Association of hypertriglyceridemic waist-to-height ratio and its dynamic status with incident hypertension: the Rural Chinese Cohort Study Objective: We aimed to evaluate whether hypertriglyceridemic waist-to-height ratio (HWHtR) and its dynamic status was associated with hypertension (HTN). Methods: We examined data for 10 312 nonhypertensive participants aged at least 18 years from the Rural Chinese Cohort Study at the baseline examination who were followed until 2014 with a median follow-up of 6 years. HWHtR was defined by combined triglyceride level and waist-to-height ratio (WHtR). Multiple logistic regression models were used to examine the probability of incident HTN according to HWHtR and its transformation, estimating odds ratios (ORs) and 95% confidence intervals (CIs). Results: A total of 127 men and 225 women with high triglyceride level and high WHtR (HTHWH) had incident HTN during follow-up. After adjusting for potential confounders, the probability of HTN was increased with HTHWH for men [OR 1.49 (95% CI 1.01–2.20)] but this association was not significant for women [1.21 (0.88–1.66)]. The results of the sensitivity analyses were robust for men and women. The ORs were generally consistent on subgroup analysis by age,BMI, SBP and DBP for men. As compared with persistent normal triglyceride level and normal WHtR (NTNWH), the transformation from baseline NTNWH to follow-up HTHWH was associated with increased probability of HTN for men [OR 4.16 (95% CI 2.21–7.84)]. However, for women, the association of changed HWHtR from baseline to follow-up with probability of HTN was not significant for almost all transformation groups. Conclusion: HWHtR and its dynamic status was associated with incident HTN for rural Chinese men. From this cohort study, HWHtR may be an indicator for interventions aiming to reduce HTN among these men. Correspondence to Dr Dongsheng Hu, Department of Epidemiology and Health Statistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, People's Republic of China. Tel: +86 755 86671951; fax: +86 755 86671906; e-mail: dongshenghu563@126.com Received 6 May, 2019 Revised 8 June, 2019 Accepted 9 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.

Feature of trajectory of blood pressure among pregnant women with gestational hypertension Objective: We aimed to describe the feature and the trajectory of blood pressure (BP) among pregnant women with onset of gestational hypertension. Methods: This epidemiology cohort study of pregnant women enrolled in Zhoushan, Zhejiang, included 4050 participants from the Zhoushan Pregnant Women Cohort. Each participant contributed up to eight serial perinatal visits of BP measurements from 2001 to 2018. Segmented mixed models were utilized to identify the dramatic change points in the relationship of BP elevation and gestational week among pregnant women with onset of gestational hypertension. Results: Despite of in which gestational week gestational hypertension developed, the SBP and DBP levels of pregnant women in each gestational hypertension category maintained the stable and normal levels (SBP <119∼130 and DBP <76∼83 mmHg) before the accelerated point. However, after the accelerated point, BP dramatically developed to gestational hypertension in a very short time period. Meanwhile, the earlier gestational hypertension onset was, the higher the baseline BP were; meanwhile, the earlier the gestational hypertension onset was, the higher the difference in BP at the gestational week of gestational hypertension onset between women with and without gestational hypertension was. Conclusion: BP trajectories of gestational hypertension onset in different gestational week presented similar patterns. Meanwhile, the earlier gestational hypertension onset was, the higher the baseline BPs were. These findings show that BP monitoring during pregnancy is necessary, especially for women with high normal baseline BP. Correspondence to Yunxian Yu, MD, PhD, Associate Professor, Department of Public Health, and Department of Anesthesiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. Tel: +8657188208191; e-mail: yunxianyu@zju.edu.cn Received 7 May, 2019 Revised 10 June, 2019 Accepted 20 June, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Changes in segmental pulse