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Challenges of hypertension and hypertension treatment

Zanchetti, Alberto

doi: 10.1097/HJH.0000000000000359

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 present issue of the Journal of Hypertension is largely focused on challenging problems of hypertension management.

A first problem, long debated but unsolved yet, regards the type and time of the blood pressure (BP) measurement that may provide a greater predictive indication of cardiovascular damage and, possibly, a better guidance for preventive interventions. Ambulatory BP monitoring (ABPM) over the night has repeatedly been considered more predictive than daytime monitoring, and the size of the BP decrease characterizing night sleep (in medical jargon named ‘dipping’) is often used as a quantitative predictor. In a cross-sectional analysis of 682 hypertensive patients of the Korean ABP study, Yi et al. (pp. 1999–2004) now report that the level of nocturnal BP is a far more important determinant of left ventricular hypertrophy than the extent of dipping. In the same issue, another study, analyzing a group of Korean patients with obstructive sleep apnea (OSA), emphasizes the role of absence of dipping and of reverse BP changes during night-time (what in medical jargon is often referred to as ‘reverse’ dipping, a term which suggests some strange physical activity of astronauts in absence of space) in possibly determining brain damage diagnosed in magnetic imaging as ‘white matter hyperintensities’ (Lee et al., pp. 2005–2012). In two thoughtful comments that accompany the two studies, Narayan and Cameron (pp. 1962–1963) and Pucci et al. (pp. 1964–1966) raise the point that a cross-sectional design, such as that followed in both studies, cannot demonstrate cause-and-effect relationships, so that terms like ‘predictor’ or ‘predicting’ should be avoided in reporting results of cross-sectional studies.

Another cross-sectional study in this issue adds some unexpected data to the debate of sleep influence on BP. Although previous epidemiological studies have suggested that a shorter duration of nocturnal sleep may increase the risk of hypertension for older adults (in keeping with the protective role of a lower BP during night sleep), Cao et al. (pp. 1993–1998), in a very large cohort of Chinese people (more than 27 000 participants), found that the practice of a longer afternoon nap is associated with a higher prevalence of hypertension. This also is a cross-sectional study with its well known limitations and difficulties in identifying confounding factor, as remarked by Lombardi et al. in their accompanying editorial.

Obstructive sleep apnea is not only associated with higher BP during the night, but represents a condition often responsible for resistant hypertension. Three articles are devoted to this challenging type of hypertension. On the diagnostic side, Margallo et al. (pp. 2030–2037) report the widely used Berlin questionnaire used to screen patients with OSA has a low accuracy. On the therapeutic side, Azizi et al. (pp. 2038–2044) expand their previous studies comparing the effectiveness of a therapeutic strategy based on the use of mineralocorticoid receptor blockade with one based on dual renin–angiotensin system blockade, and show the former approach is not only more successful in reducing BP, but is also more efficient in reducing left ventricular mass. It is known that aldosterone is often elevated in resistant hypertension, and plays a role in maintaining elevated BP, and in this issue a study by Petramala et al. (pp. 2022–2029) shows primary aldosteronism is accompanied by an increased oxidative stress, a mechanism probably involved in the frequent organ damage present in this type of secondary hypertension. Interest in new procedures, alternative to drug titration, to lower BP in resistant hypertension has survived the recent negative results of Symplicity-3, and Vink et al. (pp. 2045–2053) show that the BP-lowering effect of renal denervation is inversely proportional to baseline estimated glomerular filtration rate (eGFR), thus being more effective in situations known to be associated with a particularly high level of sympathetic activity.

Therapeutic challenges are discussed in another group of studies. Ogihara et al. (pp. 2054–2063) present the result of a Japanese randomized controlled trial aiming at verifying the unexpected result of the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial [1], that is, that association of a blocker of the renin–angiotensin system in association with a calcium channel blocker is more powerful in reducing cardiovascular event incidence than its association with a thiazide diuretic. Instead of the angiotensin-converting enzyme (ACE) inhibitor used in the ACCOMPLISH trial, Ogihara et al. have used an angiotensin receptor blocker, olmesartan. Formally, the Combinations in Olmesartan (COLM) study has been unable to confirm the results of the ACCOMPLISH trial, the difference in event incidence between the two olmesartan combinations not achieving statistical significance. In an accompanying editorial, Cífková (pp. 1967–1969) remarks there were a number of differences between the COLM study and the ACCOMPLISH trial, both in the characteristics of the patients included and in the primary endpoint used, but particularly the COLM study was underpowered and it cannot be excluded that with a larger population of patients or a more prolonged follow-up the nonsignificant hazard ratio [0.83, 95% confidence interval (CI) 0.65–1.07] might have achieved statistical significance.

Other therapeutic contributions are provided by a systematic review by Peters et al. (pp. 1945–1958) on calcium channel blocker use and cognitive decline or dementia in the elderly, showing no clear evidence to suggest that these agents increase or decrease risk of cognitive decline or dementia; a randomized controlled study by Faulkner et al. (pp. 2064–2070) reporting the long-term beneficial effect of exercise on vascular risk factors and aerobic fitness in patients with a recent transient ischemic attack; an analysis of data from the Women's Health Initiative randomized controlled trials showing that among postmenopausal women hormone replacement therapy (both based on estrogens only or their combination with progesterone) is associated with a small but statistically significant increase in SBP and its visit-to-visit variability (Shimbo et al., pp. 2071–2081); a study by Ruiz-Hurtado et al. (pp. 2082–2091) reporting that in patients with stage 2 chronic kidney disease under chronic renin–angiotensin system blockade persistence of albuminuria is accompanied by more marked oxidative damage; an epidemiological study in the Rotterdam population finding that the risk of thiazide-induced hypokalemia is rather high, particularly in men, and only partially reduced by simultaneous use of a potassium sparing agent (Rodenburg et al., pp. 2092–2097).

A systematic review and two epidemiological studies focus on behavioral influences on hypertension: perceived stress and occupational status interact to increase the risk of future high BP (Wiernik et al., pp. 1979–1986); personality traits characterized by anxiety influence the white coat effect (Terracciano et al., pp. 1987–1992), and a meta-analysis of available randomized trials on stress reduction techniques appear to support a BP-lowering effect of these techniques in hypertensive patients, though the authors warn the conclusions must be interpreted with caution because major methodological limitations of the relevant trials (Nagele et al., pp. 1936–1944).

Other epidemiological studies in the current issue of the Journal report a significant increase in the prevalence of hypertension in China over the period 2002–2012 (Wang et al., pp. 1919–1927), the high prevalence of aortic root dilatation among hypertensive patients (Covella et al., pp. 1928–1935), and the low prevalence of chronic kidney disease in a very large cohort (128 588 individuals) of relatively young (mean age 39 years) Spanish workers once GFR is correctly estimated on two repeated blood samples (Sánchez-Chaparro et al., pp. 1970–1978).

Finally, the findings of an experimental study by Sampson et al. (pp. 2013–2021) suggest that introgression of the chromosome 2 congenic interval from the Wistar–Kyoto rat into the spontaneously hypertensive rat-stroke prone is associated with restored aldosterone regulation sufficient to reduce salt-sensitive hypertension and reduce proteinuria.

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Conflicts of interest

There are no conflicts of interest.

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1. Jamerson K, Weber MA, Bakris GL, Dalhöf B, Pitt B, Shi U, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008; 359:2417–2428.
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