Urinary sodium-to-potassium ratio and plasma renin and aldosterone concentrations in normotensive children: implications for the interpretation of results Objectives: To identify associations among the plasma renin concentration (PRC), plasma aldosterone and urinary sodium (Na)/potassium (K) ratio, and to integrate these variables into a nomogram with the aim of estimating the expected versus observed aldosterone concentration. Methods: We studied 40 healthy normotensive children (5–8 years old, 57.5% girls) who were born at term and were adequate for their gestational age. Following overnight fasting, the PRC and plasma aldosterone in blood samples were measured, and the Na/K ratio was calculated from a simultaneously obtained urinary spot sample. A mathematical function was defined with these three variables, and a nomogram was built that would return the expected aldosterone concentration from the obtained plasma renin and urinary Na/K ratio values. Results: The PRC (B =  5.9, P < 0.001) and urinary Na/K ratio (B = −98.1, P = 0.003) were significant independent predictors of plasma aldosterone. The correlation between the observed plasma aldosterone and the expected plasma aldosterone, as obtained from the nomogram, was r = 0.88, P < 0.001. The average difference between the observed and expected plasma aldosterone was −0.89, with a standard deviation of ±30%. Conclusion: The strong correlation between the urinary Na/K ratio, from urine samples taken at the same as the blood samples, and plasma renin and aldosterone concentrations allowed us to build a nomogram to predict aldosterone levels. This approach may be useful for evaluating the renin–angiotensin–aldosterone system (RAAS) in pediatric patients with hypertension and RAAS dysfunction. Correspondence to Alejandro G. Martinez-Aguayo, MD, Pediatrics Division, School of Medicine, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, Santiago, Region Metropolitana, Postal Code 8330077, Chile. Tel: +56 2 3543402; e-mail: alemarti@med.puc.cl Received 26 March, 2019 Revised 4 October, 2019 Accepted 31 October, 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.

Stage 1 hypertension by the 2017 American College of Cardiology/American Heart Association hypertension guidelines and risk of cardiovascular disease events: systematic review, meta-analysis, and estimation of population etiologic fraction of prospective cohort studies Background: Epidemiological studies reported an inconsistent association between stage 1 hypertension (SBP 130–139 mmHg or DBP 80–89 mmHg) defined by the 2017 American College of Cardiology/American Heart Association hypertension guidelines and cardiovascular disease (CVD) events. In addition, the proportion of CVD events that could be prevented with effective control of stage 1 hypertension is unknown. Objectives: To assess the association between stage 1 hypertension and CVD events and estimate the population etiologic fraction. Methods: PubMed, Embase, and Web of Science databases were searched from 1 January 2017 to 22 September 2019. Normal BP was considered SBP less than 120 mmHg and DBP less than 80 mmHg. Hazard ratios and 95% confidence intervals (95% CIs) were pooled by using a random-effects model. Results: We included 11 articles (16 studies including 3 212 447 participants and 65 945 events) in the analysis. Risk of CVD events was increased with stage 1 hypertension versus normal BP (hazard ratio 1.38, 95% CI 1.28–1.49). On subgroup analyses, stage 1 hypertension was associated with coronary heart disease (CHD) (hazard ratio 1.30, 95% CI 1.20–1.41), stroke (1.39, 1.27–1.52), CVD morbidity (1.42, 1.32–1.53), and CVD mortality (1.34, 1.05–1.71). The population etiologic fraction for the association of CVD events, CHD, stroke, CVD morbidity, and CVD mortality with stage 1 hypertension was 12.90, 10.48, 12.71, 14.03, and 11.69%, respectively. Conclusion: Stage 1 hypertension is associated with CVD events, CVD morbidity, CVD mortality, CHD, and stroke. Effective control of stage 1 hypertension could prevent more than 10% of CVD events. Correspondence to Ming Zhang, Department of Epidemiology, School of Public Health, Shenzhen University Health Science Center, Shenzhen, Guangdong, People's Republic of China. Tel: +86 755 86671951; fax: +86 755 86671906; e-mail: zhangming@szu.edu.cn Received 26 July, 2019 Revised 16 October, 2019 Accepted 31 October, 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.

