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Background: Homocysteine (Hcy) is an independent risk factor for cardiovascular diseases, and elevated plasma Hcy levels could aggravate vascular injury in hypertension. Hyperhomocysteinemia can change the methylation status of global DNA and specific genes. In the present study, we aim to examine the comprehensive influence of Hcy levels on DNA methylation status in patients with hypertension., Methods: Epigenome-wide methylation profiles of the peripheral leukocyte DNA of 218 patients with hypertension were analyzed using the Illumina Infinium Methylation EPIC BeadChip. Differentially methylated positions (DMPs) associated with serum Hcy levels were identified by mixed linear regression with the adjustment of potential confounders. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted to determine the potential functions of the identified DMPs. The association between the methylation level of DMPs and carotid-femoral pulse wave velocity (Cf-PWV) was also analyzed., Results: Five DMPs at cg13169662, cg03179312, cg21976560, cg25262698, and cg09433843 showed significant association with serum Hcy levels (false discovery rate-corrected P  < 0.05). An additional six CpG sites met the threshold for suggestive significance ( P  < 1 × 10 -6 ), among which three DMPs (cg25781123, cg26463106, and cg06679221) were annotated to THUMPD3 . Furthermore, the methylation levels of cg13169662 and cg25262698 (RPRD1A) were significantly associated with Cf-PWV., Conclusion: Our results suggest that Hcy could induce DNA methylation alteration in patients with hypertension. Further functional research is warranted to elucidate the concrete role of DMPs in hypertension., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Hyperhomocysteinemia (HHcy) and hypertension are associated with cardiovascular events. However, effects of Hcy-lowing interventions on cardiovascular outcome were conflicting. Serum folate level was proposed to be a possible determinant of efficacy of extra folate supplementation on cardiovascular outcome. The aims of the present study were to describe representative information on the levels of serum homocysteine and folate in hypertensive patients, and to explore the major determinants of HHcy., Methods: 11,007 participants with hypertension were analyzed in this cross-sectional study. Blood pressure and serum levels of biochemical indicators were measured. Multivariate logistic regression model was used to assess the associated factors of HHcy., Results: Geometric mean of serum total homocysteine was 14.1 (95% CI: 13.9, 14.4) μmol/L and prevalence of HHcy was 36.1 (95% CI: 34.0, 38.1) % in hypertensive patients. HHcy was strongly associated with factors including male sex, older age, elevated serum creatinine (SCr), lower serum folate and vitamin B12, and uncontrolled blood pressure in hypertensive patients. Elevated SCr attributed to HHcy with the etiologic fraction of 0.29. The change of the odds ratio of HHcy associated with folate was significantly higher in patients with elevated SCr compared with that of patients with normal SCr., Conclusion: The results suggested the protection of female sex and higher levels of folate and vitamin B12 from HHcy and attribution of older age and elevated SCr to HHcy. Restoring renal function deserved attention for hypertensive patients to benefit from Hcy-lowing measures., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Blood pressure variability is a common physiological phenomenon; however, the association between within-visit and visit-to-visit variability in blood pressure and all-cause mortality remains uncertain., Methods: We conducted a retrospective analysis of blood pressure variability among 11 721 adults who underwent blood pressure measurement on three occasions within a period of 6 months. Within-visit and visit-to-visit variability was quantified using the standard deviation and maximum--minimum difference between measures. The predictive effect of this variability on all-cause mortality was evaluated using Kaplan--Meier survival curves and Cox regression analysis., Results: The incidence of all-cause mortality was significantly higher for participants in the top quintile of within-visit and visit-to-visit blood pressure variability and for those with sustained high within-visit variability. Within-visit variability was not retained as a risk factor after adjustment in Cox regression models. The hazard ratio for mortality increased from 48 to 55% for the top quintile of visit-to-visit blood pressure variability and from 56 to 61% for sustained high within-visit variability. The risk of mortality remained statistically higher even if visit-to-visit blood pressure variability was added to the model, including consistency of within-visit blood pressure variability and vice versa., Conclusion: Visit-to-visit and sustained high within-visit blood pressure variability were significant positive prognostic factors for all-cause mortality. Our findings underlined the clinical significance of achieving stable blood pressure in an effective plan of hypertension management., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Systolic blood pressure (SBP) and resting pulse rate (RPR) have been linked to mortality and cardiovascular events in younger population. Till now, no studies simultaneously investigate the non-linear association of SBP and RPR with all-cause and cardiovascular mortality among population aged 80 and older. Data of 2828 eligible participants were selected from electronic health records linked attended automated office blood pressure measurement system. The dose-response relationship between the SBP, RPR, and the risk of all-cause and cardiovascular mortality was analyzed by Cox model with restricted cubic splines. During the 3.6-year follow-up, 442 deaths occurred. Comparing with the optimal SBP (117-145 mmHg), the lower (HR: 1.39, 95% CI: 1.07-1.81) and higher SBP (HR: 1.34, 95% CI: 1.08-1.65) were significantly associated with an increasing risk of all-cause mortality. The higher SBP (>144 mmHg) was associated with cardiovascular mortality, with the HR (95% CI) as 1.51 (1.07-2.12). The faster RPR showed the higher risk of all-cause (HR: 1.36, 95% CI: 1.05-1.76) and cardiovascular (HR: 1.51, 95% CI: 1.07-2.13) mortality. We found both higher SBP and faster RPR were independently associated with all-cause and cardiovascular mortality, and lower SBP was only associated with the increased risk of all-cause mortality in oldest old community-dwelling Chinese population. Our results demonstrate the prognostic importance of both SBP and RPR in the elderly., (© 2021 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Intracranial atherosclerotic stenosis (ICAS) contributes to nearly 50% of stroke in China, especially in patients with hypertension. Urine albumin-to-creatinine ratio (ACR) has been related to stroke and other atherosclerotic cardiovascular diseases. However, there is limited information about the association of ACR and early impairment of cerebral vessels. Hereby we assessed the association of ICAS with ACR, estimated glomerular filtration rate (eGFR), and dipstick proteinuria in a stroke-free hypertensive population. We included 889 hypertension patients aged ≥60 years without prior stroke. Computed tomography angiography was performed to detect ICAS. ACR and dipstick proteinuria were tested from a random spot urine. eGFR was calculated using the CKD-EPI equation. Logistic regression was carried out to analyze the association of renal function with the presence, extent, and lesion number of ICAS. Elevated ACR (≥30 mg/g) was associated with ICAS after adjustment of confounding factors (odds ratio (OR) = 1.66, 95% confidence interval (CI): 1.21-2.29). Patients with elevated ACR were more prone to develop moderate-to-severe stenosis (OR = 1.57, 95% CI: 1.16-2.14) and more lesions (OR = 1.58, 95% CI: 1.16-2.15). Such association was independent of previously identified cardiovascular risk factors. No significant association was detected between ICAS and dipstick proteinuria or eGFR after adjustment. Our findings suggested that elevated ACR was associated with asymptomatic ICAS in an aged stroke-free hypertensive population.

Background and Aims: Genetic factors play an important role in the cervico-cerebral large-artery atherosclerotic stenosis (LAS), and ATP2B1 gene has been associated with the process of atherosclerosis disorders, such as coronary artery disease and arterial stiffness. But there is little information about the relationship between ATP2B1 gene and atherosclerosis in the intracranial arteries. We hereby investigated the association of common variants in ATP2B1 gene with LAS in asymptomatic Chinese hypertension patients., Methods: The stenosis of intracranial and extracranial arteries were evaluated in 899 subjects through computerized tomography angiography from the aortic arch to the skull base. A total of 11 ATP2B1 common variants were genotyped. Multivariate logistic regression was carried out in a dominant model with confounding factors adjusted., Results: rs17249754-A (OR = 0.43, p = 0.0002) and rs1401982-G (OR = 0.47, p = 0.0007) were associated with decreased susceptibility of concurrent extra and intracranial stenosis even after Bonferroni correction. These two minor alleles were also significantly associated with less stenotic arteries and moderate-to-severe stenosis., Conclusion: rs17249754 and rs1401982 were associated with asymptomatic LAS in stroke-free Chinese hypertension patients and might benefit early recognition of LAS patients in clinical practice.

