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Angiotensin receptor-neprilysin inhibitors (ARNIs) have been approved as antihypertensive agents in Japan, and thiazide diuretics (TZDs) are widely used concomitantly with renin-angiotensin system inhibitors (RASIs) for hypertension. This retrospective study included patients with hypertension who switched from RASI to ARNI therapy (ARNI group) and those who were prescribed TZDs with RASIs (TZD/RASI group). Drug-related changes in the estimated glomerular filtration rate (eGFR), blood pressure (BP), body weight (BW), serum electrolytes, uric acid (UA), and triglyceride levels were compared between the two groups. Overall, 70 participants (31 and 39 in the ARNI and TZD/RASI groups, respectively) were enrolled and observed for a median of 2 months. According to linear mixed models, compared with the TZD/RASI group, the ARNI group exhibited a significant change in mean eGFR of 3.71 mL/min/1.73 m 2 [95% confidence interval (CI), 0.57-6.84; P = 0.02] from the time of switching drug to the next outpatient visit. Further, compared with the TZD/RASI group, the ARNI group exhibited significant changes in mean serum UA (-1.27; 95% CI, -1.66 to -0.88), sodium (1.22; 95% CI, 0.12 to -2.32), chloride (2.14; 95% CI, 0.75-3.52), and triglyceride (-52.1; 95% CI, -100.9 to -3.29) levels. Conversely, serum potassium levels, BW, and systolic and diastolic BP did not differ significantly between the two groups (P = 0.69, 0.44, 0.49, and 0.66, respectively). Compared with the combination therapy of TZD and RASI, ARNI therapy causes less renal dysfunction, hyperuricemia, and hypertriglyceridemia with fewer electrolyte abnormalities and no significant difference in antihypertensive effects., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Characterized by ventricular and vascular stiffness, heart failure with preserved ejection fraction (HFpEF) has led to high morbidity and mortality. As azilsartan is an angiotensin receptor blocker with the highest myocardial and vascular affinities, azilsartan may improve the left ventricular (LV) diastolic function in patients with hypertension and either HFpEF or HF with mildly reduced ejection fraction (HFmrEF) more than candesartan. In this randomized, open-label trial, we randomly assigned 193 hypertensive patients with HF and LV ejection fraction ≥ 45% to 20 mg of azilsartan (n = 95) or 8 mg of candesartan (n = 98), once daily for 48 weeks. After the initiation of treatment, changes in the doses of the study drugs were permitted based on the patient's conditions, including blood pressure (median dose at 48 weeks: azilsartan 20.0 mg/day, candesartan 8.0 mg/day). The primary endpoint was the baseline-adjusted change in the ratio of peak early diastolic transmitral flow velocity (E) to early diastolic mitral annular velocity (e') (E/e'). Adjusted least-squares mean (LSM) change in E/e' was - 0.8 (95% confidence interval [CI] - 1.49 to - 0.04) in the azilsartan group and 0.2 (95% CI - 0.49 to 0.94) in the candesartan group, providing the LSM differences of - 1.0 (95% CI - 2.01 to 0.03, P = 0.057). The median change in left atrial volume index was - 2.7 mL/m 2 with azilsartan vs 1.4 mL/m 2 with candesartan (P = 0.091). The frequency of adverse events related to hypotension and hyperkalemia did not differ between the groups. The current study did not provide strong evidence that azilsartan improves LV diastolic dysfunction, and further confirmatory study is required., (© 2023. The Author(s).)

Objectives: Masked hypertension, which is characterized by out-of-office hypertension but normal office blood pressure, is a risk factor for cardiovascular disease. However, the factors that contribute to masked hypertension are unclear. We aimed to determine the involvement of sleep-related characteristics in masked hypertension., Methods: The study included 3844 normotensive (systolic/diastolic blood pressure < 140/90 mmHg) community residents with no antihypertensive drug use at baseline (mean age 54.3 years). Home morning and evening blood pressure, oxygen desaturation during sleep (pulse oximetry), and sleep efficiency (actigraphy) were measured for 1 week. The number of nocturnal urinations during this period was obtained using a sleep diary., Results: Masked hypertension (mean morning and evening blood pressure ≥135/85 mmHg) was detected in 11.7% of study participants, and 79.0% of the participants with masked hypertension had sleep hypertension (≥120/70 mmHg). Multinominal logistic regression analysis identified different factors involved in masked hypertension with and without sleep hypertension; factors for masked hypertension with sleep hypertension included the frequency of at least 3% oxygen desaturation (coefficient = 0.038, P  = 0.001), nocturia (coefficient = 0.607, P  < 0.001), and carotid intima-media thickness (coefficient = 3.592, P  < 0.001). Only carotid intima-media thickness and measurement season were associated with masked hypertension without sleep hypertension. Low sleep efficiency was associated with isolated sleep hypertension but not masked hypertension., Conclusion: Sleep-related factors associated with masked hypertension differed depending on the presence of sleep hypertension. Sleep-disordered breathing and nocturnal urination frequency may help identify individuals who need home blood pressure monitoring., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Left ventricular hypertrophy (LVH) is a well-known risk factor for poor clinical outcomes in patients undergoing dialysis. However, little evidence supports the above notion in Japan, and the influence of subtypes of LVH on prognosis., Methods: We investigated 367 patients undergoing dialysis who underwent routine echocardiographic examinations between April and September 2018. LVH was defined as any LV mass ≥ 115 g/m 2 in men and ≥ 95 g/m 2 in women obtained by echocardiography. The primary endpoint was a composite outcome including all-cause death, admission due to heart failure, and ischemic heart event or stroke. LVH was divided into subtype-groups according to eccentric hypertrophy or concentric hypertrophy, and with and without hypertension., Results: LVH was observed in 171 (47%) patients. The primary endpoint was observed in 58 patients (16%) during the median follow-up period of 500 days. Multivariable Cox regression analyses identified four independent risk factors for the primary endpoint: age, pulse rate, serum albumin level, and LV mass index (per 10-g/m 2 increase; hazard ratio: 1.12, 95% confidence interval: 1.06-1.18, P < 0.001). Kaplan-Meier analyses demonstrated that patients with LVH had a worse prognosis than those without LVH in terms of the primary endpoint (log-rank P < 0.001). The incidence of the primary outcome was not significantly different between patients with eccentric or concentric hypertrophy, and between LVH patients with and without hypertension., Conclusion: Japanese patients with LVH undergoing dialysis had a worse prognosis than those without LVH in terms of the composite clinical endpoint., (© 2022. The Author(s), under exclusive licence to The Japan Society of Ultrasonics in Medicine.)

Faster pulse wave velocity (PWV) is known to be associated with the incidence of cardiovascular diseases (CVD). The aim of this study was to clarify the hypothesis that PWV may be associated with future CVD events even when its time-dependent changes were adjusted. We also investigated a prognostic significance of cardio-ankle vascular index, another index of arterial stiffness. Study participants included 8850 community residents. The repeated measures of the clinical parameters at 5.0 years after the baseline were available for 7249 of the participants. PWV was calculated using the arterial waveforms measured at the brachia and ankles (baPWV). The cardio-ankle vascular index was calculated by estimated pulse transit time from aortic valve to tibial artery. During the 8.53 years follow-up period, we observed 215 cases of CVD. The incidence rate increased linearly with baPWV quartiles (per 10 000 person-years: Q1, 2.7; Q2, 12.6; Q3, 22.5; Q4, 76.2), and the highest quartile was identified as an independent determinant of incident CVD by conventional Cox proportional hazard analysis adjusted for known risk factors [hazard ratio (HR), 4.00; p = .007]. Per unit HR of baPWV (HR, 1.15; p < .001) remained significant in the time-dependent Cox regression analysis including baPWV and other clinical values measured at 5-year after the baseline as time-varying variables (HR, 1.14; p < .001). The cardio-ankle vascular index was also associated with CVD with similar manner though the associations were less clear than that of baPWV. baPWV is a good risk marker for the incidence of CVD., (© 2021 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Kenya is experiencing a rising burden of non-communicable diseases (NCDs), yet data to inform effective interventions are limited. We investigated the prevalence of elevated blood pressure, elevated blood glucose and their determinants in a rapidly urbanizing area in Kenya. Data on socio-demographics, dietary and behavioural risk factors, anthropometric measurements, blood pressure, blood glucose, plasma lipids and urinary biomarkers were collected from 221 men and 372 women (25-64 years). Multivariable logistic regression models assessed correlates of elevated blood pressure (EBP) and elevated blood glucose (EBG). Participants' mean age was 38.0. ± 11.1 years. The prevalence rates of pre-hypertension and hypertension were 49.0% and 31.6% in men and 43.7% and 20.1% in women, respectively, while those of pre-diabetes and diabetes were 8.4% and 8.0% in men and 11.6% and 7.4% in women, respectively. The prevalence of Body Mass Index (BMI) ≥ 25 kg/m 2 was higher in women (60.2%) than in men (39.7%). However, both the risk of EBP and EBG were stronger among men than among women. The high prevalence rates of EBP, EBG and overweight/obesity coupled with low physical activity and low fruit and vegetable intake predispose this population to a higher NCD risk. Interventions to mitigate this risk considering the sex differences are urgently required.

