Hypertension in children, adolescents, and pregnant women: challenges and opportunities

With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article. For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on hypertension contains the Special Article entitled ‘Hypertension in children and adolescents: a consensus document from ESC Council on Hypertension, European Association of Preventive Cardiology, European Association of Cardiovascular Imaging, Association of Cardiovascular Nursing & Allied Professions, ESC Council on Cardiology Practice and Association for European Paediatric and Congenital Cardiology’ by Giovanni de Simone from the Federico II University Hospital in Naples, Italy, and colleagues.1 The authors note that the definition and management of arterial hypertension in children and adolescents are uncertain, due to different positions of current guidelines. The ESC task force, constituted by Associations and Councils with interest in arterial hypertension, has reviewed current literature and evidence, to produce a consensus document focused on aspects of hypertension in the age range of 6–16 years, including definitions, methods of measurement of blood pressure, clinical evaluation, assessment of hypertension-mediated target organ damage, evaluation of possible vascular, renal, and hormonal causes, assessment and management of concomitant risk factors (with specific attention on obesity), and antihypertensive strategies, especially focused on lifestyle modifications. The Consensus Panel also suggests aspects that should be studied with high priority, including generation of multiethnic sex-, age-, and height-specific European normative tables, implementation of randomized clinical trials (RCTs) on different diagnostic and therapeutic aspects, and long-term cohort studies to link with adult cardiovascular risk. Finally, suggestions for the successful implementation of the contents of the present consensus document are also given. The issue also contains a co-published Special Article entitled ‘Harmonization of the American College of Cardiology/American Heart Association and European Society of Cardiology/European Society of Hypertension Blood Pressure/Hypertension Guidelines: comparisons, reflections, and recommendations’ by Paul K. Whelton from the Tulane University School of Medicine in New Orleans, LA, USA and colleagues. The authors indicate that the 2017 American College of Cardiology/American Heart Association and 2018 European Society of Cardiology/European Society of Hypertension clinical practice guidelines for management of high blood pressure/hypertension are influential documents.2 Both guidelines are comprehensive, were developed using rigorous processes, and underwent extensive peer review. The most notable difference between the two guidelines is the blood pressure cut-off point recommended for the diagnosis of hypertension. There are also differences in the timing and intensity of treatment, with the American College of Cardiology/American Heart Association guidelines recommending a somewhat more intensive approach. Overall, there is substantial concordance in the recommendations provided by the two guideline-writing committees, with greater congruity between them than their predecessors. Additional harmonization of future guidelines would help to underscore the commonality of their core recommendations and could serve to catalyse changes in practice that would lead to improved prevention, awareness, treatment, and control of hypertension worldwide. In a State of the Art Review article entitled ‘Research strategies in treatment of hypertension: value of retrospective real-life data’, Giovanni Corrao and Giuseppe Mancia from the University of Milano-Bicocca in Italy discuss the limitations of data collected by RCTs in relation to their applicability to daily life clinical management.3 In the article the authors argue that these limitations are only partially overcome by modifications of RCT design and conduct (e.g. ‘pragmatic trials’) while being substantially attenuated by real-life-derived research, which can fill many gaps left by trial-collected evidence and thus have an important complementary value. The focus is on the real-life research approach based on the retrospective analysis of the now widely available healthcare utilization databases (formerly known as administrative databases), which are discussed in detail for their multiple advantages as well as challenges. Emphasis is given to the potential of these databases to provide low-cost information over long periods on many different healthcare issues and drug therapies. This review also mentions that thanks to the current availability of these data in electronic format, results can be obtained quickly, helping timely decisions in emergencies. The potential shortcomings of this approach (confounding by indication, misclassification, and selection bias) are also discussed along with their possible minimization by suitable analytic tools. Finally, examples of the contributions of studies on hypertension and other cardiovascular risk factors are offered based on retrospective healthcare utilization databases that have provided information on real-life cardiovascular treatments unavailable via RCTs. Beyond its role as an atherosclerotic risk factor, hypertension contributes an estimated 40% to heart failure (HF) risk, making it a significant public