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Highlights of the November issue

Mancia, Giuseppe

doi: 10.1097/HJH.0000000000002248
EDITOR'S CORNER
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Università Milano-Bicocca, Milan, and Policlinico di Monza, Monza, Italy

Correspondence to Professor Giuseppe Mancia, P.za dei Daini, 4 -20126 Milan, Italy Tel: +39 3474327142; e-mail: giuseppe.mancia@unimib.it

The November issue of the Journal of Hypertension includes three reviews, one of which is accompanied by an Editorial Commentary. The first review (Menard and Devos, pp. 2116–2122) provides a very interesting bibliometric report of the scientific articles on hypertension published in the last 19 years (1997–2016). The authors identified more than one hundred thousand articles published in more than 400 journals during this period, a number 52.7% greater than that of the preceding period. The European Union (EU) was the main contributor (38%) followed by North America (32%) and Asia (26.7%), the Asian articles thanks to a steep increase in the submissions from China. All different aspects of hypertension research were represented, with some differences between America (more epidemiological and experimental papers) and EU (more genetic and clinical papers as well as meta-analyses). Overall, the articles received more than two and a half million citations, with a maximal citation rate for the EU. This shows that, contrary to what has sometimes been perceived, scientific interest and research activity on hypertension remain high, a conclusion further supported by the fact that the increase in the number of hypertension articles is superimposable to that of the whole cardiovascular area, albeit somewhat less than that of medicine as a whole, presumably because of the expanding research activity on oncology. Europe remains the most productive continent in hypertension research which is, however, highly active in other continents as well.

Tian et al. (pp. 2123–2134) review the association between low birth weight and disease in adult life. The factors representing a risk for low birth weight are briefly mentioned together with the diseases that appear in adulthood and have been shown to have an association with body weight abnormalities at birth. Attention, however, is mainly directed to the mechanisms that may explain this association, and evidence is presented to support the hypothesis that insulin resistance (a factor shown to lead to type 2 diabetes and independently increase the risk of cardiovascular and renal disease) plays an important role. The review extends to the potential genetic and environmental mechanisms that may increase insulin resistance (genes controlling glucose homeostasis, nutritional alterations of the mother, etc.), which unfortunately remain largely speculative. Frey et al. (pp. 2135–2144) review the occurrence of serious side effects, as shown by randomized and post hoc studies on blood pressure (BP) reduction to predetermined targets. Compared with moderate BP reductions, intensive treatment was associated with a significantly greater incidence of serious side effects. This confirms previous evidence from many individual studies (as well as from their meta-analysis) that the incremental reduction of cardiovascular outcomes that is obtained by more aggressive BP reductions may be at least in part offset by a reduction of tolerability to treatment, given that side effects (the serious ones, in particular) frequently lead to treatment discontinuation, which is accompanied by an increased cardiovascular risk. The review of Frey and co-workers, however, also highlights that the increased incidence of side effects with lower on-treatment BP values is extremely variable between studies. Furthermore, they report that the criteria employed to detect and define side effects is so heterogeneous between studies as to make their pooling into a meta-analysis unjustified. This is further addressed in the Editorial Commentary of Schutte (pp. 2154–2155), which appropriately emphasizes that an improvement of this aspect of clinical studies, that is, better detection and standardization of the way treatment-related adverse effects are defined, is needed if we want to have better information on the balance between favourable and adverse effects of BP-lowering treatments, and thus improve the evidence on a key element for treatment recommendations to real life medicine.

A section entitled ‘Viewpoints’ includes an article by Vlahakos et al. (pp. 2145–2153) who address the intriguing hypothesis that in the cardiorenal syndrome anemia may be favoured by drugs blocking the renin–angiotensin system, such as ACE-inhibitors and angiotensin receptor antagonists. Several effects of these agents that may potentially lead to a reduced red cell and haemoglobin concentration in plasma are discussed including an unfavourable influence on erythropoiesis. The authors clearly state, however, that, although in heart failure and advanced renal disease and the cardiorenal syndrome anemia is common and has an adverse prognostic impact, this does not mean that RAS blockers should be avoided, given their undisputable overall protective effect in all these clinical conditions.

The following five articles deal with the epidemiology of hypertension. Guzik et al. (pp. 2159–2167) report that in a sample of middle-age women, central and peripheral BP were lower than in age-matched men. However, BP values, derivable from the radial and reconstructed aortic pulse waveform (excess and reservoir pressures), were higher in women than in men, showing that between-gender BP differences may be more complex than that inferred from simpler peripheral BP measurements. The clinical and prognostic significance of these differences require further studies. Noriega de la Colina et al. (pp. 2168–2179) show that, in a small group of individuals with an ambulatory BP either normal or reduced to a normal value by treatment, diurnal BP loads showed an inverse cross-sectional association with cognitive function, as comprehensively assessed by tests addressing cognitive flexibility, working and episodic memory, and processing speed. Use of a measure of cognitive function that takes into account its interaction with the environment and complexity (rather than simplistically deriving the results from the reply to few generic questions, as mostly done in the past) is a noticeable aspect of the study. The question of major importance, which faces us in this area, namely whether antihypertensive treatment provides protection against cognitive deterioration, needs to make use of these more sophisticated approaches. Cherfan et al. (pp. 2180–2189) report that, in a large number of volunteer participants, the prevalence of hypertension was related with the presence of an unhealthy behaviour, the adjusted risk of having a BP elevation being about 1.8 with two and 2.3 with three or more markers of behavioural abnormalities. Kuate Defo et al. (pp. 2190–2199) show that, in 46 491 residents of Cameroon screened between 1994 and 2010, hypertension was detected in 30.9% of the individuals examined. Only 24.4% of hypertensive participants were aware of their hypertensive status, and only 20.8% were treated, with a rate of BP control of 8.8%. The results were, if anything, worse in the second survey (2011–2018) in which the hypertension prevalence increased to 32% and the rate of BP control decreased to 8.3%. As emphasized by the authors, this means that urgent action is needed, considering that, as Cameroon is regarded as an African ‘microcosm’, these results are likely to reflect the more general situation of that continent. Finally, Sarafidis et al. (pp. 2200–2208) show that in patients under hemodialysis, failure to show a reduction of arterial stiffness (pulse wave velocity) when BP (48-h ambulatory monitoring) is reduced is accompanied by a higher risk of death and cardiovascular events. As emphasized by the authors, this suggests that a pulse wave velocity insensitive to the alterations physiologically induced by BP changes probably reflects a particularly marked damage of the mechanistic properties of large arteries, with adverse prognostic implications. A further implication of these findings is that they advocate a more dynamic assessment of arterial stiffness by pulse wave velocity, that is, measurements in stable baseline conditions, but also during acute BP changes.