Elevated plasma homocysteine (Hcy) is suggested as an independent risk factor for stroke. We aimed to investigate the association of Hcy concentration with intracranial atherosclerosis (ICAS) and extracranial AS (ECAS) in hypertensive patients without stroke in Chinese population and to explore modified effect of methylenetetrahydrofolate reductase (MTHFR) C677T on their relationship. The stenosis of intracranial and extracranial arteries were evaluated in a total of 929 subjects through computerized tomographic angiography (CTA) from aortic arch to the skull base. Hcy concentration showed significantly association with both ICAS (OR: 1.105; 95% CI: 1.057-1.155) and ECAS (OR: 1.096; 95% CI: 1.047-1.146) for 1 µmol/L increment in Hcy. Meanwhile, hyperhomocysteinemia (≥15 µmol/L) was also displayed association with ICAS (OR: 1.587; 95% CI: 1.029-2.446) and ECAS (OR: 2.164; 95% CI: 1.392-3.364) after fully adjustment. Furthermore, in the subgroup analysis, such association remained significant only in the subjects that were younger, with normal renal function and with MTHFR 677 C allele. Our study showed the significant association of Hcy with ECAS and ICAS in asymptomatic hypertension patients. Hcy played a universal effect on the cervico-cerebral atherosclerosis. Such association was modified by the MTHFR C677T genotype.

Morning blood pressure (BP) surge is an important aspect of hypertension research. Morning BP monitoring could be a clinically relevant concept in the therapeutic management of hypertension and in the prevention of cardiovascular complications by defining and treating morning hypertension. Because antihypertensive medication is often taken in the morning, uncontrolled morning BP during the trough effect hours could be a hallmark of inadequate choice of antihypertensive regimen, such as the use of short- or intermediate-acting drugs, underdosing of drugs, or no use or underuse of combination therapy. To improve the management of hypertension in general and morning hypertension in particular, long-acting antihypertensive drugs should be used in appropriate, often full dosages and in proper combinations. The clinical usefulness of antihypertensive drugs with specific mechanisms for morning BP or split or timed dosing of long-acting drugs in controlling morning BP remains under investigation., (©2018 Wiley Periodicals, Inc.)

Background: Increased morning blood pressure (BP) has been associated with fatal and nonfatal cardiovascular events, especially in Asians., Method: To detect the control status of home BP, we performed a home BP monitoring study, including elderly patients with hypertension who had controlled documented office BP in Chinese primary care clinics. In 707 participants from Xinzhuang County Hospital in Shanghai, the home BP was measured by a memory-equipped device three times daily for seven consecutive days., Results: The prevalence of uncontrolled hypertension was 51.3% in the morning and 42% in the evening. Uncontrolled morning hypertension was associated with age [odds ratio (OR): 1.074; 95% confidence interval (CI): 1.041-1.108], office SBP (OR: 1.027; 95% CI: 1.015-1.039), office DBP (OR: 1.042; 95% CI: 1.021-1.064), and the number of antihypertensive drugs taken (OR: 1.387; 95% CI: 1.059-1.817), whereas it was inversely associated with the use of long-acting antihypertensive drugs (OR: 0.588; 95% CI: 0.355-0.973). Compared with office BP, the home morning BP showed a more significant association with age and short-acting antihypertensive drugs., Conclusion: The prevalence of uncontrolled home BP is high in elderly Chinese hypertensive patients, especially in the morning, and home BP monitoring might be a feasible method for detecting it. The use of long-acting antihypertensive drugs might help to improve morning hypertension.

Background: Intracranial arterial stenosis is a common cause of ischemic stroke in Asians. We therefore sought to explore the relationship of brachial-ankle pulse wave velocity and intracranial arterial stenosis in 834 stroke-free hypertensive patients., Methods: Intracranial arterial stenosis was evaluated through computerized tomographic angiography. Brachial-ankle pulse wave velocity was measured by an automated cuff device., Results: The top decile of brachial-ankle pulse wave velocity was significantly associated with intracranial arterial stenosis (P = .027, odds ratio = 1.82; 95% confidence interval: 1.07-3.10). The patients with the top decile of brachial-ankle pulse wave velocity showed 56% higher risk for the presence of intracranial arterial stenosis to the whole population, which was more significant in patients younger than 65 years old. We also found that brachial-ankle pulse wave velocity related to both intracranial arterial stenosis and homocysteine., Conclusion: Our study showed the association of brachial-ankle pulse wave velocity with asymptomatic intracranial arterial stenosis in hypertension patients, especially in relative younger subjects. Brachial-ankle pulse wave velocity might be a relatively simple and repeatable measurement to detect hypertension patients in high risk of intracranial arterial stenosis., (Copyright © 2016. Published by Elsevier Inc.)

Inter-arm blood pressure (BP) difference has been associated with ischemic stroke. Local atherosclerosis of stroke differ among vulnerable individuals, whereas intracranial arterial stenosis (ICAS) is more frequently affected Asians, and extracranial arterial stenosis (ECAS) is more prevalent among whites. We hereby sought to explore the association of inter-arm BP difference with ICAS and ECAS in stroke-free hypertensive patients in Chinese population. All the 885 subjects were evaluated of ICAS and ECAS through computerized tomographic angiography. Both arm BP was measured simultaneously by Vascular Profiler-1000 device. In the continuous study, ICAS was significantly associated with age, male, average brachial SBP, diabetes, anti-hypertensive treatment and inter-arm DBP difference. ECAS was associated with age, inter-arm SBP and LDL. In the categorical study, subjects with the top quartile of inter-arm DBP difference (≥4 mmHg) showed significantly higher risk of ICAS (OR = 2.109; 95% CI, 1.24-3.587). And the participants with the top quartile of inter-arm SBP difference (≥6 mmHg) showed significantly higher risk of ECAS (OR = 2.288; 95% CI, 1.309-3.998). In conclusion, we reported a diverse association of inter-arm SBP/DBP difference with the ICAS/ECAS. Inter-arm DBP difference might be the early symbol of ICAS in Chinese population, which need further verification in long-term cohort study.

Background and Purpose: Intracranial arterial stenosis (ICAS) is a common cause of ischemic stroke in Asians, whereas whites tend to have more extracranial lesions. Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been associated with ischemic stroke by a large amount of work. However, there are few studies focusing on the relationship of Lp-PLA2 and asymptomatic ICAS or extracranial arterial stenosis (ECAS). Wehereby sought to explore the relationship of Lp-PLA2 and ICAS, ECAS and concurrent stenosis in stroke-free hypertensive patients in Chinese population., Methods: All the subjects were evaluated for the presence and severity of ICAS and ECAS through computerized tomographic angiography (CTA) covered the whole brain down to the level of aortic arch. Lp-PLA2 mass was measured by enzyme linked immunoassay. The association of Lp-PLA2 and vascular stenosis was analyzed through multivariate logistic regression., Results: Among 414 participants, 163 (39.4%) had no ICAS or ECAS, 63 (15.2%) had ECAS only, 111 (26.8%) had ICAS only and 77 (18.6%) had concurrent extraintracranial stenosis. Lp-PLA2 mass was significantly associated with isolated ICAS (OR: 2.3; 95% CI: 1.14-4.64), and concurrent stenosis (OR: 3.93; 95% CI: 1.62-9.51), but was not related to isolated ECAS (OR: 1.54; 95% CI: 0.68-3.48). Lp-PLA2 mass was also associated with moderate to severe ICAS no matter how was the ECAS. Moreover, patients with higher Lp-PLA2 mass showed more sever ICAS and had more intracranial arterial lesions., Conclusion: This study revealed the association of Lp-PLA2 mass with ICAS in stroke-free hypertensive patients in Chinese population. The further long-term cohort study was warranted to elucidate the concrete effect of Lp-PLA2 on the asymptomatic ICAS.

