Unanswered questions in hypertension: prematurity and long-term trajectories, masked and white coat hypertension

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. The importance of hypertension as a cardiovascular risk factor was recognized decades ago in the Framingham and other cohorts,1 and the benefit of blood pressure lowering was proved by Edward Freis in his seminal trial published in 1977.2 However, while numerous antihypertensive drugs and procedures have been developed, the causes of hypertension are still not fully understood. However, it has been suggested that early events in life may be important. Pregnancy complications,3 preterm birth,4 as well as assisted reproductive technologies5 have all been associated with elevated blood pressure and cardiovascular risk early in life, an issue that Casey Crump and colleagues from the Icahn School of Medicine at Mount Sinai in New York, USA analysed further, using a population-based study of 4 193 069 singleton live births, in their article entitled ‘Risk of hypertension into adulthood in persons born prematurely: a national cohort study’.6 In 86.8 million person-years of follow-up, 62 424 or 1.5% persons were identified with hypertension with a median age of 30 years at diagnosis. Adjusted hazard ratios for new-onset hypertension at ages 18–29 years associated with preterm birth below 37 weeks and extremely preterm, i.e. birth at 22–27 weeks, were 1.28 and 2.45, respectively, and at ages 30–43 years were 1.25 and 1.68, respectively, vs. full-term births, in both males and females (Figure 1). Thus, preterm birth appears to be associated with increased risk of hypertension into early adulthood. Persons born prematurely may need early preventive evaluation and long-term monitoring for the development of hypertension, as further outlined in an Editorial by Malte Kelm from the University Hospital Düsseldorf in Germany.7 Adjusted hazard ratios (solid lines) and risk differences per 100 000 person-years (dashed lines) for hypertension by gestational age at birth compared with full-term birth, Sweden, 1973–2015 (from Crump C, Sundquist J, Sundquist K. Risk of hypertension into adulthood in persons born prematurely: a national cohort study. See pages 1542–1550). Another question is how long-term blood pressure changes affect complications such as arrythmias8,9 and major cardiovascular events.10,11 In their article ‘Long-term blood pressure trajectories and incident atrial fibrillation in women and men: the Tromsø Study’ Ekaterina Sharashova and colleagues from the University of Tromsø, Norway explored sex-specific associations between long-term individual blood pressure patterns and risk of incident atrial fibrillation in 8376 women and 7670 men.12 Elevated systolic blood pressure independently and differentially increased risk of atrial fibrillation in women and men. In women, elevated systolic blood pressure trajectories doubled atrial fibrillation risk compared with persistently low levels, with hazard ratios of 1.88–2.32. In men, those with elevated systolic blood pressure that continued to increase over time had a 50% increased atrial fibrillation risk of 1.51. Compared with those who were persistently normotensive, women developing hypertension, and women and men with hypertension, had hazard ratios of 1.40, 2.75, and 1.36, respectively. Thus, long-term blood pressure and hypertension trajectories were associated with increased incidence of atrial fibrillation in both women and men, but the associations were stronger in women. These findings are put into context in an Editorial by Dipen Shah from the Hopital Cantonal in Geneva, Switzerland.13 Blood pressure is usually measured in the sitting position in the doctor’s office or at home. However, blood pressure changes throughout the day and hence 24 h measurements revealed that individuals may have masked uncontrolled hypertension or MUCH, i.e. normal blood pressure at the clinic, but hypertension on 24 h monitoring14–16 of elevated blood pressure, or the reverse, i.e. white coat uncontrolled hypertension or WUCH whereby blood pressure is elevated at the clinic, but not during 24 h monitoring.17 Whether these categories are really reproducible and hence clinically useful is addressed in the article ‘Limited reproducibility of MUCH and WUCH: evidence from the ELSA study’ by Giuseppe Mancia and colleagues from the University in Monza, Italy.18 Office and 24 h blood pressure was measured at baseline and every year, allowing repeated classification of either condition. After 1 year of treatment, 21% and 18% of the patients were classified as masked or white coat hypertensives, respectively. For both conditions, the prevalence during follow-up was maintained, but with large changes in patient composition. Only one-third classified as masked or white coat hypertensives at one time point maintained their classification subsequently (Figure 2). Only 5% and 6% retained the classification of masked or white coat hypertensives, respectively. Thus, both masked and white coat hypertension display poor reproducibility. This should be taken into account when assessing their long-term prognostic value, as further discussed in an Editorial by Sverre