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Journal of Hypertension:
doi: 10.1097/HJH.0000000000000129
Editor's Corner

From pathophysiology to therapeutic interventions: the span of hypertension research

Zanchetti, Alberto

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Istituto Auxologico Italiano and Centro Interuniversitario di Fisiologia Clinica e Ipertensione, Università di Milano, Milan, Italy

Correspondence to Professor Alberto Zanchetti, Centro di Fisiologia Clinica e Ipertensione, Università di Milano, Via F. Sforza, 35, 20122 Milan, Italy.Tel: +39 02 50320484; e-mail:

The content of the April issue of the Journal of Hypertension faithfully represents the span of worldwide research on hypertension, from pathophysiology to therapeutic interventions. Experimental and clinical pathophysiological investigations explore new areas of knowledge, new mechanisms, and suggest new targets and means of intervention; other studies aim at evaluating diagnostic devices and procedures, and yet others consider prognostic aspects and therapeutic opportunities. As usual for the Journal, some of the studies stimulate a wider discussion of particular topics and are accompanied by editorial commentaries by experts, and the results of all studies are briefly commented by reviewers to help readers to critically evaluate their impact.

In this issue, a considerable number of articles summarize the results of experimental pathophysiologic studies. Barhoumi et al. (pp. 784–794) have investigated the blood pressure-raising effect of erythropoietin in mice and found that erythropoietin-induced adverse vascular effects are dependent on pre-existing elevated endothelin-1 expression, and are prevented by exercise training through inhibition of oxidative stress, inflammation and immune activation induced by endothelin-1 overexpression. Another study by Lee et al. (pp. 795–805) is also focused on endothelin-1: endothelin-1 levels and Rho activity were found elevated in deoxycorticosterone acetate (DOCA) salt-hypertensive rats via activation of the mineralocorticoid receptor, resulting in renal fibrosis and proteinuria, both effects being blocked by endothelin-A receptor blockade, as well as Rho activity. The roles of angiotensin II receptors are investigated in two studies. Yang et al. (pp. 762–770) report that autoantibodies to angiotensin II receptors AT1 in serum from hypertensive patients promote generation of endothelial particles in human endothelial cells through activation of mitogen-activated protein kinase, a mechanism that could be suppressed by losartan. According to a study by Ocaranza et al. (pp. 771–783), AT2 receptors mediate the blood pressure reduction, amelioration of organ damage and reduction of oxidative stress induced by angiotensin-(1–9) in hypertensive rats. Research by Matsukawa et al. (pp. 817–825) has focused on the neurotrophic factor, neuregulin-1 (NRG-1). They report that NRG-1/ErbB signaling in the brainstem of rats with aortic binding is impaired, and central administration of recombinant NRG-1β attenuates cardiac damage through sympathoinhibition. The authors suggest their findings may provide a new treatment concept and support the benefit of NRG-1 treatment in heart failure. In an accompanying commentary, Johns (pp. 735–737) briefly reviews the important roles of the NRG-1/ErbB cascade on cellular processes in the vascular system and the heart, and the extensive distribution of the cascade in the central and peripheral nervous system, and comments that the findings of Matsukawa et al. may open up an important way forward for devising means by which the sympathetic system can be manipulated to remove its contribution to cardiovascular dysregulation. Kuo et al. (pp. 806–816) further contribute to exploring the role of autonomic dysregulation in blood pressure control by showing that in the rat, lower baroreflex control and parasympathetic activity during quiet sleep, as well as lower sympathetic activity during active waking, are associated with reduced blood pressure dipping.

Clinical pathophysiological studies range from blood pressure regulation in obesity and pregnancy to cardiac effects of hypertension. Pieterse et al. (pp. 826–833) report that leptin is independently associated with different markers of cardiac autonomic activity, especially in men, thus adding evidence to the hypothesis that leptin enhances sympathetic activity and may contribute to obesity-related hypertension. These observations are commented in an editorial by Grassi (pp. 738–739) who briefly reviews available evidence on the relationship between leptin and sympathetic activity, and remarks that, at variance with experimental evidence on animal models, evidence in human beings is scanty and conflicting. The demonstration by Pieterse et al. that leptin is associated with cardiac sympathetic activations in Africans does not necessary imply – in Grassi's opinion – that this activation is generalized and also extends to blood pressure control. By a combined analysis of two Swedish prospective studies, Lytsy et al. (pp. 834–839) show that being overweight or obese without insulin resistance increases risk of developing or progressing hypertension, thus further supporting the evidence that overweight and obesity may be harmful per se, and that overweight and obesity without metabolic derangements are not benign conditions. In an accompanying editorial, Jordan (pp. 740–741) reviews experimental and clinical evidence on blood pressure, sympathetic and metabolic regulation in obesity, and speculates that the neural insulin–melanocortin pathway may contribute to the connection or disconnection between metabolic and cardiovascular regulation in obese patients. Lim et al. (pp. 857–864) report that maternal adiposity is associated with higher peripheral and central blood pressures during pregnancy, with larger changes in Chinese women and in those with gestational diabetes. Libhaber et al. (pp. 912–920) investigate the relationships between diastolic left-ventricular function and blood pressure assessed from brachial and central aortic measurements and conclude that both peripheral and central SBP and DBP are important determinants, though of separate components, of diastolic dysfunction. Tadic et al. (pp. 929–937) have employed two-dimensional speckle tracking imaging and three-dimensional echocardiography to find that right-ventricular and right atrial mechanics, as well as exercise capacity, are significantly deteriorated in untreated or uncontrolled hypertension.