Importance: Uncertainty remains about the efficacy of folic acid therapy for the primary prevention of stroke because of limited and inconsistent data., Objective: To test the primary hypothesis that therapy with enalapril and folic acid is more effective in reducing first stroke than enalapril alone among Chinese adults with hypertension., Design, Setting, and Participants: The China Stroke Primary Prevention Trial, a randomized, double-blind clinical trial conducted from May 19, 2008, to August 24, 2013, in 32 communities in Jiangsu and Anhui provinces in China. A total of 20,702 adults with hypertension without history of stroke or myocardial infarction (MI) participated in the study., Interventions: Eligible participants, stratified by MTHFR C677T genotypes (CC, CT, and TT), were randomly assigned to receive double-blind daily treatment with a single-pill combination containing enalapril, 10 mg, and folic acid, 0.8 mg (n = 10,348) or a tablet containing enalapril, 10 mg, alone (n = 10,354)., Main Outcomes and Measures: The primary outcome was first stroke. Secondary outcomes included first ischemic stroke; first hemorrhagic stroke; MI; a composite of cardiovascular events consisting of cardiovascular death, MI, and stroke; and all-cause death., Results: During a median treatment duration of 4.5 years, compared with the enalapril alone group, the enalapril-folic acid group had a significant risk reduction in first stroke (2.7% of participants in the enalapril-folic acid group vs 3.4% in the enalapril alone group; hazard ratio [HR], 0.79; 95% CI, 0.68-0.93), first ischemic stroke (2.2% with enalapril-folic acid vs 2.8% with enalapril alone; HR, 0.76; 95% CI, 0.64-0.91), and composite cardiovascular events consisting of cardiovascular death, MI, and stroke (3.1% with enalapril-folic acid vs 3.9% with enalapril alone; HR, 0.80; 95% CI, 0.69-0.92). The risks of hemorrhagic stroke (HR, 0.93; 95% CI, 0.65-1.34), MI (HR, 1.04; 95% CI, 0.60-1.82), and all-cause deaths (HR, 0.94; 95% CI, 0.81-1.10) did not differ significantly between the 2 treatment groups. There were no significant differences between the 2 treatment groups in the frequencies of adverse events., Conclusions and Relevance: Among adults with hypertension in China without a history of stroke or MI, the combined use of enalapril and folic acid, compared with enalapril alone, significantly reduced the risk of first stroke. These findings are consistent with benefits from folate use among adults with hypertension and low baseline folate levels., Trial Registration: clinicaltrials.gov Identifier: NCT00794885.

Background: End-digit preference (EDP) of blood pressure (BP) has been reported in both general hospitals and primary clinics worldwide. We aimed to observe the longitudinal changes in EDP of BP recordings in hypertension patients and to estimate the impact of hypertension treatment target (140/90 mmHg) on the EDP of BP in Chinese primary care clinics., Participants and Methods: A total of 318 898 BP readings from 16 433 hypertensive patients were obtained from the electronic health record of Xinzhuang town hospital in Shanghai from 1 January 2007, to 27 September 2011. The terminal digits of the recorded systolic blood pressure (SBP) and diastolic blood pressure (DBP) were analyzed. Zero preference was also analyzed according to the year and follow-ups, respectively., Results: In all, 62.5% of SBP readings and 63.5% of DBP readings ended in zero. The zero preference of SBP was reduced from the 75.2% in 2007 to 55.9% in 2011. In addition, the zero preference decreased from the 78.6% at the registration to 58.7% at the 25th follow-up. Moreover, compared with other BP levels, hypertension treatment target was associated with increased preference for the eight end-digit for both SBP and DBP (P<0.001)., Conclusion: This study showed a decrease in zero EDP in hypertension patients managed in the Chinese community. The hypertension treatment target was associated with sub-target-EDP. Future efforts should focus on comprehensive education, coupled with the use of well-calibrated electronic BP monitors.

Background and Objectives: The SBP values to be achieved by antihypertensive therapy in order to maximize reduction of cardiovascular outcomes are unknown; neither is it clear whether in patients with a previous cardiovascular event, the optimal values are lower than in the low-to-moderate risk hypertensive patients, or a more cautious blood pressure (BP) reduction should be obtained. Because of the uncertainty whether 'the lower the better' or the 'J-curve' hypothesis is correct, the European Society of Hypertension and the Chinese Hypertension League have promoted a randomized trial comparing antihypertensive treatment strategies aiming at three different SBP targets in hypertensive patients with a recent stroke or transient ischaemic attack. As the optimal level of low-density lipoprotein cholesterol (LDL-C) level is also unknown in these patients, LDL-C-lowering has been included in the design., Protocol Design: The European Society of Hypertension-Chinese Hypertension League Stroke in Hypertension Optimal Treatment trial is a prospective multinational, randomized trial with a 3 × 2 factorial design comparing: three different SBP targets (1, <145-135; 2, <135-125; 3, <125  mmHg); two different LDL-C targets (target A, 2.8-1.8; target B, <1.8  mmol/l). The trial is to be conducted on 7500 patients aged at least 65 years (2500 in Europe, 5000 in China) with hypertension and a stroke or transient ischaemic attack 1-6 months before randomization. Antihypertensive and statin treatments will be initiated or modified using suitable registered agents chosen by the investigators, in order to maintain patients within the randomized SBP and LDL-C windows. All patients will be followed up every 3 months for BP and every 6 months for LDL-C. Ambulatory BP will be measured yearly., Outcomes: Primary outcome is time to stroke (fatal and non-fatal). Important secondary outcomes are: time to first major cardiovascular event; cognitive decline (Montreal Cognitive Assessment) and dementia. All major outcomes will be adjudicated by committees blind to randomized allocation. A Data and Safety Monitoring Board has open access to data and can recommend trial interruption for safety., Sample Size Calculation: It has been calculated that 925 patients would reach the primary outcome after a mean 4-year follow-up, and this should provide at least 80% power to detect a 25% stroke difference between SBP targets and a 20% difference between LDL-C targets.

Lowering blood pressure (BP) in patients with high blood pressure reduces cardiovascular risk. Studies support health benefits when BP goals are achieved earlier in the course of treatment. Many patients require combination therapy to achieve BP goals; initial use of combination therapy may improve earlier BP goal attainment. This analysis reports the results of a search of the Boehringer Ingelheim clinical trial database for randomized, double-blind studies of telmisartan/hydrochlorothiazide (T/H) combination therapy compared with blood pressure monotherapies. Nine studies were identified. This report examined six separate analyses of these nine studies (three analyses of individual trials; three analyses for which two trials each were pooled). The focus of this report is the BP effects of combination T/H therapy compared with respective monotherapies at the earliest available time points (Weeks 1, 2, 3 and/or 4). These analyses included a total of 5,358 patients. During these earlier time periods, combination T/H reduced systolic BP (SBP) and diastolic BP (DBP) significantly more than placebo or respective monotherapies in most treatment comparisons for patients initiated on monotherapy. Combination T/H also allowed significantly more patients to achieve BP (<140/90 mmHg), SBP (<140 mmHg), and DBP (<90 mmHg) goal attainment rates compared with placebo (p < 0.0002), and numerically higher compared with T or H monotherapy. In patients uncontrolled by monotherapy, combination T/H significantly reduced SBP/DBP more than monotherapy (p < 0.0001). Similarly, BP, SBP and DBP goal attainment rates were significantly higher with combination T/H therapy (p < 0.0022). Reported adverse events with T/H therapy were generally similar to monotherapy, and placebo. In summary, the six separate analyses of nine different trials demonstrated that T/H significantly lowered BP as early as 1-4 weeks after initiation of therapy, with greater BP lowering, and greater BP goal attainment than with monotherapies or placebo.

Background: Several evidences have supported the benefits of home blood pressure monitoring (HBPM) in improving hypertension awareness and control. However, little was known about the use of HBPM by hypertensive patients in primary care in China., Materials and Methods: A cross-sectional questionnaire survey on HBPM use was conducted on 1915 hypertensive patients in Xinzhuang County Hospital in Shanghai, and the factors related to regular use of HBPM were also determined., Results: Overall, 1011 of the 1915 participants engaged in using HBPM, among whom 786 individuals used HBPM more than once a month. Of the 1011 HBPM users, 25.42% chose a mercury sphygmomanometer, 33.55% used wrist-cuff electronic devices, and 46.5% selected arm-cuff electronic devices. In addition, 73% of HBPM users reported HBP readings to their general practitioners. Compared with the less frequent users, patients who used HBPM daily were likely to report their blood pressure (BP) values to the doctors depending on notebook or mechanical memory than on their own memories (P<0.001). Moreover, patients with college education were 2.7 times more likely than those with middle school education or less to engage in frequent HBPM use (odds ratio=2.71, 95% confidence interval=2.03-3.61)., Conclusion: This local community survey showed that ∼40% of hypertension patients used HBPM frequently in primary care in China. However, certain patients chose the improper BP monitoring device or questionable reporting methods. Therefore, the use of arm-cuff electric devices with multiple memory storage or a home BP telemonitoring system should be promoted by health education targeted at hypertensive patients.

