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Seminar: Epidemiology
Seminar: Epidemiology
Arterial hypertension
Sofie Brouwers, Isabella Sudano, Yoshihiro Kokubo, Elisabeth M Sulaica
Arterial hypertension is the most important contributor to the global burden of disease; however, disease control Published Online
remains poor. Although the diagnosis of hypertension is still based on office blood pressure, confirmation with out- May 18, 2021
https://doi.org/10.1016/
of-office blood pressure measurements (ie, ambulatory or home monitoring) is strongly recommended. The definition S0140-6736(21)00221-X
of hypertension differs throughout various guidelines, but the indications for antihypertensive therapy are relatively
Department of Cardiology,
similar. Lifestyle adaptation is absolutely key in non-pharmacological treatment. Pharmacologically, angiotensin- Cardiovascular Center Aalst,
converting enzyme inhibitors or angiotensin receptor blockers, calcium channel blockers, and diuretics are the first- OLV Hospital Aalst, Aalst,
line agents, with advice for the use of single-pill combination therapy by most guidelines. As a fourth-line agent, Belgium (S Brouwers MD);
Department of Experimental
spironolactone should be considered. The rapidly evolving field of device-based therapy, especially renal denervation, Pharmacology, Faculty of
will further broaden therapeutic options. Despite being a largely controllable condition, the actual rates of awareness, Medicine and Pharmacy, Vrije
treatment, and control of hypertension are disappointingly low. Further improvements throughout the process of Universiteit Brussel, Brussels,
patient screening, diagnosis, treatment, and follow-up need to be urgently addressed. Belgium (S Brouwers);
University Heart Center,
Cardiology, University Hospital
Epidemiology China, it was found that 44·7% of patients were Zurich, University of Zurich,
Hypertension is one of the most important modifiable hypertensive and only 44·7% of those with hypertension Zurich, Switzerland
risk factors for cardiovascular disease and one of were aware of their condition.4 Even more compelling, (I Sudano MD); Department of
Preventive Cardiology,
the largest contributors to morbidity and mortality only 30·1% of patients were prescribed antihypertensive National Cerebral and
worldwide. In a systematic analysis done for the Global agents and 7·2% had their blood pressure controlled. Cardiovascular Center, Suita,
Burden of Disease Study 2017, high systolic blood When standardised for age and sex, hypertension had Japan (Y Kokubo MD); Institute
pressure (SBP) was the leading risk factor for mortality rates of 37·2% for prevalence, 36·0% for awareness, of Cardiovascular and Medical
Sciences, University of
(10·4 million deaths) and disability-adjusted life-years 22·9% for treatment, and 5·7% for control. Glasgow, Glasgow, UK
(218 million).1 In a study including 8·69 million In the African population, a systematic review and (Y Kokubo); Pharmacy Practice
participants from 154 countries, it was estimated that meta-analysis of data from 25 studies showed a pooled and Translational Research,
between 1990 and 2015, the number of participants with prevalence of 5·5% in children and adolescents with University of Houston College
of Pharmacy, Houston, TX, USA
an SBP of at least 110–115 mm Hg increased from elevated blood pressure (≥95th percentile) and of 12·7% (E M Sulaica PharmD)
73·1% to 81·3%, and those with an SBP of at least in children and adolescents with slightly elevated blood Correspondence to:
140 mm Hg increased from 17·3% to 20·5%.2 Add pressure (≥90th percentile and <95th percentile).5 Prof Sofie Brouwers, Department
itionally, the estimated rate of annual deaths associated Increased body-mass index was largely associated with of Cardiology, Cardiovascular
with an SBP of at least 110–115 mm Hg increased by prevalence of elevated blood pressure, which was Center Aalst, OLV Hospital Aalst,
Aalst 9300, Belgium
7·1% from 1356 per million, and deaths associated with six times higher in children and adolescents (aged [email protected]
an SBP of at least 140 mm Hg increased by 8·6% from 2–19 years) with obesity than in age-matched individuals
979 per million. without obesity. From a public health standpoint, it is
According to the 2019 May Measurement Month
campaign initiated by the International Society of