health burden. While adverse left ventricular remodelling and hypertrophy are well-recognized intermediate phenotypes for HF, overt myocardial structural changes are late-stage findings that are not universally present in all patients with hypertensive heart disease, thus highlighting the need for improved understanding of the pathophysiological mechanisms of hypertensive heart disease-associated HF. Coronary microvascular dysfunction, even in the absence of obstructive epicardial coronary artery disease, has long been recognized as a central mechanism in several cardiovascular diseases.4–9 In a Clinical Research article ‘Low coronary flow relative to myocardial mass predicts heart failure in symptomatic hypertensive patients with no obstructive coronary artery disease’, Jenifer M. Brown from the Harvard Medical School in Boston, MA, USA, and colleagues hypothesized that insufficient perfusion to match global metabolic demand, reflected by a low ratio of myocardial blood flow to global myocardial mass, may be a HF risk marker.10 A retrospective cohort (n = 346) of patients with hypertension who underwent clinical positron emission tomography (PET) myocardial perfusion imaging for chest pain and/or dyspnoea at Brigham and Women's Hospital (Boston, MA, USA) were studied. Patients without obstructive coronary artery disease by history or PET perfusion, HF, cardiomyopathy, or ejection fraction (EF) <40% were followed for HF hospitalization (primary outcome), all-cause death, and their composite. Myocardial blood flow, left ventricular (LV) mass, volumes, and EF were obtained from PET, and a ‘flow/mass ratio’ was determined as hyperaemic myocardial blood flow over LV mass indexed to body surface area. A lower flow/mass ratio was independently associated with larger end-diastolic (β = −0.44, P <0.001) and end-systolic volume (β = −0.48, P <0.001) and lower EF (β = 0.33, P <0.001). A flow/mass ratio below the median was associated with an adjusted hazard ratio (HR) of 2.47 (P = 0.01) for HF hospitalization, 1.95 (P = 0.02) for death, and 2.20 (P < 0.001) for the composite. The authors conclude that an integrated physiological measure of insufficient myocardial perfusion to match global metabolic demand identifies subclinical hypertensive heart disease and elevated risk of HF and death in patients with hypertension but without flow-limiting coronary artery disease. The article is accompanied by an Editorial by Antoni Bayés-Genís from the Universitat Autónoma de Barcelona, and Javier Díez from the University of Navarra, in Spain.11 Bayés-Genís and Díez note that notwithstanding limitations, this work is a step forward on the bumpy road cardiologists are facing towards precision medicine. Oncologists have already demonstrated that personalized therapies based on a refined histological and molecular phenotyping of tumours translate into improved individualized outcomes. The authors of this Editorial strongly believe that a similar approach is necessary not only for treating but also for preventing HF in patients with hypertension and/or other risk factors. The time has come for a precision medicine-based approach to cardiovascular patients that includes knowledge of the histological, molecular, and metabolic changes occurring at the myocardial level that are responsible for progressive impairment of LV morphology and function, with further translation to non-invasive biomarkers and novel preventive and therapeutic strategies. Analysis of 25 years of follow-up data from Atherosclerosis Risk in Communities studies reveals increased risk to develop heart failure (HF) and left ventricular hypertrophy (LVH) among study participants with middle age serum sodium >142 mmol/l. Left panels (beginning of the study): participants are divided into four groups based on serum sodium levels. Middle panels (follow-up: time-to-event analysis): increased incidence of HF in higher sodium groups with adjusted hazard ratio reaching 1.39 when serum sodium exceeds 143 mmol/l. Right panels (end of the 25 years follow-up: 70- to 90-year-old participants): increased prevalence of HF and LVH and accelerated hypertrophic left ventricular remodelling in higher sodium groups.14 With increasing prevalence of HF owing to the ageing population, identification of modifiable risk factors is important.12,13 In a mouse model, chronic hypohydration induced by lifelong water restriction promotes cardiac fibrosis. Hypohydration elevates serum sodium. In a Clinical Research article entitled ‘Middle age serum sodium levels in the upper part of normal range and risk of heart failure’, Natalia I. Dmitrieva from the National Heart Lung and Blood Institute in Bethesda, MD, USA, and colleagues evaluate the association of serum sodium at middle age as a measure of hydration habits with risk of developing HF.14 The authors analysed data from the Atherosclerosis Risk in Communities study with middle age enrolment (45–66 years) and 25 years of follow-up. Participants without water balance dysregulation and with the following characteristics were selected: serum sodium within the normal range (135–146 mmol/L), not diabetic, not obese, and free of HF at baseline (n = 11 814). In time-to-event analysis, HF risk was significantly increased by 39% if middle age serum sodium exceeded 143 mmol/L corresponding to a 1% body weight water deficit (HR 1.39). In a retrospective case–control analysis performed on 