Objective: To investigate the efficacy and safety of telmisartan 80 mg/amlodipine 5 mg (T80/A5) single-pill combination versus A5 in patients with essential hypertension not adequately controlled on A5 monotherapy., Methods: Asian patients ≥18 years old, with inadequately controlled blood pressure (BP) at enrolment, who failed to achieve a seated diastolic BP (DBP) goal (≥90 mmHg) following 6-weeks' open-label A5 treatment, were randomly allocated 1 : 1 to 8 weeks' double-blind treatment with T80/A5 single-pill combination or A5., Results: A total of 324 patients entered the double-blind treatment phase. The adjusted mean ± SE reduction in seated trough DBP from baseline to week 8 was significantly greater with T80/A5 (12.4 ± 1.0 mmHg) than A5 (10.2 ± 0.9 mmHg [primary endpoint, n = 314]). Results were similar in the subset of 262 Chinese patients. Treatment-related adverse events were 1.9% with T80/A5 and 2.4% with A5., Conclusions: In Asian patients with hypertension, T80/A5 single-pill combination provided improved BP reduction after 8 weeks' treatment compared with A5 monotherapy. Both treatments were well tolerated.

Background: A majority of hypertensives require treatment with ≥2 antihypertensive therapies to achieve blood pressure (BP) goals. Single-pill combinations (SPC) may improve convenience and adherence to therapy and reduce health care resource use and costs. The antihypertensive effects of amlodipine and valsartan are well established. This study evaluated the efficacy and safety of amlodipine/valsartan 5/160 mg SPC for the treatment of hypertension in predominantly Chinese patients not adequately controlled on valsartan 160 mg alone., Methods: In this multicentre study (24 centres), adults with stage 1 or 2 hypertension not adequately controlled with valsartan monotherapy were randomised to receive double-blind amlodipine/valsartan 5/160 mg SPC or valsartan 160 mg once daily for 8 weeks., Results: The least-square mean change (standard error) from baseline to endpoint in mean sitting diastolic blood pressure (MSDBP) at trough, the primary efficacy variable, was -10.3 (0.39) mm Hg with amlodipine/valsartan and -6.6 (0.40) mm Hg with valsartan (difference: -3.7 [0.54] mm Hg, p<0.0001). The corresponding results for mean sitting systolic blood pressure (MSSBP) were -14.9 (0.61) mm Hg and -7.0 (0.61) mm Hg, respectively (difference: -7.9 [0.84] mm Hg, p<0.0001). A significantly greater proportion of patients achieved overall BP control (MSSBP/MSDBP<140/90 mm Hg) with combination therapy (61.3%) versus monotherapy (39.3%; p<0.0001). Both treatments were well tolerated., Conclusion: Amlodipine/valsartan 5/160 mg SPC is a safe and effective therapy for lowering BP in predominantly Chinese adults with stage 1 or 2 hypertension not adequately controlled with valsartan 160 mg monotherapy., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Most studies have suggested that elevated body mass index (BMI) was associated with the risk of death from all cause and from specific causes. However, there was little evidence illustrating the effect of BMI on the mortality in elderly hypertensive patients in Chinese population., Methods: The information of 10,957 hypertensive patients at baseline not less than 60 years were from Xinzhuang, a town in Minhang district of Shanghai, was extracted from the Electronic Health Record (EHR) system. All study participants were divided into eight categories of baseline BMI (with cut-points at 18, 20, 22, 24, 26, 28 and 30 kg/m(2)). Relative hazard ratio of death from all cause, cardiovascular and non-cardiovascular cause by baseline BMI groups were calculated, standardized for sex, age, smoking, drinking, physical activity, systolic blood pressure, history of cardiovascular disorders, serum lipid disturbance, diabetes mellitus and antihypertensive drug treatment., Results: DURING FOLLOW UP (MEDIAN: 3.7 years), 561 deaths occurred. Underweight (BMI<18 kg/m(2)) was associated with significantly increased mortality from all cause mortality (OR: 2.00; 95% CI: 1.43-2.79) and non cardiovascular mortality (OR: 2.76; 95% CI: 1.87-4.07), but not with cardiovascular mortality. For the cause specific analysis, the underweight was associated significantly with neoplasms (OR: 2.15; 95% CI: 1.16-4.00) and respiratory disorders (OR: 3.41; 95% CI: 1.64-7.06). The results for total mortality and specific cause mortality were not influenced by sex, age and smoking status., Conclusion: Our study revealed an association between underweight and increased mortality from non-cardiovascular disorders in elderly hypertensive patients in Chinese community. Overweight and obesity were not associated with all cause or cause specific death.

Background: KCNH2 (hERG) potassium channels have an integral role in regulating the excitability of smooth muscle cells. Some pathways driven by angiotensin II, nitric oxide and adrenergic receptors blocker are involved in modulating the properties of KCNH2 potassium channels. And these pathways are closely related to blood pressure regulation. Therefore, we hypothesized that KCNH2 genetic polymorphisms may affect blood pressure response to the antihypertensive drug therapies., Materials and Methods: To evaluate the interactions between KCNH2 genetic polymorphisms and individual blood pressure response to antihypertensive drugs, 370 subjects with essential hypertension (EH) were studied. In evaluating the interactions between KCNH2 genetic polymorphisms and drug response to blood pressure, multivariable ANOVA analysis followed by Bonferroni correction were carried out., Results: There were statistically significant interactions between KCNH2 (1956, C>T) polymorphism and DBP change (P = 0.010), MAP change (P = 0.014) on azelnidipine or nitrendipine therapy patients at the end of 6 weeks. We found that the KCNH2 (1956,C>T) polymorphism was associated with the hypotensive effects of α,β-ADR blockers of DBP change at the end of 4 and 6 weeks' treatment in an age- and gender-dependent manner (P = 0.007 and 0.019, respectively). Similar results were also observed for changes in MAP at the end of 4 and 6 weeks (P-values were 0.035 and 0.078, respectively). While patients who received imidapril, candesartan and irbesartan therapy, no significant difference in drug response among KCNH2(1956,C>T) genotype was observed., Conclusion: We have reported for the first time that KCNH2 (1956, C>T) polymorphism is associated with efficacy of antihypertensive drugs CCBs and ADR blockers, and may serve as a novel biomarker for individualized therapy for certain antihypertensive drugs.

Genome-wide association studies have identified the ATP2B1 gene associated with blood pressure (BP), the evidence from large scale Chinese population was still rare. We performed the current replication study to test the association of the ATP2B1 gene and hypertension and BP in two unrelated Chinese cohorts including 2,831 unrelated individuals with hypertension and 1,987 controls in total. We also examined the influences of the ATP2B1 gene on the arterial stiffness through evaluation of carotid-femoral pulse wave velocities (cf-PWV) in 164 untreated hypertensives. The major findings of this study were that four loci--rs10858911, rs2681472, rs17249754 and rs1401982--associated with any or all of four traits: hypertension (P = 0.001-4.6E-05; odds ratio, 0.83-0.87), systolic BP (P = 0.003-0.004), diastolic BP (P = 0.002-0.003) and cf-PWV (P = 0.002-0.004). All the comparisons were adjusted for sex, age, age(2) and body mass index. We validated the association of the ATP2B1 gene and susceptibility to hypertension, BP traits and cf-PWV in Chinese population. In addition, further genetic and functional research was warranted to elucidate the concrete locus in the ATP2B1 gene that influenced the manifestation of BP and vascular function.