Hypertension (ISH), involving more than 1·5 million Search strategy and selection criteria
individuals screened from 92 countries, 32·0% had never We searched PubMed and MEDLINE for articles published
had their blood pressure measured and 34·0% had been from Jan 1, 2010, to Oct 25, 2020. We used the search terms
diagnosed with hypertension, among whom 58·7% were “blood pressure”, “hypertension”, “arterial hypertension”,
aware that they had hypertension and 54·7% were on in combination with the terms “guidelines”, “chronotropy”,
antihypertensive medications.3 In patients with hyper “resistant hypertension”, “diabetes”, “ambulatory blood
tension, 31·7% had blood pressure readings below pressure monitoring”, “home blood pressure measurement”,
140/90 mm Hg and 23·3% below 130/80 mm Hg. Of “digital health”, “mobile health”, “lifetime risk”, “prospective
patients on at least one antihypertensive, 57·8% had blood studies”, “epidemiology”, “population”, “lifetime blood
pressure readings below 140/90 mm Hg and 28·9% below pressure”, “diet”, “lifestyle”, “periodontitis”, “inflammation”,
130/80 mm Hg. Of patients taking antihypertensive “renin-angiotensin system”, “angiotensin-(1–7)”, “novel
medications, half were single-drug users. Since May, 2017, coronavirus disease 2019”, “genome-wide association”,
more than 4·2 million participants had their blood and “global”. We largely selected publications from the past
pressure measured and almost 1 million adults with 5 years, but did not exclude commonly referenced and highly
hypertension were untreated or undertreated. regarded older publications. We also searched the reference
Globally, hypertension awareness varies, with at least lists of articles identified by this search strategy and selected
70% of people with hypertension from the Americas and those we judged relevant. Review articles and book chapters
Europe being aware of their condition compared with are cited to provide readers with more details and references
only up to 40% of patients from south Asia and sub- than this Seminar has room for.
Saharan Africa. In a sample of 1·7 million adults in
essential to prevent obesity to improve hypertension, systemic inflammation, leading to increased blood
given that the factors contributing to increased body- pressure.
mass index are applicable to Africans spanning from Interactions between genes and the environment
childhood5 to adulthood.6 The meta-analysis also found illustrate the benefit of common lifestyle modifications
that elevated blood pressure was more pervasive in rural based on the recommendations of hypertension guide
areas than in urban areas; however, no differences in lines, which consist of the following elements: weight
prevalence were observed between boys and girls.5 reduction, a healthy diet, dietary sodium reduction,
Another study showed that the prevalence of hyper increased physical activity, and the cessation of smoking
tension is higher in people of African origin than in and excessive alcohol consumption.24
those of European origin.7 As well as these environmental factors, a complex genetic
In a study done in the USA, the strongest increase background has a role, which research is continuing to
from ideal blood pressure to pre-hypertension occurs at expand on.25 Data from genome-wide association studies
age 8 years for boys of White ethnicity, and at age on blood pressure traits (systolic, diastolic, and pulse
25 years for young African Americans, illustrating pressure) have led to greater understanding of important
how heterogeneity in blood pressure starts appearing loci involved in blood pressure. The discovery of novel loci
at a young age.8 Pre-emptive prophylaxis beginning has clarified new mechanisms of blood pressure regulation
in early adulthood might be necessary to prevent and the association between blood pressure and lifestyle.26,27
pre-hypertension and hyperten sion, as well as the
development of associated racial, ethnic, and gender The renin–angiotensin–aldosterone system (RAAS) and
disparities that could be variably interpreted.9,10 An COVID-19
analysis of the original cohort in the Framingham Heart Throughout the COVID-19 pandemic, a key consideration
Study showed that individuals in the community of hypertension pathophysiology and management has
generally maintained SBP below 120–125 mm Hg; been the effect of SARS-CoV-2 on the RAAS system.
