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.

Severe impaired blood pressure control caused by baroreflex failure as a late sequela of neck irradiation A 64-year-old man, whose medical history was significant only for locally advanced squamocellular carcinoma of the right palatine tonsil treated with extended neck radiotherapy 9 years before, was evaluated for traumatic cerebral haemorrhage secondary to syncope after a postural change. The selective angiographic study of cerebral vessels was negative. No heart arrhythmias were recorded at ECG monitoring. The 24-h ABPM revealed sudden pressor and depressor episodes during day-time and a reverse dipper pattern during night-time. Noninvasive autonomic nervous system function testing showed supine hypertension and orthostatic hypotension caused by afferent baroreflex failure. According to literature, even if only few cases are described, neck irradiation can be assumed to be the major cause of baroreflex failure. No treatment is currently approved. The patient was treated with a selective beta-blocker (bisoprolol) administered at bedtime. Repeated ABPM after 1 month of therapy showed absence of sudden pressor and depressor episodes and no dipper pattern during night-time. Correspondence to Giulia Fiorini, PhD, Department of Surgical and Medical Sciences, University of Bologna, Bologna, Italy. E-mail: giulia.fiorini@fastwebnet.it Received 6 June, 2019 Revised 10 September, 2019 Accepted 24 September, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Cardiovascular, renal and liver protection with novel antidiabetic agents beyond blood glucose lowering in type 2 diabetes: consensus article from the European Society of Hypertension Working Group on Obesity, Diabetes and the High-risk Patient The prevalence of type 2 diabetes (T2D) has increased over the past few decades. T2D has a strong genetic propensity that becomes overt when a patient is exposed to a typical Western lifestyle, gain weight and becomes obese, whereas weight loss protects from the development of T2D. Except of lifestyle modifications, the choice of the appropriate treatment is essential in the management of patients with T2D and appears critical for the obese population with T2D. The new pharmacological approach for the treatment of T2D, sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists, seems to be effective not only in the management of T2D but also for weight loss, reduction of blood pressure and improvement of nonalcoholic fatty liver disease. Sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 analogues reduced cardiovascular risk, prevented cardiovascular disease and mortality, thereby playing an important role in the treatment of obese patients with hypertension and T2D. Correspondence to Vasilios Kotsis, MD, PhD, Hypertension-ABPM Center, Papageorgiou Hospital, Chairman WG on Obesity, Diabetes and the High Risk Patient, 39 Zaka, Panorama, 55236 Thessaloniki, Greece. Tel: +30 6974748860; fax: +30 2310452429; e-mail: vkotsis@auth.gr Received 10 June, 2019 Revised 23 August, 2019 Accepted 16 September, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Objectively measured physical activity relates to night-time blood pressure in older adults: cross-sectional analysis in the HEIJO-KYO cohort Objectives: Prognostically, night-time blood pressure (BP) is more important than other BP parameters. Previous physiological studies suggested physical exercise continuously decreases subsequent BP levels, although the association between daytime physical activity and night-time BP has not been evaluated in large populations. Methods: This cross-sectional study of 1111 older adults (mean age, 71.8 years) measured physical activity using actigraphy and ambulatory BP parameters. Results: The mean night-time SBP and DBP were 115.9 mmHg (SD, 16.2) and 67 mmHg (8.6), respectively, and the mean average daytime physical activity was 299.2 counts/min (104.3). A multivariable linear regression analysis, adjusted for potential confounders, suggested greater average daytime physical activity was significantly associated with lower night-time SBP (regression coefficient per 100 counts/min increment, −1.18; 95% CI −2.10 to −0.26), and DBP (−0.69; 95% CI −1.17 to −0.17). Significant associations between time above activity thresholds and night-time SBP were consistently observed (≥500 counts/min: regression coefficient per log min increment, −1.61, 95% CI −3.14 to −0.08; ≥1000 counts/min: −1.00, 95% CI −1.97 to −0.03; ≥1500 counts/min: −1.13, 95% CI −2.11 to −0.14). A subgroup analysis without antihypertensive medications (n = 619) strongly associated time above activity thresholds with night-time SBP (≥500 counts/min: −2.94; 95% CI −5.20 to −0.68). These results were consistent in the analysis using dipping as a dependent variable. Conclusion: Objectively measured daytime physical activity was significantly and inversely associated with night-time BP in older adults. Further longitudinal studies would ascertain effects of physical activity on night-time BP. Correspondence to Kenji Obayashi, MD, PhD, Department of Epidemiology, Nara Medical University School of Medicine, 840 Shijocho, Kashiharashi, Nara 634-8521, Japan. Tel: +81 744 29 8841; fax: +81 744 29 0673; e-mail: obayashi@naramed-u.ac.jp Received 27 July, 2019 Revised 11 September, 2019 Accepted 9 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.