Background: Patients with grade 2 or 3 hypertension may require high-dose combination therapy to achieve blood pressure (BP) targets in a timely manner., Objectives: This study compared the effectiveness and tolerability of a single-pill combination (SPC) of telmisartan/hydrochlorothiazide 80/25 mg (T80/H25) with T80 monotherapy., Methods: In a Phase IV, multinational, randomized, double-blind, double-dummy, active-controlled, parallel-group trial, 894 patients with mean seated trough cuff systolic BP [SBP] ≥160 mm Hg and diastolic BP [DBP] ≥100 mm Hg were randomly assigned in a 2:1 ratio to receive T40/H12.5 SPC or telmisartan 40 mg monotherapy for 1 week before the dose was uptitrated to T80/H25 SPC or T80, respectively, administered for 6 weeks. The primary efficacy measure was the change from baseline in mean seated cuff trough SBP. Adverse events (AEs) were recorded., Results: A total of 888 patients received treatment (294 and 594 patients in the T80/H25 and T80 groups, respectively) (mean age, 57.0 years; age ≥65 years, 25.7%; male, 53.8%; white, 68.0%); 61 patients prematurely discontinued. Mean baseline SBP/DBP values were 172.3/104.3 mm Hg (T80/H25) and 173.3/104.5 mm Hg (T80). After 7 weeks, SBP was changed by -37.0 and -28.5 mm Hg in the T80/H25 and T80 groups (P < 0.0001); DBP was changed by -18.6 and -15.4 mm Hg respectively (P < 0.0001). These differences were significant after 2 weeks at the higher dosage (P < 0.0001). BP target (SBP/DBP <140/<90 mm Hg) was achieved in 55.5% and 34.7% of patients in the T80/H25 and T80 groups (P < 0.0001). T80/H25 SPC and T80 had a similar frequency of overall AEs (16.0% vs 17.0%). The prevalences of treatment-related AEs with T80/H25 SPC and T80 were low (4.6% and 2.8%), as were the rates of AEs that led to discontinuation (1.0% and 2.8%)., Conclusions: In these patients with grade 2 or 3 hypertension, initial therapy with T80/H25 was associated with a significantly greater reduction in mean seated cuff trough SBP compared with T80 alone, as well as with improved hypertension goal attainment rates. Both treatments appeared to be well tolerated., (Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.)

Arterial stiffness exemplified by the ambulatory arterial stiffness index (AASI) and pulse pressure (PP) predicts cardiovascular morbidity and mortality. The present cross-sectional study assessed the association of renal function with AASI and 24-h PP in hypertensive inpatients. Subjects included 948 hypertensive inpatients with drug treatment (mean age, 53.3 years; male, 67.1%). The AASI was defined as 1 minus the regression slope of diastolic over systolic blood pressure readings obtained from 24-h recordings. Renal function was evaluated by serum creatinine and urinary albumin excretion was expressed by the urinary albumin-to-urinary creatinine ratio (ACR), and estimated glomerular filtration rate (eGFR) was calculated by the modification of diet in renal disease formula and chronic kidney disease-epidemiology collaboration formula. As AASI and 24-h PP increased, serum creatinine concentrations and ACR increased, and eGFR decreased. Multiple linear regression showed that AASI and 24-h PP were associated with eGFR-EPI (B=-12.00, P=0.001 vs. B=-0.14, P=0.002) and ACR (B=0.56, P=0.004 vs. B=0.01, P=0.017) independent of other cardiovascular risk factors. After additional adjustment for 24-h PP, the association of AASI with eGFR-EPI had borderline significance (P=0.053), whereas the significant associations of 24-h PP with serum creatinine and ACR persisted (P=0.009 and P=0.006) after adjusting for confounding factors and AASI. Multiple logistic regression analysis showed that each s.d. increase in 24-h PP (that is, 13 mm Hg) was associated with a higher risk of suffering from microalbuminuria (MA) by 39% (P=0.038) after additional adjustment for AASI. In conclusion, AASI is more closely associated with eGFR compared with 24-h PP in hypertensive inpatients. However, for MA 24-h PP is a better predictor.

Background: Genetic studies in mouse and human suggest that kynureninase activity may influence blood pressure and renal function. The gene coding kynureninase (KYNU) is also located on chromosome band 2q14-q23, where a linkage peak for essential hypertension was previously detected in the Chinese Han population., Methods and Results: After having found no association with common polymorphisms, this study aimed to assess the role of 1 rare variant of KYNU, Arg188Gln, and kynureninase activity in relation to hypertension. Thirty-three of 1124 Chinese patients with hypertension were heterozygous for Arg188Gln, whereas only 14 of 1084 normotensive controls were heterozygous for Arg188Gln (188G1n allele frequency, 0.015 versus 0.006; P=0.0075). A genotype-discordant sibling-pair study was performed in another 924 individuals from 213 families, indicating that 188G1n carriers had higher systolic blood pressure (168.29 ± 24.67 versus 139.00 ± 12.82 mm Hg, P<0.001) and diastolic blood pressure (105.50 ± 14.08 versus 90.75 ± 11.07 mm Hg, P=0.001) than did Arg188 homozygous siblings. The Arg188Gln variant was found to be rarer in 2 other ethnic groups (3 heterozygous among 880 hypertensive French whites and 0 of 90 black Africans with hypertension). The kynureninase activity in plasma was correlated with blood pressure in subjects from hypertensive families (P<0.05). The Kinetic Michaelis constants of 188Gln carriers was lower than that of Arg188 homozygous subjects (0.05 ± 0.02 versus 0.10 ± 0.02 mmol/L, P=0.005). Arg188Gln mutation in vitro also showed less catalytic efficiency than the wild-type KYNU enzyme (maximal reaction velocity/Kinetic Michaelis constant ratio, 0.050 ± 0.012 versus 0.11 ± 0.016 mL/min per mg; P=0.029)., Conclusions: The results show that the rare KYNU variant Arg188Gln affects kynureninase activity and are consistent with the hypothesis that this mutation can predispose to essential hypertension.

Background: Intracranial large artery disease (ICLAD), such as stenosis and calcification, is common in Chinese patients with stroke. However, little is known about ICLAD and its association with large arterial stiffness in hypertensive patients., Methods: We recruited 270 (mean age 61.0 years, 45.6% male) untreated hypertensive patients without stroke from a community in Shanghai, China. ICLAD was detected by computerized tomographic angiography (CTA). Carotid-femoral pulse wave velocity (cf-PWV), office, and 24-h ambulatory pulse pressure (PP) as well as ambulatory arterial stiffness index (AASI) were determined as the measures of arterial stiffness., Results: Among all participants, 26 (9.6%) had concurrent intracranial arterial stenosis and calcification, 11 (4.1%) stenosis only, and 71 (26.3%) calcifications only. After adjustment for age, mean arterial pressure, and other covariables, there was significant difference in cf-PWV (13.1 vs. 13.7 vs. 15.0 m/s; P = 0.0015) and 24-h PP (46.7 vs. 48.8 vs. 55.7 mm Hg; P = 0.0007) between patients with normal vessels (n = 162), with stenosis or calcification (n = 82), and with both lesions (n = 26). Multiple ordinal logistic regression analyses showed that both cf-PWV and 24-h PP were independently associated with ICLAD. Odds ratios (95% confidence interval (CI)) of ICLAD after multivariable and mutually adjustment were 1.51 (1.09-2.10) and 1.46 (1.06-2.01) for 1-s.d. increase in cf-PWV and 24-h PP, respectively. No significant association (P ≥ 0.10) with AASI or office PP was observed in multivariable analysis., Conclusion: Increased arterial stiffness was independently associated with ICLAD. cf-PWV and 24-h PP might be useful in identifying those more likely to have ICLAD among hypertensive patients.

Background: Confirmation of genome wide association (GWA) results in independent samples has recently become new research tendency., Methods: We focused on 8 positive top polymorphisms identified in the to-date largest hypertension GWA study and determined whether these polymorphisms were associated with hypertension among Han Chinese. Genotyping was performed among 548 patients diagnosed with essential hypertension and 560 age- and gender-matched controls using ligase detection reactions method. Statistical analyses were conducted using Logistic regression and genotype risk score., Results: Except for a rare polymorphism (rs653178), no deviation from Hardy-Weinberg equilibrium was observed for genotype distributions of others. There was significant differences in the genotype/allele distribution (P=0.006/P=0.002) of rs16998073 in FGF5 (fibroblast growth factor 5) upstream and the allele distribution (P=0.037) of rs16948048 in ZNF652 (zinc finger protein 652) upstream between hypertensive patients and controls. Strong significance was also noted under assumption of different genetic models for the two coalescent polymorphisms, even after controlling covariates of interest. For example, rs16998073 had a 72% increased risk for hypertension under the co-dominant model (95% confidence interval: 1.20-2.45; P=0.003). However, construction of genetic risk scores on common polymorphisms did not reveal any significance with both hypertension and blood pressure, suggesting that contribution of these polymorphisms to hypertension moderate or small in magnitude., Conclusions: Our results implicate variation in FGF5 and ZNF652 gene upstream regions with altered susceptibility to hypertension in Han Chinese., (Copyright 2010 Elsevier B.V. All rights reserved.)