however, when SBP began to rise above this range, it SARS-CoV-2 has been proposed to gain entry into cells
increased relatively rapidly towards overt hypertension.11 through endocytosis, by binding to angiotensin-
This tendency was consistent, regardless of whether or converting enzyme (ACE) 2.28 This theory has led to
not hypertension appeared early or late in life. discussion around discontinuing ACE inhibitors or
Interestingly, a large-scale analysis of individual patient angiotensin receptor blockers (ARBs) due to concern
trajectories provided evi dence that lifetime SBP and for ACE2 upregulation and subsequent increase in
diastolic blood pressure were most elevated at least SARS-CoV-2 virility. To our knowledge, clinical studies
14 years before death, and subsequently decreased until in this population are observational in nature and an
death.12 64·0% of the patients included in this analysis association between use of ACE inhibitors or ARBs and
had SBP decreases of at least 10 mm Hg. This reduction increased SARS-CoV-2 infection or severity of COVID-19
was present in all individuals, including those who did has not been found.29–35 Multiple prospective, ongoing,
not receive anti hypertensive treatment, and was most randomised trials will evaluate the outcomes of ACE
pronounced in older patients and in patients treated for inhibitor or ARB use or discontinuation in the setting of
hypertension, dementia, heart failure, or late-life weight COVID-19 (NCT04591210; NCT04353596). Interestingly,
loss. SARS-CoV-2 infection has also been shown to result
in ACE2 downregulation after initial binding to recep
Pathophysiology tors.28,36 ACE2 is important in counteracting effects of
Hypertension can be classified as essential or secondary, the RAAS system and, thus, there is also discussion
with most patients having essential hypertension.13 around the possible benefits of RAAS attenuation in
The cause of hypertension is multifactorial in nature, with COVID-19.37 Current recommendations are to avoid
environment, genetics, and social determinants having discontinuing RAAS inhibitors when they are clinically
the potential to contribute to its development.13 A better indicated and especially if they are the cornerstone of the
understanding of the interplay between these components therapy, like in heart failure and ischaemic heart
has continued to unfold.14 disease.37–39
Increasing knowledge has also been gathered on the
pathophysiology of hypertension. Besides the traditional Diagnosis
environmental factors (eg, obesity, physical inactivity, Blood pressure measurements
excessive sodium intake, and chronic stress), preterm Accurate and reliable blood pressure measurements
birth or low birthweight,15,16 and air and noise pollution,17,18 are essential for the diagnosis of hypertension. Blood
have also been shown to contribute to the development pressure changes constantly in response to endogenous
of the condition. Additionally, immune mechanisms and factors and exogenous stimuli; therefore, standardisation
systemic inflammation have proven to be important in is essential for an accurate measurement.40 Unfortunately,
the pathogenesis of hypertension.19,20 In particular, gut the problem of unstandardised measurements has
microbiota21,22 and periodontitis23 seem to play a role in persisted for decades, despite efforts in education and
simplification of the measurement process. The wide consensus on definitions, thresholds and targets, and
spread availability of non-validated blood pressure devices demonstration that interventions mitigating blood
might lead to incorrect diagnosis41 and management.42 pressure variability improve outcomes.
The Lancet Commission on hypertension43,44 aimed to
identify key actions for improving global management Classification
of blood pressure, both at population and individual The definition of arterial hypertension is based in all
levels. To obtain correct blood pressure measurements, available guidelines on office blood pressure.48–50 Although
trained observers using standardised methodologies are the definition of arterial hypertension differs between the
needed.45–47 Multiple readings over time are required to 2018 European Society of Cardiology (ESC)–European
estimate blood pressure, allowing for regression to the Society of Hypertension (ESH) guidelines,48 the 2017
mean, and mitigating risk of obtaining elevated readings American College of Cardiology (ACC)–American Heart
secondary to white-coat hypertension.43,48 The most used Association (AHA) guidelines,49 and the 2020 ISH
methods for measuring blood pressure in a clinical care guidelines (table 1),50 the indications for antihypertensive
setting are either direct (ie, intra-arterial) or indirect (ie, therapy are similar: patients with a blood pressure of
cuff-based). Indirect blood pressure measurements are at least 140/90 mm Hg should be treated if the cardio
typically done via auscultation or with a semi-automated vascular risk is high or if signs of target organ damage are
or fully automated device, which most often uses the present. In patients with grade 1 hypertension (definitions
oscillometric technique. Use of automated measurements vary depending on the guideline),48,49 at low-to-moderate
might avoid observer bias; however, there are situations cardiovascular risk, and without evidence of hypertension-
(eg, increased arterial stiffness or arrhythmias) in which mediated organ damage, drug treatment to lower blood
use of automated devices can lead to error. Although office pressure is recommended if the patient remains
blood pressure is still the gold standard for diagnosing hypertensive after a period of lifestyle intervention.58
arterial hypertension, contemporary guidelines recom All guidelines agree that many blood pressure
mend confirming the diagnosis with out-of-office mea measurements are necessary to correctly diagnose
surements, such as ambulatory or home blood pressure arterial hypertension.48–50 In all patients who have an
monitoring.48–51 24 h ambulatory and home blood pressure elevated office blood pressure, diagnosis should be
monitoring were shown to be superior to office mea confirmed by use of out-of-office blood pressure
surements for prediction of cardiovascular events and are measurements (ie, home or ambulatory blood pressure
ideal for follow-up monitoring in the long term.48–50 monitoring). Out-of-office measurements are also useful
Unattended blood pressure measurements eliminate for diagnosing white coat or masked hypertension. It
patient–observer interaction, minimise patient anxiety, should be noted that values classified as normal are
and reduce observer error associated with manual different for office and out-of-office measurements
measurement.52 This method was used for the first time (table 2).