No difference in medication regimes and dosing in study participants with and without blood pressure control: longitudinal data of the population-based Heinz Nixdorf Recall Study Background: To achieve blood pressure (BP) control adequate dosing of first-line antihypertensive medications is recommended in addition to life-style changes. Given observations that dosing of antihypertensive agents is frequently insufficient, we compared the changes of BP control rates and antihypertensive drug regimens in a prospective German population using a new strategy to analyze medication dosing. Methods: This analysis is based on data of the baseline (2000–2003) and the first follow-up examination (2005–2008) of the population-based Heinz Nixdorf Recall study. Participants with hypertension at baseline (BP ≥140/90 mmHg or at least one antihypertensive agent) who participated in both examinations were included. Results: Of the 4157 participants, 2289 (55.1%) had hypertension at baseline. The prevalence of participants on antihypertensive agents was 60.3% at baseline and increased to 75.1% at follow-up. The mean number of antihypertensive agents was 2 [±1 SD (standard deviation)] initially and at follow-up. The prevalence of medication-controlled BP did not improve over time (baseline: 54.5%, follow-up: 56.5%). When stratifying by medication-controlled BP, the medication dosing rate slightly increased over time without differences between groups [controlled versus uncontrolled BP: 40.9 versus 46.2% (baseline); 50.1 versus 51.9% (follow-up)]. Conclusion: Although the prevalence of antihypertensive medication use increased in the study period, the BP control rate did not. In contrast to clinical reasoning, participants with uncontrolled BP did neither receive more agents nor higher dosing despite outcome-relevant hypertension. Our approach to analyze medication dosing suggests a potential to improve cardiovascular outcomes by increasing dosages of antihypertensive agents. Correspondence to Professor Birgitta Weltermann, MD, MPH, Institute for General Medicine and Family Practice, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany. Tel: +49 228 287 11156; e-mail: Birgitta.Weltermann@ukbonn.de Received 22 August, 2019 Revised 20 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.

Weight gain and blood pressure Objective: Although the causality of the obesity--hypertension association is established, the potential for prevention is not. We hypothesized that weight gain between early adulthood and mid-life is associated with higher mid-life blood pressure. Methods: We investigated the hypothesis using a large contemporaneous population-based mid-life cohort of men and women aged 50–64 years. Recalled body weight at age 20 years was self-reported, and mid-life body weight and office blood pressures were measured in accordance with a detailed protocol. Results: On average, men had gained 14.9 (95% CI 14.6–15.2) kg of weight, and women 14.6 (95% CI 14.4–14.9) kg, between age 20 years and the mid-life examination, corresponding to 0.40 (95% CI 0.39–0.41) kg/year for men and women. Both weight at age 20 years and weight at the mid-life examination were associated with mid-life blood pressures. On average, a 10 kg weight increase between age 20 years and mid-life was associated with 2.2 (95% CI 0.9–3.5) mmHg higher systolic and 1.7 (95% CI 0.9–2.5) mmHg higher diastolic mid-life blood pressure in men, and 3.2 (2.5–4.0) mmHg higher systolic and 2.4 (1.9–2.9) mmHg higher diastolic mid-life blood pressure in women. Mid-life weight was more closely associated than weight at age 20 years with mid-life blood pressure. For a given mid-life weight, blood pressure was higher in persons with higher weight gain from age 20 years. Conclusion: In sum, weight gain between early adulthood and mid-life was associated with higher mid-life blood pressure. The magnitude of the association indicates a potentially great public health impact of strategies to prevent weight gain throughout adulthood. Correspondence to Johan Sundström, Akademiska sjukhuset Ing 40, 5 tr, 751 85 Uppsala, Sweden. Tel: +46 704 225220; fax: +46 18 509297; e-mail: Johan.Sundstrom@medsci.uu.se Received 30 July, 2019 Revised 13 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.

