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From blood pressure measurement to treatment: the scope of hypertension research

Zanchetti, Albertoa,b

doi: 10.1097/HJH.0000000000001710

aScientific Direction, Istituto Auxologico Italiano IRCCS

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

Correspondence to Professor Alberto Zanchetti, Scientific Direction, Istituto Auxologico Italiano IRCCS, Università degli Studi di Milano, Via F. Sforza, 35, 20122 Milan, Italy. Tel: +39 2 50320484; e-mails:;

The articles published in the current issue of the Journal of Hypertension cover a number of different areas within the scope of hypertension research.

A prominent space is devoted to problems concerning the reporting of hypertension and the clinical significance of blood pressure (BP) variability. Gonçalves et al. (pp. 970–978) have done a literature search and meta-analysis to estimate sensitivity and specificity of self-reported hypertension as compared with clinical diagnosis in epidemiological studies, and found that less than half of patients with hypertension would not be identified by self-reporting. There was a high heterogeneity of the different studies included, depending on regional, socioeconomic, and cultural differences.

The clinical significance of BP variability is calling a considerable attention from investigators. Martín-Rioboó et al. (pp. 1051–1058) have done an examination of the degree of knowledge and management of automated devices for office BP management, home BP measurement and ambulatory BP monitoring in primary care in Spain, and report that, even among highly motivated primary care physicians (the 20% who responded to the questionnaire), there were enormous gaps between current guidelines’ recommendations and the doctors’ knowledge and behaviour. Serafidis et al. (pp. 1076–1085) have taken advantage of the very large data of the Spanish Ambulatory Blood Pressure Monitoring Registry [16 546 patients, 39% of whom with various stages of chronic kidney disease (CKD)] to analyze 24-h BP variability across a wide spectrum of CKD severity: in CKD they report higher BP variability and more common abnormalities of BP circadian profile, with a progressive increase in BP variability with worsening CKD severity. The multiple mechanisms by which CKD may influence BP variability are discussed in an accompanying editorial by Bilo and Parati (pp. 1019–1021). Another study in this issue focuses on the relationship between BP variability and renal disease. Ushigome et al.'s study (pp. 1068–1075) is a prospective one relating progression to macroalbuminuria in patients with type-2 diabetes mellitus to increased day-by-day variability of morning BP. Both short-term ambulatory BP variability and long-term visit-to-visit BP variability have been investigated prospectively by Chowdhury et al. (pp. 1059–1067) in the elderly population of the Second Australian National Blood Pressure Study: short-term SBP variability from ambulatory BP recording was found to be a better predictor of mortality in this elderly treated hypertensive population. In another review and meta-analysis by Shi et al. (pp. 995–1004) of prospective cohort studies investigating the risk of hypertension and heart failure in relation to resting heart rate, a linear association was found.

Two articles approach in a different way the genetics of hypertension. Botzer et al. (pp. 1094–1103) intended to investigate genes associated with essential hypertension from a system perspective, making use of an informatics tool, and compiled a set of about 200 genes that play a major role in hypertension and identified the interaction between them. Their analysis suggests that insulin may play a primary role in hypertension, highlighting the tight link between hypertension and diseases associated with the metabolic syndrome. Niiranen et al. (pp. 1086–1093) have studied 3238 Framingham Heart Study participants with available parental risk of hypertensive organ damage and report that parental organ damage is associated with organ damage in the offspring, independent of other risk factors, including BP. They conclude that familial clustering of hypertensive organ damage in the community is independent of BP. These interesting findings are commented by Bella in an accompanying editorial (pp. 1022–1023), in which he remarks that further studies are needed to assess the effect of treatment on initiation, regression or delaying progression of organ damage in individuals with genetic predisposition to development of organ damage.

Blood vessel alterations in hypertension continue to attract the investigators’ and clinicians’ attention. Ling et al. (pp. 1104–1114) report that fibronectin type-III-domain-containing 5 (FNDC5) reduces NADPH oxidase 2 (NOX2)-derived reactive oxygen species (ROS) production, NLRP3 inflammasome activation and phenotypic transformation in aortic adventitial fibroblasts of spontaneously hypertensive rats (SHR), playing a beneficial role in attenuating vascular inflammation, vascular remodelling, and hypertension in this animal model.

