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Mechanisms, diagnosis and therapy of hypertension

Zanchetti, Alberto

doi: 10.1097/HJH.0000000000001638

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

Correspondence to Prof Alberto Zanchetti, Istituto Auxologico Italiano IRCCS and Centro Interuniversitario di Fisiologia Clinica e Ipertensione, Università degli Studi di Milano, Via F. Sforza, 35, 20122 Milano, Italy. Tel: +39 02 50320484; e-mail:,

Received 7 November, 2017

Accepted 7 November, 2017

The articles in the current issue of the Journal of Hypertension approach mechanistic, diagnostic and therapeutic aspects of hypertension.

Mechanisms of hypertension and hypertension-related organ damage have been explored by a large body of studies. Four articles focus on the role of several blood pressure (BP) parameters on cardiovascular risk and organ damage. Kollias et al. (pp. 243–249) report that a two-night home BP schedule (six readings) appears to provide reasonable agreement with ambulatory BP and to be associated with asymptomatic organ damage, and Sherwood et al. (pp. 250–258) find that blunted night-time dipping is associated with impairment of the systemic vasodilatation occurring during the night-time sleep period, impairment that is especially prominent among African Americans. According to the authors, these findings suggest that nondipping may be a manifestation, or marker, of more advanced vascular disease. In the Maastricht Study database, Zhou et al. (pp. 259–267) have calculated short-to-mid-term BP variability in individuals with normal glucose metabolism, prediabetes and type-2 diabetes and found that both diabetes and prediabetes are associated with a slightly greater variability that may explain a small part of the increased cardiovascular risk seen in prediabetes. Another cross-sectional study (Dore et al., pp. 268–276) has investigated the possible role of intraindividual BP variability in cognitive decline in community dwelling participants in the Maine-Syracuse Longitudinal Study and report that, in individuals aged over 60 years, intraindividual BP variability was inversely correlated with a number of indices of cognitive function.

Three articles focus on the mechanisms and consequences of arterial stiffness. Han et al. (pp. 299–305) have used computed tomography to measure abdominal and subcutaneous fat in a group of Japanese Americans followed up for 5 years and report the accumulation of abdominal fat (but not of subcutaneous fat) over time independently predicted future pulse pressure, taken as a marker of arterial stiffness. Rasmussen et al. (pp. 277–285) have investigated the cardiovascular effects of abuse of anabolic androgenic steroids in a group of current and former abusers: current abusers displayed increased 24-h SBP and higher aortic stiffness, together with a decreased plasma concentration of vasodilating natriuretic peptides. Sadekova et al. (pp. 286–298) have used a mouse model of increased arterial stiffness (application of CaCl2 to the adventitia of the right carotid artery) and investigated its consequences in the brain: increased cerebral gliosis was found, mediated by oxidative stress and attenuated by Tempol treatment. The authors conclude that correcting arterial stiffness may offer a novel paradigm to protect the brain in populations in which stiffness is prominent.

Two other mechanistic articles concern the kidney. Cervantes-Perez et al. (pp. 361–366) find that angiotensin-II-induced hypertension in mice requires, at least in part, activation of the renal NaCl cotransporter via the WNK/SPAK signaling pathway, whereas aldosterone-induced hypertension depends on epithelial sodium channel activation in a WNK/SPAK-independent manner. Martínez-Martínez et al. (pp. 368–376) show that galactin-3 inhibition attenuates early renal damage in the spontaneously hypertensive rat, as indicated by reduced albuminuria, improved renal function and decreased renal fibrosis, epithelial–mesenchymal transition and inflammation, independently of BP levels.

Two articles investigate problems related to preeclampsia. Wang et al. (pp. 306–318) report that in preeclamptic placenta, a lowered level of miR-195 may be induced by chorionic oxidative stress and may subsequently form a compensation mechanism to defend the disturbed energy production and cell apoptosis upon oxidative stress. Brussé et al. (pp. 319–325) show neurophysiological adaptation to pregnancy of the visual cortex in normotensive pregnant women, which is apparently lost in women with severe preeclampsia. A final mechanistic article reports left ventricular subclinical systolic dysfunction in patients with primary aldosteronism (Chen et al., pp. 353–360).

Three articles focus on the diagnosis of primary aldosteronism. Yamashita et al. (pp. 326–334) have developed and validated a scoring system for screening newly diagnosed hypertensive patients who should proceed to endocrinologic examinations for primary aldosteronism. On the basis of a series of 130 consecutive patients, 24 of whom were diagnosed with primary aldosteronism by an elevated plasma aldosterone concentration-to-plasma renin activity ratio, Yamashita et al. conclude that a score based on urine pH at least 7.0 (P), female sex (F) and hypokalemia (K) (PFK score) may be a better parameter than hypokalemia alone for screening patients with a high probability of having primary aldosteronism. Rossitto et al. (pp. 335–343) have investigated the hypothesis that sequential blood sampling from the adrenal veins on both sides may decrease the diagnostic accuracy of the lateralization index for identification of an aldosterone-secreting adenoma and found it generates factitious between-side gradients, which lower its diagnostic accuracy, likely because of the stress reaction arising upon starting adrenal vein catheterization. Genovesi et al. (pp. 344–352) have measured plasma aldosterone and plasma renin concentrations and aldosterone-to-renin ratios in a cohort of 287 children attending a specialized clinic and found the aldosterone-to-renin ratio is lower than in adults and diverges with increasing age between sexes.

