Aspirin enhances trophoblast invasion and represses soluble fms-like tyrosine kinase 1 production: a putative mechanism for preventing preeclampsia Objective: Recent studies suggested that prophylactic aspirin prior to 16 weeks of gestation in high-risk patients may reduce the risk of developing preeclampsia; however, the exact mechanism of aspirin's effect on the pathophysiology of preeclampsia is not clear. This study was designed to investigate the effect of aspirin on trophoblast cell function and its effect on soluble fms-like tyrosine kinase 1 (sFlt-1) production to elucidate the preventive mechanisms for preeclampsia. Methods and results: We used two human trophoblastic cell lines (HTR-8/SVneo and JAR) and freshly isolated cytotrophoblasts from normal and preeclamptic placenta at term to determine the effect of aspirin on trophoblast cell function. Trophoblasts were pretreated with aspirin, and then cell functions and sFlt-1 expression were assessed. Our results showed that aspirin promoted trophoblast invasion not only in HTR-8/SVneo and JAR cells, but also in isolated cytotrophoblasts. sFlt-1 production was repressed by aspirin in a dose-dependent manner. By adding Flt-1 recombinant protein, the trophoblast invasion ability was inhibited in HTR-8/SVneo cells, which was reversed by Flt-1 small interfering ribonucleic acid knockdown. In addition, metalloproteinase 2/9 expression and activity were activated by aspirin but inhibited by sFlt-1. Aspirin also downregulated Akt phosphorylation, and trophoblast invasiveness was facilitated under Akt inhibitor treatment. Conclusion: Aspirin enhances cell invasiveness and inhibits sFlt-1 production in trophoblasts. Moreover, sFlt-1 itself also inhibits trophoblast invasion. Our novel findings suggest that the preeclampsia prevention effect of aspirin may be exerted through these two mechanisms. Correspondence to Mei-Tsz Su, MD, PhD, Division of Genetics, Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan 704, Taiwan. Fax: +886 6 276 6185; e-mail: sumeitsz@mail.ncku.edu.tw Received 16 October, 2018 Revised 19 April, 2019 Accepted 8 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.

Linear periodization of strength training in blocks attenuates hypertension and diastolic dysfunction with normalization of myocardial collagen content in spontaneously hypertensive rats Background and method: This study evaluated the effects of a linear block strength training programme on the parameters of cardiac remodelling in spontaneously hypertensive rats. Thirty-nine rats were equally distributed in four groups: normotensive sedentary (N), normotensive trained, hypertensive sedentary (H) and hypertensive trained. The strength training protocol was organized in three mesocycles of 4 weeks, with an increase in the training load organized in a linear fashion for each block, considering the weight established in the maximum loaded load test. The following parameters were evaluated: ventricular function assessed by echocardiogram, caudal blood pressure, ventricular haemodynamics and cardiac masses. Two-way analysis of variance was used to determine the differences between the group and time. Results: After 12 weeks of training, the hypertensive trained group presented the following results: increased muscle strength, reduced blood pressure, reduced heart rate, isovolumetric relaxation time and total collagen content, with increased cardiac function, without promoting changes in the mass and nuclear volume of cardiomyocytes. Also, blood pressure reduction seems to be associated with both muscle strength adjustments and total load progress. Conclusion: The findings of this study showed that the training programme carried out attenuated systemic arterial pressure and preserved the ventricular function of spontaneously hypertensive rats without cardiac mass change. Correspondence to Danilo S. Bocalini, PhD, Experimental Physiology and Biochemistry Laboratory, Physical Education and Sports Center of the Federal University of Espirito Santo, Rua Ludwik Macal, 403, apto 101, Jardim da Penha, Vitoria, Espirito Santo 29060-030, Brazil; E-mail: bocaliniht@hotmail.com Received 23 January, 2019 Revised 8 June, 