged 30 to 59 years from a rural community (n = 193) and from urban companies (n = 161) in Japan between 1979 and 1983. BP was remeasured 6 to 8 years after baseline in 148 rural men (77%) and 127 urban men (79%). For men whose BP was remeasured, the mean +/- SD LVM index (LVM/body surface area [g/m2]) at baseline was 117 +/- 22 in rural men and 99 +/- 15 in urban men (the difference, P < .001). For both populations, LVM index was positively associated with age and physical activity but not with body mass index. Associations of LVM index with usual alcohol intake and initial BPs were generally weak. According to linear regression analyses after controlling for these covariates at baseline, a 20-g/m2 greater LVM index at baseline was associated with a 5 mm Hg increase in systolic and a 4 mm Hg increase in diastolic BP during the subsequent 6 to 8 years for urban men. A 1-mm greater average ventricular wall thickness was associated with a similar BP increase. For rural men, positive associations of LVM index with BP increase existed but were weak. The weaker association between LVM index and BP increase in rural compared with urban men was probably the result of effects of higher physical activity, leading to a larger left ventricular internal dimension. The increase in systolic and diastolic BPs over the 6 to 8 years of observation was significantly related to baseline LVM index in rural and urban men with a smaller internal dimension (rural men, < or = 49 mm; urban men, < or = 47 mm) but not in those with larger dimensions., Conclusions: An increased LVM index predicts subsequent BP increase in middle-aged normotensive men in the presence of a normal or small internal dimension.

The relation between dietary calcium and blood pressure was examined in 1,928 men, ages 40-69 years, from five geographic and two occupational populations in Japan. Dietary calcium intake was estimated using 24-hour dietary recall in systematic samples of participants of population-based cardiovascular surveys from 1983 to 1987. The means of daily calcium intake of the study populations ranged from 449 to 695 mg, approximately 300 mg lower than the recommended US dietary calcium intake. Linear regression analyses were used to examine the relation between dietary calcium and blood pressure within each population, controlling for age, body mass index, alcohol consumption, and sodium intake. Total calcium intake was inversely associated with the systolic blood pressure level in each population, and the pooled estimate of the regression coefficients for millimeters of mercury of blood pressure per 100-mg increase in calcium intake was -0.54 (95% confidence interval -0.89 to -0.19). The inverse association between calcium intake and diastolic blood pressure was less consistent, and the pooled estimate did not reach statistical significance (-0.10, 95% confidence interval -0.34-0.14). Inverse associations existed for both dairy and nondairy food sources of calcium when analyzed separately, and the association was significant only for dairy calcium. Although a causal relation between dietary calcium and blood pressure cannot be established, these results suggest a possible public health implication in Japan of increasing calcium intake for the prevention and control of hypertension, where average dietary calcium intake is low.

For period from 1971 to 1975, 18 cases of osteosarcoma were experienced among 9132 spontaneously hypertensive rats. The onset was at 72 to 145 days of age and death occurred before 423 days of age. The tumors were multiple being distributed in the skull (11 of 14 cases), caudal vertebrae (8 of 14 cases), and fore- and hind-limb. All the tumors were mainly composed of sarcomatous tissue with some osteoid and cartilage. Metastasis was never observed. Serum A1-P levels of tumor bearing animals were 2 times higher than those without tumor. Bronchiectasis and abscess formation of submaxillary lymph nodes were noted in most affected animals.

A significant positive relationship was found between alcohol intake and blood pressure for men 40-69 years old living in urban Osaka (492 men) and in rural Akita (395 men), Japan, surveyed from 1975 to 1977. Both mean blood pressure and the prevalence of hypertension were related to alcohol intake in a graded fashion. Stepwise multiple regression also showed that both systolic and diastolic pressure were associated with alcohol intake independent of ponderosity index, serum cholesterol, triglycerides, hemoglobin, uric acid, smoking, and age. This cross-sectional study indicates a continuous--and not a threshold--relationship between alcohol and blood pressure, with the effect of even moderate consumption, e.g. 28-55 g per day (equivalent to about 2-4 U.S. drinks per day).