Objectives: To demonstrate how the confidence, attitude and job satisfaction of pharmacists who provide interventions and lifestyle support services to patients with hypertension are altered., Methods: This study was a before-and-after study that used data from 50 pharmacists who participated in the Community Pharmacists Assist for Blood Pressure (COMPASS-BP) study, which was an interventional study that was conducted in Japan to evaluate the effects of lifestyle support services provided to hypertension patients. The pharmacists received 4 h of training before the study was initiated to learn how to quickly provide patients with guidance about diet and exercise and tobacco and alcohol consumption. During the interventional period, each pharmacist provided concise lifestyle guidance to 1-3 hypertension patients. The pharmacists met with the patients a total of 5 times. The parameters that were assessed were the pharmacists' attitudes towards and confidence in their lifestyle support services, as well as their level of job satisfaction. We verified the scores of each parameter assessed before and after the study, as well as changes in the relationships among the different parameters., Key Findings: Significant increases from baseline to the end of the study were observed for Confidence (P < 0.01), Job satisfaction, including 'Knowledge' (P < 0.01), 'Patient counselling management' (P = 0.04) and 'Sense of personal growth' (P < 0.01). Additionally, path analysis results revealed that after the study, the causal relationship between 'Knowledge' and 'Attitude' disappeared, and a new causal relationship appeared between 'Patient counselling and management' and 'Attitude'., Conclusions: Providing lifestyle guidance improved pharmacists' confidence and attitude. Also, 'Attitude' tended to improve as the 'Patient counselling and management' score increased., (© 2019 Royal Pharmaceutical Society.)

Background: Orthostatic hypertension was associated with worse cardiovascular outcomes, although the factors responsible for an orthostatic rise in blood pressure (BP) are uncertain. We investigated a possible relationship between a stooping posture and orthostatic BP change., Methods: Study participants consisted of 1,992 older individuals. Orthostatic BP change was calculated by systolic BP measured at sitting position, and again 1 and 3 minutes after standing up. Spinal alignment and curvature was assessed by guiding the SpinalMouse device on the surface of the skin along the spine., Results: Mean lumbar lordosis at standing position was 13.4° ± 12.4°. The degree of lumbar lordosis was significantly smaller in orthostatic hypertensive individuals (systolic BP change, ≥+20 mm Hg: 3.3° ± 15.6°, ≥+10 mm Hg: 10.4° ± 14.3°) than in individuals who were orthostatic normotensive (14.2° ± 11.9°). Multiple linear regression analysis identified lumbar lordosis (β = -0.171, P < 0.001) and thoracic kyphosis (β = 0.062, P = 0.007), but not sacral inclination (β = 0.033, P = 0.303), as independent determinants for orthostatic BP change. As waist circumference was another independent determinant, the frequency of orthostatic hypertensive individuals was linearly increased with the combination of abdominal obesity and small degree of lumbar lordosis (control: 9.9%, abdominal obesity: 17.4%, small degree of lordosis: 19.4%, both: 24.1%, P < 0.001). Participants who sustained orthostatic hypertension for 3 minutes after standing up had the smallest degree of lumbar lordosis (5.2° ± 16.4°)., Conclusion: Stooped posture was an overlooked determinant for orthostatic increases in BP.

Study Objectives: The individual prevalence of sleep-disordered breathing (SDB), short sleep duration, and obesity is high and increasing. The study aimed to investigate potential associations between SDB, objective sleep duration, obesity, diabetes and hypertension across genders, and the effect of pre- or post-menopausal status., Methods: A cross-sectional study evaluated 7051 community participants with wrist actigraphy for a week, and nocturnal oximetry ≥ 2 nights. SDB was assessed by 3 per cent oxygen desaturation index (ODI) corrected for sleep duration obtained from wrist actigraphy. Moderate-to-severe SDB was defined as ODI3% levels ≥ 15 per hour., Results: Both logODI3% and body mass index showed independent negative associations with sleep duration (β = -0.16, p < 0.001 and β = -0.07, p < 0.001, respectively). Moderate-to-severe SDB (men/premenopausal women/postmenopausal women; 23.7/1.5/9.5%, respectively) was associated with a higher risk of diabetes in premenopausal women (OR 28.1; 95%CI 6.35-124.6; p < 0.001) and postmenopausal women (OR 3.25; 95%CI 1.94-5.46; p < 0.001), but not in men (OR 1.47; 95%CI 0.90-2.40; p = 0.119). Moderate-to-severe SDB was associated with a higher risk of hypertension in men (OR 3.11; 95%CI 2.23-4.33; p < 0.001), premenopausal women (OR 3.88; 95%CI 1.42-10.6; p = 0.008), and postmenopausal women (OR 1.96; 95%CI 1.46-2.63; p < 0.001). Short sleep duration was not associated with diabetes or hypertension. The associations of obesity with diabetes or hypertension were indirectly mediated by SDB (24.0% and 21.5%, respectively), with possible sex differences emerging (men/women; 15.3/27.8% and 27.0/16.9%, respectively)., Conclusions: Notwithstanding the cross-sectional design, SDB and obesity, but not short sleep duration, were independently associated with diabetes and hypertension, with gender and menopausal status-related differences in risk emerging.

Background: Urinary sodium-to-potassium ratio (Na/K) represents a simple measure of sodium load and has been reported to be associated with blood pressure (BP) levels in a cross-sectional setting even with spot measurements. The aim of the present large-scale cohort study is to determine prognostic significance of spot urine Na/K for longitudinal changes in BP levels and renal function., Methods: The present study population consisted of 7,063 individuals from the general population. Clinical parameters were measured at baseline and at a follow-up interval of 5 years., Results: Mean systolic BP was slightly increased during the follow-up period (overall, 124 ± 17 to 125 ± 18 mm Hg; nontreated participants, 119 ± 15 to 122 ± 17 mm Hg). Although, the urinary Na/K demonstrated a linear association with BP in a cross-sectional analysis (P < 0.001), analysis of repeated measured BP values identified baseline Na/K * time interaction, i.e., an intraindividual effect, as an inverse determinant (F = 76.9, P < 0.001) independently of hypertension status and fasting conditions possibly due to regression to the mean of temporary high baseline Na/K values at baseline. Spot urine Na/K values were found to be positively associated with renal function in a cross-sectional analysis (P < 0.001). Although baseline Na/K * time interaction showed inverse associated with renal functional decline (F = 85.8, P < 0.001), this inverse association might not represent physiological relationship in likewise fashion with the analysis for BP., Conclusions: Spot urine Na/K may have limited utility as a prognostic marker of longitudinal BP change, as well as renal functional decline., (© American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Background: We conducted a retrospective cohort study to evaluate and compare the longitudinal effect of monotherapy with L-, L/T-, L/N-, and L/N/T-type calcium channel blockers (CCBs) on estimated glomerular filtration rate (eGFR), and to investigate the association of treatment duration with eGFR in diabetic patients with hypertension., Methods: Using a clinical database, we identified new users of five CCBs, i.e. amlodipine (L-type, n = 693), nifedipine (L-type, n = 189), azelnidipine (L/T-type, n = 91), benidipine (L/N/T-type, n = 183), and cilnidipine (L/N-type, n = 61). We used a multivariable regression model to evaluate and compare the effects of these drugs on eGFR and serum creatinine, up to 12 months after initiation of study drug administration., Results: There was no significant association between treatment duration and both eGFR and serum creatinine level with all CCB types. In addition, there was no significant difference in mean change in eGFR among the five CCBs, with any treatment duration., Conclusions: Our findings suggest that monotherapy with an L-, L/T-, L/N/T-, or L/N-type CCB may have little influence on renal function parameters and may be safely used in hypertensive patients with diabetes.

