Acute vascular effects of vascular endothelial growth factor inhibition in the forearm arterial circulation Objective: Although vascular endothelial growth factor inhibition (VEGFi) represents a major therapeutic advance in oncology, it is associated with hypertension and adverse vascular thrombotic events. Our objective was to determine whether VEGFi caused direct vascular dysfunction through increased endothelin-1 (ET-1) activity or impaired endothelial vasomotor or fibrinolytic function. Methods: Using forearm venous occlusion plethysmography, we measured forearm blood flow during intra-arterial infusions of bevacizumab (36–144 μg/dl forearm volume per minute) administered for 15–60 min in healthy volunteers (n = 6–8). On two separate occasions in 10 healthy volunteers, we further measured forearm blood flow and tissue plasminogen activator (t-PA) release during intra-arterial bradykinin infusion (100 and 1000 pmol/min) in the presence and absence of bevacizumab (144 μg/dl forearm volume per minute), and the presence and absence of endothelin A receptor antagonism with BQ-123 (10 nmol/min). Plasma t-PA and plasminogen activator inhibitor-1 (PAI-1) concentrations were measured at baseline and with each dose of bradykinin. Results: Baseline blood flow and plasma ET-1, t-PA and PAI-1 concentrations were unaffected by bevacizumab. Bradykinin caused dose-dependent vasodilatation (P < 0.0001) and t-PA release (P < 0.01) but had no effect on plasma PAI-1 concentrations. Neither bevacizumab nor BQ-123 affected bradykinin-induced vasodilatation and t-PA release. Conclusion: Acute exposure to bevacizumab does not directly cause endothelial vasomotor or fibrinolytic dysfunction in healthy young volunteers. Correspondence to Dr Alan C. Cameron, BSc (Hons), MB ChB, MRCP, BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom. Tel: +44 141 330 8271; fax: +44 141 330 3360; e-mail: alan.cameron.2@glasgow.ac.uk. Received 4 June, 2019 Revised 1 August, 2019 Accepted 1 August, 2019 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Clinical characteristics, antihypertensive medication use and blood pressure control among patients with treatment-resistant hypertension: the Survey of PatIents with treatment ResIstant hyperTension study Objective: We evaluated the characteristics of patients with treatment-resistant hypertension (TRH) and the prevalence of TRH in a large multicountry sample of specialist tertiary centres. Methods: The Survey of PatIents with treatment ResIstant hyperTension (SPIRIT) study was a retrospective review of medical records of patients seen at tertiary centres located in Western Europe, Eastern Europe, North America, South America, Australia and Asia. Data on demographics, medical history and medication use were extracted from medical records. Prevalence and incidence of TRH were based upon estimated catchment populations. Results: On thousand, five hundred and fifty-five patients from 76 centres were included, mostly from centres that specialize in hypertension (55%), cardiology (11%) or nephrology (19%). Mean age was 64, 60% were men, 62% were Caucasian, 36% had chronic kidney disease, 41% had diabetes, 12% were smokers and 31% had a previous cardiovascular event. Daytime and night-time ambulatory blood pressure (BP) was the most frequently used measurement for diagnosis (82%). Ninety-five percent of patients were prescribed diuretics, 93% an inhibitor of the renin–angiotensin system, 86% a calcium channel blocker, 74% a beta-blocker and 36% an aldosterone antagonist. The overall estimated mean incidence of TRH was 5.8 per 100 000 per year (ranging between 2.3 and 14.0 across regions) and the corresponding estimated mean prevalence of TRH was 23.9 per 100 000 (ranging between 7.6 and 90.5 across regions). Conclusion: Observed variation likely reflects real differences in patient characteristics and physician management practices across regions and specialities but may also reflect differences in patient selection and errors in estimation of catchment population across participating centres. Correspondence to Professor John Chalmers, MD, PhD, The George Institute for Global Health, Level 10, King George V Building, 83-117 Missenden Road, Camperdown, NSW 2050, Australia. E-mail: chalmers@georgeinstitute.org.au Received 14 December, 2018 Revised 16 May, 2019 Accepted 6 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.