The following seven articles address pathophysiological aspects of hypertension in the area of organ damage. Saeed and co-workers (pp. 2209–2215) report on the effects of hypertension on the performance and results of the exercise test in patients with aortic stenosis. The coexistence of hypertension and aortic stenosis is further addressed by an Editorial Commentary of Manolis et al. (pp. 2156–2158) who focus on the clinical interpretation of the exercise test in individuals in whom a high BP accompanies aortic stenosis. Further information is given on the importance of hypertension for developing this aortic valve abnormality as well as for determining its natural history and overall cardiovascular risk. Carcel et al. (pp. 2216–2224) describe the clinical characteristics of resistant hypertensive patients in a cohort of individuals recruited from centers located in various parts of the world and specialized in various hypertension-related branches: hypertension in general (55%), cardiology (11%) or nephrology (19%). On the whole, previous cardiac disease was a common finding and so was diabetes mellitus. Drug treatment with the major classes recommended by guidelines (RAS blockers, diuretics, calcium channel blockers) was also common (close to 90% of the patients or more), whereas use of an aldosterone antagonist was much rarer (36%). Diagnosis was based on ambulatory BP in more than 80% of the cases, which denotes adherence to guidelines recommendations. Marques et al. (pp. 2225–2231) show that the product of the APCB1 gene, P-glycoprotein, participates in the process that leads to secretion and activation of aldosterone in humans. Concistrè et al. (pp. 2232–2239) report that in a cohort of essential hypertensive patients, higher plasma aldosterone levels were associated with a higher rate of subclinical organ damage, such as increased 24-h urinary albumin excretion, increased carotid intima–media thickness and carotid plaques. This was the case also for the ankle–brachial index (ABI) which was more clearly elevated at plasma aldosterone concentrations greater than 150 pg/ml. Vallée et al. (pp. 2240–2246) show a clear-cut relationship between a number of serum lipid parameters [low-density lipoprotein (LDL)-cholesterol and total cholesterol, but also triglycerides and HDL-cholesterol] and aortic stiffness. Duzova et al. (pp. 2247–2255) provide the new observation that in 456 children with chronic kidney disease isolated nocturnal hypertension (13.4% of the study population) was associated with a marked increase in pulse wave velocity, carotid intima–media thickness and left ventricular mass index compared with normotensive controls. Isolated nocturnal hypertension is, thus common in this clinical condition (one out of seven children) and its occurrence reflects a greater compromisation of arterial morphology and function. Finally, Sun et al. (pp. 2256–2268) show that in a genetic knock-out mice model of vascular stenosis, wildtype p53-induced phosphatase 1 (Wip 1) plays a major role in the progression of vascular smooth muscle cell proliferation and neointimal hyperplasia, that is, the major causes of plaque progression, and those that in men limit the long-term efficacy of vascular interventions.

The final three articles address therapeutic issues. Bager et al. (pp. 2269–2279) report the results of an analysis of hypertensive patients (aged 40–90 years) from a primary care register (n = 31704). After adjustment for covariates, the hazard ratio for cardiovascular outcomes exhibited by older patients in the 110–129 mmHg SBP group was significantly lower than that of the reference group (−40%, 95% confidence interval −60 to −8%]) suggesting that in aged people aggressive BP targets may be protective or at least devoid of harm. Although the nonrandomized nature of the study makes alternative explanations possible, these results remind us that the question of the optimal BP target to be pursued with treatment has by no means received a consistent answer. On the contrary, it continues to generate discrepant results, which makes further well conceived and conducted studies (including those from real life research) important. Dominiczak et al. (pp. 2280–2289) describe the results of a randomized double-blind study that showed the combination of single pill slow release indapamide and amlodipine (1.5/5 mg) to more effectively reduce office, ambulatory and home BP than the single pill combination of amlodipine and valsartan (5/80 mg). Zweiker et al. (pp. 2290–2297) report the results obtained in a relatively large number of patients (n = 291) with resistant hypertension included in the Austrian Renal Denervation Registry. From a mean 24-h BP value of 150/89 mmHg BP exhibited a reduction after renal denervation (−9/−6 mmHg), the effect being greater in women and in nondiabetic patients. After the negative finding of the Symplicity-3 study, several randomized trials (as well as observational studies like the present one) have shown that renal denervation can reduce BP, although with a magnitude that does not allow full BP control to be achieved. This has re-established some confidence in the effectiveness of this intervention at least to complement the BP-lowering influence of antihypertensive drugs, when they are unable to control BP. This is likely to be the case more often in the future because of the lower BP targets now recommended by guidelines.

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