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Challenges of antihypertensive treatment

Zanchetti, Alberto

doi: 10.1097/HJH.0000000000001046

aIstituto Auxologico Italiano

bCentro 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:

In the current issue of the Journal of Hypertension, a large number of articles published focused on antihypertensive treatment and its challenges.

Thomopoulos et al. (pp. 1451–1463) present the results of an extensive meta-analysis of permanent treatment discontinuations attributed to adverse events in randomized trials of blood pressure lowering. They show that the well established reduction of cardiovascular events is associated with an excess of discontinuations for adverse events which increases the greater is the extent of blood pressure lowering and the lower is the level of SBP attained. In an accompanying editorial commentary, Kjeldsen et al. (pp. 1489–1491) underline the concept that awareness of the adverse events often accompanying antihypertensive treatment should not lead to deny patients the benefits of blood pressure lowering, but can call attention on tolerability of a given treatment and influence selection of drugs, intensity of treatment and investigation care. In another thoughtful article, Chalmers et al. (pp. 1473–1479) point out that randomized controlled trials, which necessarily last only a few years, cannot be the only source of recommendations for lifelong treatment of chronic diseases, such as hypertension. In the authors’ opinion, one of the most promising sources of information consists of data gathered through the ever-expanding pool of administrative databases worldwide. The suboptimal control of high blood pressure by antihypertensive treatment worldwide is discussed in an editorial by Redon et al. (pp. 1480–1488), who summarize the suggestions of a working group on five key actions.

Another group of articles are concerned with a long-standing challenge of antihypertensive treatment, namely, by which type of blood pressure measurement treatment should be guided. Shimada et al. (pp. 1520–1527) report the results of the large-scale observational HONEST study, in which more than 20 000 hypertensive Japanese patients were followed under antihypertensive therapy for 2 years: morning home SBP during follow-up was found to have better prognostic ability than clinic SBP in predicting cardiovascular events. These findings are discussed by Angeli et al. (pp. 1494–1496) in an accompanying commentary in which they underline the opportunity of a large, multinational, intervention study testing the superiority of home versus clinic blood pressure as a target for clinical decision.

The parallel question, whether central blood pressure is more predictive of cardiovascular events than brachial blood pressure, has been investigated by Mitchell et al. (pp. 1528–1534) in participants of the Framingham Heart Study: the authors report that after considering standard risk factors and including brachial cuff SBP, augumentation index, central pulse pressure and pulse pressure amplification, derived using radial artery tonometry and a generalized transfer function, were not predictive of cardiovascular events during a follow-up of 7.8 years. These important findings are discussed in an editorial commentary by Laurent et al. (pp. 1497–1499), who agree that the results of Mitchell et al. (pp. 1528–1534) clearly show that central blood pressure, as measured by current noninvasive technology, does not show predictive superiority over brachial blood pressure, but urge the research community to develop more accurate noninvasive methods to retest the hypothesis.

The mechanism by which β-blockers appear to reduce central blood pressure to a lesser extent than brachial blood pressure have been investigated by Goupil et al. (pp. 1535–1543), who conclude that the mechanism has both heart rate-dependent and independent components, which are similar for atenolol, metoprolol and bisoprolol. Further evidence for visit-to-visit variability as a risk factor is contributed by Ogliari et al. (pp. 1544–1550), who have studied 4745 elderly individuals followed up for more than 3 years in the PROSPER study and found that higher visit-to-visit SBP, but not DBP, variability was associated with steeper functional decline in these old individuals. Normative blood pressure and pulse rate values are provided by Satoh et al. (pp. 1578–1585) for Japanese newborns.

Other aspects of pharmacological treatment are discussed in the current issue of the Journal of Hypertension. van Twist et al. (pp. 1607–1614) find that renal vasodilatation induced by local infusion of the angiotensin receptor blocker eprosartan is unexpectedly not influenced by low and high-sodium intake and angiotensin II infusion. Andersen et al. (pp. 1621–1629) have investigated the hypothesis that the epithelial sodium channel is proteolytically activated by urine plasmin in diabetic nephropathy and mediates renal sodium retention, but found that amiloride increase renal sodium excretion and reduce SBP in type-1 diabetic patients independently of nephropathy. Commenting these findings, Chappell et al. (pp. 1500–1501) remark that the potential for amiloride to attenuate proteinuria and glomerular injury in the diabetic kidney through the uPAR-ß-3 pathway should be a focus of continuing investigation for the novel actions of this diuretic.