An important group of studies covers diagnostic aspects of hypertension and its complications. Four studies are focused on pulse wave velocity (PWV) measurements. Park et al. (pp. 865–872) compare pressure wave form and central blood pressure measurements by a cuff-based device and by tonometry and show that cuff-based devices promise to simplify measurements of central blood pressure whilst maintaining a similar fidelity to tonometry. This could lead to a wider adoption of estimates of central blood pressure in clinical practice. Stea et al. (pp. 873–880) have tested the new Complior Analyse device and found that it provides equivalent results of PWV and central blood pressure values to the Sphygmocor and Complior SP. Sugawara et al. (pp. 881–889) report that other methodological factors apart from arterial path length estimation must contribute to the higher absolute brachial–ankle PWV values as compared with other PWV measurements. That PWV assessment has a relevant prognostic role is shown by a prospective 42-month study by Baumann et al. (pp. 881–889), which provides the first evidence that in patients with chronic kidney disease (CKD) stage 2–4 increased aortic stiffness estimated by PWV is a strong independent predictor of all-cause mortality. In their editorial commentary, Weir and Townsend (pp. 744–745) elaborate about the possible mechanisms relating arterial stiffness with mortality, and suggest larger studies are necessary to explore arterial stiffness as a predictor of CKD progression.

Other diagnostic studies include a study by Koch et al. (pp. 890–898) on the advantages of adaptive optics imaging for quantitative estimation of retinal microvascular changes in hypertension; a study by Cuspidi et al. (pp. 921–928), who have analyzed ECG data in a prospective population study, and found that, despite the limited sensitivity of ECG voltage criteria in detecting left-ventricular hypertrophy, Cornell voltage index may improve cardiovascular risk stratification in a general population; a study by Mahendru et al. (pp. 849–856) which provides a comprehensive description of the hemodynamic changes throughout pregnancy by a prospective study from preconception to 16 weeks postpartum, showing significant changes commence very early in pregnancy, continuing through pregnancy and some of the changes persisting postpartum. In his editorial commentary, Webster (pp. 742–743) points out it would be of great interest to know if those variations in early placentation that predispose to hypertensive disorders of pregnancy are reflected in the early hemodynamic changes reported by Mahendru et al.

Among therapeutic interventions, lifestyle changes have been investigated by a consistent number of studies in this current issue. Johnson et al. (pp. 706–723) publish a critical review of the quality of studies on blood pressure response to exercise with the conclusion that meta-analyses have contributed less than ideally to our understanding of how exercise may impact blood pressure, or how these effects may be moderated by patient or exercise characteristics. The authors complain that meta-analyses are often considered pillars of clinical recommendations and guidelines, yet only 58% of those on blood pressure and exercise addressed the clinical translations of their findings. Diaz et al. (pp. 840–848) report that visit-to-visit blood pressure variability was not influenced by randomized individuals with high-normal DBP to weight loss, sodium reduction or both. Zatu et al. (pp. 749–755) found that, in a 5-year prospective study in black South-Africans, self-reported alcohol use, but not biochemical measurements of alcohol intake, associated strongly with blood pressure increases. Causland et al. (pp. 756–761) have analyzed data from the Dietary Approaches to Study Hypertension study and found that being married is independently associated with a greater likelihood of nocturnal blood pressure dipping and with lower night SBP, particularly in men. They underline that marital status is a variable that may be considered in analyses of ambulatory blood pressure. Differences in blood pressure between aboriginal and westernized populations are often taken as evidence of lifestyle influences on blood pressure. Foulds and Warburton (pp. 724–734) overview and meta-analyze 141 articles on blood pressure in North American aboriginal people, and find that current rates of hypertension may actually be lower among indigenous populations than the general population, but rates are quite variable from population to population.

Kim et al. (pp. 904–911) present results of the 5-year prospective North East Melbourne Stroke Incidence Study showing a greater risk of poor outcome occurred in long-term survivors of stroke with low SBP, and suggest that ideal blood pressure levels for stroke survivors may need to be reassessed. This interpretation is challenged by Chalmers (pp. 746–748) in an editorial commentary, who remarks that all studies suggesting a J-shaped curve relationship between treatment-achieved blood pressure and cardiovascular events have been observational and cannot exclude reverse causality, whereas randomized trials in poststroke patients support the benefits of blood pressure reduction. Chalmers concludes ‘there is a clear need for new randomized clinical trials to address these issues and help us to determine what blood pressure thresholds and targets are appropriate for a number of patient groups with increased cardiovascular risk including those with stroke’. Finally, Chiu et al. (pp. 938–947) have examined data from 24 531 matching pairs exposed or nonexposed to angiotensin receptor blocker (ARB) treatment within the Taiwan National Health Insurance Research Database, and found that during the 11-year follow-up ARB-exposed individuals had a significantly lower incidence of all types of dementia. Although these type of data do not have the strength of randomized studies, Chiu et al.'s findings suggest that ARB treatment may be associated with reduced risk of dementia.

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