Family patterns of arterial stiffness across three generations in the Malmö Offspring Study Background: Central haemodynamics have in recent years emerged as a promising predictor of cardiovascular health and risk of cardiovascular disease (CVD). Central haemodynamics are affected early in the development of vascular aging and contributes to target organ damage. Carotid–femoral pulse wave velocity (c-f PWV), augmentation index (Aix) and central SBP (cSBP) are variables that reflect arterial stiffness and central haemodynamics. Aim: To study the association between patterns of central haemodynamics across three related generations focusing on c-f PWV. Methods: In all, 1131 participants from the Malmö Diet Cancer Study (MDCS) and Malmö Offspring Study (MOS) were included. c-f PWV was measured (Sphygmocor) in grandparents and in all offsprings. Correlation analyses of c-f PWV between offspring and c-f PWV in parents and grandparents were conducted. Parents and grandparents were stratified into quartiles by c-f PWV. Offspring c-f PWV means were compared with one-way ANOVA analyses. Multiple regression analyses were adjusted for age, sex, BMI, SBP and fasting glucose. Bonferroni corrections were used. Results: c-f PWV in offsprings was positively correlated with c-f PWV in parents (r = 0.26, P < 0.001) and in grandparents (r = 0.29, P < 0.001). Parents with high c-f PWV had offspring with significantly higher means of c-f PWV. Conclusion: A measure of aortic stiffness (c-f PWV) is positively correlated across three related generations in this population-based study. Correspondence to Peter M. Nilsson, MD, PhD, Department of Clinical Sciences, Lund University, Skane University Hospital, Jan Waldenstroms gata 15, 5th floor, S-20502 Malmo, Sweden. Tel: +46 40 33 24 15; e-mail: Peter.Nilsson@med.lu.se Received 30 January, 2019 Revised 24 September, 2019 Accepted 25 September, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Association of increased arterial stiffness with diastolic dysfunction in ischemic stroke patients: the Norwegian Stroke in the Young Study Background: Young and middle-aged ischemic stroke survivors have a high prevalence of hypertension, increased arterial stiffness and abnormal left ventricular (LV) geometry, which all are associated with the presence of LV diastolic dysfunction. However, the prevalence and covariates of diastolic dysfunction in these patients have not been reported. Objectives: To explore diastolic dysfunction in ischemic stroke patients aged 15–60 years included in the Norwegian Stroke in the Young Study. Methods: Data from 260 patients with acute ischemic stroke was analyzed. Diastolic dysfunction was assessed by combining transmitral peak early flow (E), early diastolic mitral annular velocity (e′), E/e′ ratio, left atrial volume index and peak tricuspid regurgitant jet velocity, following current European guidelines. Carotid–femoral pulse wave velocity at least 10 m/s by aplanation tonometry was defined as increased arterial stiffness. Results: Prevalent diastolic dysfunction was found in 20% of patients (13% with diastolic dysfunction grade 1 and 7% with diastolic dysfunction grades 2–3). Patients with diastolic dysfunction were older and more likely to have hypertension, overweight, increased arterial stiffness, higher LV mass and less percentage nightly reduction in mean blood pressure (BP) (all P < 0.001). In a multivariable logistic regression analysis, diastolic dysfunction was associated with increased arterial stiffness [odds ratio 2.86 (95% confidence interval 1.05–7.79), P < 0.05] independent of age more than 45 years, overweight, hypertension, night-time BP reduction and LV mass. Conclusion: Among young and middle-aged ischemic stroke survivors, diastolic dysfunction was found in 20%. The presence of diastolic dysfunction was associated with increased arterial stiffness independent of higher age, overweight, hypertension, night-time BP reduction and LV mass. Correspondence to Sahrai Saeed, MD, PhD, FESC, Department of Heart Disease, Haukeland University Hospital, Jonas Lies veg, 5021 Bergen, Norway. Tel: +47 55972196; fax: +47 55975150; e-mail: sahrai.saeed@helse-bergen.no Received 13 June, 2019 Revised 24 September, 2019 Accepted 7 October, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.