Angiotensin–neprilysin inhibition confers renoprotection in rats with diabetes and hypertension by limiting podocyte injury Objectives: Combined angiotensin receptor--neprilysin inhibition (ARNI) reduces glomerulosclerosis better than single angiotensin receptor blockade (ARB) in diabetic, hypertensive rats. The renoprotective mechanism remains unknown, but may depend on superior blood pressure control, improved renal hemodynamics, suppressed renal inflammation or prevention of podocyte loss. Methods: To address this, TGR(mREN2)27 rats (a model of angiotensin II-dependent hypertension) were made diabetic for 12 weeks and treated with vehicle (n = 10), valsartan (ARB; n = 7) or sacubitril/valsartan (ARNI; n = 8) for the final 3 weeks. Arterial pressure was measured via radiotelemetry. Results: Sacubitril/valsartan lowered mean arterial pressure by −50 ± 4 mmHg and valsartan by −43 ± 4 mmHg (P = 0.3). Both treatments lowered albuminuria, but only sacubitril/valsartan maintained high urinary atrial natriuretic peptide, improved glycemic control and protected podocyte integrity, reflected by increased nephrin expression and suppression of transient receptor potential canonical 6 and regulator of calcineurin 1. This resulted in markedly reduced glomerulosclerosis (P < 0.05 vs. control and valsartan). Despite higher effective renal plasma flow and glomerular filtration rates, sacubitril/valsartan did neither improve filtration fraction nor renal immune cell infiltration. Conclusion: Sacubitril/valsartan offers drug-class-specific renoprotection in a preclinical model of diabetes and hypertension. Renoprotection is unrelated to antihypertensive efficacy, renal hemodynamics or inflammation, but may be related to protective effects of natriuretic peptides on podocyte integrity. Correspondence to A.H. Jan Danser, PhD, Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Room Ee1418b, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands. Tel: +31 10 7043540; fax: +31 10 7044733; e-mail: a.danser@erasmusmc.nl Received 29 July, 2019 Revised 3 November, 2019 Accepted 4 November, 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.

Metabolic syndrome, clustering of cardiovascular risk factors and high carotid intima–media thickness in children and adolescents Objective: The clinical utility of screening for pediatric metabolic syndrome (MetS) in children and adolescents is still controversial. We examined the performance of pediatric MetS vs. clustering of cardiovascular risk factors (which are the components of MetS) for predicting high carotid intima–media thickness (cIMT) in children and adolescents. Methods: Participants included 2427 children and adolescents aged 6–17 years from population-based studies in three countries (Brazil, China and Italy). Pediatric MetS was defined using either the modified National Cholesterol Education Program Adult Treatment Panel III criteria or the modified International Diabetes Federation criteria. Clustering of cardiovascular risk factors was calculated as the sum of five components of MetS (i.e. central obesity, elevated blood pressure, elevated triglycerides, reduced HDL-cholesterol and elevated fasting blood glucose). High cIMT was defined as cIMT at least 95th percentile values for sex and age developed from European children. Results: Presence of one, two or at least three cardiovascular risk factors (using the National Cholesterol Education Program Adult Treatment Panel III criteria), as compared with none, was associated with gradually increasing odds of high cIMT [odds ratios (95% confidence intervals): 1.60 (1.29–1.99), 2.89 (2.21–3.78) and 4.24 (2.81–6.39), respectively]. High cIMT was also associated with presence (vs. absence) of MetS (odds ratio = 2.88, 95% confidence interval = 1.95–4.26). However, clustering of cardiovascular risk factors predicted high cIMT markedly better than MetS (area under the curve of 0.66 vs. 0.54, respectively). Findings were similar using the International Diabetes Federation criteria for pediatric MetS. Conclusion: In children and adolescents, a graded score based on five cardiovascular risk factors (used to define MetS) predicted high cIMT markedly better than MetS. These findings do not support the clinical utility of MetS for screening youth at increased cardiovascular risk, as expressed in this study by high cIMT. Correspondence to Bo Xi, Department of Epidemiology, School of Public Health, Shandong University, 44 Wen Hua Xi Road, Jinan 250012, China. Tel: +86 0531 88382141; e-mail: xibo2007@126.com,xibo2010@sdu.edu.cn Received 6 August, 2019 Revised 30 October, 2019 Accepted 30 October, 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.