The current interest in device-based treatment of resistant hypertension is documented in two articles, both accompanied by editorial commentaries, in the present issue. Wallbach et al. (pp. 1630–1638) publish results of baroreflex activation therapy performed in 28 patients, in whom previous renal denervation had failed to control high blood pressure, reporting SBP could be reduced by at least 10 mmHg in 68% of the patients; albuminuria was also significantly reduced. Jordan et al. (pp. 1502–1504) in their commentary point to the limitations of the study by Wallbach et al., particularly the open design and lack of a control group, but find the idea that electrical carotid sinus stimulation may chronically lower blood pressure in patients with denervated kidney to be thought provoking. They suggest that while waiting for the results of properly designed clinical trials, new devices, such as baroreceptor activation therapy, may be taken advantage of to learn more about human pathophysiology. Mathiassen et al. (pp. 1639–1647) have conducted a single-center, sham-controlled, double-blind trial of renal denervation by a single electrode catheter in 69 patients, finding the same small decrease in mean daytime ambulatory SBP in the denervation and sham denervation group. In an accompanying commentary, Schlaich (pp. 1505–1506) commend the authors for having performed a sham-controlled study taking in account several of the previous criticisms raised in regard to Symplicity HTN-3, but conclude that we will have to await results from ongoing sham-controlled trials with multi-electrode catheters targeting both the main renal artery and its branches to ultimately define the utility of renal denervation for treatment of hypertension.

Other articles with therapeutic impact include an article by Jusufovic et al. (pp. 1594–1598) with further analyses of the Scandinavian Candersartan Acute Stroke Trial (SCAST) showing that among patients treated within 6 h from an acute stroke, antihypertensive treatment by candesartan reduced vascular events categorized in order of severity, and an article from a multicenter registry in China (Song et al., pp. 1648–1653) reporting that hypertension and diabetes were often combined, and management of both hypertension and diabetes were often insufficient.

Other aspects of hypertension have been investigated in other articles. Alshaarawy and Elbaz (pp. 1507–1512), analyzing data in the US National Health and Nutrition Examination Surveys (NHANES) 2005–2012, find a modest but significant association between recent cannabis use and SBP and conclude that with the current trend towards legalization of cannabis, there is a need for preclinical, clinical and prospective population-based research on the cardiovascular effect of cannabis use. Rautianen et al. (pp. 1513–1519) have examined data from the Women's Health Study (28 157 middle-aged and older women followed up for 11.5 years) and found no evidence that multivitamin use is associated with the risk of developing hypertension.

Other articles are focused on blood vessels in hypertension. Mordi et al. (pp. 1464–1472) review the mechanisms of endothelial dysfunction in hypertension, its prognostic significance and methods of pharmacological reversals. This topic is commented by Taddei and Bruno (pp. 1492–1493), who agree that the prognostic role of endothelial dysfunction in hypertension is an important open question, but are confident that pharmacological improvement of endothelial function in patients with hypertension is an appealing possibility. Carlisle et al. (pp. 1556–1569) find that endoplasmic reticulum stress causes endothelial-mediated vascular dysfunction, thus contributing to elevated blood pressure in the spontaneously hypertensive rat. Holtackers et al. (pp. 1551–1555) call attention on the correct orientation head should have in ultrasound studies on carotid artery distensibility; Veerbeek et al. (pp. 1570–1577) have done a systematic study of vascular pathology in uterine spiral artery biopsy samples in women with preeclampsia and with normal pregnancy and related spiral artery pathology to postpartum cardiovascular risk; and Kinjo et al. (pp. 1586–1593) report that a high normal ankle–brachial index combined with a high brachial–ankle pulse wave velocity is strongly correlated with cerebral microbleed, suggesting a novel use for ankle–brachial index as a predictor for organ damage. Soullier et al. (pp. 1615–1620) find that hypertensive patients have a significant impairment of the three components of left atrial function, and these changes are correlated with left ventricular hypertrophy and dysfunction. Chen et al. (pp. 1599–1606) report that renal dopamine D3 receptor regulates the expression and function of the D4 receptor in renal proximal tubule cells via phospholipase/protein kinase C signalling pathway, and suggest the loss of this interaction might be involved in the pathogenesis of hypertension.

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Conflicts of interest

There are no conflicts of interest.

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