Is the rule of halves still relevant today? A cross-sectional analysis of hypertension detection, treatment and control in an urban community Aims: To estimate percentages of patients with undiagnosed hypertension, diagnosed untreated hypertension and diagnosed, treated and uncontrolled hypertension and to identify sociodemographic factors for diagnosed, uncontrolled hypertension and not having a blood pressure (BP) reading recorded. Methods: Data from 320 094 patients aged 18 to less than 80 years from general practices in inner London was analysed using both last recorded BP (blood pressure) and mean BP. Logistic regression models identified factors associated with uncontrolled hypertension and no recorded BP. Results: Twenty-nine thousand, seven hundred and nineteen (9.3%) patients had a recorded diagnosis of hypertension. On the basis of analysis of the last BP value, 14.2% (n = 4207) were untreated and 46.3% (n = 13 749) had uncontrolled hypertension; 10.0% (n = 28 274) without a prior hypertension diagnosis had undiagnosed hypertension. Corresponding values based on mean BP analysis were 8.9% (n = 2367) untreated, 51.5% (n = 13 734) uncontrolled; 4.1% (n = 11 446) undiagnosed. 17.5% (n = 55 960) had no recorded BP value. Black ethnicity was a predictor of uncontrolled hypertension: compared with the White British population, the adjusted odds ratio (AOR) for the Black African population was 1.39 (95% CI: 1.25–1.53) and for the Black Caribbean was 1.31 (95% CI: 1.19–1.45). The White Other group were most likely to have no record of BP measurement (AOR: 1.52; 95% CI: 1.47–1.57); conversely, unrecorded BP was less likely in the Black African (AOR: 0.79; CI: 0.74–0.83) and Black Caribbean (AOR: 0.71; CI: 0.66–0.76) groups, relative to the White British population. Conclusion: In an inner-city, multiethnic population, the ‘rule of halves’ still broadly applies to the diagnosis and control of hypertension, although only a small proportion were untreated. Correspondence to Alice S. Wu, Lambeth CCG, 1, Lower Marsh Street, Lambeth, London SE1 7NT, UK. E-mail: alicewu@nhs.net Received 25 February, 2019 Revised 6 June, 2019 Accepted 14 June, 2019 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.jhypertension.com). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Preeclamptic patient-derived circulating cell-free DNA activates the production of inflammatory cytokines via toll-like receptor 9 signalling in the human placenta Objectives: Preeclampsia, a pregnancy-specific syndrome, is associated with maternal systemic and placental inflammatory responses. Cell-free DNA (cfDNA) and cf-foetal DNA (cffDNA) in the blood are elevated in patients with preeclampsia and act as danger signals. Placenta-derived foetal DNA induces inflammatory responses and pregnancy complications in mice. However, whether extracellular DNA from the placenta really causes inflammatory responses remains unclear. Therefore, we investigated the effect of serum cfDNA and placental cffDNA on inflammatory responses using normal pregnant women and preeclampsia patients. Methods: Sera were taken from normal pregnant women and preeclampsia patients, and human trophoblast cell line Sw.71 cells were treated with serum with or without toll-like receptor 9 (TLR9; a sensor of exogenous DNA) inhibitor and genome elimination reagent. For cffDNA collection, placental tissue from the participants was cultured, and the released cffDNA was administrated to Sw.71 cells. Results: The amount of serum cfDNA was higher in preeclampsia patients than in normal pregnant women. Treatment of preeclampsia serum stimulated inflammatory cytokine secretion, which was inhibited by a genome elimination reagent. Expression levels of TLR9 and amount of cffDNA from the placenta were higher in preeclampsia patients than of normal pregnant women. Preeclampsia-derived cffDNA increased inflammatory cytokine levels compared with normal pregnant derived cffDNA. Conclusion: In human trophoblast cells, preeclampsia patient-derived cfDNA increased inflammatory cytokine levels via TLR9. Preeclampsia placenta released more cffDNA, which stimulated inflammatory cytokine. We suggest that elevated circulating cfDNA and cffDNA induces placental inflammatory responses, resulting in accelerated pathological features of preeclampsia. Correspondence to Koumei Shirasuna, PhD, Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, 1737 Funako, Atsugi, Kanagawa 234-0034, Japan. Tel: +81 46 270 6588; fax: +81 46 247 4338; e-mail: ks205312@nodai.ac.jp Received 18 December, 2018 Revised 27 April, 2019 Accepted 10 July, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Renal damage in primary aldosteronism: a systematic review and meta-analysis Objectives: In experimental animal models, exogenous aldosterone excess has been linked to the progression of renal disease. However, the