Relationship between office isolated systolic or diastolic hypertension and white-coat hypertension across the age spectrum: a home blood pressure study Objective: The current study investigated the prevalence of white-coat hypertension (WCH) and white-coat uncontrolled hypertension (WUCH) throughout the age spectrum among individuals with office isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH) and systolic–diastolic hypertension (SDH) who were untreated or treated with antihypertensive medications, respectively. Methods: We cross-sectionally evaluated 8809 untreated (42% males, 52.1 ± 16.2 years) and 9136 treated (39% males, 59.7 ± 14.5 years) individuals from two independent Brazilian populations who underwent home blood pressure monitoring. Participants were also categorized as younger (<40 years), intermediate (≥40 and <60 years) and older (≥60 years) age. Results: Unadjusted and adjusted analyses showed that the frequency of WCH and WUCH was significantly greater (P < 0.05) in ISH and IDH than SDH at all age groups. Logistic regression analysis adjusted for sex, BMI and studied population showed that, compared with SDH, ISH had in average 4.1, 3.1 and 1.6-fold greater risk of WCH and 3.3, 3.6 and 2.0-fold greater risk of WUCH at younger, intermediate and older ages, whereas IDH had in average 2.3, 2.6 and 2.0-fold greater risk of WCH and 3.8, 3.2 and 3.8-fold greater risk of WUCH at younger, intermediate and older ages, respectively. Conclusion: ISH and IDH were associated with higher prevalence of WCH and WUCH than SDH across all age spectrum. In addition, treated and untreated ISH individuals with age less than 60 years and treated IDH individuals of all ages had the highest risk of having WCH phenotypes. Correspondence to Wilson Nadruz Jr., MD, PhD, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Cidade Universitária ‘Zeferino Vaz’, 13081-970 Campinas, São Paulo, Brasil. Tel: +55 19 3521 7836; fax: +55 19 3521 7836; e-mail: wilnj@fcm.unicamp.br Received 22 August, 2019 Revised 14 October, 2019 Accepted 30 October, 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.

Central aortic blood pressure estimation in children and adolescents: results of the KidCoreBP study Background: Central aortic SBP (cSBP) may have superior prognostic value compared with peripheral SBP (pSBP), but noninvasive cSBP measurement techniques have not been formally validated in children and adolescents. Method: This study assessed the accuracy of two automated devices and the radial tonometry/transfer function method (RT-TF) for estimating central pressures and pulse pressure amplification (PPA) in this population, with adherence to validation guidelines for central pressure devices. In 69 children/adolescents aged 3–18 years undergoing clinically indicated aortic catheterization, high fidelity ascending aortic cSBP was measured with a micromanometer-tipped wire and compared with values from SphygmoCor XCEL, Mobil-O-Graph (systolic/diastolic calibration, MoG-C1, or mean/diastolic calibration, MoG-C2) and RT-TF. Reference intra-arterial pSBP was derived from the tonometry pulse calibrated to central mean/diastolic pressures. Results: XCEL, MoG-C1 and MoG-C2 overestimated cSBP by 7.9 ± 6.8 mmHg (mean ± SD), 5.7 ± 10.3 mmHg, and 19.1 ± 14.9 mmHg, exceeding the validation cut-off (5 ± 8 mmHg). Brachial pSBP was also overestimated by XCEL (10.9 ± 8.4 mmHg) and Mobil-O-Graph (11.5 ± 12.3 mmHg). By contrast, central and brachial diastolic pressures were underestimated by the automated devices, albeit mostly within acceptable limits; pulse pressures were, therefore, substantially overestimated. Central-brachial PPA (4.5 ± 4.4 mmHg) was overestimated by XCEL (8.7 ± 3.2 mmHg) and MoG-C1 (11.1 ± 6.4 mmHg), but underestimated by MoG-C2 (−3.0 ± 6.6 mmHg). Given accurate pulse calibration, RT-TF achieved acceptable accuracy for cSBP (−0.2 ± 4.6 mmHg) and central-radial PPA (1.9 ± 5.1 mmHg). Conclusion: In conclusion, XCEL and Mobil-O-Graph overestimated pSBP and cSBP in children and adolescents. cSBP can be obtained via the same transfer function used in adults, but accurate pressure pulse calibration is critical. Video Abstracts: http://links.lww.com/HJH/B222 Correspondence to Jonathan P. Mynard, Heart Research, Murdoch Children's Research Institute, 50 Flemington Road, Parkville, VIC 3052, Australia. Tel: +61 3 9936 6038; e-mail: jonathan.mynard@mcri.edu.au Received 6 September, 2019 Revised 11 November, 2019 Accepted 14 November, 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.