Background and Objective: We have recently resequenced apelin and AGTRL1 genes to identify candidate polymorphisms in family-based association with hypertension and related phenotypes. In this study, we aimed to determine and replicate these polymorphisms via a larger, independent case-control study in Shanghai Han Chinese., Methods: Two polymorphisms [rs3761581 (A/C) and T-1860C] in apelin gene and two [rs7119375 (G/A), rs10501367 (G/A)] in AGTRL1 gene were genotyped using the TaqMan assay among 969 patients diagnosed with essential hypertension and 980 age and sex-matched controls. Data were analyzed using Haplo.stats program., Results: In single-locus analysis, significant differences were observed in allele distribution of rs3761581 (P = 0.0156) in men and in rs7119375 (P = 0.0488) genotype distribution in women between patients and controls. Haplotype analysis indicated that haplotypes C-C-G-G (in order of T-1860C, rs3761581, rs7119375 and rs10501367) [adjusted odds ratio (ORadjusted) = 1.67, P = 0.0061] and T-A-A-A (ORadjusted = 1.62, P = 0.0008) conferred an increased risk for hypertension after adjustment for age, onset age, body mass index (BMI) and waist-to-hip ratio, whereas haplotype C-C-A-A (ORadjusted = 0.33, P = 0.0048) conferred a protective effect. In women, increased risk for hypertension was seen for haplotypes T-A-G-G (ORadjusted = 1.30, P = 0.0051), C-C-G-G (ORadjusted = 2.86, P < 0.0001), T-A-A-A (ORadjusted = 1.66, P = 0.0003) and C-C-A-A (ORadjusted = 2.65, P < 0.0001), whereas decreased risk was seen for haplotypes C-A-G-G (ORadjusted = 0.48, P < 0.0001) and T-C-G-G (ORadjusted = 0.40, P < 0.0001). Further haplotype-phenotype analyses indicated the robustness of these associations. For example, haplotype T-A-A-A was significantly associated with obesity index (BMI and waist-to-hip ratio) in both sexes and blood pressures in men (P-sim < 0.05)., Conclusion: In this exploratory pilot case-control study, we found robust haplotype-based and haplotype-phenotype associations of four well characterized polymorphisms in apelin-AGTRL1 system with hypertension and related phenotypes.

Background: Essential hypertension (EH) is a common disorder, which can increase the risk for type 2 diabetes (T2D). Calpain-10 (CAPN10) gene was the first candidate gene of T2D identified through genome-wide linkage and positional cloning, but few works have focused on the relationship of CAPN10 with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) in EH patients., Methods: To identify the effect of UCSNP-43 and UCSNP-44 in CAPN10 gene on susceptibility to IFG/IGT, we conducted a case-control study in 961 EH patients with and without IFG/IGT among Han Chinese population. We also evaluated the impact of two SNPs on insulin sensitivity and glucose tolerance estimated through oral glucose tolerance test and renal functions by blood chemical assays., Results: The major findings of this study were that UCSNP-43 displayed higher G120 and AUCg. In addition, UCSNP-44 was found associated with IFG/IGT in EH patients, and associated with increased G30, G60, AUCg, Cederholm index, Scr and eGFR. The haplotype UCSNP-43-44 was detected associated with IFG/IGT susceptibility, G60, G120, I0, AUCg, Scr and eGFR by the linear regression with the adjustment for sex, age, BMI, mean blood pressures and ACEI/ARB treatment., Conclusions: These findings provided some evidence that CAPN10 gene may play an important role in the pathogenesis of IFG/IGT in EH patients., (Copyright 2010 Elsevier B.V. All rights reserved.)

Objective: The antihypertensive efficacy of amlodipine/valsartan combination has not been evaluated in Asian patients as previous large-scale studies enrolled very few patients. This multicentre, randomised, double-blind study assessed the efficacy and safety of a single-pill combination of amlodipine/valsartan versus amlodipine in Asian hypertensive patients., Methods: After a 1-4-week washout period, patients (mean sitting diastolic BP [msDBP]: >or=95-<110 mmHg) were treated with amlodipine 5 mg for 4 weeks. Patients inadequately controlled on amlodipine (msDBP >or=90 and <110 mmHg) were randomised to receive amlodipine/valsartan 5/80 mg (n = 349) or amlodipine 5 mg (n = 349) for 8 weeks. Efficacy variables were change in msDBP, mean sitting systolic BP (msSBP) from baseline (at randomisation) to week 8 endpoint, and BP control rate (<140/90 mmHg) at week 8 endpoint. Safety assessments included monitoring and recording of adverse events (AEs)., Results: Baseline characteristics were comparable between the groups. Most patients were Chinese (86.4%), men (65.1%), with a baseline BP 139.5/94.5 mmHg. At week 8 endpoint, the least square mean reduction in BP was significantly greater with amlodipine/valsartan combination than amlodipine monotherapy (-11.4/-9.7 vs. -7.4/-7.1 mmHg; p < 0.0001) with a higher BP control rate (69.2 vs. 57.6%; p = 0.0013). Ambulatory BP monitoring in a subgroup of patients (n = 82), showed a significant 24-h mean BP reduction from baseline with amlodipine/valsartan (-7.3/-6.3 mmHg; p < 0.0001), whereas the reduction was not significant with amlodipine (-0.2/+0.3 mmHg; p > 0.05). The overall incidence of AEs was similar in both groups. Peripheral oedema occurred only in the amlodipine group n = 4 (1.1%) and not in the amlodipine/valsartan combination. Hypotension was reported in only one patient in the amlodipine/valsartan combination. Six patients (0.9%) experienced serious AEs, of which only one SAE, i.e. gastric ulcer, was reported to be related to amlodipine treatment., Conclusion: The single-pill combination of amlodipine/valsartan was efficacious and well-tolerated in Asian hypertensive patients who were inadequately controlled on amlodipine alone. As with all clinical trials, the entry criteria may limit the extrapolation of these results to a broader population. ClinicalTrials.gov Identifier: NCT00413049.

Background and Objective: Numerous studies have attempted to associate -58C/T polymorphism of bradykinin B2 receptor gene (BDKRB2) with hypertension, whereas results were often irreproducible. We performed a meta-analysis aiming to provide a comprehensive evaluation of this polymorphism and hypertension., Methods: Case-control reports published in English were searched totaling four studies with six populations (823 cases and 916 controls). Random-effects model was applied irrespective of between-study heterogeneity, and study quality was assessed in duplicate., Results: Compared with -58C allele carriers, those with -58T allele had a lower yet nonsignificant risk for hypertension (OR=0.86; 95% CI: 0.68-1.09; P=0.21). Lack of significance persisted after combining those with genotypes -58TC and -58TT together (OR=0.87; 95% CI: 0.67-1.09; P=0.21) or with -58TC and -58CC together (OR=0.75; 95% CI: 0.48-1.18; P=0.22) in association with hypertension. Sensitivity analyses by race indicated that comparison of -58T versus -58C generated a protective effect for hypertension in Asians (OR=0.77; 95% CI: 0.58-1.02; P=0.07) and African-Americans (OR=0.65; 95% CI: 0.43-0.98; P=0.04), but a risk effect in Caucasians (OR=1.22; 95% CI: 0.92-1.61; P=0.17). No publication bias was observed., Conclusions: Our results suggested that -58T allele exhibited a protective effect on hypertension in Asians and African-Americans, yet a risk effect in Caucasians., (Copyright 2009 Elsevier B.V. All rights reserved.)