The authors investigated the relationship between the awareness of dietary salt and genetics and the intent to maintain a low-salt diet. In particular, they assessed whether hypothetical genetic information regarding salt-sensitive hypertension motivates the intent to reduce dietary salt for communicating the health benefits of lower salt consumption to citizens. A self-administered questionnaire survey was conducted with 2500 randomly sampled residents aged 30 to 69 years living in Nagahama, Japan. Genetic information regarding higher salt sensitivity increased motivation to reduce salt intake for both those who agreed that genes cause hypertension and those who did not. Less than 50% of those who agreed that genes cause hypertension lost their intention to lower their salt consumption when they found they did not possess the susceptibility gene. Communicating genetic information positively affected motivation to reduce salt intake. The present study clarifies the difficulty in changing the behavioral intent of those who have significantly less incentive to reduce salt intake. Therefore, a multidimensional approach is crucial to reduce salt consumption., (©2016 Wiley Periodicals, Inc.)

We conducted a retrospective cohort study to evaluate and compare the long-term effects of two single-pill fixed-dose combinations (FDCs), candesartan/amlodipine and olmesartan/azelnidipine, on laboratory parameters in patients in routine clinical practice. We identified an equal number of new users (n = 182) of a candesartan/amlodipine (8/5 mg/day) FDC tablet (CAN/AML users) and a propensity-score matched cohort (n = 182) receiving an olmesartan/azelnidipine (20/16 mg/day) FDC tablet (OLM/AZ users). Generalized estimating equations were used to estimate and compare the effects of the drugs on serum levels of creatinine, estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), uric acid, sodium, potassium, aspartate aminotransferase, and alanine aminotransferase levels up to 12 months after the start of study drug administration. There was a significant increase of serum creatinine level and a significant decrease of eGFR from the baseline period to during the exposure period in both CAN/AML and OLM/AZ users, and a significant increase of BUN level in CAN/AML users. However, there were no significant differences in the mean changes of laboratory parameters between CAN/AML and OLM/AZ users. Our findings suggested that the effects of CAN/AML and OLM/AZ on laboratory parameters, including an unfavorable effect on renal function, were similar at least during 1 year of administration.

Objectives: We undertook descriptive epidemiology of spot urine sodium-to-potassium ratio (Na/K) in a population sample to clarify the close relationship between Na/K and blood pressure level independently of potential confounding factors., Methods: Study participants consisted of 9144 apparently healthy citizens (aged 54 ± 13 years). All clinical parameters were obtained at baseline., Results: Na/K was significantly higher in hypertensive individuals irrespective of antihypertensive medication status (normotension, 3.12 ± 1.82; untreated hypertension 3.50 ± 1.96; treated hypertension, 3.72 ± 2.53). As urinary Na (β = 0.092, P < 0.001) and K (β = -0.050, P < 0.001) levels were inversely associated with BP, Na/K (β = 0.118, P < 0.001) was more closely associated with BP than Na or K alone, as well as daily salt intake estimated from urinary Na (β = 0.088, P < 0.001). Several factors were significantly associated with Na/K, namely age, sex, obesity, blood pressure, renal function, salt restriction status, serum phosphate and urinary creatinine level, and fasting period and season at urine sample collection. However, the association between Na/K and BP was independent of these factors (adjusted β = 0.112, P < 0.001). No direct association was observed between Na/K and large arterial remodeling assessed by pulse wave analysis (P = 0.496) or retinal arteriolar morphological change (P = 0.431). Further, a genome-wide association study failed to identify any particular genotype influencing urinary Na and K levels., Conclusions: Although we clarified several factors that might affect spot urine Na/K, these relationships were not substantial enough to confound the association between urinary Na/K and BP. A simple measure of Na/K might be more representative of salt loading obtained from spot urine samples than Na excretion alone.

Background: This study aimed to determine the prevalence and predictors of working-age individuals who did not follow-up for possible hypertension that was detected in the population-based screening., Methods: We conducted a retrospective cohort study, using the database of health insurance claims and health checkups from several health insurance societies for employees in Japan. Screened participants aged ≥20 years, with possible hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg) and without known antihypertensive treatment, were included. The outcome was lack of clinical follow-up for possible hypertension within 6 months of the latest screening. Multivariate logistic regression analysis was performed to identify predictors., Results: Among 17,173 participants (15,793 males and 1380 females) who were identified as possible hypertensives, 89.7 and 82.3% of them, respectively, did not consult physicians for screened possible hypertension. Predictors of no clinical follow-up for males included younger age, lower body mass index (BMI), lower hemoglobin A1c and milder hypertension. Predictors for females included younger age, lower BMI and being insured., Conclusions: Approximately 80% of participants failed to consult physicians even with positive screening results. Younger individuals with lower BMI are at high risk of no clinical follow-up., (© The Author 2014. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: To determine the relationships between regional white matter lesions (WMLs), lifestyle factors, and cognitive, motor function and mood., Methods: A comprehensive evaluation, including brain MRI, blood tests, the Unified Parkinson's Disease Rating Scale, the Mini Mental State Examination, and the Geriatric Depression Scale, was performed for people aged 65 years or older living in Ama-cho on October 1, 2009. Participants were classified by severity of periventricular hyperintensities (PVH) and deep white matter hyperintensities (DWMH) using the Fazekas score., Results: Of 900 eligible participants, 688 (76.4%) were enrolled, including 303 men. Significant predictors of severe PVH were older age, lower low-density lipoprotein cholesterol (LDL-C) levels, elevated blood pressure (BP), cerebral infarction, and no current alcohol use. Significant predictors of severe DWMH were older age, lower 1,5-anhydroglucitol (1,5-AG) levels, elevated BP, cerebral infarction, and no current alcohol use. Higher cognitive function was associated with younger age, female sex, mild DWMH, more years of education, and higher high-density lipoprotein cholesterol levels. Depressive symptoms were associated with lower 1,5-AG levels, lower LDL-C levels, moderate to severe PVH, and no current alcohol use., Conclusions: White matter lesions in elderly people were related to hypertension and impaired glucose tolerance. The severity of WMLs was associated with cognitive function and mood.

Objectives: Although central blood pressure (BP) is considered to be more closely associated with large arterial remodeling and cardiovascular outcomes than brachial BP, few studies have investigated these associations with changes in small arteries. As morphological changes in retinal vessels might be associated with cardiovascular outcomes, we conducted a cross-sectional study to investigate the association of central BP with retinal vessel caliber., Methods: The study included 8054 Japanese participants. Central BP was estimated by the radial arterial waveform by calibrating brachial BP. Central retinal arteriolar equivalent (CRAE) was computationally measured using fundus photography., Results: CRAE was most strongly associated with central SBP (r = -0.324, P < 0.001), followed by DBP (r = -0.292, P < 0.001) and central pulse pressure (PP; r = -0.226, P < 0.001). The correlation coefficient between SBP and CRAE was significantly greater in central SBP than in brachial SBP (r = -0.300, P < 0.001). After adjustment for possible covariates, brachial SBP (β = -0.221, P < 0.001) and central SBP (β = -0.239, P < 0.001) were independently associated with CRAE. Further, higher brachial SBP (β = -0.226, P < 0.001) and smaller PP amplification (β = 0.092, P < 0.001) were identified as independent determinants of narrowing of CRAE in the same equation, which indicated the superiority of central BP. Central BP-determined hypertensive individuals had a significantly narrower CRAE independent of brachial BP (central/brachial: hypertension/hypertension 121.4 ± 11.5, hypertension/normotension 120.9 ± 11.2, normotension/hypertension 125.1 ± 11.9, normotension/normotension 128.1 ± 11.5 μm)., Conclusion: Central BP was more closely associated with the narrowing of CRAE than brachial BP. Slight increases in central BP might be involved in the morphological changes in small retinal arteries, even in individuals with optimal brachial BP.

Over the past few years, use of the genome-wide association study (GWAS) has made it possible to identify the primary genetic mechanisms of essential hypertension. GWAS results have helped identify many loci in or near genes that generally were not expected to be associated with blood pressure or essential hypertension. However, considering the great expectations of improving clinical outcomes and the billions of dollars that have been spent on various GWASs, the progress made so far has been slow. There are several factors that could be responsible for the relative lack of success of GWASs. First, it is possible that the number of people enrolled in the various GWASs was not enough, thereby limiting the power to detect additional markers. Second, although the alleles that are associated with a modest increase in risk are constantly being found, their discriminatory ability and use as predictive markers has been quite low. Difficulties with control group selection along with unrepeatability have also been problematic when using GWASs. The current paper summarizes the recent progress attained when using a GWAS of hypertension to identify the many loci associated with essential hypertension. In this review, we discuss the progress and issues of a GWAS for hypertension.

