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Highlights of the August issue

Mancia, Giuseppea,b

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doi: 10.1097/HJH.0000000000002539
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The August issue of the Journal of Hypertension devotes a large fraction of the available space to reviews, meta-analyses and a consensus document of the Working Group on Endocrine Hypertension of the European Society of Hypertension. Burnier et al. (pp. 1396–1406) address the question of whether antihypertensive drugs should be taken in the evening rather than in the morning as more commonly done in current medical practice. Criticism is raised on the article of Hermida et al. (Eur Heart J 2019, doi:10.1093/eurheartj/ehz754) which reported that evening assumption of antihypertensive drugs was associated with a major reduction (−48%) of outcomes compared with morning assumption, the multiple shortcomings of the study being summarized in a table. The article also reviews the strong evidence that nocturnal blood pressure (BP) values are prognostically important, but also that, except for Hermida's paper, few data are available that enhancing nocturnal hypotension by taking BP-lowering agents in the evening increases treatment-related protection. Myers et al. (pp. 1407–1411) support use of automated ‘unattended’ office BP measurements against the classical ‘attended’ office measurements. Importance is given to the similarity between BP values obtained with the former approach and ambulatory awake BP, which is regarded to be prognostically more important than office BP in both untreated and treated patients. The issue, however, is controversial as it can be appreciated by the considerations made in the Editorial Commentary of Filipovský (pp. 1457–1459). Weir et al. (pp. 1412–1419) offer a narrative review of the use and relevance of complementary and alternative medicine for the treatment of hypertension. Mention is made that this approach has not undergone the rigorous testing that have been adopted for traditional therapies, but also that this should not be a reason for altogether dismissing their possible benefits, for both BP control and cardiovascular protection. Makovac et al. (pp. 1420–1435) review the available literature that suggests a relationship between BP elevations and hypoalgesia. The mechanisms of this effect are recognized as being largely unknown, however. Grassi et al. (pp. 1436–1442) report the results of a meta-analysis which shows that microneurographically quantified sympathetic nerve traffic to skeletal muscle circulation is increased in patients with type 2 but not in those with type 1 diabetes mellitus. Other interesting results were that the increase in nerve traffic was manifest also when sympatho-excitatory comorbidities that are common in type 2 diabetes (hypertension, obesity, metabolic syndrome) were excluded and exhibited a close relationship with plasma insulin, strengthening the hypothesis of an insulin-independent causal role. Finally, Lenders et al. (pp. 1443–1456) highlight the great progress that has been made in the recent past on the biochemical testing, bio-imaging, genetic and pathophysiological practical approach and understanding of pheochromocytoma and paraganglioma. The document also addresses the future directions of research in this area, including genetic testing.

Three original articles of the August issue are devoted to the epidemiological aspects of hypertension. Bennie et al. (pp. 1466–1473) describes a cross-sectional study that pooled data from four US health insurance surveys for a total of more than 1.5 million individuals. Muscle-strengthening exercise (using weight machines and body weight exercises) showed a clear-cut independent association with a lower risk of self-reported hypertension (28% of the study population), the risk of exhibiting a hypertensive state being lower even when exercise was performed only once or twice during the week. Muscle strengthening exercises are mostly of the isometric type, which thus may have beneficial effects on BP similarly to what is reported for dynamic exercise. Man et al. (pp. 1474–1480) show that in the 1231 participants of the Oman Family Study, heritability was lower for BP than for obesity, whose genetic background was higher than the environmental one. These interesting observations include the evidence that heritability was greater for ambulatory than for office BP and that, within the 24-h, daytime BP was more clearly genetically determined than BP during the sleeping time. Wei et al. (pp. 1481–1487) extend the available data on the relationship between microRNA genes and the risk of ischemic stroke to a new polymorphism, thereby expanding the evidence on the chance to predict the risk of cerebrovascular events by genetic testing.

One original article of the current issue addresses sympathetic activation in human hypertension while seven focus on the mechanisms of organ damage, three in the experimental setting and four in human hypertension. Esler et al. (pp. 1488–1495) show that in patients with unmedicated essential hypertension, cardiac, renal and total noradrenaline spillover rates were increased, whereas adrenaline secretion was normal. There was no internal correlation between cardiac and renal spillovers, and a commonly used marker of sympathetic activity such as heart rate exhibited a close relationship with cardiac but not with renal spillover or adrenal secretion. This extends the results obtained by the authors in the past that in hypertension, sympathetic activation is not global but rather characterized by regional differences. This has important pathophysiological and clinical implications but also methodological relevance for studies on sympathetic influences in individuals with high BP. This is addressed in the Editorial Commentary of Grassi et al. (pp. 1460–1461).