Hypertensive emergencies and urgencies: a single-centre experience in Northern Italy 2008–2015 Background: An increasing attention is given to emergency departments (EDs) admissions for an acute and severe rise in blood pressure (BP). Data on epidemiology and treatment of hypertensive emergencies and urgencies admitted to ED are still limited. The aim of our study was to evaluate the prevalence, clinical presentation and treatment of patients admitted for hypertensive emergencies or hypertensive urgencies. Methods: Medical records of consecutive patients aged at least 18 years, admitted to the ED of the Spedali Civili in Brescia in 2008 and in 2015 and presenting with SBP at least 180 mmHg and/or DBP at least 120 mmHg were prospectively collected and analysed. Results: The prevalence of patients admitted with acute BP rise was 2.0% (n = 1551, age 70 ± 14 years) in 2008 and 1.75% (n = 1214, age 69.7 ± 15 years) in 2015. According to the clinical presentation and the presence of acute organ damage, patients were defined hypertensive emergencies (20.4 and 15.4%, respectively, in 2008 and 2015) or as hypertensive urgencies (79.6 and 84.5%, respectively, in 2008 and 2015). SBP and DBP values were higher in patients with emergencies than in those with urgencies (BP 193 ± 15/102 ± 15 vs. 189 ± 13/96 ± 13 mmHg in 2008 and 192 ± 17/98 ± 15 vs. 189 ± 12/94 ± 15 mmHg in 2015, P < 0.001 for both). Among hypertensive emergencies, the different forms of organ damage were 25% acute coronary syndromes and 1% aortic dissection in both periods, 34 and 38% acute heart failure, 40 and 37% stroke. Conclusion: Admission to the ED for hypertensive emergencies and hypertensive urgencies is still high. Diagnosis and treatment are still not appropriate and require the rapid application of recently published guidelines. Correspondence to Maria Lorenza Muiesan, Department of Clinical & Experimental Sciences, University of Brescia, Department of Internal Medicine, ASST Spedali Civili di Brescia, Piazzale Spedali Civili n 1, Brescia 25123, Italy. Tel: +39 030 3998721; fax: +39 030 3388147; e-mail: marialorenza.muiesan@unibs.it Received 23 May, 2019 Revised 3 July, 2019 Accepted 15 July, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Highlights of the October issue No abstract available

Blood pressure measurement in atrial fibrillation: review and meta-analysis of evidence on accuracy and clinical relevance Atrial fibrillation (AF) often coexists with hypertension in the elderly and multiplies the risk of stroke and death. Blood pressure (BP) measurement in patients with AF is difficult and uncertain and has been a classic exclusion criterion in hypertension clinical trials leading to limited research data. This article reviews the evidence on the accuracy of BP measurement in AF performed using different methods (office, ambulatory, home) and devices (auscultatory, oscillometric) and its clinical relevance in predicting cardiovascular damage. The current evidence suggests the following: (i) Interobserver and intra-observer variation in auscultatory BP measurement is increased in AF because of increased beat-to-beat BP variability and triplicate measurement is required; (ii) The evidence from validation studies of automated electronic BP monitors in AF is limited and methodologically heterogeneous and suggests reasonable accuracy in measuring SBP and a small yet consistent overestimation of DBP; (iii) 24-h ambulatory BP monitoring is feasible in AF, with similar proportion of errors as in individuals without AF; (iv) both auscultatory and automated oscillometric BP measurements appear to be clinically relevant in AF, providing similar associations with intra-arterial BP measurements and with indices of preclinical cardiac damage as in patients without AF, and predict cardiovascular events and death; (v) Screening for AF in the elderly using an AF-specific algorithm during routine automated office, home or ambulatory BP measurement has high diagnostic accuracy. In conclusion, in AF patients, BP measurement is important, reliable, and clinically relevant and should not be neglected in clinical research and in practice. Correspondence to Professor George S. Stergiou, MD, FRCP, Hypertension Center STRIDE-7, National and Kapodistrian University of Athens, School of Medicine, Third Department of Medicine, Sotiria Hospital, 152 Mesogion Avenue, Athens 11527, Greece. Tel: +30 2107763117; fax: +30 2107719981; e-mail: gstergi@med.uoa.gr Received 8 June, 2019 Accepted 3 July, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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.