Erik Kjeldsen from the Oslo University Hospital in Ulleval in Norway.19 Limited reproducibility of Masked Uncontrolled Hypertension (MUCH) and White coat Uncontrolled Hypertension (WUCH) during the 4-year treatment of the ELSA Study Data are shown as prevalence (%) of patients classified as MUCH, WUCH, once, twice, three times or all four times during the study follow-up (from Mancia G, Facchetti R, Cuspidi C, Bombelli M, Corrao G, Grassi G. Limited reproducibility of MUCH and WUCH: evidence from the ELSA study. See pages 1565–1571). An important complication of hypertension is stroke. However, only a minority of hypertensives develop such an event during their lifetime, suggesting that other factors also play a role. Indeed, age is an established risk factor for stroke.20 As such, genes regulating ageing and longevity have also been implicated.21 In their Basic Science manuscript entitled ‘Endothelial SIRT6 blunts stroke size and neurological deficit by preserving blood–brain barrier integrity: a translational study’, Giovanni G. Camici and colleagues from the University of Zurich in Switzerland hypothesized that endothelial-specific expression of the recently described longevity gene SIRT6 may have protective properties in stroke.22 Indeed, SIRT6 endothelial expression was reduced following stroke. Endothelial-specific Sirt6 knockout mice displayed increased infarct volumes, mortality, and neurological deficit after transient middle cerebral artery occlusion. Conversely, post-ischaemic Sirt6 overexpression decreased stroke size and neurological deficit. As regards the molecular mechanism, increased blood–brain barrier damage and endothelial expression of cleaved caspase-3 appeared to be involved. Similarly, in primary human brain microvascular endothelial cells, hypoxia and reoxygenation reduced SIRT6 expression, and SIRT6 silencing impaired the barrier function. Importantly, in stroke patients, SIRT6 expression was higher in those with short-term neurological improvement as assessed by the NIHSS scale and correlated with stroke outcome. Thus, endothelial SIRT6 exerts a protective role in ischaemic stroke by blunting ischaemia and reperfusion-mediated blood–brain barrier damage, and thus may represent a novel therapeutic target for future clinical investigation. Blood pressure is controlled by numerous reflex control mechanisms in the kidneys and carotid arteries.23 These sites have been used to develop interventional tools aiming at interrupting these pathways either by radiofrequency or by ultrasound energy.24 In a Current Opinion manuscript entitled ‘Proceedings from the 3rd European Clinical Consensus Conference for clinical trials in device-based hypertension therapies’, Felix Mahfoud from the University Hospital Saarland in Homburg, Germany and colleagues25 remind us that clinical trials assessing novel technologies for device-based hypertension treatment are currently ongoing, including endovascular catheter-based renal denervation, baroreceptor activation therapy, endovascular baroreflex amplification, and cardiac pacemaker-mediated hypertension treatment. The disappointing results of SYMPLICITY HTN-3 prompted discussions as to the trial’s design and execution.26 Later on, three carefully designed, randomized sham-controlled renal denervation trials, i.e. SPYRAL HTN-OFF MED,27 SPYRAL HTN-ON MED,28 and RADIANCE-HTN SOLO,29 reported clinically meaningful ambulatory and office blood pressure reductions up to 6 months with no serious adverse events in patients both on and off medications. With rigorous trial oversight and methods, these studies provided consistent and robust proof for blood pressure-lowering efficacy of renal denervation. The 3rd European Clinical Consensus Conference for device-based therapies for hypertension identified key issues and consensus recommendations for the design and conduct of new, clinically more relevant, pragmatic trials. The issue is also complemented by five Discussion Forum contributions, all related to ‘Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial’ by Ramon Hermida and colleagues from the University of Vigo in Spain which was recently published online.30 Accompanying these contributions is a ‘Expression of concern’, discussing the ongoing investigation involving the ESC Journals Ethics Committee, and the independent statistical investigation currently being planned.31 In a first Discussion Forum entitled ‘Chrono-pharmacological effects of antihypertensive drugs’, Selçuk Şen and colleagues from the Istanbul Universitesi Istanbul Tip Fakultesi in Istanbul, Turkey discuss the issue.32 In ‘Is bedtime treatment appropriate for all hypertensive patients?’ Carmen Sánchez Sánchez and colleagues from the Clinica Rementeria in Madrid, Spain also discuss the manuscript.33 Finally, Greg Guthrie and colleagues from the University of Dundee School of Medicine in their comment ‘Chronotherapy in hypertension: the devil is in the details’.34 The author Hermida has responded to each contribution in a separate piece.35–37 The editors hope that readers of this issue of the European Heart Journal will find it of interest. With thanks to Amelia Meier-Batschelet for help with compilation of this article.