The three experimental articles on organ damage document the involvement of an α1D-adrenoreceptor antagonist on the reversal of cardiac hypertrophy of spontaneously hypertensive rats (Rodríguez et al., pp. 1496–1503); the improvement of stress-induced thrombosis in mice treated with the DPP-4 inhibitor anagliptin (Jin et al., pp. 1504–1513); and the ability of cysteinyl cathepsin K to reduce the neointimal hyperplasia that develops in mice as a result of chronic stress (Meng et al., pp. 1514–1524). The four original articles in humans address different aspects of organ damage, that is ventricular remodeling of the right ventricle (RV), arterial stiffening, microvascular dysfunction and retinal abnormalities. Tadic et al. (pp. 1525–1530) provide evidence from 505 patients that hypertension is associated with functional and structural alterations of the RV and that the right atrium is involved as well. Evidence includes the association of these abnormalities with the nondipping phenomenon as well as with their ability to independently predict adverse events. Kubalski and Hering (pp. 1531–1540) show that pulse wave velocity can change over a 4-week period and that thus its reproducibility should be a factor to take to account when studying arterial stiffness alterations over time and by treatment. Zhou et al. (pp. 1541–1550) show that in the large number of individuals of the Maastricht study (n = 2773) short (24 h) and mid-term (week) BP variability was related to albuminuria but much less to retinal arteriolar alterations, leading the authors to suggest an especially greater adverse role of short or mid-term BP variations on the kidney. Gosk-Przybylek et al. (pp. 1551–1558) report that in patients with pheochromocytoma or paraganglioma retinal vessels exhibited structural alterations that were not associated with BP values, thereby being probably induced by the influence of a catecholamine excess per se. These important observations were accompanied by the evidence that the retinal structural alterations were reversible after surgical removal of the tumor.

The last six articles provide data on antihypertensive treatment. Lim et al. (pp. 1559–1566) show that in 44 462 patients from the Korean National Health Insurance Service a SBP reduction below 120 mmHg was associated with an increased risk of cardiovascular outcomes, that is a U curve phenomenon, compared to an on-treatment SBP between 120 and 129 mmHg. This is in line with the recommendations of the European guidelines not to go below a systolic value of 120 mmHg with treatment. Importantly, in the study of Lim et al. the U curve was especially evident in elderly patients, presumably because aging is accompanied by an impairment of reflex and local (e.g. blood flow autoregulation) mechanisms preserving vital organ perfusion. It is also in line with the following article (Blum et al., pp. 1578–1585) which shows that in patients with a recent lacunar stroke and an age of at least 65 years, lowering SBP to below 130 mmHg reduced to only a small degree stroke and cardiovascular events and did not modify cognitive function and white matter hyperintensities compared to remaining with a SBP between 130 and 149 mmHg. It is, on the other hand in contrast with the following article of Contreras et al. (pp. 1567–1577) which shows that, in middle age and elderly patients with grade 1 hypertension of the SPRINT and ACCORD trials, lowering SBP below 120 mmHg was accompanied by a reduction in the risk of cardiovascular outcomes of nonmarginal proportions (−25%). This is a further example of the discrepant results that make the issue of the optimal BP target for treatment still an unresolved one. The problem lies in the observational nature of the studies which, no matter how carefully performed and analyzed, cannot avoid confounders that do not allow a final conclusion to be safely reached. It also lies, however, in the limitations of trials from which many post-hoc observational analyses have been derived. This is the case also for the ACCORD and SPRINT trials, as discussed in several reviews and debates. A new trial that avoids the interpretation problems of previous trials (e.g. the open design for the SPRINT trial and the interference of glucose-lowering treatment for the ACCORD trial) will be highly desirable, keeping in mind that searching for a single optimal cutoff target that fits all patients may be unrealistic. It is more likely that the optimal target differs between patients and changes within patients as age and clinical characteristics change. Further considerations will be found in the Editorial Commentary of Volpe and Gallo (pp. 1462–1463). Finally, Falster et al. (pp. 1586–1592) provide a detailed description of the use of combination treatment in Australia between 2012 and 2018. Combination treatment was used by half of the Australian hypertensive population, which is more than what is reported from many other Countries, the European ones included. Furthermore, use of inappropriate combinations was detected in only a very small percentage of patients, that is less than 1% for dual and slightly more than 2% for combinations up to four to five drugs. Because, as emphasized by guidelines, combinations lower BP much more effectively than monotherapy, these are encouraging findings that reassure on the value of guidelines recommendations for clinical practice. See also the Editorial Commentary of Jensen (pp. 1464–1465). Pandey et al. (pp. 1593–1602) provide the important demonstration that nanoparticles of hydrochlorothiazide, candesartan and amlodipine loaded by emulsion, diffusion and evaporation into a polylactide-co-glycolic acid nano polypill were effectively (90%) and constantly released over a 7-day period in simulated gastric or intestinal fluid. Once-a-week administration of antihypertensive combination treatment is an exciting possibility that might substantially improve adherence to treatment and thus BP control. Finally, An et al. (pp. 1603–1611) made use of the large database provided by the Kaiser Permanente Southern California database to quantify in real life the prevalence of individuals diagnosed as having resistant hypertension, that is three drugs with no BP control or four drugs regardless the BP value. Out of 469 509 individuals, those with resistant hypertension amounted to 16.9 and 21.8% depending on whether the BP values reflecting BP control were the JNC7 (<140/90 mmHg) or the ACC/AHA guidelines (<130/80 mmHg). This is a higher figure than that reported by other surveys, which have set the prevalence of resistant hypertension to less than 5% of the overall hypertensive population. Factors responsible for these differences should be further analyzed.

Continuing what has been done in the past few issues, the August issue of the Journal of Hypertension includes scientific information on the relationship of hypertension or antihypertensive treatment with the COVID-19 infection. It also includes a case report on a very peculiar patient in whom carotid baroreflex damage by neck surgery was accompanied by the expected BP instability but also by an unexpected marked hyponatremia, which suggests that this reflex does not only stabilize BP, but it is also involved in blood volume and electrolyte control. Evidence that this may be the case has been obtained in animals but not in men.


Conflicts of interest

There are no conflicts of interest.

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