Central blood pressure (BP) has been suggested to be a better predictor of cardiovascular disease risk than brachial BP. Given that central BP and arterial waveform are both influenced by insulin resistance, major initiators of insulin resistance, such as serum-free fatty acid (FFA), are suspected of potentially being involved in central hemodynamics. To confirm that insulin signaling is an important modulator of central hemodynamics, we investigated this hypothesis in a large-scale general population. Brachial BP and radial arterial waveform were measured simultaneously in 9393 middle-aged to elderly individuals. The augmentation index was calculated from the radial waveform as the ratio of the height of the late systolic peak to that of the first peak. Central systolic BP was defined as the absolute pressure of the late systolic peak of the waveform. Differences in central and brachial pulse pressure (PP) were considered to represent PP amplification. PP amplification differed significantly among serum FFA level quartiles (Q1, 7.8±5.3; Q2, 8.6±5.0; Q3, 9.3±5.7; Q4, 10.3±6.1 mm Hg; P<0.001), and the maximum difference in combination with diabetes mellitus status was 4.9 mm Hg. Multivariate analysis adjusted for major covariates indicated that higher serum FFA was an independent determinant for higher PP amplification (β=0.145, P<0.001) and lower augmentation index (β=-0.122, P<0.001) and central systolic BP (β=-0.044, P<0.001), whereas the association between FFA and PP amplification significantly decreased (β=0.022, P<0.001) after further adjustment for augmentation index. Serum FFA is an overlooked factor favorably influencing central hemodynamics. A low-magnitude reflection pressure wave might be involved in this paradoxical relationship., (© 2014 American Heart Association, Inc.)

To evaluate the cardiovascular mortality risk in association with blood pressure level among people with and without antihypertensive treatment, we performed the participant-level meta-analysis that included 39,705 Japanese from 6 cohorts (58.4% women; mean age, 60.1 years; 20.4% treated). Multivariable-adjusted Cox models were used to analyze the risk of cardiovascular mortality and its subtypes among 6 blood pressure levels according to recent guidelines, optimal to Grade 3 hypertension, and the usage of antihypertensive medication at baseline. During median 10.0 years of follow-up, there were 2032 cardiovascular deaths (5.1 per 1000 person-years), of which 410 deaths were coronary heart disease, 371 were heart failure, and 903 deaths were stroke. Treated participants had significantly higher risk for cardiovascular mortality (hazard ratios, 1.50; 95% confidence intervals, 1.36-1.66), coronary heart disease (hazard ratios, 1.53; confidence intervals, 1.23-1.90), heart failure (hazard ratios, 1.39; confidence intervals, 1.09-1.76), and stroke (hazard ratios, 1.48; confidence intervals, 1.28-1.72) compared with untreated people. Among untreated participants, the risks increased linearly with an increment of blood pressure category (P≤0.011). The risk increments per blood pressure category were higher in young participants (<60 years; 22% to 79%) than those in old people (≥60 years; 7% to 15%) with significant interaction for total cardiovascular, heart failure, and stroke mortality (P≤0.026). Among treated participants, the significant linear association was also observed for cardiovascular mortality (P=0.0003), whereas no stepwise increase in stroke death was observed (P=0.19). The risks of cardiovascular mortality were ≈1.5-fold high in participants under antihypertensive medication. More attention should be paid to the residual cardiovascular risks in treated patients.

Objective: The present study examined the association between uric acid levels and high blood pressure in a multiethnic study of Chinese children and adolescents., Methods: The participants were divided into four different groups according to the uric acid quartiles. Three logistic regression models were conducted to investigate the relationship between the high blood pressure and uric acid levels. Model 1 adjusted age, sex and ethnicity. Model 2 adjusted age, sex, ethnicity, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, estimated glomerular filtration rate, fasting glucose and waist circumference. Model 3 adjusted all the confounding factors in model 2 except the waist circumference and BMI. The concentrations of uric acid in high blood pressure participants and normotensive participants were compared with or without adjustment for confounding factors., Results: A total of 3778 participants aged 10-15 years from the Xinjiang Congenital Heart Disease Survey were included in the present study. The percentages of the high blood pressure in the four different uric acid quartiles were 7.4, 8.6, 9.6 and 11.8%, respectively. In model 1, 2 and 3 of the logistic regression, the participants in the third and fourth uric acid quartiles had significantly higher chance of suffering the high blood pressure when compared with the participants in the first uric acid quartile [odds ratio 1.608, 1.587, 1.597, P = 0.005, 0.015, 0.015, respectively, between participants in the first quartile and the third quartile; odds ratio 1.981, 1.945, 1.810, P = 0.001, 0.002, 0.007, respectively, between participants in the first quartile and the fourth quartile). The concentrations of serum uric acid were 220.7 μmol/l in high blood pressure participants and 204.1 μmol/l in normotensive participants (P = 0.024). After adjustment for confounding factors, the concentrations of serum uric acid were 219.7 vs. 204.5 μmol/l in one model (P < 0.001) and 219.3 vs. 204.5 μmol/l in the other model (P < 0.001)., Conclusions: Among Chinese children and adolescents, increasing levels of serum uric acid are associated with high blood pressure.

Background: Angiotensin II type 1 receptor blockers (ARB) are a frequently used class of antihypertensive drug. The ARB losartan is known to decrease the serum uric acid (SUA) level. However, there are very few clinical data comparing the effects of other ARBs on SUA level under the conditions of clinical practice. This study evaluated and compared the long-term effects of monotherapy with five ARBs on SUA level in Japanese hypertensive patients with type 2 diabetes mellitus (DM)., Methods: We identified hypertensive patients with type 2 DM who had been treated with monotherapy with losartan (n = 214), valsartan (n = 266), telmisartan (n = 185), candesartan (n = 458), or olmesartan (n = 192), in whom laboratory data of SUA between November 1, 2004 and July 31, 2011 were available, from the Nihon University School of Medicine's Clinical Data Warehouse (NUSM's CDW). We used a propensity-score weighting method and a multivariate regression model to adjust for differences in the background among ARB users, and compared the SUA level. The mean exposure of losartan was 264.7 days, valsartan 245.3 days, telmisartan 235.9 days, candesartan 248.9 days, and olmesartan 234.5 days., Results: In losartan users, mean SUA level was significantly decreased from baseline, while it was conversely increased in users of other ARBs; valsartan, telmisartan, candesartan, and olmesartan. The mean reduction of SUA level from baseline was significantly greater in losartan users compared with that in other ARB users. Comparison of ARBs other than losartan showed no significant difference in mean change in SUA level from baseline., Conclusions: Our study showed that losartan had the most beneficial effect on SUA level among five ARBs, and that there was no significant difference in the unfavorable effects on SUA level among four ARBs other than losartan, at least during one year. These findings provide evidence of an effect of ARBs on SUA level, and support the benefit of the use of losartan in hypertensive patients with type 2 DM.

Objectives: The Golgi SNAP receptor complex member 2 (GOSR2) gene is a Golgi-associated soluble factor attachment receptor (SNARE) protein involved in intra-Golgi protein trafficking on chromosome 17q21, which is the hypertension linkage peak on the human chromosome. The aim of the present study was to assess the association between the human GOSR2 gene and essential hypertension (EH) using a haplotype-based case-control study., Methods: A total of 320 EH patients and 205 age-matched controls were genotyped for the five single-nucleotide polymorphisms (SNPs) used as genetic markers for the human GOSR2 gene (rs197932, rs3785889, rs197922, rs17608766, and rs16941382). Data were analyzed for three separate groups: the total subjects, men, and women., Results: The overall distribution of the haplotypes in men was significantly different between the EH patients and the control subjects (P=0.002). Additionally, the frequency of the T-A-G haplotype (rs197932-rs3785889-rs197922) for men was significantly higher in the EH patients than in the control subjects (P=0.049). After adjustment for the major risk factors, multiple logistic regression analysis also revealed that the frequency of men with the T-A-G haplotype (homozygous and heterozygous diplotypes) was significantly higher than that in men without the haplotype (OR=1.756, P=0.039)., Conclusions: The results of this study indicate that the T-A-G haplotype may be a useful genetic marker for EH in Japanese men., (Copyright © 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Essential hypertension (EH) is thought to be a multifactorial disease. In Japan, there are more than 20 million cases of EH, which accounts for 80 to 90% of hypertension cases in Japan. It is very difficult to isolate the susceptibility genes of EH in familial linkage analysis such as sib-pair analysis and association studies such as case-control studies of candidate genes. Over the past few years, genome-wide association studies (GWAS) have begun to identify the primary genetic mechanisms of hypertension. For example, GWAS have identified many loci in or near genes that generally were not expected to be associated with the level of blood pressure or essential hypertension. Considering the high expectations for the studies and the billions of dollars spent to conduct these studies, however, progress has been slow. We believe that next-generation research technologies, such as the whole genome sequencing, may remedy some of these problems encountered thus far. The present paper contains a review of issues and progress in isolation of susceptibility genes of EH, and an introduction to an effective novel method for isolation of susceptibility genes of EH.