Left ventricular mass and incident out-of-office hypertension in a general population Aim: Findings regarding the association of left ventricular mass (LVM) and new-onset hypertension are based on blood pressure measured in the office. We sought to assess the value of LVM in predicting in-office and out-of-office incident hypertension in members of the general population enrolled in the Pressioni Monitorate E Loro Associazioni study. Methods: The study included participants with normal office (n = 792), home (n = 714) and 24-h (n = 825) ambulatory blood pressure (ABP) at baseline evaluation who had a readable echocardiogram at entry and at the end of follow-up. Each normotensive group was divided into quartiles of LVM indexed (LVMI) to height2.7. Results: Over a follow-up of 148 months cumulative incidence of new office, home and 24-h ABP hypertension were 35.9, 30.7 and 36.1%, respectively. In fully adjusted models (including age, sex, BMI change during follow-up, baseline serum glucose, creatinine, total cholesterol office, home and 24-h SBP and DBP). higher LVMI values (i.e. the highest vs. the lowest quartile) were independently associated with an increased risk of home [odds ratio (OR) = 2.14, 95% confidence interval (CI) 1.21–3.77, P = 0.008] and 24-h ABP hypertension (OR = 1.70, 95% CI 1.05–2.76, P = 0.03). This was not the case for new-onset office hypertension (OR = 1.61, 95% CI 0.94–2.74, P = 0.07). Conclusion: Our study provides the first evidence that in normotensive individuals the magnitude of LVMI is independently associated with the risk of incident out-of-office hypertension. Correspondence to Cesare Cuspidi, Clinical Research Unit, Istituto Auxologico Italiano, Viale della Resistenza 23, 20036 Meda, Italy. Tel: +39 0362 772433; fax: +39 0362 772416; e-mail: cesare.cuspidi@unimib.it Received 5 August, 2019 Revised 4 October, 2019 Accepted 16 October, 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.

Selective afferent renal denervation mitigates renal and splanchnic sympathetic nerve overactivity and renal function in chronic kidney disease-induced hypertension Background: Clinical and experimental evidence have shown that renal denervation, by removing both the sympathetic and afferent nerves, improves arterial hypertension and renal function in chronic kidney disease (CKD). Given the key role of renal sympathetic innervation in maintaining sodium and water homeostasis, studies have indicated that the total removal of renal nerves leads to impaired compensatory mechanisms during hemodynamic challenges. Method: In the present study, we hypothesized that afferent (or sensory) fibers from the diseased kidney contribute to sympathetic overactivation to the kidney and other target organ, such as the splanchnic region, contributing to hypertension in CKD. We used a method to remove selectively the afferent renal fibers (periaxonal application of 33 mmol/l capsaicin) in a rat model of CKD, the 5/6 nephrectomy. Results: Three weeks after afferent renal denervation (ARD), we found a decrease in mean arterial pressure (∼15%) and normalization in renal and splanchnic sympathetic nerve hyperactivity in the CKD group. Interestingly, intrarenal renin--angiotensin system, as wells as renal fibrosis and function and proteinuria were improved after ARD in CKD rats. Conclusion: The findings demonstrate that afferent fibers contribute to the maintenance of arterial hypertension and reduced renal function that are likely to be mediated by increased sympathetic nerve activity to the renal territory as well as to other target organs in CKD. Correspondence to Erika E. Nishi, PhD, Cardiovascular Division, Department of Physiology, Escola Paulista de Medicina - Universidade Federal de São Paulo - (UNIFESP-EPM), Rua Botucatu, 862, CEP 04023-060, São Paulo, SP, Brazil. Tel: +55 11 5576 4848 x3038; e-mail: enishi@unifesp.br Received 20 April, 2019 Revised 2 September, 2019 Accepted 10 October, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Proximal aortic diameter evolution in hypertensive patients with mild-to-moderate aortic dilatation: a 5-year follow-up experience Background: Aortic dilatation is common in hypertensive patients and is associated with higher risk of cardiovascular events. Parameters