A large body of articles focus on different aspects of antihypertensive treatment. A position article of the Latin American Society of Hypertension (Coca et al., pp. 208–220) discusses the best antihypertensive strategies to improve BP control in that part of the world and, more generally, how to overcome barriers to achieve good BP control in low-income countries. The document underlines randomized trials have shown there are little substantial differences between the benefits of major classes of BP-lowering drugs and prevention of major cardiovascular events depends on BP lowering independently of the drugs used. Within each drug class, although some compounds have been tested in trials more widely than others, there is no evidence of major differences between molecules, and the suggestion is given to prescribe those that can be purchased by health providers or by the patients at the lowest price, provided that good manufacturing quality is guaranteed. In the current issue of the journal, an article by Macquart de Terline et al. (pp. 395–401) raises the problem of the quality of antihypertensive generic medication in low-income countries: the authors report that nearly one-quarter of the generic antihypertensive drugs available in the sub-Saharian countries were found to be of poor quality, although poor quality was not necessarily associated with the purchase price of the drug. In a thoughtful accompanying editorial, Alcocer (pp. 230–233) underlines the importance of assuring quality of generic drugs, particularly in low-to-middle income countries, in which purchasing costly medications can lead a family toward poverty, and points out the responsibility for ensuring that the drug prescribed under a generic name is interchangeable with the original medication rests with government health authorities.

Some of the difficult problems associated with so-called treatment-resistant hypertension are approached by two articles. Analyzing data from the Swedish Primary Care Cardiovascular Database from 2006 to 2012, including over 4300 patients who could be defined as resistant to antihypertensive treatment, Holmqvist et al. (pp. 402–409) found they had a poor prognosis beyond BP level, with a particularly high risk for heart failure. Renal denervation is being recently considered as a possible therapeutic approach in these patients, and Persu et al. (pp. 221–229) have carried out a patient-level meta-analysis of 24-h BP recordings in 167 patients with treatment-resistant hypertension receiving renal denervation treatment: they report that renal denervation was associated with a decrease in BP variability independent of BP level, suggesting that responders may derive benefit from the BP variability reduction.

The SPRINT trial data have been reanalyzed by Ferreira et al. (pp. 428–435) to relate absolute benefit and absolute harm of more intense BP-lowering treatment: antihypertensive treatment intensification was associated with lower cardiovascular event rates, but increased the risk of adverse events. However, mortality within 1 year of an efficacy outcome was nearly three-fold higher than following a safety (adverse) outcome. The authors conclude that having adverse events has less weight when it comes to therapeutic decisions. On the other hand, the risk of excessive lowering of DBP was analyzed by Wokhlu et al. (pp. 419–427) in data from the INVEST trial in hypertensive patients with coronary heart disease: in these patients, the mortality risk related to an achieved DBP lower than 69 mmHg was accentuated when SBP also achieved values lower than 120 mmHg. Although being post-hoc and with lost randomization, these analyses raise concern about intense BP lowering in coronary patients.

The recommendation by the Eighth Joint National Committee (JNC-8) to raise the BP target of antihypertensive treatment in the elderly to values below 150/90 mmHg has generated two studies published in the current issue of the Journal of Hypertension. Asayama et al. (pp. 410–418) publish an analysis of cardiovascular mortality in young-old and old-old participants from seven Japanese general populations, reporting that, irrespective of antihypertensive medication, the risk increase of total cardiovascular and stroke mortality with elevation of BP was significant among young-old, but did not reach significance among old-old participants. Nayor et al. (pp. 436–443) have calculated the incidence of cardiovascular disease in individuals whose BP management strategy would change with adoption of the JNC-8 guidelines in two large, community-based cohorts, the Framingham and Jackson Heart Studies and conclude that adoption of the JNC-8 recommendation to treat BP levels less aggressively in the elderly may be associated with substantial residual cardiovascular disease risk. In commenting these data in an accompanying editorial, Currie and Delles (pp. 234–236) try to put them into the current precision medicine landscape and suggest that, to enter the precision medicine age also for the diagnosis and treatment of hypertension, we have to generate deeper phenotypic data by which to answer questions about BP targets and several other current controversies.

Three additional articles in this issue of the Journal may have therapeutic implications. Dolmatova et al. (pp. 237–242), examining data from the National Health and Nutrition Examination Survey (1999–2012), find that sodium intake has increased over the last two decades among US individuals with hypertension, especially Hispanics and African Americans, and call for more effective strategies and aggressive approaches to reduce the sodium consumption among hypertensive adults. Mali et al. (pp. 377–386) provide new evidence in mice that smooth muscle cell stromal interacting molecule-1 disruption protects the heart from myocardial infarction through reduction of endoplasmic reticulum stress, oxidative stress, mitogen-activated protein-kinase, apoptosis and inflammation. Azegami et al. (pp. 387–394) have developed an intranasal vaccine that simultaneously targets hypertension and pneumonia, consisting of nanogel incorporating angiotensin II type 1 receptor partial peptide conjugated with pneumococcal surface protein A. Given intranasally to spontaneously hypertensive rats, the vaccine attenuated the development of hypertension and protected the rats from lethal pneumococcal infection.

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Conflicts of interest

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