Smoothelin is a specific cytoskeletal protein that is associated with smooth muscle cells. The human SMTN gene encodes smoothelin-A and smoothelin-B, and studies using SMTN gene knockout mice have demonstrated that these animals develop hypertension. The aim of the present study was to investigate the association between the human SMTN gene and essential hypertension (EH) using a haplotype-based case-control study. This is the first study to assess the association between essential hypertension and this gene. A total of 255 EH patients and 225 controls were genotyped for the five single-nucleotide polymorphisms (rs2074738, rs5997872, rs56095120, rs9621187 and rs10304) used as genetic markers for the human SMTN gene. Data were analyzed for three separate groups: total subjects, men and women. Although there were no differences for genotype distributions, or the dominant and recessive model distributions noted for total subjects, men and women for all of the SNPs selected for the present study, for the total subjects group, the frequency of the G-C-A-C haplotype constructed with rs2074738-rs5997872-rs56095120-rs9621187 was significantly lower in the essential hypertension patients than in the controls (P = 0.002). The G-C-A-C haplotype appears to be a useful protective marker of essential hypertension in Japanese, and the SMTN gene might also be a genetic marker for essential hypertension., (© 2012 The Authors.)

Background: Both angiotensin II type I receptor blockers (ARBs) and calcium channel blockers (CCBs) are widely used antihypertensive drugs. Many clinical studies have demonstrated and compared the organ-protection effects and adverse events of these drugs. However, few large-scale studies have focused on the effect of these drugs as monotherapy on laboratory parameters. We evaluated and compared the effects of ARB and CCB monotherapy on clinical laboratory parameters in patients with concomitant hypertension and type 2 diabetes mellitus., Methods: We used data from the Clinical Data Warehouse of Nihon University School of Medicine obtained between Nov 1, 2004 and July 31, 2011, to identify cohorts of new ARB users (n = 601) and propensity-score matched new CCB users (n = 601), with concomitant mild to moderate hypertension and type 2 diabetes mellitus. We used a multivariate-adjusted regression model to adjust for differences between ARB and CCB users, and compared laboratory parameters including serum levels of triglyceride (TG), total cholesterol (TC), non-fasting blood glucose, hemoglobin A1c (HbA1c), sodium, potassium, creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), hemoglobin and hematocrit, and white blood cell (WBC), red blood cell (RBC) and platelet (PLT) counts up to 12 months after the start of ARB or CCB monotherapy., Results: We found a significant reduction of serum TC, HbA1c, hemoglobin and hematocrit and RBC count and a significant increase of serum potassium in ARB users, and a reduction of serum TC and hemoglobin in CCB users, from the baseline period to the exposure period. The reductions of RBC count, hemoglobin and hematocrit in ARB users were significantly greater than those in CCB users. The increase of serum potassium in ARB users was significantly greater than that in CCB users., Conclusions: Our study suggested that hematological adverse effects and electrolyte imbalance are greater with ARB monotherapy than with CCB monotherapy.

Background: Angiotensin II receptor blockers (ARBs), including olmesartan and candesartan, are widely used antihypertensive agents. Many clinical studies have demonstrated that ARBs have organ-protecting effects, e.g., cardioprotection, vasculoprotection and renoprotection. However, the effect of prolonged olmesartan monotherapy on lipid metabolism in patients with hypertension is less well studied. We performed a retrospective observational study to compare the effects of olmesartan with those of candesartan, focusing on lipid metabolism and renal function., Methods: We used data from the Clinical Data Warehouse of Nihon University School of Medicine obtained between Nov 1, 2004 and Feb 28, 2011, to identify cohorts of new olmesartan users (n = 168) and candesartan users (n = 266). We used propensity-score weighting to adjust for differences in all covariates (age, sex, comorbid diseases, previous drugs) between olmesartan and candesartan users, and compared serum chemical data including serum triglyceride (TG), LDL-cholesterol (LDL-C), total cholesterol (TC), potassium, creatinine and urea nitrogen. The mean exposure of olmesartan and candesartan users was 126.1 and 122.8 days, respectively., Results: After adjustment, there were no statistically significant differences in all covariates between olmesartan and candesartan users. The mean age was 60.7 and 61.0 years, and 33.4% and 33.7% of olmesartan and candesartan users were women, respectively. There were no statistically significant differences in mean values for all laboratory tests between baseline and during the exposure period in both olmesartan and candesartan users. In olmesartan users, the reduction of serum TG level was significant in comparison with that in candesartan users. Other parameters of lipid profile and renal function showed no statistically significant difference in the change from baseline to during the exposure period between olmesartan and candesartan users., Conclusions: In this study, we observed a more beneficial effect on lipid metabolism, a reduction of serum TG, with olmesartan monotherapy than with candesartan monotherapy. However, there were no clinically significant changes in the levels of all test parameters between baseline and during the exposure period with both drugs. These results suggest that the influence of olmesartan or candesartan monotherapy on lipid metabolism and renal function is small, and that they can be safely used in patients with hypertension.

Background: Trichlormethiazide, a thiazide diuretic, was introduced in 1960 and remains one of the most frequently used diuretics for treating hypertension in Japan. While numerous clinical trials have indicated important side effects of thiazides, e.g., adverse effects on electrolytes and uric acid, very few data exist on serum electrolyte levels in patients with trichlormethiazide treatment. We performed a retrospective cohort study to assess the adverse effects of trichlormethiazide, focusing on serum electrolyte and uric acid levels., Methods: We used data from the Clinical Data Warehouse of Nihon University School of Medicine obtained between Nov 1, 2004 and July 31, 2010, to identify cohorts of new trichlormethiazide users (n = 99 for 1 mg, n = 61 for 2 mg daily dosage) and an equal number of non-users (control). We used propensity-score matching to adjust for differences between users and control for each dosage, and compared serum chemical data including serum sodium, potassium, uric acid, creatinine and urea nitrogen. The mean exposure of trichlormethiazide of 1 mg and 2 mg users was 58 days and 64 days, respectively., Results: The mean age was 66 years, and 55% of trichlormethiazide users of the 1 mg dose were female. In trichlormethiazide users of the 2 mg dose, the mean age was 68 years, and 43% of users were female. There were no statistically significant differences in all covariates (age, sex, comorbid diseases, past drugs, and current antihypertensive drugs) between trichlormethiazide users and controls for both doses. In trichlormethiazide users of the 2 mg dose, the reduction of serum potassium level and the elevation of serum uric acid level were significant compared with control, whereas changes of mean serum sodium, creatinine and urea nitrogen levels were not significant. In trichlormethiazide users of the 1 mg dose, all tests showed no statistically significant change from baseline to during the exposure period in comparison with control., Conclusions: Our study showed adverse effects of decreased serum potassium and increased serum uric acid with trichlormethiazide treatment, and suggested that a lower dose of trichlormethiazide may minimize these adverse effects. These findings support the current trend in hypertension therapeutics to shift towards lower doses of thiazides.

Hypertension is one of the most common complex genetic disorders. We have described previously 38 single nucleotide polymorphisms (SNPs) with suggestive association with hypertension in Japanese individuals. In this study we extend our previous findings by analyzing a large sample of Japanese individuals (n=14 105) for the most associated SNPs. We also conducted replication analyses in Japanese of susceptibility loci for hypertension identified recently from genome-wide association studies of European ancestries. Association analysis revealed significant association of the ATP2B1 rs2070759 polymorphism with hypertension (P=5.3×10(-5); allelic odds ratio: 1.17 [95% CI: 1.09 to 1.26]). Additional SNPs in ATP2B1 were subsequently genotyped, and the most significant association was with rs11105378 (odds ratio: 1.31 [95% CI: 1.21 to 1.42]; P=4.1×10(-11)). Association of rs11105378 with hypertension was cross-validated by replication analysis with the Global Blood Pressure Genetics consortium data set (odds ratio: 1.13 [95% CI: 1.05 to 1.21]; P=5.9×10(-4)). Mean adjusted systolic blood pressure was highly significantly associated with the same SNP in a meta-analysis with individuals of European descent (P=1.4×10(-18)). ATP2B1 mRNA expression levels in umbilical artery smooth muscle cells were found to be significantly different among rs11105378 genotypes. Seven SNPs discovered in published genome-wide association studies were also genotyped in the Japanese population. In the combined analysis with replicated 3 genes, FGF5 rs1458038, CYP17A1, rs1004467, and CSK rs1378942, odds ratio of the highest risk group was 2.27 (95% CI: 1.65 to 3.12; P=4.6×10(-7)) compared with the lower risk group. In summary, this study confirmed common genetic variation in ATP2B1, as well as FGF5, CYP17A1, and CSK, to be associated with blood pressure levels and risk of hypertension.