wave velocity of the thoracic aorta with age and left ventricular remodelling. An MRI 4D flow study Objectives: Pulse wave velocity (PWV) of the aortic arch is usually estimated by using 2D phase contrast in MRI. Thanks to 4D flow MRI, segmental PWV of the ascending and descending aorta, as well as PWV of the entire thoracic aorta can now be estimated within the same examination. Our objective is to compare PWVs obtained by 2D and 4D PC, through their relationships with carotid-femoral PWV (cf-PWV), age and left ventricular remodelling. Basic methods: MRI examinations were performed at 3 Tesla, including 2D PC acquisitions with through-plane velocity encoding and sagittal 4D phase contrast acquisitions covering the thoracic aorta volume. PWVs were calculated after estimating aortic lengths and flow transit times between the ascending aorta and descending aorta in 2D and between valve, isthmus and diaphragm in 4D resulting in 2D-PWV, 4D-TA-PWV; 4D-AA-PWV, 4D-DA-PWV. Main results: Fifty-seven healthy volunteers (25 men, age 51 years ± 17) were studied. All MRI-PWVs were correlated with cf-PWV (r = 0.67; r = 0.63: r = 0.47; r = 0.61 for 2D-PWV, 4D-TA-PWV; 4D-AA-PWV, 4D-DA-PWV, respectively, P < 0.001). 2D-PWV and 4D-TA-PWV were strongly related with age (r = 0.76 and r = 0.77, respectively). The highest correlation, between left ventricular thickness or LV mass/end diastolic volume (EDV) ratio and segmental PWVs of the thoracic aorta was found with 4D-AA-PWV (r = 0.43, P < 0.01 and r = 0.48, P < 0.01). Principal conclusions: Global and segmental PWV analysis of the thoracic aorta can be accurately assessed using 4D flow MRI. 4D-PWVs were highly correlated with ageing and cf-PWV. The strong association between the ascending aorta stiffness and the left ventricular remodelling in healthy volunteers is encouraging to better estimate left ventricular afterload. Correspondence to Elie Mousseaux, MD, PhD, Paris-Cardiovascular Research Center; INSERM 970, 20 rue Leblanc, Paris 75015, France. Tel: +33 1 56093709; e-mail: elie.mousseaux@aphp.fr Received 18 May, 2019 Revised 11 July, 2019 Accepted 30 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.

Apparent therapy-resistant hypertension as risk factor for the development of type 2 diabetes mellitus Objective: To evaluate whether the relationship between hypertension and type 2 diabetes mellitus (T2DM) is different for patients with uncontrolled hypertension, controlled hypertension or patients with apparent therapy-resistant hypertension (aTRH), compared with patients without hypertension. Methods: Using Cox proportional hazard models we evaluated the risk of new-onset T2DM in 8756 patients, at high risk for vascular disease. Hypertensive patients were subdivided according to blood pressure (BP) and use of BP-lowering drugs. BP ≥ 140/90 mmHg was defined as uncontrolled BP. aTRH was defined as uncontrolled BP despite being treated with at least three BP-lowering drugs including a diuretic, or the use at least four BP-lowering drugs irrespective of BP levels. Further analysis evaluated the risk of new-onset T2DM for patients with uncontrolled hypertension and for patients with aTRH, compared with patients with controlled hypertension and without hypertension, respectively. Results: Forty-five percent had controlled hypertension, 20% had uncontrolled hypertension, 5.7% had aTRH, and 29% were nonhypertensive. During a follow-up of 7.0 (interquartile range: 0–14) years there were 705 new cases of T2DM. Patients with hypertension had a 1.48 (95% confidence interval 1.22–1.80) times higher risk of new-onset T2DM than nonhypertensive patients. There was no significant difference in risk among different hypertension groups. Conclusion: Patients at high risk for cardiovascular disease with hypertension have a 1.48 times higher risk of new-onset T2DM than nonhypertensive counterparts. The risk did not differ between patients with controlled hypertension, uncontrolled hypertension, or aTRH. Correspondence to Jan Westerink, MD, PhD, Department of Vascular Medicine, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands. Tel: +31 88 7550532; fax: +31 88 7555488; e-mail: J.Westerink-3@umcutrecht.nl Received 14 May, 2019 Accepted 30 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.