evidence of an increased risk of renal damage in patients affected by primary aldosteronism remains controversial. We aimed at evaluating the association between primary aldosteronism and renal damage through a meta-analysis. Methods: We performed a quantitative review of studies evaluating parameters of renal function in patients affected by primary aldosteronism compared with hypertensive patients without primary aldosteronism and in patients affected by primary aldosteronism before and after treatment. We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from January 1960 up to April 2019. Results: Forty-six studies including 6056 patients with primary aldosteronism and 9733 patients affected by arterial hypertension without primary aldosteronism were included. After 8.5 years from hypertension diagnosis, patients with primary aldosteronism had an increased estimated glomerular filtration rate (eGFR) compared with hypertensive patients without primary aldosteronism [by 3.37 ml/min IQR (0.82–5.93)] and a more severe albuminuria [standard mean difference 0.55 (0.19–0.91)], resulting into an association with microalbuminuria [odds ratio (OR) 2.09 (1.40; 3.12)] and proteinuria [OR 2.68 (1.89;3.79)]. Following primary aldosteronism treatment, after a median follow-up of 12 months, a reduction in eGFR was observed [by −10.69 ml/min (−13.23; −8.16)], consistent in both medically and surgically treated patients. Similarly, a reduction in albumin excretion and an increase in serum creatinine were observed after treatment. Conclusion: Patients affected by primary aldosteronism, compared with patients affected by arterial hypertension without primary aldosteronism, display a more pronounced target organ damage, which can be mitigated by the specific treatment. Correspondence to Silvia Monticone, MD, PhD, Division of Internal Medicine and Hypertension, Department of Medical Sciences, University of Torino, Via Genova 3, 10126, Torino, Italy. Tel: +39 116336997; fax: +39 116336931; e-mail: silvia.monticone@unito.it Received 4 April, 2019 Revised 15 July, 2019 Accepted 19 July, 2019 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.jhypertension.com). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The impact of glycated hemoglobin on risk of hypertension: a Mendelian randomization study using UK Biobank Background: Observational studies suggest higher glycated hemoglobin (HbA1c) associated with higher hypertension risk although these associations could be confounded. We examined the relation using a Mendelian randomization design in a large Biobank, the UK Biobank. Methods: We identified 38 single nucleotide polymorphisms (SNPs) strongly and independently related to HbA1c from a large genome wide association study (n = 123 665) and applied them to the UK Biobank (n = 376 644). We used inverse variance weighting (IVW) to assess the relation of HbA1c with risk of hypertension (defined using the American College of Cardiology/American Heart Association 2017 guidelines), and SBP and DBP. Sensitivity analyses included Mendelian randomization-Egger, weighted median, Mendelian randomization pleiotropy residual sum and outlier and exclusion of pleiotropic SNPs. Results: HbA1c was not clearly associated with hypertension risk using IVW (odds ratio 1.11, 95% confidence interval 0.76–1.62) in the main analysis. However, Mendelian randomization pleiotropy residual sum and outlier suggested potential horizontal pleiotropy. After excluding potentially invalid SNPs, HbA1c was associated with hypertension risk (IVW odds ratio 1.22 per %, 95% confidence interval 1.01–1.46), with consistent estimates from sensitivity analyses. HbA1c was positively associated with SBP in some, but not all analyses, albeit with directionally consistent estimates. The relation with DBP was unclear. Conclusion: Our study suggests HbA1c may increase hypertension risk and could be one underlying mechanistic pathway between HbA1c and coronary artery disease risk. Correspondence to Shiu L. Au Yeung, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 7 Sassoon Road, Pokfulam, Hong Kong SAR, People's Republic of China. Tel: +852 3917 6740; fax: +852 3520 1945; e-mail: ayslryan@hku.hk Received 22 February, 2019 Revised 27 June, 2019 Accepted 14 July, 2019 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.jhypertension.com). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The association of smoothness index of central blood pressure with ambulatory carotid femoral pulse wave velocity after 20-week treatment with losartan in combination with amlodipine versus hydrochlorothiazide Objectives: The aim of this study was to identify associations between the smoothness index of central SBP (CSBP) and changes of ambulatory carotid femoral pulse wave velocity in response to 20-week treatments with losartan and amlodipine vs. losartan and hydrochlorthiazide combinations. Methods: For 142 (losartan and hydrochlorthiazide: 72, losartan and hydrochlorthiazide: 70) patients examined with ambulatory central blood pressure (BP) monitoring device, we calculated smoothness indices and trough-to-peak ratios of brachial SBP, CSBP, ambulatory pulse pressure amplification (APPA), ambulatory augmentation index at heart rate 75 beats per minute (AAIx75) and ambulatory carotid femoral pulse wave velocity (AcfPWV). Results: Mean age was 58.9 ± 12.3 years, and women accounted for 25.9%. Changes in office SBP/DBP were not different between groups (losartan and hydrochlorthiazide: −15.2 ± 15.0/−7.8 ± 8.0 vs. losartan and amlodipine: −14.9 ± 13.7/−9.2 ± 7.5 mmHg). Reduction of 24-h CSBP was not significantly different (losartan and hydrochlorthiazide: 6.4 ± 1.1 vs. losartan and amlodipine: 9.2 ± 1.1 mmHg, P = 0.074). Reduction in nocturnal AcfPWV was greater in the losartan and amlodipine group (losartan and hydrochlorthiazide: 0.09 ± 0.05 vs. losartan and amlodipine: 0.26 ± 0.05 m/s, P = 0.0216). Intraindividual SIs for CSBP were higher in the losartan and amlodipine group (0.40 ± 0.57 vs. 0.65 ± 0.74, P = 0.022). In multivariable regression analysis, smoothness index of CSBP was independently associated with the losartan and amlodipine group. In model additionally considering the changes in arterial stiffness, decrease in AcfPWV instead of the treatment group was independently associated with smoothness indices. In mediation analysis, smoothness index was fully mediated by reduction in night-time AcfPWV. Conclusion: Losartan and amlodipine combination was superior to the losartan and hydrochlorthiazide combination in terms of achieving higher smoothness index for CSBP after 20-week treatments. The effect of losartan and amlodipine on smoothness index was fully mediated by reduction of night-time AcfPWV. Correspondence to Chong-Jin Kim, Kyunghee University Hospital at Gangdong, Seoul, 05278 South Korea. Tel: +82 10 3280 1804; fax: +82 2 968 7250; e-mail: chongjinkim@naver.com Received 27 June, 2019 Accepted 3 July, 2019 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.jhypertension.com). This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Association between invasively measured aortic pulse pressure and orthostatic hypotension in patients undergoing invasive coronary angiography Objective: Underlying pathophysiology of orthostatic hypotension has been poorly understood. We hypothesized that aortic pulse pressure (APP) reflecting aortic stiffness may be involved in the development of orthostatic hypotension. Methods: A total of 200 patients (age 64.3 ± 10.9 years, 62.5% men) who underwent invasive coronary angiography (ICA) were prospectively recruited. Orthostatic hypotension was defined as SBP drop at least 20 mmHg or DBP drop at least 10 mmHg within 3 min of the standing position compared with the supine position. Hemodynamic parameters were measured at the ascending aorta using a pig-tail catheter immediately before ICA. APP was calculated as a difference between the aortic peak systolic pressure and the end-diastolic pressure. Results: A total of 156 patients (78.0%) had obstructive coronary artery disease on ICA. Orthostatic hypotension was present in 58 patients (29.0%). Diabetes mellitus was more prevalent in patients with orthostatic hypotension than those without (48.3 vs. 23.2%; P < 0.001). Other clinical parameters including age, cardiovascular risk factors, laboratory findings and concomitant medications were not different between patients with and without orthostatic hypotension (P > 0.05 for each). In hemodynamic parameters, APP was higher in patients with orthostatic hypotension than those without (78.4 ± 25.8 vs. 68.3 ± 21.3 mmHg; P = 0.005). Higher APP was significantly associated with the presence of orthostatic hypotension even after controlling for potential confounders (odds ratio, 2.99; 95% confidence interval 1.15–7.78; P = 0.025). Conclusion: In patients undergoing ICA, APP was associated with increased risk of orthostatic hypotension. Central aortic stiffness may play a role in the development of orthostatic hypotension. Correspondence to Myung-A Kim, MD, PhD, Division of Cardiology, Department of Internal Medicine, Seoul National University College of Medicine, Boramae Medical Center, 20, Boramae-ro 5-gil, Dongjak-gu, Seoul 07061, Republic of Korea. Tel: +82 2 870 2213; fax: +82 2 870 3866; e-mail: kma@snu.ac.kr Received 5 November, 2018 Revised 26 February, 2019 Accepted 12 March, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