in the SPRINT trial.53 On average, unattended SBP is
10 mm Hg lower than the office sphygmomanometer
Systolic and diastolic blood pressure,
or oscillometric value (depending on baseline blood mm Hg
pressure), and should not be used interchangeably with
American College of Cardiology–American Heart Association49
other office measurements.54 Large randomised con
Normal <120 and <80
trolled trials exploring use of unattended blood pressure
Increased 120–129 and <80
measurements for predicting hypertension-mediated
organ damage, as well as the correlation between this Stage 1 130–139 or 80–89
method and cardiovascular morbidity and mortality, are Stage 2 ≥140 or ≥90
Snoring, daytime sleepiness, morning headache, irritability, increase in Obstructive sleep apnoea Screening questionnaire,
neck circumference, obesity, peripheral oedema polysomnography
American College of Cardiology– European Society of Cardiology– National Institute for International Society of
American Heart Association European Society of Health and Care Hypertension 202050
201749 Hypertension 201848 Excellence 201967
Sodium <1500 mg/day (ideal) Limit to up to 2000 mg/day Encourage a reduction Avoid foods with high salt content
consumption in sodium intake
Diet DASH High in fruits and vegetables, Encourage a healthy DASH diet; high in fruits and vegetables,
low-fat dairy, fish, whole grains; diet polyunsaturated fats, and dairy; low in foods
low in red meat and saturated fats high in sugar, saturated fats, and trans fats
Alcohol ≤2 standard drinks* per day for <14 units/week for men†; Encourage a reduction ≤2 standard drinks‡ per day for men;
consumption men; ≤1 standard drinks* per day <8 units/week for women† in intake if excessive ≤1·5 standard drinks‡ per day for women
for women
Physical Aerobic exercise: 90–150 mins/ Aerobic exercise for ≥30 mins/day Encourage regular Moderate aerobic activity for 30 mins/day
activity week; dynamic resistance training: ≥5 days/week exercise ≥5 days/week or high-intensity interval
90–150 mins/week training; resistance or strength exercises
2–3 days/week
Weight Target ideal bodyweight Avoid BMI >30 kg/m² or waist NA Ethnic-specific BMI and waist
reduction circumference >102 cm in men or circumference cutoffs to avoid obesity
>88 cm in women
DASH=dietary approach to stop hypertension. NA=not applicable. BMI=body-mass index. *One standard drink contains roughly 14 g of pure alcohol, which is typically found in
12 oz of regular beer (usually about 5% alcohol), 5 oz of wine (usually about 12% alcohol), and 1·5 oz of distilled spirits (usually about 40% alcohol). †1 unit is equal to 125 mL of
wine or 250 mL of beer. ‡One standard drink is equivalent to 10 g of alcohol.
or thiazide or thiazide-like diuretic) at maximally tolerated control in this age group. Decisions for antihypertensive
doses.48–50,67 Options for add-on therapy include miner management should be all encompassing, not solely based
alocorticoid receptor antagonists, β blockers, and on age, and take into account considerations such as
α1 blockers. A meta-analysis found mineralocorticoid patient comorbidities, other medications that can affect
receptor antagonists to be the most effective add-on blood pressure, and level of frailty.
therapy for resistant hypertension. Compared with Although not approved for hypertension, SGLT2
doxazosin and bisoprolol, a significantly greater reduction inhibitors have been found to decrease SBP by around
in SBP was achieved with spironolactone in a double- 4 mm Hg.82 The mechanism for this reduction is thought
blind, placebo-controlled, crossover trial.76,77 Spironolactone to be secondary to inhibition of sodium reuptake and
should be considered as a fourth-line agent for hyper subsequent sodium excretion.83 This effect of SGLT2
tension in the absence of contraindications. inhibitors is something to consider when managing
There might be instances in which reducing a medication patients with diabetes and hypertension; although not an
dose or even discontinuing medication altogether could be antihypertensive agent, its antihypertensive effects could
considered in patients with blood pressures below the allow for maximisation of blood pressure control in
optimal target, or in the case of adverse events. A systematic conjunction with diabetes management.