Background: HSD3B1 and HSD3B2 are crucial enzymes for the synthesis of hormonal steroids, including aldosterone. Therefore, HSD3B gene variations could possibly influence blood pressure (BP) by affecting the aldosterone level., Methods: We performed a haplotype- and diplotype-based case-control study to investigate the association between the HSD3B gene variations and essential hypertension (EH), aldosterone level, and left ventricular hypertrophy (LVH). A total of 275 EH patients and 286 controls were genotyped for four SNPs of the HSD3B1 gene (rs3765945, rs3088283, rs6203, and rs1047303) and for two SNPs of the HSD3B2 gene (rs2854964 and rs1819698). Aldosterone and LVH were investigated in 240 and 110 subjects respectively., Results: Significant differences were noted for the total and the male subject groups for the recessive model (CC versus TC+TT) of rs6203 between the controls and EH patients (P=0.030 and P=0.008 respectively). The frequency of the T-C haplotype established by rs3088283-rs1047303 was significantly higher for EH patients compared with the controls (P=0.014). Even though the polymorphism of HSB3B1 was not associated with LVH, the diplotype established by rs3088283-rs1047303 in the total subject group, along with the systolic BP, diastolic BP, and aldosterone level were significantly higher for those subjects who had the T-C haplotype versus those who did not (P=0.025, P=0.014, and P=0.006 respectively)., Conclusion: rs6203 and rs1047303 in the HSD3B1 gene are useful genetic markers for EH, while polymorphisms of HSD3B1 are associated with the BP and aldosterone level.

Background: Studies focusing on the add-on effects of angiotensin II type 1 receptor blockers (ARBs) other than their antihypertensive effect are receiving attention. However, the effects of prolonged administration of ARBs on lipid metabolism in clinical cases are unclear. Our aims were to survey the changes in plasma lipid profile in patients with hypertension over a one-year period, and to examine the correlations between these values and the time after the start of ARB monotherapy with candesartan., Methods: We carried out candesartan monotherapy in patients with mild to moderate hypertension and examined the longitudinal changes in plasma lipid profile. Data from 405 patients for triglyceride (TG), 440 for total cholesterol (TC), 313 for high density lipoprotein cholesterol (HDL-C) and 304 for low density lipoprotein cholesterol (LDL-C) were obtained from the electronic medical records (EMRs) in the Clinical Data Warehouse (CDW) of Nihon University School of Medicine (NUSM). The inverse probability of treatment weighting (IPTW) method (calculated from the inverse of the propensity score) was used to balance the covariates and reduce bias in each treatment duration. Linear mixed effects models were used to analyse the relationship between these longitudinal data of blood examinations and covariates of patient sex, age, diagnosis of diabetes mellitus (DM) and duration of candesartan monotherapy., Results: Plasma HDL-C level was associated with sex, duration of treatment, and interaction of sex and treatment duration, but not with age or diagnosis of DM. HDL-C level was significantly decreased during the 6 approximately 9 months period (p = 0.0218) compared with baseline. TG and TC levels were associated with sex, but not with age, diagnosis of DM or treatment duration. LDL-C level was not associated with any covariate. Analysis of the subjects divided by sex revealed a decrease in HDL-C in female subjects (during the 6 approximately 9 months period: p = 0.0054), but not in male subjects., Conclusions: Our study revealed that administration of candesartan slightly decreased HDL-C in female subjects. However, TG, TC and LDL-C levels were not influenced by candesartan monotherapy. Candesartan may be safely used for patients with hypertension with respect to lipid metabolism, because the effect of candesartan on lipids may be small.

Background: Elastin microfibril interfacer 1 (EMILIN-1) is a negative regulator of the transforming growth factor-beta (TGF-beta) signaling, which is involved in blood pressure (BP) homeostasis. Emilin1 knockout mice display elevated BP. The aim of the present study was to assess the association between the human EMILIN1 gene and essential hypertension (EH) using a haplotype-based case-control study., Methods: A total of 287 EH patients and 253 age-matched controls were genotyped for the five single-nucleotide polymorphisms (SNPs) used as genetic markers for the human EMILIN1 gene (rs2289408, rs2289360, rs2011616, rs2304682, and rs4665947). Data were analyzed for three separate groups: the total subjects, men, and women., Results: For the total, the genotypic distribution of rs2289360, rs2011616, and rs2304682 differed significantly between control and EH (P = 0.010, P = 0.009, and P = 0.008, respectively). For the total and men, there were significant differences noted between the controls and the EH patients for both the dominant model (GG vs. AA+AG) (P = 0.006, P = 0.021, respectively), and the recessive model (AA vs. AG+GG) (P = 0.028, P = 0.038, respectively) of rs2011616. For the total and the men, logistic regression analysis indicated that the AG+GG genotype of rs2011616 was significantly higher in EH patients (P = 0.033, P = 0.043, respectively). The frequency of the G-G-T haplotype (established by rs2536512, rs2016116, rs17881426) was significantly higher in EH men (P = 0.007), and the G-A-T haplotype (established by rs2536512, rs2016116, rs17881426) was significantly higher in control men (P < 0.001)., Conclusions: We confirmed that rs2289360, rs2011616, and rs2304682 in the human EMILIN1 gene, as well as the haplotype constructed using rs2536512, rs2011616, and rs17881426 are useful genetic markers of EH in Japanese men.

P2RY2 has an important function in the regulation of blood pressure by activating adenosine triphosphate (ATP). The aim of this study was to investigate the association between the human P2RY2 gene and essential hypertension (EH) through a haplotype-based case-control study that included two gender groups. The 273 EH patients and 255 age-matched controls were genotyped for five single-nucleotide polymorphisms (SNPs) of the human P2RY2 gene (rs4944831, rs1783596, rs4944832, rs4382936 and rs10898909). Data were analysed for men and women separately and then as a combined total group. For the total and the men only groups, the genotype distribution of the T allele of rs4944831 and the recessive model (GG vs TG+TT) of rs4944831 differed significantly between the EH patients and controls (P=0.028 and 0.019; P=0.009 and 0.008, respectively). Logistic regression showed that for the total and men groups, the TG+TT genotype of rs4944831 was more prevalent in EH patients than in the controls (P=0.026 and 0.011, respectively). For men, the overall distribution of the haplotype (SNP2-SNP4-SNP5) was significantly different between the EH patients and the controls (P=0.006). As compared with controls, the frequency of the T-A-G haplotype was significantly higher, whereas the T-C-G haplotype was significantly lower for the EH patients (P=0.001 and 0.014, respectively). In conclusion, the present results indicate that rs4944831 and the T-A-G haplotype of the human P2RY2 gene might be genetic markers for EH in Japanese men.

Background: Oxidative DNA damage is involved in the pathophysiology of essential hypertension (EH), which is a multifactorial disorder. Apurinic/apyrimidinic endonuclease 1/redox effector factor-1 (APE1/REF-1) is an essential endonuclease in the base excision repair pathway of oxidatively damaged DNA, in addition to having reducing properties that promote the binding of redox-sensitive transcription factors. Blood pressure in APE1/REF-1-knockout mice is reported to be significantly higher than in wild-type mice. The aim of this study was to investigate the relationship between EH and the human APE1/REF-1 gene through a haplotype-based case-control study using single-nucleotide polymorphisms (SNPs)., Methods: We selected five SNPs in the human APE1/REF-1 gene (rs1760944, rs3136814, rs17111967, rs3136817, and rs1130409), and performed case-control studies in 265 EH patients and 266 age-matched normotensive (NT) subjects., Results: rs17111967 was found to show nonheterogeneity among Japanese subjects. There were no significant differences in the overall distribution of genotypes or alleles for each SNP between EH and NT groups. In the overall distribution of the haplotype-based case-control study constructed based on rs1760944, rs3136817, and rs1130409, the frequency of the G-T-T haplotype was significantly higher in the EH group than in the NT group (2.1% vs. 0.0%, P = 0.001). Multiple logistic regression analysis also revealed significant differences for the G-T-T haplotype, even after adjustment for confounding factors (OR = 8.600, 95% CI: 1.073-68.951, P = 0.043)., Conclusions: Based on the present results, the G-T-T haplotype appears to be a genetic marker of EH, and the APE1/REF-1 gene appears to be a susceptibility gene for EH.