In view of the increasing use of the cardio-ankle vascular index (CAVI) as an index for arterial stiffness, Tabara et al. (pp. 1147–1153) have investigated factors associated with longitudinal changes in CAVI in over 8000 individuals followed up for about 5 years and found age, male sex, Brinkman index, and SBP to be positive determinants, whereas BMI and baseline CAVI to be inverse determinants, suggesting that these factors should be carefully considered whenever CAVI is used for the clinical assessment of arterial stiffness. Osman et al. (pp. 1005–1014) present a systematic review and data meta-analysis showing that arterial stiffness [pulse wave velocity (PWV)] and wave reflection [augmentation index (AIx)] are significantly higher among pregnant women who subsequently develop preeclampsia or have small for gestational age fetuses. In commenting these data, Tan et al. (pp. 1029–1031) highlight the importance of distinguishing between arterial stiffness and wave reflection indices in order to better understand underlying mechanisms associated with the hemodynamic changes preceding development of placental-mediated diseases. The editorial commentary also highlights the need for a more systematic method of assessment of arterial stiffness and wave reflection, if these indices were to be used as a predictive tool in clinical screening for placental-mediated complications of pregnancy.

Assessment of microvascular structural alterations is also important in hypertension research and noninvasive methods are being developed in order to extend these techniques to hypertensive diagnostic evaluations. De Ciuceis et al. (pp. 1154–1163) present comparisons of three of these noninvasive methods (retinal scanning laser Doppler flowmetry, retinal adaptive optics, and basal and total capillary density by videomicroscopy/capillaroscopy) with the invasive gold standard of micromyography of subcutaneous small vessels obtained by local biopsies. They find retinal adaptive optics has substantial advantages over the other noninvasive procedures by providing data more closely correlated with the invasive gold standard measurements, and also being better reproducible. Martens et al. (pp. 1178–1187) have investigated the association of albuminuria with microvascular endothelial dysfunction in the population-based, diabetes-enriched Maastricht Study, and report direct evidence of this association and of a stronger association in individuals with than in individuals without type-2 diabetes. In an accompanying editorial, Virdis et al. (pp. 1036–1037) comment that Martens et al.'s findings strengthen the working hypothesis that microvascular endothelial dysfunction, marked by microalbuminuria, is likely to reflect a more generalized condition of endotheliopathy within the cardiovascular system, and point out that the unresolved question is whether individuals with albuminuria may benefit from improving systemic endothelial function, as assessed by reduction of albuminuria.

A group of four articles focus on neural and adrenergic mechanisms. Mir et al. (pp. 1115–1128) have investigated the role that chromogranin A (CHGA) may play in hyperadrenergic types of hypertension, and show that mice expressing excess CHGA display a hypertensive phenotype, higher heart rate, and increased sympathetic tone. In particular, elevated CHGA expression results in underlying bioenergetic dysfunction in ATP production despite higher mitochondrial mass: the outcome is unregulated negative feedback of adrenal secretory large dense core vescicole exocytosis and secretion, resulting in elevated levels of circulating catecholamines and consequently, hypertension. Janssen et al. (pp. 1188–1194) have studied in healthy human volunteers interactions of baroreceptor and chemoreceptor reflexes on heart rate and muscle sympathetic nerve activity (MSNA), and report cardiac and sympathetic baroreceptor sensitivities decrease during baroreceptor unloading in the presence of peripheral chemoreceptor activation, concluding that normal individuals have limited reflex capabilities to sustain simultaneous reductions in oxygen and pressure and may experience hemodynamic instability episodes in such conditions. MSNA and baroreflex sensitivity have been recorded in a group of normotensive and normal weight prediabetic individuals and compared with healthy control individuals by Dell’Oro et al. (pp. 1195–1200). An adrenergic overdrive and baroreceptor impairment were found in prediabetic individuals, showing these abnormalities are of early appearance in the clinical course of the diabetic disease, and may favour the development of hypertension and adversely affect the disease progression. Orthostatic hypotension, especially in older individuals, is commonly considered to be often associated with cardiovascular disease and worse cognitive function, possibly caused by reduced cerebral blood flow. However, in the current issue of the Journal, Foster-Dingley et al. (pp. 1201–1206) have found that in a community-based sample of older people in Leiden, orthostatic hypotension was not associated with cognitive dysfunction, cerebral damage or altered cerebral blood flow. These data are commented and discussed by Casiglia and Tikhonoff (pp. 1038–1040) also on the light of their personal data. They conclude that the picture of the consequences of orthostatic hypotension on cognition is still largely undefined, and suggest that, whenever dealing with postural BP changes, it is useful to take into consideration not only the presence of orthostatic hypotension but also the amount of orthostatic BP fall.