2019 Accepted 10 June, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Prehypertension and risk of cardiovascular diseases: a meta-analysis of 47 cohort studies Objective: To assess the association of prehypertension (SBP 120–139 mmHg and/or DBP 80–89 mmHg) and total cardiovascular diseases (CVDs), coronary heart disease (CHD), myocardial infarction (MI), and stroke. Methods: PubMed, Embase, and Web of Science were searched for articles published up to 7 November 2018. Normal range BP was considered SBP less than 120 mmHg and DBP less than 80 mmHg. RRs and 95% CIs were pooled using fixed-effects models. Meta-regression was conducted to estimate the heterogeneity among subgroups. Results: We included 27 articles (47 studies including 491 666 study participants) in the analysis. Prehypertension was associated with total CVDs (RR 1.40, 95% CI 1.34–1.46), CHD (1.40, 1.28–1.52), MI (1.86, 1.50–2.32), and stroke (1.66, 1.56–1.76). Risk of total CVDs, MI, and stroke was increased with low-range prehypertension (low-range: SBP 120–129 mmHg and/or DBP 80–84 mmHg) versus normal BP – RR 1.42 (95% CI 1.29–1.55), 1.43 (1.10–1.86), and 1.52 (1.27–1.81), respectively – and risk of total CVDs, CHD, MI, and stroke was increased with high-range prehypertension (high-range: SBP 130–139 mmHg and/or DBP 85–89 mmHg) – RR 1.81 (95% CI 1.56–2.10), 1.65 (1.13–2.39), 1.99 (1.59–2.50), and 1.99 (1.68–2.36), respectively. The population-attributable risk for the association of total CVDs, CHD, MI, and stroke with prehypertension was 12.09, 13.26, 24.60, and 19.15%, respectively. Conclusion: Prehypertension, particularly high-range, is associated with increased risk of total CVDs, CHD, MI, and stroke. Effective control of prehypertension could prevent more than 10% of CVD cases. Correspondence to Dongsheng Hu, 100 Kexue Avenue, Gaoxin District, Zhengzhou, Henan, China. Tel: +86 755 86671951; fax: +86 755 86671906; e-mail: dongsheng_hu@zzu.edu.cn Received 25 February, 2019 Revised 22 May, 2019 Accepted 13 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.

Blood pressure changes after renal denervation are more pronounced in women and nondiabetic patients: findings from the Austrian Transcatheter Renal Denervation Registry Objectives: Three recently published sham-controlled studies proved the efficacy of renal denervation (RDN) in hypertensive patients. The study presented here analyzed a nationwide multicentre registry database to clarify which patient subgroups benefit most from radiofrequency RDN. Methods: This is a post hoc analysis from the multicentre Austrian Transcatheter Renal Denervation Registry hosted by the Austrian Society of Hypertension. We correlated change of SBP after RDN to sex and presence/absence of comorbidities. Univariable correlation and multiple linear regression analyses were performed. Results: Two hundred and ninety-one patients (43% women, median age 64 years) undergoing RDN between April 2011 and September 2014 were included in this analysis. Mean baseline ambulatory 24 h BP (systolic/diastolic) was 150 ± 18/89 ± 14 mmHg and mean baseline office BP was 170 ± 16/94 ± 14 mmHg. After RDN, mean ambulatory 24 h BP reduction was 9 ± 19/6 ± 16 mmHg. The following features were associated with a good response to RDN: high baseline systolic ambulatory BP, high baseline diastolic office BP, female sex, absence of diabetes mellitus, and absence of peripheral artery disease. Multivariable analysis identified female sex and absence of diabetes mellitus as strongest predictors for ambulatory BP reduction, although those groups had the lowest baseline ambulatory BP. Discussion: Ambulatory BP reductions after RDN were substantially more pronounced in female and in nondiabetic patients despite lower baseline BP. It is concluded that in terms of efficacy female patients and nondiabetic patients might benefit more from RDN. Correspondence to David Zweiker, MD, Division of Cardiology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15. 8036 Graz, Austria. Tel: +43 664 8650460; fax: +43 316 385 13733; e-mail: david.zweiker@medunigraz.at Received 30 March, 2019 Revised 9 June, 2019 Accepted 10 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.