review found that factors such as monotherapy and lower
blood pressure before withdrawal were both predictors of Device-based treatment
success with regard to blood pressure control.78 The blood Various device-based therapies have emerged, such as
pressure of approximately 40% of patients was found to renal denervation, carotid baroreceptor stimulation,
still be controlled 1 year after medication withdrawal. creation of an arteriovenous fistula, or endovascular
Regardless of why medications are reduced in dose or are carotid body modification, and principally target the
discontinued, continual follow-up and monitoring for treatment of resistant or difficult-to-treat hypertension.
return of hypertension is paramount. Additionally, abrupt Renal denervation is the treatment modality with the
withdrawal of medications, particularly β blockers or most available data to date. The principle of this therapy
clonidine, should be avoided due to risk of deleterious is to eliminate sympathetic nerves around the renal
effects. Further research is needed to identify ideal patients artery, resulting in lower renal efferent and afferent
for whom to consider withdrawal, and to assess the long- sympathetic nervous activity and ultimately lower blood
term outcomes. pressure. The first results of renal denervation were
A 2020 publication longitudinally evaluating blood obtained with devices that used radiofrequency appli
pressure differences between sexes found that women cation in the open-label SYMPLICITY HTN-184 and
had a more precipitous increase in blood pressure than SYMPLICITY HTN-285 trials, along with several case
men, starting in early adulthood.79 These results warrant series and observational studies. Despite showing
further exploration; however, they have not yet led to safety, the SYMPLICITY HTN-386 trial was unable
changes in hypertension management between sexes. In to show efficacy of renal denervation with a radio
general, sex-specific management should be considered, frequency catheter over sham treatment in patients with
especially in pregnant women. ACE inhibitors, ARBs, severe resistant hypertension on multiple medications.48
and direct renin inhibitors are contraindicated due to However, post-hoc analyses of the SYMPLICITY HTN-3
risk of foetal injury and death. Appropriate agents for trial underlined important trial limitations to consider,
hypertensive management include methyldopa, labetalol, including trial patient selection, differences in adherence
or nifedipine.48,49 Despite how women aged 65 years and to antihypertensive medications between the treatment
older are more likely to have higher blood pressure later groups, a higher use of antihypertensive drugs in the
in life than are men, there is currently no distinction in sham group, and technical failure in carrying out renal
pharmacological management between the two sexes.70 denervation in the intervention group (eg, an insufficient
It is well known that hypertension prevalence increases number of ablations, ablation in the distal part of the
with age. It was found that more than 50% of patients with artery and limited to the main renal artery, and first-time
hypertension aged 80 years and older in the USA have performance of renal denervation for some operators).