Our previous study in an isolated population showed an association between a genetic variant in the catalase gene (CAT) and essential hypertension (EH). This study indicates that three variants in the promoter and 5'-UTR region of CAT are predominant in Chinese Han, and they form two major haplotypes. A case-control study showed that the CATH2 haplotype confers susceptibility to EH (Pgenotype=0.0017, and Pallilc=0.00078). Subjects bearing CATH1/CATH2 and CATH2/CATH2 genotypes demonstrated a higher susceptibility to EH than CATH1/CATH1 homozygotes, with odds ratios of 1.474 and 1.625, respectively. Also, CATH1/CATH1 individuals had a later-onset age (P=0.015). Expression analysis using luciferase reporter vectors indicated that the CATH1 haplotype showed a lower transcriptional activity than the haplotype CATH2 (P<0.05 in all four cell lines), and we observed similar results in the endogenous allelic expression ratios of CATH1/CATH2 in cell lines. In contrast, most CATH1 haplotypes showed a higher transcription level than CATH2 haplotypes (10 out of 11 or 90.9%) in blood from normal individuals (P<0.01). We therefore hypothesize that CATH1 and CATH2 may play alternating roles at different level of oxidative stress., ((c) 2009 Wiley-Liss, Inc.)

In an effort to clarify association of an intronic polymorphism BglI in a renin gene with essential hypertension, we performed a meta-analysis of the case-control association studies. Publications in the English language and human subjects were searched in PubMed and EMBASE as of July 10, 2009. A fixed-effects model was applied to pool data in the absence of between-studies heterogeneity, and a random-effects model otherwise. Data and study quality were assessed in duplicate. Publication bias was evaluated using the fail-safe number. From three studies with four populations including 1811 patients with essential hypertension and 1626 controls, we found a significant association of renin BglI B with an increased risk for essential hypertension (OR = 1.25; 95% CI, 1.11 to 1.41; P = 0.0002). In addition, significance persisted after assuming the dominant (OR = 1.30; 95% CI, 1.13 to 1.51; P = 0.0004) mode of inheritance, while no significance was observed for the recessive mode (OR = 1.46; 95% CI, 0.82 to 2.60; P = 0.20). The fail-safe number at the level of 0.05 supported these significant associations. In sum, our meta-analysis expands previous findings by showing that the presence of renin BglI B allele is associated with an increased risk in developing essential hypertension, and this effect might act in a dominant mode of inheritance. Further studies are warranted to fully address questions about the etiologic mechanisms of this positive association.

We performed a meta-analysis in an effort to systematically explore the association between apolipoprotein E (ApoE) epsilon2/epsilon3/epsilon4 polymorphisms and hypertension. We searched for case-control studies in English-language publications performed with human subjects using MEDLINE and included appropriate studies that had been published as of 6 May 2009. Fixed-effects models were used to pool data when between-study heterogeneity was absent, and random-effects models were used otherwise. Data and study quality were assessed in duplicate. Publication bias was assessed by calculating the fail-safe number. From six heterogeneous studies that included a total of 1812 patients with hypertension and 1762 controls, we found that the ApoE epsilon4 allele was significantly associated with hypertension using a random-effects model (odds ratio (OR)=1.79; 95% confidence interval (CI): 1.04 to 1.19; P=0.04). With regard to ApoE genotypes, we observed that the association with hypertension was more prominent when ApoE4/4 was compared with E3/3, with a nearly twofold increased risk identified for the ApoE4/4 genotype using a random-effects model (OR=1.97; 95% CI: 1.11 to 3.52; P=0.02). Furthermore, after restricting our analysis to Asian populations, the contrasts between the risk of hypertension among individuals possessing ApoE epsilon4 vs. epsilon3 and ApoE4/4 vs. ApoE3/3 were positively reinforced, with ORs of 1.97 (95% CI, 0.93 to 4.15; P=0.08) and 2.27 (95% CI, 1.03 to 4.98; P=0.04), respectively. The fail-safe number supported these significant associations at a significance level of 0.05. Taken together, our meta-analysis expands the data available regarding genetic risk factors for hypertension by illustrating that the presence of the ApoE epsilon4 allele is associated with an increased risk of developing hypertension and that it appears to be recessive. Of note, this effect was more pronounced in Asians.

Background: ATP1B1 encodes the beta subunits of Na/K ATPase which plays an important role in maintaining the normal gradients of Na(+) and K(+) across plasma membrane. A recent study demonstrated an association of ATP1B1 genetic variations with blood pressure (BP) in Americans. We aimed to investigate the association between ATP1B1 polymorphisms with BP and hypertension in a Chinese population., Material and Methods: Twelve tag single-nucleotide polymorphisms (SNPs) of ATP1B1 were genotyped in 906 patients with essential hypertension (EH) and 894 normotensives (NT)., Results: None of the selected SNPs was associated with hypertension. However, an overall significant association of haplotypes containing rs1200131, rs1200137, rs3766032, rs3766039 and rs2982468 with hypertension was observed (p=0.032). A common haplotype (G-T-A-C-T) was associated with an increased risk for hypertension (OR(adjusted)=1.717, p=0.033). In NT subjects, rs3766032AA carriers had lower systolic BP (SBP) and diastolic BP (DBP) than AG/GG carriers (SBP, 112.6+/-10.0 mmHg vs. 115.5+/-10.6 mmHg, p<0.05; DBP, 75.1+/-6.8 mmHg vs. 76.8+/-6.0 mmHg, p<0.05), and rs2982468 TT carriers had lower DBP than AT/AA carriers (74.8+/-6.9 mmHg vs. 76.3+/-6.2 mmHg; p<0.01) after correction. In NT subjects, BP showed an overall significant association with haplotypes (p=0.006, for SBP and p=0.036, for DBP)., Conclusion: We conclude that haplotype in ATP1B1 may confer susceptibility to BP regulation and hypertension in this Chinese population.

Objective: We investigated the ambulatory blood pressure (BP) in rural Chinese and compared its characteristics with those reported in other population-based studies., Methods: We enrolled inhabitants from six villages of the JingNing County, China. We recorded the ambulatory BP using 90207 SpaceLabs monitors. Trained physicians measured the conventional BP at the participants' homes. Hypertension was defined as a conventional BP of > or = 140/ > or = 90 mmHg or a condition requiring the intake of antihypertensive drugs. Using MEDLINE, we searched for population-based studies on ambulatory BP monitoring., Results: The 356 participants (12-86 years) included 192 (53.9%) women and 117 (32.9%) hypertensive patients. In all participants, systolic/diastolic BP averaged 129/80 mmHg at home. The ambulatory BP means were 121/77 mmHg over 24 h, 126/81 mmHg during daytime (0800 to 1800 h) and 112/70 mmHg during night-time (2200 to 0400 h). The awake and asleep BPs averaged 126/82 and 112/70 mmHg, respectively. Using previously published definitions of daytime (1000 to 2000 h) and night-time (midnight to 0600 h) instead of those given above, inflated the BP differences with the awake and asleep BPs from 0.4/0.2 to 1.2/1.0 mmHg and from 0.3/0 to 1.4/1.6 mmHg, respectively. Compared with daytime values, conventional BP was 2.7/3.1 mmHg lower in normotensive individuals, but 14.9/1.3 mmHg higher in hypertensive patients. In our normotensive individuals, the whole-day and night-time diastolic BPs were from 1 to 4 mmHg and from 3 to 7 mmHg higher than in five other population studies in Caucasians or Japanese, whereas night-time BP in our participants was 9/5 mmHg lower than in Chinese living in Taiwan., Conclusions: We demonstrated significant differences in the characteristics of the ambulatory blood pressure across Asian and Caucasian populations. To what extent different activity patterns and genetic and environmental factors explain this context-dependency remains to be clarified.