Fetotoxic risk of AT1 blockers exceeds that of angiotensin-converting enzyme inhibitors: an observational study Objective: The fetotoxic potential of prenatal exposure to angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) has been known for many years. Symptoms range from transient oligohydramnios to neonatal anuria and permanent renal damage, joint contractures, hypocalvaria, lung hypoplasia and intrauterine or neonatal death. This study aims to investigate the critical gestational time for renin–angiotensin system inhibitor (RAS-I)-induced fetopathy, to quantify the fetopathy risk and to evaluate factors associated with the occurrence and severity of fetopathy. Methods: Prospectively and retrospectively ascertained RAS-I exposed pregnancies from the databases of six teratology information services were analyzed. Results: Eighty-nine pregnancies with ACE-I and 101 with ARB exposure beyond the first trimester were identified. Fifty-nine of these 190 pregnancies were classified as having evidence of RAS-I fetopathy. All pregnancies affected with fetopathy were exposed after 20 0/7 gestational weeks. Limited to prospectively enrolled cases with exposure at least 20 0/7 gestational weeks, the rate of fetopathy was 3.2% for ACE-I and 29.2% for ARB. The chance of recovery of amniotic fluid volume was higher with RAS-I discontinuation before 30 gestational weeks and with a longer exposure-free interval before delivery. Conclusion: Exposure to ARBs is associated with a higher fetopathy risk than exposure to ACE-Is. RAS-I should ideally be discontinued prior to pregnancy or immediately after recognition of pregnancy. Because symptoms may improve in cases of RAS-I-induced oligohydramnios, pregnancy should be maintained as long as there is fetal well being. Physicians and patients need to be alerted to the fetotoxic risks of RAS-I. Correspondence to Corinna Weber-Schoendorfer, Charité Universitätsmedizin Berlin, Pharmakovigilanzzentrum Embryonaltoxikologie, Augustenburger Platz 1, D-13353 Berlin, Germany. Tel: +00 49 30 450525711; fax: +00 49 30 4507525920; e-mail: corinna.weber-schoendorfer@charite.de Received 14 February, 2019 Revised 5 July, 2019 Accepted 2 August, 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.

Right ventricular–pulmonary arterial uncoupling in mild-to-moderate systemic hypertension Background: Mild-to-moderate hypertension with preserved left ventricular (LV) function may be associated with right ventricular (RV) dysfunction and increased pulmonary vascular resistance (PVR). Methods: The present study explored the adequacy of RV–pulmonary arterial (PA) coupling in 211 never-treated hypertensive patients (mean blood pressure, BP 112 ± 12 mmHg) and 246 controls (BP 93 ± 12 mmHg). They underwent a comprehensive transthoracic Doppler echocardiography, and RV–PA coupling was estimated by the tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure (PASP) ratio (TAPSE/PASP). Results: Compared with the controls, hypertensive patients had increased LV wall thickness and decreased trans-mitral E/A with only slight but significant increase in transmitral Doppler E wave to tissue Doppler mitral annulus e′ wave ratio (6.3 ± 1.9 vs. 5.8 ± 1. 5, P < 0.05). RV dimensions and indices of either systolic or diastolic function were not different. PASP was increased in the hypertensive patients (25 ± 7 vs. 21 ± 7 mmHg, P < 0.001), as was PVR estimated from the tricuspid regurgitation velocity to right ventricular outflow tract velocity ratio (1.7 ± 0.4 vs. 1.5 ± 0.5 Wood units, P < 0.001). The TAPSE/PASP ratio was decreased (1.08 ± 0.35 vs. 1.43 ± 0.67 mm/mmHg, P < 0.001). This difference was mainly driven by male hypertensive patients. At multivariable analysis, the only independent predictors of decreased TAPSE/PASP were age and blood pressure. Conclusion: The TAPSE/PASP is markedly decreased in hypertension without heart failure, chiefly in men, with only slight increases in estimates of LV filling pressure or PVR, suggesting RV–PA uncoupling. Correspondence to Olga Vriz, MD, Heart Centre Department, King Faisal Specialist Hospital & Research Center, Riyadh, Kingdom of Saudi Arabia. Tel: +39 3385052616; e-mail: olgavriz@yahoo.com Received 5 May, 2019 Revised 8 August, 2019 Accepted 8 August, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Differences in regional grey matter volume of the brain are related to mean blood pressure and muscle sympathetic nerve activity in normotensive humans Objectives: The brainstem plays a critically