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.

Highlights of the September issue No abstract available

Feasibility of 24-h central blood pressure monitoring: experience from multinational clinical trial assessing the efficacy of perindopril/indapamide/amlodipine Objectives: Brachial blood pressure (BP) is a predictor of cardiovascular events. Evidence suggests that central BP (CBP) provides additional information for cardiovascular risk assessment. Methods to assess 24-h CBP are now available. Our objective was to assess the feasibility of 24-h CBP monitoring in clinical trials and its ability for drug evaluation. Methods: Data are issued from an international phase 3 randomized clinical trial comparing the efficacy of perindopril/indapamide/amlodipine vs. perindopril/indapamide (Per/Ind), in uncontrolled hypertensive patients treated with Per/Ind. 24-h ambulatory BP monitoring (ABPM) was performed at baseline and after 1-month treatment using the Mobil-O-Graph device which provide brachial BP and CBP and arterial parameters. Results: From the 345 patients included in the ABPM substudy, 276 had two valid ABPM (M0 and M1) for brachial BP assessment (80%). After applying device/software built-in and expert quality control criteria on these recordings, 210 (76%) had valid data at M0 and M1 for the assessment of CBP. After 1 month, superior ambulatory central SBP reductions were observed in the perindopril/indapamide/amlodipine (n = 101) vs. Per/Ind group (n = 109) for 24-h/daytime/night-time periods (−4.5 mmHg, P = 0.002/−5.0, P < 0001/−4.1 mmHg, P = 0.016, respectively). Similar trends were observed for pulse wave velocity and other central parameters. Conclusion: Recording 24-h central ABPM and its derived arterial parameters needs a strict expert quality control and must consider a loss of up to 39% of the population included in the ABPM substudy. This method can be used to assess drug effect. Correspondence to Dr Jirar Topouchian, MD, Paris-Descartes University, AP-HP, Diagnosis and Therapeutic Center, Hôtel-Dieu, 1 rue de la Cité, 75181 Paris, France. Tel: +33 0 620102109; e-mail: jtopouchian@jtcrc.com Received 29 January, 2019 Revised 14 June, 2019 Accepted 1 July, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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.