Objective: To investigate the genetic linkage between several cytokine and cytokine-related receptor gene loci and essential hypertension (EH) in Chinese., Methods: Linkage between seven genetic markers and EH in 95 Chinese nuclear families with EH (including 477 subjects) was analyzed using a technique of fluorescence-based gene scan with DNA short tandem repeat loci. These markers were selected from the chromosomal regions nearby eight cytokines and their receptor genes. The two-point non-parametric linkage analysis (NPL), maximum Lod score and transmission/disequilibrium test (TDT) with GENEHUNTER software package were used in this study., Results: Result of TDT showed significant transmission disequilibrium between D14S61 and EH (Chi square 14.29,P=0.00016) although NPL and Lod score revealed no significant linkage (Z=0.78, P>0.05 and Lod score =0.72 respectively) at this locus. No linkage between other loci typed and EH was found by the three genetic analysis methods (P>0.05 or Lod score<-1)., Conclusion: Alleles at D14S61 were of significant transmission disequilibrium in affected siblings. Transforming growth factor beta 3 is 0.1 cM away from D14S61, which suggests that the relationship between genes at or near this regions and EH needs to be further explored.

Objective: To investigate whether linkage between essential hypertension (EH) and genetic loci near renin-angiotensin system, endothelin system, nitric oxide synthase, adrenergic receptor genes in Chinese., Methods: Linkage analysis of thirteen candidate gene loci and EH was performed in 95 Chinese nuclear families including 477 subjects using a technique of fluorescence-based gene scan with DNA short tandem repeat. The markers were selected on the chromosomal regions containing candidate genes regulating vasoactivity. GENEHUNTER package were used for two-point, non-parametric linkage analysis (NPL), maximum Lod score and transmission/disequilibrium test (TDT) in this study., Results: The results of TDT indicated relatively small P values at D1S1678, D3S1744, D4S1604, D13S800, D7S483 and D8S255 (0.01 < P < 0.05). No significant linkages was found at any locus by Lod score and NPL analysis (Lod /= 0.05)., Conclusions: TDT is considered as a sensitive test for detecting linkage disequilibrium. Significant linkage was found at 6 of the 13 loci typed in Chinese nuclear families with hypertension by using TDT, but no evidence suggested linkage of any locus to EH by NPL and Lod score. It is worthwhile to pay attention to chromosomal regions near the loci with small P values.

Objective: To verify the linkage of the candidate regions identified in a previous study (markers D2S168, D2S151, D2S142 on chromosome 2) with hypertension in Chinese families., Methods: A genetic linkage study focused on chromosome 2 was performed on 240 Chinese families containing 856 patients with essential hypertension. A total of 1080 individuals were genotyped using 9 highly polymorphic microsatellite markers around the candidate regions on chromosome 2 with an average spacing of 5 cM. Non-parametric linkage (NPL), parametric linkage analysis and transmission-disequilibrium test (TDT) with the GENEHUNTER software were used to assess evidence for linkage., Results: Linkage of a region on chromosome 2 around D2S151 and D2S142 with hypertension was confirmed by different statistical methods (NPL, LOD score and TDT). However, the linkage of D2S168 could not be replicated in this extension study., Conclusions: The data suggest that a region on chromosome 2 at or near the loci of D2S142 and D2S151 may harbor genes responsible for the development of essential hypertension in Chinese.

Background and Purpose: Intracranial arterial stenosis (ICAS) is a common cause of ischemic stroke in Asians, whereas whites tend to have more extracranial lesions. Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been associated with ischemic stroke by a large amount of work. However, there are few studies focusing on the relationship of Lp-PLA2 and asymptomatic ICAS or extracranial arterial stenosis (ECAS). Wehereby sought to explore the relationship of Lp-PLA2 and ICAS, ECAS and concurrent stenosis in stroke-free hypertensive patients in Chinese population. Methods: All the subjects were evaluated for the presence and severity of ICAS and ECAS through computerized tomographic angiography (CTA) covered the whole brain down to the level of aortic arch. Lp-PLA2 mass was measured by enzyme linked immunoassay. The association of Lp-PLA2 and vascular stenosis was analyzed through multivariate logistic regression. Results: Among 414 participants, 163 (39.4%) had no ICAS or ECAS, 63 (15.2%) had ECAS only, 111 (26.8%) had ICAS only and 77 (18.6%) had concurrent extraintracranial stenosis. Lp-PLA2 mass was significantly associated with isolated ICAS (OR: 2.3; 95% CI: 1.14-4.64), and concurrent stenosis (OR: 3.93; 95% CI: 1.62-9.51), but was not related to isolated ECAS (OR: 1.54; 95% CI: 0.68-3.48). Lp-PLA2 mass was also associated with moderate to severe ICAS no matter how was the ECAS. Moreover, patients with higher Lp-PLA2 mass showed more sever ICAS and had more intracranial arterial lesions. Conclusion: This study revealed the association of Lp-PLA2 mass with ICAS in stroke-free hypertensive patients in Chinese population. The further long-term cohort study was warranted to elucidate the concrete effect of Lp-PLA2 on the asymptomatic ICAS. [ABSTRACT FROM AUTHOR]

Objectives: This study investigates the effects on aortic stiffness and vasodilation by arotinolol and the underlying mechanisms in spontaneously hypertensive rats (SHR). Methods: The vasodilations of rat aortas, renal and mesenteric arteries were evaluated by isometric force recording. Nitric oxide (NO) was measured in human aortic endothelial cells (HAECs) by fluorescent probes. Sixteen-week old SHRs were treated with metoprolol (200 mg·kg-1·d-1), arotinolol (30 mg·kg-1·d-1) for 8 weeks. Central arterial pressure (CAP) and pulse wave velocity (PWV) were evaluated via catheter pressure transducers. Collagen was assessed by immunohistochemistry and biochemistry assay, while endothelial nitric oxide synthase (eNOS) and eNOS phosphorylation (p-eNOS) of HAECs or aortas were analyzed by western blotting. Results: Arotinolol relaxed vascular rings and the relaxations were attenuated by Nω-nitro-L-arginine methyl ester (L-NAME, NO synthase inhibitor) and the absence of endothelium. Furthermore, arotinolol-induced relaxations were attenuated by 4-aminopyridine (4-AP, Kv channels blocker). Arotinolol produced more nitric oxide compared to metoprolol and increased the expression of p-eNOS in HAECs. These results indicated that arotinolol-induced vasodilation involves endothelium-derived NO and Kv channels. The treatement with arotinolol in 8 weeks, but not metoprolol, markedly decreased CAP and PWV. Biochemistry assay and immunohistochemistry showed that aortic collagen depositions in the arotinolol groups were reduced compared with SHRs with metoprolol. Moreover, eNOS phosphorylation was significantly increased in aortinolol-treated SHR compared with SHRs with metoprolol. Conclusions: Arotinolol improves arterial stiffness in SHR, which involved in increasing NO and decreasing collagen contents in large arteries. [ABSTRACT FROM AUTHOR]

Background: KCNH2 (hERG) potassium channels have an integral role in regulating the excitability of smooth muscle cells. Some pathways driven by angiotensin II, nitric oxide and adrenergic receptors blocker are involved in modulating the properties of KCNH2 potassium channels. And these pathways are closely related to blood pressure regulation. Therefore, we hypothesized that KCNH2 genetic polymorphisms may affect blood pressure response to the antihypertensive drug therapies. Materials and Methods: To evaluate the interactions between KCNH2 genetic polymorphisms and individual blood pressure response to antihypertensive drugs, 370 subjects with essential hypertension (EH) were studied. In evaluating the interactions between KCNH2 genetic polymorphisms and drug response to blood pressure, multivariable ANOVA analysis followed by Bonferroni correction were carried out. Results: There were statistically significant interactions between KCNH2 (1956, C>T) polymorphism and DBP change (P = 0.010), MAP change (P = 0.014) on azelnidipine or nitrendipine therapy patients at the end of 6 weeks. We found that the KCNH2 (1956,C>T) polymorphism was associated with the hypotensive effects of α,β-ADR blockers of DBP change at the end of 4 and 6 weeks' treatment in an age- and gender-dependent manner (P = 0.007 and 0.019, respectively). Similar results were also observed for changes in MAP at the end of 4 and 6 weeks (P-values were 0.035 and 0.078, respectively). While patients who received imidapril, candesartan and irbesartan therapy, no significant difference in drug response among KCNH2(1956,C>T) genotype was observed. Conclusion: We have reported for the first time that KCNH2 (1956, C>T) polymorphism is associated with efficacy of antihypertensive drugs CCBs and ADR blockers, and may serve as a novel biomarker for individualized therapy for certain antihypertensive drugs. [ABSTRACT FROM AUTHOR]