important role in the beat-to-beat control of blood pressure, as well as setting mean blood pressure (MBP). We recently showed that regional cerebral blood flow to specific brainstem nuclei is inversely related to resting MBP in healthy normotensive individuals. Here we tested the hypothesis that grey matter volume in these same nuclei, and areas above the brainstem to which they are connected, is also associated with resting MBP and muscle sympathetic nerve activity (MSNA). Methods: Structural MRI of the brain and recordings of MSNA and BP were collected in 54 healthy participants. Subjects were divided into a lower MBP group (mean ± SEM 78.8 ± 1.5 mmHg, n=27) and higher MBP group (96.6 ± 1.2 mmHg, n = 27), as well as into a lower MSNA (9.5 ± 0.8 bursts/min, n = 27) and higher MSNA (25.4 ± 1.2 bursts/min, n = 27) group. Results: Regional grey matter volume was higher in the region of the rostral ventrolateral medulla, nucleus tractus solitarius, and medullary raphe in the group with higher MBP and correlated significantly with mean MBP across all participants. Grey matter volume was significantly higher in the dorsomedial hypothalamus and anterior and posterior cingulate cortices in the group with lower MSNA and was inversely related to MSNA across all participants. Conclusion: We conclude that small differences in MBP and MSNA are associated with significant differences in grey matter volume in cortical and subcortical regions known to be involved in blood pressure regulation, suggesting that these structural differences contribute to resting MBP and MSNA and can predict the establishment of hypertension. Correspondence to Vaughan G. Macefield, PhD, DSc, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia. Tel: +61 3 8532 1866; e-mail: vaughan.macefield@baker.edu.au Received 4 May, 2019 Revised 12 August, 2019 Accepted 13 August, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Antihypertensive drug classes and the risk of hip fracture: results from the Swedish primary care cardiovascular database Objective: Hypertension and fractures related to osteoporosis are major public health problems that often coexist. This study examined the associations between exposure to different antihypertensive drug classes and the risk of hip fracture in hypertensive patients. Method: We included 59 246 individuals, 50 years and older, diagnosed with hypertension during 2001–2008 in the Swedish Primary Care Cardiovascular Database. Patients were followed from 1 January 2006 (or the date of diagnosis of hypertension) until they had their first hip fracture, died, or reached the end of the study on 31 December 2012. Cox proportional hazards models were used to calculate the risk of hip fracture across types of antihypertensive medications, adjusted for age, sex, comorbidity, medications, and socioeconomic factors. Results: In total, 2593 hip fractures occurred. Compared to nonusers, current use of bendroflumethiazide or hydrochlorothiazide was associated with a reduced risk of hip fracture (hazard ratio 0.86; 95% CI 0.75–0.98 and hazard ratio 0.84; 95% CI 0.74–0.96, respectively), as was use of fixed drug combinations containing a thiazide (hazard ratio 0.69; 95% CI 0.57–0.83). Current use of loop diuretics was associated with an increased risk of hip fracture (hazard ratio 1.23; 95% CI 1.11–1.35). No significant associations were found between the risk of hip fracture and current exposure to beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone-receptor blockers or calcium channel blockers. Conclusion: In this large observational study of hypertensive patients, the risk of hip fracture differed across users of different antihypertensive drugs, results that could have practical implications when choosing antihypertensive drug therapy. Correspondence to Tove Bokrantz, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska University Hospital, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden. Tel: +46 732300468; e-mail: tove.bokrantz@gmail.com Received 19 July, 2019 Revised 28 July, 2019 Accepted 14 August, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Cardiac organ damage in patients with Parkinson's disease and reverse dipping Objective: Patients with autonomic neuropathy associated with Parkinson's disease often show reverse dipping pattern/nocturnal hypertension at 24-h ambulatory blood pressure (BP) monitoring (24-h ABPM) and diurnal orthostatic hypotension. The aim of the study was to evaluate cardiac alterations in Parkinson's disease