uncontrolled hypertension.80 Elevated blood pressure has These limitations led to a revision of renal denervation
been associated with poor cardiovascular outcomes in technology and technique. Since SYMPLICITY HTN-3,
older patients, yet questions of how much to lower SBP by several novel, sham-controlled studies have been done or
in this population continue to arise.81 In a subgroup are underway. The SPYRAL HTN-OFF MED,87,88 SPYRAL
analysis from the SPRINT trial, patients aged 75 years and HTN-ON MED,89 and RADIANCE-HTN SOLO90 trials
older were found to benefit more from intensive blood showed significant and consistent reductions in blood
pressure treatment (SBP <120 mm Hg) than from stan pressure (both office and ambulatory) in patients with
dard treatment (SBP <140 mm Hg). Current guidelines and without concomitant antihypertensive use. The
recommend that providers work with patients to reach SPYRAL HTN-OFF MED trial showed catheter-based
blood pressure targets in patients aged 65 years and older, renal denervation to be superior to a sham procedure,
given that data indicate benefits from blood pressure with the intervention safely lowering blood pressure in
the absence of antihypertensive medications.88 Possible pressure control is therapeutic inertia, which includes
response indicators to renal denervation therapy can be failure to start or intensify antihypertensive therapy,
divided into patients with increased arterial stiffness and despite not having blood pressure under control. This
those with increased neurogenic activity.91 Consideration conundrum can consequently lead to additional years of
of these factors and use of the revised techniques will exposure to high blood pressure. When the decision is
considerably improve future studies and ultimately made to start antihypertensive treatment, the patient
expand our knowledge on renal denervation. Data should have regularly scheduled follow-ups in the early
showing efficacy of renal denervation for hypertension phase that continue until blood pressure is controlled
in patients without pharmacological therapy led to under stable treatment. Another major concern in
discussion about device treatment of hypertension as a unsuccessful treatment is non-adherence. This common
possible area of a shared decision making approach. and persistent problem should be addressed from the
Less evidence is available on the effect of carotid start of treatment and throughout its course. From early
baroreceptor stimulation and endovascular carotid body on, it is important to extensively counsel the patient and
modification. Both techniques aim to reduce blood their support system about the clinical reasoning for
pressure through reduction of sympathetic tone. The treatment and the long-term risk of elevated blood
first-generation carotid baroreceptor stimulation device pressure. The sharing of responsibility for a patient’s
reduced blood pressure in controlled and uncontrolled cardiovascular health is pivotal to improve patient
clinical trials. Currently, there are no controlled clinical investment in their health, diet, lifestyle, and medication
trials proving efficacy in blood pressure reduction for the compliance. In addition, obtaining blood pressure targets
second-generation carotid sinus stimulator.92 Some (mostly in the short term will reinforce the patient’s confidence
uncontrolled) studies suggest that other techniques, such in their treatment and promote persistent blood pressure
as baroreflex amplification and carotid body modulation, control to increase the likelihood of cardiovascular
might lead to blood pressure reduction in patients with benefit. Simplified and tailored treatment regimens (eg,
difficult-to-treat hypertension. However, more evidence considering costs, use of single-pill combinations, etc)
regarding the safety and efficacy of these techniques from will be of great importance for treatment success.96,97
large, randomised, sham-controlled trials is needed before The greatest challenge beyond the short-term manage
implementing baroreflex amplification and carotid body ment of hypertension is maintaining therapy adherence.
modulation into routine clinical practice.93
Furthermore, the creation of an iliac arteriovenous Health-care system
anastomosis to safely reduce blood pressure in patients
Awareness
with uncontrolled hypertension was assessed.94 The
ROX CONTROL HTN study95 evaluated this intervention
with the novel arteriovenous ROX Coupler (ROX
Screening
Medical; San Clemente, CA, USA). This small study, Treatment
Simplified and
involving 44 patients in the treatment group and tailored
39 patients in the standard care group, found that
creation of an arteriovenous anastomosis was associated
with a significant reduction in blood pressure. Due to
Sex, age, ethnicity, and
adverse events, including the development of venous concomitant disease
stenosis, the pivotal ROX HTN 2 trial was stopped.
The 2018 ESC–ESH guidelines do not recommend use
of device-based therapies for the routine treatment of Socioeconomic
hypertension, unless in the context of clinical studies status, lifestyle,
and behaviour
and randomised controlled trials.48 Nevertheless, device- Diagnosis Follow-up
based therapy for hypertension is a fast-moving field and • Blood pressure monitoring,
compliance, treatment
newly emerging data are now becoming available, which • Strongly supported by
could change this recommendation. digital health
Education
Timescales of treatment and follow-up
Hypertension Primary Patient
A short-term, medium-term, and long-term timescale Pharmacist
clinic care*
Patient
environment
can be distinguished in the course, challenges, and
treatment of arterial hypertension. A timely diagnosis, Figure 2: Key contributors in the process of blood pressure control and therapy adherence
which can only be obtained by regular blood pressure The patient is an integral part of their environment, and all interactions between the patient and various actors
measurements throughout an individual’s lifetime, is within the health-care system fall within this environment. The left side of the figure represents interactions
during the screening and diagnosis phase, whereas the right side represents the treatment and follow-up phase,
crucial in the management of hypertension. Additionally, containing many factors involved in therapy adherence. Treatment and follow-up are inseparably linked. The role
timely initiation of therapy is essential. Unfortunately, an of the pharmacist and hypertension clinic can vary widely among different health-care settings. *General
important issue in improving population-wide blood practitioner or community health worker.
