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Prognostic, diagnostic, and therapeutic advances in hypertension

Zanchetti, Alberto

doi: 10.1097/HJH.0000000000000913

aIstituto Auxologico Italiano

bCentro Interuniversitario di Fisiologia Clinica e Ipertensione, Università degli Studi di Milano, Milan, Italy

Correspondence to Professor Alberto Zanchetti, Direzione Scientifica, Istituto Auxologico Italiano, Via L. Ariosto, 13, 20145 Milano, Italy. Tel +39 02 61911.2237; e-mail:

The present issue of the Journal of Hypertension focuses on prognostic, diagnostic, and therapeutic advances in the area of hypertension research.

The articles with prognostic impact include a consensus document from a conference endorsed by the European Society of Hypertension (pp. 813–821) reviewing the body of evidence that heart rate is an important risk factor for cardiovascular disease and suggesting to routinely include heart rate measurement in the assessment of the hypertensive patient. The Consensus Document acknowledges, however, that, in the absence of convincing data, any threshold to define tachycardia risk is arbitrary. The relationship between physical activity and all-cause mortality is investigated by Loprinzi (pp. 848–852), who has analyzed data from the 2003 to 2006 National Health And Nutrition Examination Survey (NHANES), with follow-up through 2011. The study reports that, among hypertensive adults, physical activity objectively measured via accelerometry is significantly associated with all-cause mortality, in such a way that every 60 min increase in physical activity reduces risk of all-cause mortality by 19%. In a thoughtful accompanying editorial, Ferreira and Healy (pp. 830–832) remind ‘the most pertinent question how do beneficial effects of exercise on cardiovascular disease and mortality among individuals with hypertension compare with the beneficial effects of pharmacotherapy’ remains unanswered. The very promising findings of Loprinzi strongly support the rationale for a head-to-head comparison between the effects of exercise and pharmacological treatment of hypertension. In another study on the effects of lifestyle on cardiovascular risk, Karimi et al. (pp. 853–859), analyzing data from the Rotterdam study, find that combining multiple healthy lifestyle factors, such as vigorous physiological activity, daily consumption of fruits and vegetables, and others, is associated with reduced aortic stiffness, a measure of functional vascular ageing. In a nationwide population sample in Finland followed-up for 10 years, Lehtonen et al. (pp. 959–966) have observed a high prevalence of electrocardiographic abnormalities among hypertensive individuals, with left ventricular hypertrophy still being the cornerstone for predicting coronary disease, but with additional contribution from ST/T changes, a positive T-wave in lead aVR and poor R-wave progression. In an editorial commentary, Bang and Okin (pp. 842–844) remark that these novel electrocardiographic measures deserve to be tested in a patient sample with higher comorbidity and compared to imaging measures of left ventricular structure and function. In another prospective study (7–8 years of follow-up), Nargesi et al. (pp. 974–980) report that pulse pressure amplitude is nonlinearly related with incident coronary events in patients with diabetes or hypertension, in such a way that both narrow and wide pulse pressures increase coronary risk. Low penile blood flow is reported by Ioakeimidis et al. (pp. 860–868) to predict major cardiovascular events during a 5-year follow-up in hypertensive patients free of symptomatic atherosclerosis. In a large cohort of Taiwanese women with newly diagnosed hypertension disorders in pregnancy, retrospectively studied, I.-K. Wang et al. (pp. 914–919) have found that incident gout was 2.83-fold higher than in control women, and suggest women with a history of hypertension in pregnancy should be closely surveilled for hyperuricemia and receive suitable lifestyle intervention.

Three studies in the current issue of the Journal have investigated the ability of genetic markers to predict organ damage and cardiovascular events. Song et al. (pp. 942–959) report evidence both from experiments on neonatal cardiomyocytes and from two cohorts (discovery and replication) of hypertensive patients that the rs238234GG genotype in the coding region of calmodulin binding (CAM) increases the risk of left ventricular hypertrophy by affecting the activation of NKX 2.5 dependent transcription, whereas Prestes et al. (pp. 950–958) propose the Trim 55 gene, located in Cm22, as a novel candidate gene for polygenic left ventricular hypertrophy independent of blood pressure (BP) in the spontaneously hypertensive rat. Finally, Testa et al. (pp. 928–934), in an exploratory study, suggest a gene variant in keap-1, a major gene regulating the antioxidant response, as a possible predictor of incident cardiovascular events in patients with chronic kidney disease.

A group of three articles focus on diagnostic aspects. Marie et al. (pp. 967–973) present the results of a MRI study indicating that the determination of aortic stroke volume with a phase contrast sequence leads to a significant enhancement in the characterization and monitoring of cardiac remodelling. Burrello et al. (pp. 920–927) have carried out a meticulous comparison of the diagnostic accuracy of the aldosterone-to-renin and the aldosterone-to-plasma-renin-activity ratio (respectively measured by chemoluminescent immunoassay and radioimmunoassay) and aldosterone assay (measured by chemiluminescent and radioimmunoassay) as diagnostic tests for primary aldosteronism, reporting that the automated aldosterone and renin chemiluminescence assay is a reliable procedure. On the same topic of screening tests for primary aldosteronism, the European Society of Hypertension Working Group on Endocrine Hypertension describe an App for calculating the aldosterone-to-renin ratio, as a useful diagnostic tool (pp. 1019–1021).