patients with reverse dipping, in comparison with nonreverse dippers Parkinson's disease and essential hypertensive patients. Methods: A total of 26 consecutive Parkinson's disease patients with reverse dipping at 24-h ABPM and no previous history of hypertension were compared with 26 nonreverse Parkinson's disease patients matched for age, sex and 24-h mean BP, and 26 essential hypertensive patients matched for nighttime mean BP. None of the Parkinson's disease patients suffered from cardiovascular diseases or were treated with antihypertensive or antihypotensive drugs. Reverse dipping was defined by a systolic day-night BP difference less than 0% at 24-h ABPM. Left ventricular (LV) hypertrophy was defined by a LV mass index at least 115 g/m2 in men and at least 95 g/m2 in women. Results: LV mass, indexed for BSA, was significantly higher in reverse dipping than nonreverse Parkinson's disease patients (respectively 90.2 ± 25.3 vs. 77.4 ± 13.3 g/m2, P = 0.04), and was similar to essential hypertensive patients (91.6 ± 24.8, P = 0.92). LV hypertrophy was detected in five reverse dipping Parkinson's disease patients and four hypertensive patients, but was not present in nonreverse Parkinson's disease patients (P = 0.046). Nocturnal BP values, nocturnal BP load, weighted BP variability and age were found to correlate with the increased LV mass index. Conclusion: Reverse dipping and nocturnal hypertension are related to higher LV mass and increased prevalence of LV hypertrophy in Parkinson's disease patients. Correspondence to Cristina Di Stefano, Autonomic Unit and Hypertension Unit, Department of Medical Sciences, Città della Salute e della Scienza Hospital, University of Torino, Corso Bramante 88, 10126 Torino, Italy. Tel: +39 0116336959; fax: +39 0116336931; e-mail: c.distefano1986@gmail.com Received 9 June, 2019 Revised 1 August, 2019 Accepted 16 August, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Concurrent heterozygous Von-Hippel–Lindau and transmembrane-protein-127 gene mutation causing an erythropoietin-secreting pheochromocytoma in a normotensive patient with severe erythrocytosis Background: Mutations of genes related to Krebs cycle enzymes, kinases or to pseudohypoxic signaling pathways, including Von-Hippel–Lindau (VHL) and transmembrane-protein-127 predispose to pheochromocytoma and paraganglioma development. Homozygous loss of function mutation of VHL (VHL 598C>T) gene can associate with polycythemia because of an altered hypoxia sensing. Patient: A 19-year-old normotensive man presented with headache, fatigue associated with severe erythrocytosis (hematocrit 76%), high hemoglobin (25.3 g/dl) in normoxic condition. Bone marrow biopsy showed marked hyperplasia of erythroid series. The Janus kinase 2 (V617F) mutation was absent. Abdominal computed tomography scan showed a 8-mm left adrenal pheochromocytoma with tracer uptake on 68GaDOTA-octreotate PET. Twenty-four-hour urinary metanephrine excretion was slightly increased, while normetanephrine, 3-methoxytyramine were normal. Adrenal veins sampling showed high left-side erythropoietin secretion. Results: Next-generation sequencing genetic analysis evidenced two concurrent heterozygous mutation of VHL598C>T and of transmembrane-protein-127 c.268G>A. Left side adrenalectomy improved symptoms, erythrocytosis, hemoglobin, and erythropoietin circulating levels. Adrenal histologic sections showed a pheochromocytoma with extensive immunostaining for erythropoietin, but also coexpression of chromogranin A, a marker of chromaffin tissue. Conclusion: Congenital polycythemia was clinically diagnosed, mimicking Chuvash polycythemia. Chuvash polycythemia is an autosomal recessive disorder that usually harbors a homozygous mutation of VHL598C>T but not predispose to pheochromocytoma development; in contrast our patient showed for the first time that the concurrent heterozygous VHL and TMEM mutations, resulted in a clinical phenotype of a normotensive patient with polycythemia due to erythropoietin-secreting pheochromocytoma that improved after adrenalectomy. Correspondence to Aderville Cabassi, Unità di Fisiopatologia Medica, Dipartimento di Medicina e Chirurgia, Clinica e Terapia Medica, Centro Ipertensione Arteriosa e Studio Malattie Cardiorenali, Università di Parma, Via Gramsci 14, 43126 Parma, Italy. Tel: +39 0521033184; fax: +39 0521033185; e-mail: aderville.cabassi@unipr.it Received 19 June, 2019 Revised 18 August, 2019 Accepted 19 August, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.