Consequences of the evolutionary cardiovascular challenge of human bipedalism: orthostatic intolerance syndromes, orthostatic hypertension In quadrupeds, the arterial baroreflex has dominance in the reflex homeostatic responses, which protect against haemorrhage. In humans, it is the low pressure cardiopulmonary reflex, which protects against the analogous cardiovascular challenge of gravity-dependent venous pooling with standing. To preserve orthostatic cardiovascular homeostasis with the emergence of bipedalism in humans the low pressure reflex, a minor, subsidiary reflex in quadripeds, was co-opted. Mirroring the imperfect skeletal evolution to bipedalism, this cardiovascular development has been problematic, with dysregulation manifesting as disabling orthostatic intolerance syndromes and, paradoxically, an orthostatic hypertensive response that appears to play a role in the development of essential hypertension in some people. Improved understanding of these evolutionary faults provides new options for postural and pharmacological treatments. Correspondence to Murray Esler, MBBS, FRACP, PhD, Baker Heart and Diabetes Institute, PO Box 6492, Melbourne, VIC 3004, Australia; Tel: +61 409 178 058; fax: +61 3 8532 1100; e-mail: murray.esler@baker.edu.au Received 28 May, 2019 Revised 25 June, 2019 Accepted 30 June, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Allopurinol treatment adversely impacts left ventricular mass regression in patients with well-controlled hypertension Objectives: Previous studies have demonstrated that high-dose allopurinol is able to regress left ventricular (LV) mass in cohorts with established cardiovascular disease. The aim of this study was to assess whether treatment with high-dose allopurinol would regress LV mass in a cohort with essential hypertension, LV hypertrophy and well-controlled blood pressure but without established cardiovascular disease. Methods: We conducted a mechanistic proof-of-concept randomized, placebo-controlled, double-blind trial of allopurinol (600 mg/day) versus placebo on LV mass regression. Duration of treatment was 12 months. LV mass regression was assessed by Cardiac Magnetic Resonance. Secondary outcomes were changes in endothelial function (flow-mediated dilatation), arterial stiffness (pulse wave velocity) and biomarkers of oxidative stress. Results: Seventy-two patients were randomized into the trial. Mean baseline urate was 362.2 ± 96.7 μmol/l. Despite good blood pressure control, LV mass regression was significantly reduced in the allopurinol cohort compared with placebo (LV mass −0.37 ± 6.08 versus −3.75 ± 3.89 g; P = 0.012). Oxidative stress markers (thiobarbituric acid reactive substances) were significantly higher in the allopurinol group versus placebo (0.26 ± 0.85 versus −0.34 ± 0.83 μmol/l; P = 0.007). Other markers of vascular function were not significantly different between the two groups. Conclusion: Treatment with high-dose allopurinol in normouricemic controlled hypertensive patients and LV hypertrophy is detrimental. It results in reduced LV mass regression and increased oxidative stress over a 12-month period. This may be because of an adverse impact on redox balance. Cohort selection for future cardiovascular trials with allopurinol is crucial. Correspondence to Jacob George, Division of Molecular and Clinical Medicine, University of Dundee, Mailbox 2, Ninewells Hospital and Medical School, Dundee, UK. Tel: +44 1382 383204; e-mail: j.george@dundee.ac.uk Received 16 April, 2019 Revised 11 June, 2019 Accepted 11 June, 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.