predicting further dilatation during lifetime are poorly understood. Aim: To predict the midterm aortic diameter evolution in a cohort of hypertensive patients with known aortic dilatation at Sinus of Valsalva (SOV) level. Methods: We prospectively analyzed a cohort of essential hypertensive outpatients without any other known risk factor for aortic dilatation. They underwent serial echocardiographic evaluations from 2003 to 2016. Results: Two hundred and forty-two hypertensive outpatients with a mild-to-moderate (37–53 mm) aortic dilatation were followed up for at least 5 years. Mean growth rate was 0.08 ± 0.35 mm/year. No clinical or anthropometric parameters were significantly different in patients with and without aortic diameter increase. Aortic z score (number of standard deviations from the average value observed in the general population) at baseline was inversely associated with growth rate (R2 0.04, P < 0.05). Aortic diameter at first visit, demographic and echocardiographic variables were major determinants of aortic diameter at second visit, accounting for about 90% of its total variability. Conclusion: Mean growth rate of proximal aorta in hypertensive patients with known aortic dilatation was of about 0.1 mm/year. Dilatation over time is slower in patients with increased rather than normal aortic z score. Eventually, it could be possible to reliably predict aortic diameter at few months from first visit. Correspondence to Dario Leone, MD, Hypertension Unit, Division of Internal Medicine, Department of Medical Sciences, ‘Città della Salute e della Scienza’ Hospital, University of Torino, Turin, Italy. Tel/fax: +39 11 633 69 52; e-mail: dgleone@live.it Received 30 May, 2019 Revised 27 September, 2019 Accepted 18 October, 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.

Risk of new-onset autoimmune diseases in primary aldosteronism: a nation-wide population-based study Objective: The association between hyperaldosteronism and autoimmune disorders has been postulated. However, long-term incidence of a variety of new-onset autoimmune diseases (NOAD) among patients with primary aldosteronism has not been well investigated. Methods: From Taiwan's National Health Insurance Research Database with a 23-million population insurance registry, the identification of primary aldosteronism, essential hypertension and NOAD as well as all-cause mortality were ascertained by a validated algorithm. Results: From 1997 to 2009, 2319 primary aldosteronism patients without previously autoimmune disease were identified and propensity score-matched with 9276 patients with essential hypertension. Among those primary aldosteronism patients, 806 patients with aldosterone-producing adenomas (APA) were identified and matched with 3224 essential hypertension controls. NOAD incidence is augmented in primary aldosteronism patients compared with its matched essential hypertension (hazard ratio 3.82, P < 0.001, versus essential hypertension). Furthermore, NOAD incidence is also higher in APA patients compared with its matched essential hypertension (hazard ratio = 2.96, P < 0.001, versus essential hypertension). However, after a mean 8.9 years of follow-up, primary aldosteronism patients who underwent adrenalectomy (hazard ratio = 3.10, P < 0.001, versus essential hypertension) and took mineralocorticoid receptor antagonist (MRA) still had increased NOAD incidence (hazard ratio = 4.04, P < 0.001, versus essential hypertension). Conclusion: Primary aldosteronism patients had an augmented risk for a variety of incident NOAD and all-cause of mortality, compared with matched essential hypertension controls. Notably, the risk of incident NOAD remained increased in patients treated by adrenalectomy or MRA compared with matched essential hypertension controls. This observation supports the theory of primary aldosteronism being associated with a higher risk of multiple autoimmune diseases. Correspondence to Vin-Cent Wu, MD, PhD, Room 1419, Clinical Research Building, Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan. Tel: +886 2 23562082; fax: +886 2 23934176; e-mail: q91421028@ntu.edu.tw Received 2 June, 2019 Revised 19 September, 2019 Accepted 7 October, 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.