Urotensin II (UII) and urotensin II-related peptide (URP) are novel vasoactive peptides that share urotensin II receptor (UT). We have recently reported that expressions of URP and UT were up-regulated in kidneys of rats with renal failure or hypertension. To clarify possible changes of the UII system expression in cardiovascular organs with hypertension, we examined the gene expression of UII, URP and UT in hearts and aortae of hypertensive rats. Furthermore, the expression was compared with that of endothelin-1 (ET-1). Quantitative reverse transcription polymerase chain reaction analysis showed that expression levels of UII mRNA and UT mRNA were significantly elevated in the atrium of 11-12-week-old spontaneously hypertensive rats (SHR) compared with age-matched Wistar-Kyoto rats (WKY). Moreover, UT mRNA expression was elevated in the ventricle of 11-12-week-old SHR. In the aorta, expression levels of URP mRNA and UT mRNA were significantly elevated in 11-12-week-old SHR compared with age-matched WKY, similarly to those in the kidney. In contrast, expression levels of ET-1 were significantly decreased in both the heart and the kidney of 11-12-week-old SHR compared with age-matched WKY. Immunohistochemistry showed that URP and UT were immunostained in cardiomyocytes, with weaker immunostaining in vascular endothelial and smooth muscle cells, in both SHR and WKY. These findings indicate that the gene expression of the UII system components (UII, URP and UT) and ET-1 is differently regulated in hypertension, and that the UII system in the heart and aortae may have certain pathophysiological roles in hypertension.

Aim: We previously identified a quantitative trait locus (QTL) on rat chromosome 5 that appeared to be primarily controlled by the sympathetic nervous system. Because sympathetic overactivity is related to hypertension, solute carrier family 6, member 9 (SLC6A9) is a candidate gene for the connection of this QTL with blood pressure regulation. In the present study, we therefore explored the role of SLC6A9 genetic variations in human essential hypertension (EH)., Methods: We evaluated three single nucleotide polymorphisms (SNPs) (rs2286245, rs3791124 and rs2486001) in 758 essential hypertension patients and 726 controls. Polymorphism-related genotypes were determined with TaqMan assays., Results: The allelic frequency of rs2286245 (C versus T, p=0.032) showed significant differences between EH and normotensive controls (NT) groups. The genotypic distribution of rs3791124 in its dominant model (AA+GA versus GG, p=0.027) also showed significant differences between EH and NT groups. The genotype and allele distributions of rs2486001 did not exhibit any significant differences., Conclusion: We found an association between SLC6A9 gene polymorphisms and essential hypertension in a Japanese population, suggesting that SLC6A9 is a susceptibility locus for essential hypertension.

Urotensin II-related peptide (URP) is a novel vasoactive peptide that shares urotensin II receptor (UT) with urotensin II. In order to clarify possible changes of URP expression in hypertension and chronic renal failure (CRF), the expressions of URP and UT were studied by quantitative RT-PCR and immunohistochemistry in kidneys obtained from spontaneous hypertensive rats (SHR), Wistar-Kyoto rats (WKY), and WKY with CRF due to 5/6 nephrectomy. Expression levels of URP mRNA and UT mRNA were significantly higher in the kidneys obtained from SHR compared with age-matched WKY (at 5-16 and 16 weeks old, respectively). A dissection study of the kidney into three portions (inner medulla, outer medulla and cortex) showed that the expression levels of URP mRNA and UT mRNA were highest in the inner medulla and the outer medulla, respectively, in both SHR and WKY. The expression levels of URP and UT mRNAs were greatly elevated in the remnant kidneys of CRF rats at day 56 after nephrectomy, compared with sham-operated rats (about 6.5- and 11.9-fold, respectively). Immunohistochemistry showed that URP immunostaining was found mainly in the renal tubules, vascular smooth muscle cells and vascular endothelial cells. UT immunoreactivity was localized in the renal tubules and vascular endothelial cells. These findings suggest that the expressions of URP and UT mRNAs in the kidney are enhanced in hypertension and CRF, and that URP and its receptor have important pathophysiological roles in these diseases.

Aims: To investigate possible mechanisms of action of THC-002 (HARNCARE), a galenical produced from the traditional Chinese herbal mixture Ba-Wei-Die-Huang-Wan, which has been reported to improve lower urinary tract symptoms (LUTS) in patients., Methods: Forty-five female SHRs were randomly separated into three groups. Two groups were given 20 ml physiological saline solution (PSS) per kg-body weight orally daily for 1 week. An hour after the administration of PSS, one of the groups received 20 mg THC-002 per kg body weight, and the other a similar volume of THC-002-free saline. The third group received no treatments. The bladders were analyzed by real time RT-PCR (n = 6) and immunohistochemistry (n = 3) for the expression of tachykinins and P2X3 and TRPV1 receptors. Cystometric investigation (n = 6) was conducted after intravesical instillation of saline followed by 5 mg/ml ATP solution., Results: Treatment with PSS caused and upregulation of tachykinins and P2X3 and TRPV1 receptors, which was prevented in the group treated with THC-002. In the normal (non-treated) and non-THC-002-treated SHRs, instillation of the ATP solution decreased voiding interval, micturition volume, and bladder capacity compared to the instillation of saline. However, in the THC-002-treated SHRs, ATP instillation had no effect., Conclusions: In SHRs, THC-002 reduced the bladder expression of tachykinins and P2X3 and TRPV1 receptors, and inhibited ATP-induced detrusor overactivity. These effects may explain part of its beneficial effects on LUTS., ((c) 2009 Wiley-Liss, Inc.)

Essential hypertension (EH) accounts for 80-90% of hypertension, and pregnancy-induced hypertension (PIH) is responsible for hypertension during pregnancy. Both considered multifactorial disorders. While both have many features in common, conditions and causes of these diseases have yet to be clarified. Since both diseases are associated with hypertension, the genetic backgrounds may contain common features. The present study reviewed similarities and differences between women with EH and PIH, with a particular focus on their genetic backgrounds.

CYP4F2 acts primarily as an enzyme that converts arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), a metabolite involved in the regulation of blood pressure in humans. The aim of the present study was to assess the association between the human CYP4F2 gene and essential hypertension (EH) using a haplotype-based case-control study that included separate analysis of the two gender groups. The 249 EH patients and 238 age-matched controls were genotyped for 5 single-nucleotide polymorphisms (SNPs) of the human CYP4F2 gene (rs3093105, rs3093135, rs1558139, rs2108622, rs3093200). Data were analyzed for 3 separate groups: all subjects, and men and women separately. For the total population and for male subjects, the distribution of the dominant model of rs1558139 (CC vs. CT+TT) differed significantly between the EH patients and control subjects (p=0.037 and p=0.005, respectively), with a higher percentage of EH patients showing the CC genotype. Logistic regression showed that, for men, the CC genotype of rs1558139 was more prevalent in the EH patients than in the control subjects (p=0.026), while, for the total population, the difference disappeared (p=0.247). For men, the overall distribution of the haplotypes was significantly different between the EH patients and the control subjects (p=0.042), and the frequency of the T-T-G haplotype was also significantly lower for EH patients than for control subjects (p=0.009). In conclusion, the present results indicate that rs1558139 might be a genetic marker for EH and the T-T-G haplotype might be a protective genetic marker for EH in Japanese men.

It has been reported that oxidative stress is involved in the pathophysiology of essential hypertension (EH), which is a multifactorial disorder. Extracellular superoxide dismutase (EC-SOD) protects the human body from oxidative stress by converting the toxic superoxide anion (O2-) into less toxic hydrogen peroxide (H2O2). In EC-SOD knockout mice, blood pressure was reported to be significantly higher than that seen in wild-type mice. The aim of this study was thus to investigate the relationship between EH and the human EC-SOD gene by using single-nucleotide polymorphisms (SNPs) in a haplotype-based case-control study. We selected 6 SNPs within the human EC-SOD gene (rs13306703, rs699473, rs699474, rs17881426, rs2536512 and rs1799895), and then performed case-control studies in 243 EH patients and 251 age-matched normotensive (NT) subjects. In Japanese subjects, no heterogeneity was found for rs699474, and no significant differences were observed between the EH and NT groups for the overall distribution of the genotypes or the alleles for each of the SNPs. However, in the haplotype-based case-control study that used rs13306703 and rs2536512, significant differences were observed in the overall distribution (chi2=14.26, p=0.003). The frequency of the T-A haplotype was significantly higher in the EH group than in the NT group (2.4% vs. 0.0%, p<0.001). Based on the results of our haplotype-based case-control study, the T-A haplotype may be a genetic marker for EH, and thus the EC-SOD gene might be a susceptibility gene for EH.