Blood pressure distribution and control in coronary patients from 24 European countries in the European Society of Cardiology EURoObservational Research Programme European survey of cardiovascular disease prevention and diabetes. EUROASPIRE IV Registry Background: Hypertension is the most prevalent major independent risk factor for developing coronary heart disease (CHD). The present analysis aimed to assess blood pressure (BP) distribution and factors associated with insufficient BP control in coronary patients from 24 countries participating in the European Society of Cardiology (ESC) EURoObservational Research Programme (EORP) EUROASPIRE IV survey. Methods: EUROASPIRE IV is a cross-sectional study conducted in 2012–2013 in patients aged 80 years or less hospitalized for CHD with a follow-up visit at a median of 16 months later. Logistic regression analysis was applied to confirm factors associated with BP control defined as less than 140/90 mmHg for nondiabetic patients and less than 140/85 mmHg for diabetic patients. Results: A total of 7998 patients (response rate, 48.7%) attended the follow-up visit. Complete data were available in 7653 participants (mean age 62.5 ± 9.6 years). The BP goal was achieved in 57.6%. Patients failing to achieve the BP goal were older, had higher BMI, had more often a history of coronary artery bypass grafting (CABG) and reported diabetes more frequently. Logistic regression confirmed the following independent significant predictors of not achieving the BP goal: a history of diabetes [odds ratio (OR) 1.75], obesity (OR 1.70 vs. normal BMI), overweight (OR 1.28 vs. normal BMI), age at least 65 years (OR 1.53) and CABG as the index event (OR 1.26 vs. acute MI). Conclusion: EUROASPIRE IV found insufficient BP control in a large proportion of patients with stable CHD, with diabetes, increased BMI, older age and CABG as the index event being independent predictors of poor BP control. Correspondence to Renata Cífková, Center for Cardiovascular Prevention, Charles University in Prague, First Faculty of Medicine and Thomayer Hospital, Vídeňská 800, 140 59 Prague 4, Czech Republic. Tel: +420 2 6108 3694; fax: +420 2 6108 3821; e-mail: renata.cifkova@ftn.cz Received 25 November, 2018 Revised 25 March, 2019 Accepted 26 March, 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.

Comparison of central SBP in children estimated from a brachial cuff alone, brachial cuff-calibrated applanation radial tonometry and brachial cuff-calibrated carotid wall-tracking Objectives: We compared the agreement between different techniques to estimate central SBP (cSBP) in children and the relative impact of different methods of measuring peripheral blood pressure (BP). Methods: A total of 135 children, aged 12.9 ± 3.0 years including 67 boys, 85 with chronic kidney disease were studied. We measured cSBP using radiofrequency ultrasound carotid wall-tracking (Esaote ART.LAB system, a previously validated reference method), transformation of the radial artery pressure waveform obtained by tonometry (SphygmoCor) and a cuff-based system (cBP301; Centron Diagnostics) during a single visit. Carotid and radial tonometric-derived values were calibrated from mean and diastolic values of brachial BP obtained by aneroid sphygmomanometer. Brachial cuff only values were calibrated from the same aneroid sphygmomanometer values and from oscillometric values obtained from the brachial cuff. Results: cSBP values estimated from radial tonometry were closely correlated with those obtained from the carotid (r = 0.959, mean difference −0.61 ± 3.5 mmHg). cSBP values estimated by the brachial cuff only method agreed reasonably well with those obtained from the carotid (r = 0.847, mean difference 5 ± 7.4 mmHg) when calibrated by the same method but when calibrated by oscillometric values from the brachial cuff, agreement was less good (r = 0.659, mean difference 8.7 ± 11.4 mmHg). Conclusion: Radial tonometry with a radial-to-central transfer function can be used to estimate cSBP in children with acceptable accuracy when compared with the invasively validated carotid reference method. All methods are subject to errors introduced by calibration from peripheral BP. Correspondence to Manish D. Sinha, Department of Paediatric Nephrology, Evelina London Children's Hospital, Guy's & St Thomas’ NHS Foundation Trust, 3rd Floor Beckett House, Westminster Bridge Road, London SE1 7EH, UK. Tel: +44 20 7188 4587; e-mail: manish.sinha@gstt.nhs.uk Received 13 December, 2018 Revised 30 April, 2019 Accepted 21 May, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Sex differences in masked hypertension: the Coronary Artery Risk Development in Young Adults study Objective: To evaluate the association of sex with masked hypertension, defined by out-of-clinic hypertension based on ambulatory blood pressure monitoring (ABPM) among adults without hypertension based on blood pressure (BP) measured in the clinic, after adjusting for potential confounders. Methods: We evaluated sex differences in the prevalence of masked hypertension and the difference between awake, or alternatively 24-h, ambulatory BP and clinic BP using multivariable adjusted models among 658 participants who underwent 24-h ABPM and had clinic SBP/DBP less than 140/90 mmHg during the Year 30 Exam of the Coronary Artery Risk Development in Young Adults study. Results: The mean age ± standard deviation (SD) of the participants was 54.8 ± 3.7 years, 58.4% were women, and 58.2% were black. The prevalence of any masked hypertension was 37.5% among women and 60.6% among men. In a model including adjustment for demographics, cardiovascular risk factors, antihypertensive medication, and clinic BP, the prevalence ratios (95% confidence intervals) comparing men versus women were 1.39 (1.18–1.63) for any masked hypertension, and 1.60 (1.28–1.99), 1.71 (1.36–2.15), and 1.40 (1.13–1.73) for masked awake, 24-h and asleep hypertension, respectively. In a fully adjusted model, the differences between mean awake ambulatory BP and clinic BP were 2.75 [standard error (SE) 0.92] mmHg higher for SBP and 3.61 (SE 0.58) mmHg higher for DBP among men compared with women. Conclusion: The prevalence of masked hypertension on ABPM was high in both men and women. Male sex was an independent predictor of masked hypertension. Correspondence to Daniel N. Pugliese, MD, Columbia University Irving Medical Center, 622 West 168th Street, PH 9-331, New York, NY 10032, USA. Tel: +1 212 342 1275; fax: +1 212 342 3431; e-mail: dnp2112@cumc.columbia.edu Received 19 December, 2018 Revised 7 May, 2019 Accepted 23 May, 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.

Improved renal outcomes after revascularization of the stenotic renal artery in pigs by prior treatment with low-energy extracorporeal shockwave therapy Background: Revascularization does not restore renal function in most patients with atherosclerotic renal artery stenosis (RAS), likely because of inflammation and fibrosis within the stenotic kidney. Low-energy shockwave therapy (LE-SWT) stimulates angiogenesis in the stenotic kidney, but its ability to improve renal function and structure after revascularization remains unexplored. We tested the hypothesis that a LE-SWT regimen before percutaneous transluminal renal angioplasty (PTRA) would enable PTRA to restore renal function in hypercholesterolemic pigs with RAS (HC+RAS), and that this would be associated with attenuation of renal inflammation and fibrosis. Methods and Results: Twenty-six pigs were studied after 16 weeks of HC+RAS, HC+RAS treated with PTRA with or without a preceding LE-SWT regimen (bi-weekly for 3 weeks), and controls. Single-kidney renal blood flow (RBF), glomerular filtration rate (GFR), and oxygenation were assessed in vivo using imaging 4 weeks after PTRA, and then inflammation and fibrosis ex vivo. Four weeks after successful PTRA, blood pressure fell similarly in both revascularized groups. Yet, stenotic-kidney GFR remained lower in HC+RAS and HC+RAS+PTRA (P < 0.01 vs. normal), but was improved in HC+RAS+PTRA+SW (P > 0.05 vs. normal). Furthermore, reduced inflammation, medullary fibrosis, and cortical hypoxia were only shown in swine stenotic kidneys pretreated with LE-SWT before PTRA 4 weeks later. Conclusion: LE-SWT delivery before revascularization permitted PTRA to improve function and decrease cortical and medullary damage in the stenotic swine kidney. This study, therefore, supports the use of an adjunct SW pretreatment to enhance the success of PTRA in blunting loss of kidney function in experimental HC+RAS. Correspondence to Lilach O. Lerman, MD, PhD, Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel: +1 507 266 9376; fax: +1 507 266 9316; e-mail: lerman.lilach@mayo.edu Received 31 December, 2018 Accepted 25 April, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.