A large group of articles in this issue refer to therapeutic aspects of hypertension starting with the already mentioned consensus article on high heart rate risk in hypertension (pp. 813–821), which suggests a randomized controlled trial to investigate the possible benefits of reducing elevated heart rate in hypertension. Liantonio et al. (pp. 981–992) show that compound SRA-36, a benzofuran derivative, is an efficacious inhibitor of the chloride currents, and suggest this molecule may represent a new potential therapeutic option for hypertension. Y.-K. Wang et al. (pp. 993–1004) report that the centrally acting drug, moxonidine, when infused intracisternally in rats, decreases reactive oxygen species production in the rostral ventrolateral medulla through inactivation of the P13.K/AKT signalling pathway in hypertension. Rahman et al. (pp. 893–906) have found that diuretics do not impact on the favourable effects of a sodium-dependent glucose-cotransporter 2 (SGLT2) inhibitor, luseogliflozin, on glucose metabolism and BP in spontaneously hypertensive rats with metabolic syndrome, and argue SGLT2 inhibitors can be used in hypertensive patients with metabolic syndrome undergoing diuretic therapy. In a thoughtful accompanying editorial commentary, Joles and Palm (pp. 833–835), however, call attention to the possibility that with a too severe volume contraction caused by the simultaneous administration of a SLGT2 inhibitor and powerful diuretics, the beneficial effects during the day may turn out bad at night.

Gosmanov et al. (pp. 907–913) report data from a huge (891 670) number of US veterans with diabetes followed-up for more that 7 years. Using SBP 120–139 mmHg and HbA1C 6.5–6.9% as references, SBP was found to display a J-shaped association with all fatal and nonfatal outcomes except chronic kidney disease across all HbA1C categories, and Hb1AC above 7.0% was associated with worse outcomes in all SBP categories. The worse outcomes were experienced by diabetic patients with the combined highest values of Hb1AC and SBP, and the authors suggest that combined efforts to improve both glycaemic and BP control may synergistically improve outcomes in diabetic patients. In a comprehensive editorial commentary, Kjeldsen and Os (pp. 836–837) remark the synergistic determinant role of uncontrolled glucose and higher BP was not unexpected, but the huge size of the study of Gosmanov et al. (pp. 907–913) makes their findings impressive. The study, however, is observational, and Kjeldsen and Os (pp. 836–837) conclude with a plea for the design of a conclusive outcome trial with sufficient statistical power in patients with diabetes and hypertension.

Other articles focus on therapeutic aspects of hypertension. Barkoudah et al. (pp. 935–941) compared the effects of a novel renin inhibitor, VTP-27999, with those of aliskiren on renal haemodynamics and circulating markers of renin–angiotensin system activity, reporting that in healthy adults maintained on a low-salt regimen VTP-27999 in acute administration appeared to be twice as potent as aliskiren. In his commentary of this article, Spradley (pp. 838–841) presents a comprehensive review of the experimental and clinical studies on the cardiovascular and renal effects of various ways of inhibiting the renin–angiotensin system, and concludes that there is much work to be done regarding optimal strategies to inhibit the system in patients with hypertension and kidney disease.

In a retrospective study of hypertensive patients resistant to treatment, Ghazi et al. (pp. 1005–1010) report that 24 h urinary sodium excretion was a significant predictor of a favourable BP response to spironolactone. In his accompanying editorial, Campese (pp. 845–847) discusses a number of possible mechanisms explaining this unexpected finding. A further article with therapeutic impact is a post-hoc analysis of the HIJ-CREATE trial in Japan. Kikuchi et al. (pp. 1011–1018) report that a J-shaped association between achieved SBP and major cardiovascular events was found in patients with preserved left ventricular ejection fraction but not in those with reduced or intermediate left ventricular ejection fraction.

Finally, three articles in this issue focus on aspects of blood vessel pathophysiology. Nie et al. (pp. 877–892) have investigated Axin2 knockout mice to establish the key role played by Axin2 in the progression of pulmonary arterial hypertension, whereas Romacho et al. (pp. 869–876) have found in mice that dipeptidyl-peptidase-4, a new pharmacological target in diabetes, is a direct mediator of endothelial dysfunction. In a systematic review and meta-analysis of studies on arterial stiffness in inflammatory bowel disease, Zanoli et al. (pp. 822–829) report pulse wave velocity to be increased both in ulcerative cholitis and Crohn's disease.

The issue of the Journal of Hypertension closes with the obituary of Cesare Dal Palù, written by his two long-time associates A.C. Pessina and G.P. Rossi. Cesare Dal Palù was a protagonist of clinical research on hypertension for several decades. It was a pleasure to share with him a large number of activities and studies in Italy and abroad, and to enjoy his friendship. I would like to express my warmest feelings and sympathy to his wife, Renata.

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Conflicts of interest

There are no conflicts of interest.

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