A final group of articles have implications on various aspects of hypertension treatment. An epidemiological study may have implications on lifestyle recommendations. In two Swedish cohorts, Beijer et al. (pp. 1041–1050) show that prolonged television time was associated with higher SBP and DBP in both sexes and at most ages, whereas an increased physical activity was mainly associated with a lower DBP. Only in young men, a high physical activity could compensate for prolonged television time regarding DBP.

Two experimental studies may have some future therapeutic applications. Zurlo et al. (pp. 1164–1177) report that modification of silent information regulator 1 (known as Sirtuin 1) activity influences pulmonary artery smooth muscle cells (PASMC) proliferation and development of pulmonary hypertension in a mouse model and provide new important information on the mechanisms involved. In a thoughtful accompanying commentary, Cheng et al. (pp. 1032–1035) point out that PASMC proliferation plays a vital role in progressive vascular remodeling and discuss the importance of the various mechanisms elucidated by Zurlo et al., concluding that, in the light of the findings suggesting Sirtuin 1 as a new promising therapeutic target for the treatment of experimental pulmonary arterial hypertension, further studies should focus on whether altered PASMC proliferation and mitochondrial biogenic activity contribute to the reversal of pulmonary arterial remodeling and fibrosis in patients with pulmonary hypertension. Castiglioni et al. (pp. 1129–1146) administered fenofibrate to young stroke-prone SHR (SHRSP) on high-salt diet finding beneficial antifibrotic cardiac and renal effects with improved cardiac systolic and diastolic function, and prevention of proteinuria. In an accompanying editorial, Gremmels and Joles (pp. 1024–1028) discuss these interesting new data in the frame of the picture provided by the literature, which reports both favourable and unfavourable effects of fibrates on the heart, and suggest further experiments should be done to clarify whether the favourable effects of fibrates observed whenever they are administered to young animals still free of important organ damage also occur in older SHRSP with more advanced cardiac and renal diseases.

Brunström and Carlberg (pp. 979–986) discuss the results of the Systolic Blood Pressure Intervention Trial (SPRINT) in the light of a meta-analysis they present of BP-lowering randomized trials in patients who had baseline BP in the normotensive range (mostly because of background antihypertensive treatment), and low levels of previous cardiovascular disease. They report that in these patients, more intense versus less intense BP reduction has little effects on all-cause mortality and major cardiovascular events, and conclude SPRINT results differ significantly compared with those of other trials, and therefore, should be interpreted cautiously. Finally, Bazoukis et al. (pp. 987–994) publish a systematic survey and meta-analysis of randomized controlled trials in which mineralocorticoid receptor antagonists (MRAs) were compared with placebo or other active drugs and clearly show that the extent of BP lowering was similar in patients with and without resistant hypertension and not accompanied by increased rate of treatment-related discontinuations compared with active comparators. In an accompanying editorial, Rossi (pp. 1015–1018) remarks this meta-analysis is timely and important, and concludes MRAs are key tools to achieve low BP targets, particularly in low-income countries, as these are inexpensive drugs.

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