70- to 90-year-old attendees of Visit 5 (n = 4961), serum sodium of 142.5–143 mmol/L was significantly associated with a 62% increase in odds of left ventricular hypertrophy (LVH) diagnosis [odds ratio (OR) 1.62]. Serum sodium >143 mmol/L was significantly associated with a 107% increase in odds of LVH [OR 2.07, 95% confidence interval (CI) 1.30–3.28] and a 54% increase in odds of HF (OR 1.54). As a result, prevalence of HF and LVH was increased among 70- to 90-year-old participants with higher middle age serum sodium (Figure 1). Dmitrieva et al. conclude that middle age serum sodium >142 mmol/L is a risk factor for LVH and HF. Maintaining good hydration throughout life may slow down the decline in cardiac function and decrease the prevalence of HF. This contribution is accompanied by an Editorial by Friedrich C. Luft from the Experimental and Clinical Research Center and Charité Medical Faculty in Berlin, Germany.15 Luft notes that the bottom-line message could be just, ‘drink up’. However, are the increased sodium concentrations merely a function of decreased water intake and from where does the sodium come? Sodium metabolism is more complex than previously thought. For instance, the skin (negatively charged glycosamino-glycans) has been rediscovered as a sodium storage site, regulated by immune cells under the control of NFAT5. Hypertonic microdomains were identified with hypertonicity, with sodium playing a role in immune cell activation. The storage site was found to be relevant to blood pressure. In man, sodium magnetic resonance imaging serves to make this site visible. Mobilization of sodium occurs as dramatically in patients treated for acute HF as in dialysis patients undergoing renal transplantation. Salt storage in the skin may serve to buffer free extracellular sodium and macrophage modulation of the extracellular matrix and lymphatics. This view supposes that body electrolyte homeostasis cannot be achieved by renal regulation alone and that extrarenal regulatory mechanisms play a role. Hypertensive disorders of pregnancy increase the risk of developing chronic hypertensions in primiparous women in the early years after delivery by O’Donnell et al.18 Hypertensive disorders of pregnancy (HDP) are a leading cause of maternal and foetal morbidity and mortality.16,17 In a Clinical Research article entitled ‘Hypertensive disorders of pregnancy and onset of chronic hypertension in France: the nationwide CONCEPTION study’, Pauline Boucheron from the Santé publique France, and colleagues aimed to estimate the impact of HDP on the onset of chronic hypertension in primiparous women in the first years following childbirth.18 This nationwide cohort study used data from the French National Health Data System. All eligible primiparous women without pre-existing chronic hypertension who delivered between 2010 and 2018 were included. Women were followed up from 6 weeks post-partum until onset of hypertension, a cardiovascular event, death, or the study end date (31 December 2018). The main outcome was a diagnosis of chronic hypertension. The authors used Cox models to estimate HRs of chronic hypertension for all types of HDP. Overall, 2 663 573 women were included, with a mean follow-up time of 3.0 years. Among them, 6.73% had an HDP. Specifically, 2.16% had pre-eclampsia (PE) and 4.27% had gestational hypertension (GH). Compared with women who had no HDP, the fully adjusted HRs of chronic hypertension were 6.03 for GH, 8.10 for PE (all sorts), 12.95 for early PE, 9.90 for severe PE, and 13.17 for PE following GH. The authors conclude that HDP exposure greatly increases the risk of chronic hypertension in the first years following delivery. The contribution is accompanied by an Editorial by Anastasia S. Mihailidou from the Macquarie University from Sydney, Australia, along with Martha Gulati.19 They observe that as we continue to understand the interconnectedness of cardiovascular health and pregnancy, we are now developing a greater understanding of not just how HDP increases the risk of chronic hypertension, but also how the duration of gestational hypertension prior to pre-eclampsia may further increase the risk. Our future work must focus on understanding the impact of treatment and lifestyle interventions in preventing the development of permanent hypertension and cardiovascular disease in these high-risk women. Whether the conception of permanent hypertension following complicated pregnancies is inevitable or preventable is the question we need to answer. The issue also contains a Viewpoint article entitled ‘Settling the controversy of salt substitutes and stroke: sodium reduction or potassium increase?’ by Franz H. Messerli from the University Hospital Berne in Switzerland, and colleagues.20 The authors conclude that the SSaSS trial demonstrates that moving from a ‘low potassium, high sodium’ diet toward an average potassium/but persistently high sodium intake (an intake numerically still higher than the average consumption in Switzerland and in the USA) prevents stroke, cardiovascular events, and death. These data, therefore, provide reassurance about the efficacy and safety of increasing potassium intake. The editors hope that readers of this issue of the European Heart Journal will find it of interest. Dr. Crea reports speaker fees from Amgen, Astra Zeneca, Servier, BMS, other from GlyCardial Diagnostics, outside the submitted work.