β2AR-dependent signaling contributes to in-vivo reendothelialization capacity of endothelial progenitor cells by shear stress Background: Endothelial progenitor cells (EPCs) play a crucial role in the endothelial repair after arterial injury. Shear stress has a beneficial effect on modulating EPC functions. The molecular mechanism underlying the influence of EPCs on the endothelial integrity and shear stress effects on EPC regulation remained unclear. Herein, we investigated the influence of β2 adrenergic receptor (β2AR)-dependent signaling on in-vitro shear stress-mediated function and in-vivo reendothelialization capacity of human EPCs. Method: The human EPCs from healthy population were exposed to in-vitro 5, 10, and 20 dyn/cm2 shear stress for 15 h, and 10 dyn/cm2 for 5, 10, and 15 h, respectively. The in-vitro proliferation was assessed by CCK8 and BrDU tests. The migration and adhesion were evaluated by Transwell system and human umbilical vein endothelial cells (HUVECs) incorporation assays. Meanwhile, the angiogenic cytokine stromal derived factor-1 (SDF-1) and vascular endothelial growth factor (VEGF) concentration of supernatant were tested by ELISA. Phosphorylated β2AR, Akt, and eNOS were detected by western blot. In an in-vivo study, mice carotid injury models were produced through denuding the endothelium with a curved flexible wire, and thereafter CM-Dil-labeled EPCs were injected intravenously. After 3 days, cells recruited to the injury sites were detected by fluorescent microscopy, and the in-vivo reendothelialization capacity was assessed by Evans blue dye. Results: Shear stress improved in-vitro functions and in-vivo reendothelialization capacity of human EPCs. In parallel, shear stress up-regulated the phosphorylation of β2AR, Akt, and eNOS, and promoted vascular endothelial growth factor (VEGF) secretion of human EPCs. With ICI118,551 (a β2AR inhibitor) treatment, shear stress-induced Akt and eNOS phosphorylation as well as VEGF secretion were suppressed. After β2AR/PI3K/Akt/eNOS pathway of EPCs was blocked, the effects of shear stress on in-vitro functions and in-vivo reendothelialization capacity of EPCs were inhibited. Conclusion: The present study provided the novel data that shear stress-induced β2AR/Akt/eNOS pathway enhanced reendothelialization capacity of EPCs. Shear stress-induced β2AR-dependent pathway may be a novel and important therapeutic target for endothelial repair. Correspondence to Changnong Peng, Department of Cardiology, Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen & Shenzhen Sun Yat-sen Cardiovascular Hospital, Shenzhen 518057, China, E-mail pengchangnong1965@163.com. Received 5 January, 2019 Revised 20 June, 2019 Accepted 3 July, 2019 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.jhypertension.com). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Plasminogen activator inhibitor-1 activity and the 4G/5G polymorphism are prospectively associated with blood pressure and hypertension status Objectives: Plasminogen activator inhibitor-1 (PAI-1) has consistently shown positive associations with blood pressure (BP). Whether elevations in PAI-1 levels precede or result from raised BP is still under debate and data on prospective studies are limited. Hence, we investigated the prospective associations of PAI-1 and the 4G/5G polymorphism with brachial and central BP and pulse pressure (PP) over a 10-year period. Methods: Black South Africans aged 30 years and older were included. Baseline data collection commenced in 2005 (n = 2010) with follow-up data collection in 2010 (n = 1288) and 2015 (n = 926). Plasma PAI-1 activity (PAI-1act), 4G/5G polymorphism genotyping, waist circumference and BP measurements were performed and analysed using sequential regression and mixed models. Results: In multivariable adjusted analyses, PAI-1act and the 4G/4G (vs. the 5G/5G) genotype increased the odds of developing hypertension in the total group [1.04 (1.01; 1.08) and 1.82 (1.07; 3.12) respectively]. Furthermore, PAI-1act was prospectively associated with brachial SBP (r = 0.0815) and PP (r = 0.0832) in the total group, and with central PP in women (r = 0.1125; all P < 0.05). Addition of waist circumference to the models either decreased or nullified the contribution of PAI-1act to BP and hypertension development. Conclusion: PAI-1act and the 4G/4G (vs. the 5G/5G) genotype increased the odds of developing hypertension. Furthermore, PAI-1act associated prospectively with both brachial and central BP. These associations were mediated in part by central adiposity. The study supports the hypothesis that PAI-1 also contributes to hypertension development rather than solely being a consequence thereof. Correspondence to Professor Aletta E. Schutte, Hypertension in Africa Research Team, North-West University, Private Bag X1290, Potchefstroom 2520, South Africa. Tel: +27 (0)18 299 2444; fax: +27 (0)18 285 2432; e-mail: Alta.Schutte@nwu.ac.za Received 1 March, 2019 Revised 31 May, 2019 Accepted 3 July, 2019 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.jhypertension.com). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Collagen biomarkers are associated with decline in renal function independently of blood pressure and other cardiovascular risk factors: the Multi-Ethnic Study of Atherosclerosis Study Objective: We studied associations of circulating collagen type I carboxy-terminal telopeptide (ICTP) and procollagen type III N-terminal propeptide (PIIINP) with long-term renal function decline. Methods: In the Multi-Ethnic Study of Atherosclerosis, we included 2492 participants initially aged 45–84 years and free of clinical cardiovascular disease (CVD), excluding people with estimated glomerular filtration rate (eGFR) less than 60 ml/min per 1.73 m2 or urine albumin/creatinine (UAC) at least 30 mg/g. The primary outcome in median 9.4-year follow-up was renal function decline (≥30% decline in eGFR between any two exams or incident UAC ≥ 30 mg/g). The associations of baseline plasma ICTP and PIIINP with renal function decline were estimated using Poisson regression, adjusting for baseline variables race/ethnicity, sex, age, and continuous eGFR and UAC, with further adjustment for CVD risk factors and medications. Results: Baseline serum ICTP was 3.27 ± 1.43 μg/l and PIIINP was 5.43 ± 1.85 μg/l. Mean baseline eGFR was 91.5 ± 18.4 ml/min per 1.73 m2. Renal function decline occurred in 19.5% during 9.4-year follow-up. The renal function decline outcome was positively associated with serum ICTP and PIIINP: relative incidence density (95% confidence interval) per SD 1.22 (1.11–1.33) and 1.27 (1.16–1.40), respectively. Additional adjustment for other risk factors did not greatly alter findings. Conclusion: High collagen biomarker concentrations in serum were associated with future decline in renal function in people initially free of CVD and with normal eGFR, consistent with collagen production signaling renal decline. The continuous association observed for ICTP which, unlike PIIINP, is filtered by the kidney, may owe to its double status as a sensitive marker of glomerular function and collagen degradation. Correspondence to Daniel A. Duprez, MD, PhD, Cardiovascular Division Medical School, University of Minnesota, 420 Delaware St SE, MMC 508, Minneapolis, MN 55455, USA. Tel: +1 612 624 4948; fax: +1 612 626 4411; e-mail: dupre007@umn.edu Received 24 March, 2019 Revised 22 June, 2019 Accepted 9 July, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Association between dietary carotenoid intakes and hypertension in adults: National Health and Nutrition Examination Survey 2007–2014 Objective: Few epidemiological studies concentrated on dietary carotenoids and hypertension since new hypertension guideline released in 2017. Thus, this study was aimed to evaluate their association. Methods: Data from National Health and Nutrition Examination Survey (NHANES) 2007–2014 were used in this cross-sectional study. Dietary carotenoids data were obtained from 24-h dietary recall interviews. Hypertension was defined as SBP at least 130 mmHg or DBP at least 80 mmHg, taking antihypertensive medicine or self-report. Logistic regression models and restricted cubic spline models were applied to explore the associations between α-carotene, β-carotene, β-cryptoxanthin, lycopene, lutein with zeaxanthin, and total carotenoids from diet and supplements and hypertension. Total carotenoids showed significant reductive risk of hypertension at 100 μg/kg per day and over. Results: A total of 17 398 adults aged 20 years and over were identified. High dose of β-carotene, lycopene, lutein with zeaxanthin, and total carotenoids were significantly associated with decreased risk of hypertension in crude results. After multivariate-adjustment in model 2, the odds ratios (OR) with 95% confidence intervals (CI) of β-cryptoxanthin, lycopene, lutein with zeaxanthin and total carotenoids for hypertension were 0.79 (0.67–0.93), 0.85 (0.73–0.98), 0.69 (0.58–0.83), 0.73 (0.62–0.86) for the highest versus lowest quartile intakes, respectively. Dose–response analyses showed that all of the carotenoids were inversely associated with hypertension in a linear manner. Total carotenoids showed significant effect of lower risk of hypertension at 100 μg/kg per day. Conclusion: Intakes of α-carotene, β-carotene, β-cryptoxanthin, lycopene, lutein with zeaxanthin, and total carotenoids were inversely associated with hypertension in US adults. The intake of total carotenoids was suggested at least 100 μg/kg per day for general adult population. Correspondence to Dongfeng Zhang, Department of Epidemiology and health Statistics, The College of Public Health of Qingdao University, No. 38 Dengzhou Road, Qingdao 266021, China. Tel: +86 53282991712; fax: +86 53283801449; e-mail: zhangdf1961@126.com,zhangdf1962@aliyun.com Received 17 May, 2019 Revised 3 July, 2019 Accepted 3 July, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.