Background: We have earlier identified a quantitative trait locus (QTL) on rat chromosome 5 that appears to be primarily under the control of the sympathetic nervous system. Because sympathetic overactivity is related to both hypertension and insulin resistance, FABP3 is a candidate gene for the link between this QTL and blood pressure regulation. In this study, therefore, we explored the role of FABP3 genetic variations in essential hypertension (EH) in humans., Methods: We evaluated two single-nucleotide polymorphisms (SNPs) (rs2279885 and rs2271072) in 758 patients with EH and 726 controls. Polymorphism-related genotypes were determined using TaqMan assays, while haplotypes were estimated from the genotype data., Results: The frequencies of occurrence of the G allele of rs2279885 and the C allele of rs2271072 were significantly higher in subjects with EH than in normotensive (NT) subjects (P = 0.0339, P = 0.0209, respectively). However, the genotype distributions did not exhibit any significant differences., Conclusion: We found an association between FABP3 gene polymorphisms and EH in a Japanese population, thereby suggesting that FABP3 is a susceptibility locus for EH.

Background: Essential hypertension is a complex disorder that results from the interaction of a number of susceptibility genes and environmental factors. The TNFRSF4 (tumor necrosis factor receptor superfamily, member 4) gene was one of the genes that showed altered renal expression in long-term salt loading in mice. Moreover, association of the TNFRSF4 and TNFSF4 (tumor necrosis factor (ligand) superfamily, member 4) genes with myocardial infarction was recently reported. Since essential hypertension is a well-known risk factor for myocardial infarction, we hypothesized that TNFRSF4 could be a susceptibility gene for essential hypertension., Methods: We performed a case-control study of TNFRSF4 in two independent population., Results: Extensive investigation of single nucleotide polymorphisms of the entire gene suggested that it resided in one linkage disequilibrium block, and four single nucleotide polymorphisms in the 5' flanking region sufficiently represented major haplotypes. In the combined population, the frequency of the most frequent haplotype, C-C-A-A, was significantly lower (P = 8.07 x 10(-5)) and that of the second most frequent haplotype, C-T-G-A, was significantly higher (P = 6.07 x 10(-4)) in hypertensive subjects than in control subjects. This difference was observed only in female patients. The C-T-G-A haplotype showed a lower promoter activity than other haplotypes, suggesting a relationship with disease susceptibility., Conclusion: Our results suggest that TNFRSF4 is a female-specific susceptible gene for essential hypertension.

Background: Gitelman's syndrome is an inherited tubular disorder characterized by sodium wasting, low blood pressure, secondary hyperaldosteronism, metabolic alkalosis, hypokalemia, hypomagnesemia of renal origin, and hypocalciuria. The majority of patients with this syndrome carry inactivating mutations in the SLC12A3 gene encoding the thiazide-sensitive Na (+)-Cl (-) cotransporter (NCC) located in the distal convoluted tubule, which is involved in renal sodium reabsorption. This suggests that the SLC12A3 gene is involved in mediation of blood pressure levels. The aim of the present study was to investigate relationships between single nucleotide polymorphisms (SNPs) in the human SLC12A3 gene and essential hypertension (EH) in Japanese., Method: We selected 3 SNPs in the human SLC12A3 gene (T180K, A569V, L849H), and performed a case-control study of 315 EH patients and 305 normotensive (NT) individuals., Results: There was no significant difference in overall distribution of genotypes or alleles of any of the SNPs between the EH and NT groups., Conclusion: We conclude that the causal gene of Gitelman's syndrome is not involved in determining blood pressure levels.

Objective: CYP4A11, a member of the cytochrome P450 family, acts mainly as an enzyme that converts arachidonic acid to 20-hydroxyeicosatetraenoic acid, a metabolite involved in blood pressure regulation in humans. Disruption of the murine cyp4a14 and cyp4a10 genes, homologues of human CYP4A11, was reported recently to cause hypertension. The gene-disrupted male mice had higher blood pressure than the gene-disrupted female mice. The present study aimed to assess the association between the human CYP4A11 gene and essential hypertension, using a haplotype-based case-control study including separate analysis of the gender groups., Methods: The 304 essential hypertension patients and 207 age-matched control individuals were genotyped for three single-nucleotide polymorphisms of the human CYP4A11 gene (rs2269231, rs1126742, rs9333025). Data were assessed for three separate groups: total participants, men and women., Results: For total participants, the genotypic distribution of rs1126742 differed significantly between the two groups (P = 0.005). For total participants, men and women, the recessive model (CC versus TC + TT) of rs1126742 differed significantly between the two groups (P = 0.007, P = 0.043, and P = 0.045, respectively). Logistic regression analysis showed the TC + TT genotype was significantly higher in essential hypertension patients than in control individuals for total participants and men (P = 0.022 and P = 0.043, respectively). The A-T-G haplotype frequency (established by rs2269231, rs1126742, rs9333025) was significantly higher in essential hypertension men than in control men (P = 0.043)., Conclusions: Essential hypertension is associated with the TC + TT genotype of rs1126742 in the human CYP4A11 gene. The A-T-G haplotype appears a useful genetic marker of essential hypertension in Japanese men.

Essential hypertension is one of the most common, complex diseases, of which considerable efforts have been made to unravel the pathophysiological mechanisms. Over the last decade, multiple genome-wide linkage analyses have been conducted using 300-900 microsatellite markers but no single study has yielded definitive evidence for 'principal' hypertension susceptibility gene(s). Here, we performed a three-tiered, high-density association study of hypertension, which has been recently made possible. For tier 1, we genotyped 80 795 SNPs distributed throughout the genome in 188 male hypertensive subjects and two general population control groups (752 subjects per group). For tier 2 (752 hypertensive and 752 normotensive subjects), we genotyped a panel of 2676 SNPs selected (odds ratio >or= 1.4 and P

Background: As aromatase-deficient mice, which are deficient in estrogens, reportedly have reduced blood pressure, the aromatase gene (CYP19A1) is thought to be a susceptibility gene for essential hypertension (EH). The aim of the present study was to investigate the relationship between CYP19A1 and EH by examining single nucleotide polymorphisms (SNPs)., Methods: Five SNPs in the human CYP19A1 gene (rs1870049, rs936306, rs700518, rs10046 and rs4646) were selected, and an association study was performed in 218 Japanese EH patients and 225 age-matched normotensive (NT) individuals., Results: There were significant differences between these groups in the distribution of genotypes rs700518 and rs10046 in male subjects, and genotypes rs700518, rs10046 and rs4646 in female subjects. On multiple logistic regression analysis, a significant association between rs700518 (p=0.023) and rs10046 (p=0.036) in male subjects and rs700518 in female subjects (p=0.018) was noted. Interestingly, the risk genotypes of rs700518 and rs10046 showed a sex-dependent inverse relationship. Both SBP and DBP levels were higher in total (cases and controls) male subjects with the G/G genotype with rs700518 or the T/T genotype with rs10046 than in male subjects without the G/G genotype or T/T genotype. SBP levels were lower in female subjects with the G/G genotype with rs700518 than in female subjects without G/G. The A-T haplotype constructed with rs1870049 and rs10046 was a susceptibility marker for EH., Conclusions: We confirmed that rs700518 and rs10046, as well as a haplotype constructed with rs1870049 and rs10046, in the human CYP19A1 gene can be used as genetic markers for gender-specific EH.

A multiple candidate-gene approach was used to investigate not only candidate genes, but also candidate pathways involved in the regulation of blood pressure. We evaluated 307 single nucleotide polymorphisms (SNPs) in 307 genes and performed an association study between 758 cases and 726 controls. Genes were selected from among those encoding components of signal transduction pathways, including receptors, soluble carrier proteins, binding proteins, channels, enzymes, and G-proteins, that are potentially related to blood pressure regulation. In total, 38 SNPs were positively (p<0.05) associated with hypertension. Replication of the findings and possible polygenic interaction was evaluated in five G-protein-related positive genes (GNI2, GNA14, RGS2, RGS19, RGS20) in a large cohort population (total n=9,700, 3,305 hypertensives and 3,827 normotensive controls). In RGS20 and GNA14, dominant models for the minor allele were significantly associated with hypertension. Multiple dimension reduction (MDR) analysis revealed the presence of gene-gene interaction between GNA14 and RGS20. The MDR-proved combination of two genotypes showed a significant association with hypertension (chi2=9.93, p=0.0016) with an odds ratio of the high-risk genotype of 1.168 (95% confidence interval [CI] [1.061-1.287]). After correction for all possible confounding parameters, the MDR-proved high-risk genotype was still a risk for hypertension (p=0.0052). Furthermore, the high-risk genotype was associated with a significantly higher systolic blood pressure (133.08+/-19.46 vs. 132.25+/-19.19 mmHg, p=0.04) and diastolic blood pressure (79.65+/-11.49 vs. 79.01+/-11.32 mmHg, p=0.019) in the total population. In conclusion, a systemic multiple candidate gene approach can be used to identify not only hypertension-susceptibility genes but also hypertension-susceptibility pathways in which related genes may synergistically collaborate through gene-gene interactions to predispose to hypertension.