Non-adherence is particularly frequent in patients with brain aminopeptidase A inhibitor, firibastat, is currently
apparently resistant hypertension and contributes to undergoing phase 2 (NCT03715998), and will soon
poor cardiovascular prognosis. Monitoring of adherence begin phase 3 (NCT04277884) trials.103 Upcoming trials
should be done routinely through open and non- will evaluate firibastat versus ramipril after myocardial
accusatory communication between the clinician and infarction (NCT03715998), and firibastat versus placebo
patient. Furthermore, indirect methods (eg, pill counts, in patients with uncontrolled primary hypertension.
tracking prescription refills, and self-reports) and direct Another promising pathway for new treatment targets
methods (eg, detection of drugs or their metabolites in is the protective arm of the RAAS (eg, ACE2, angiotensin
urine or plasma) have been developed.98 A continuous [1–7], AT2 receptor, Mas receptor axis), which has a
effort between patients and their health-care team needs counter-regulatory role in opposing AT1 receptor-
to be made to maintain, improve, and regain therapy mediated actions by mediating tissue protective and
adherence. regenerative actions (eg, vasodilation, natriuresis, and
Arterial hypertension is a chronic disease that requires anti-inflammatory, antiproliferative, and antifibrotic
regular follow-up in the long term. Management is a responses).104 Sex differences have been established in
multidisciplinary matter that should involve the primary the different mechanisms of action of the RAAS.105
health-care physician, hypertension specialist, and phar However, there are still important gaps in the scientific
macist, among other caregivers of the patient (figure 2). knowledge on the preclinical and clinical level of sex
Treatment plans should be made in conjunction with the differences in the pathogenesis and treatment of
most important member of the team—the patient—and hypertension.
their support system. By effectively educating patients A challenge in the management of hypertension is the
and their family, long-term compliance and adherence, follow-up of numerous patients. The field of digital
as well as early detection of changes in blood pressure, health, combining digital technologies and health care, is
are likely to be more successful. expanding rapidly and can improve different aspects of
The efforts of controlling blood pressure, along with the blood pressure management. The use of mobile health
other modifiable cardiovascular risk factors, ultimately applications are especially promising self-management
serve to reduce cardiovascular risk by preventing the tools, although not yet fully developed for hypertension.
progression of vascular damage. Conventional 10-year This technology not only provides information on home
risk prediction models identify individuals who would blood pressure measurements but also promotes lifestyle
benefit from therapy over the relative short term, whereas changes by giving advice on physical activity and healthy
cardiovascular risk estimations over a lifetime might be diet, and sending medication reminders.106–108 By actively
better suited to younger individuals who have a longer involving the patient, improved detection and manage
cumulative exposure to elevated blood pressure but a low ment of hypertension can be obtained, with promising
10-year cardiovascular risk. While awaiting evidence to opportunities for resource-limited settings.109 However,
establish the role of lifetime risk in treatment decisions, it further research is needed to identify effective strategies
is important to recognise that early implementation of for the wide implementation of evidence-based digital
preventative measures in younger patients might be health in this field.110
delayed with use of conventional 10-year risk prediction Machine learning and deep learning, two components
models. However, this subset of the population is likely to of artificial intelligence, are being increasingly used in
have the most success in maintaining a low-risk status the management of chronic diseases; however, they
and having a life free from cardiovascular disease, remain underexplored in the field of hypertension. More
by reducing cumulative exposure to elevated blood knowledge is needed on how to implement artificial
pressure.99–102 Older individuals, who are already at an intelligence in risk prediction, accuracy of blood pressure
elevated risk, are more likely to receive treatment but are measurement, treatment decisions, and management of
less likely to capture long-term benefits due to their age. patients with hypertension. Artificial intelligence will
also become an important tool for guiding clinical trials,
Future perspectives contributing to further development and implementation
For a largely controllable condition, the rates of awareness, of precision medicine.
treatment, and control of hypertension are disappointingly Contributors
low. There is room for improvement among the various SB designed the Seminar and coordinated the writing process, with input
levels of health care and throughout the process of patient from EMS. The epidemiology and pathophysiology sections were written
by YK, EMS, and SB. The diagnosis section was written by IS, EMS, and
screening, diagnosis, treatment, and follow-up. Previous SB. In the treatment section, the subsections on non-pharmacological
initiatives have reviewed the necessary actions to improve and pharmacological management of hypertension and timescales of
management of blood pressure worldwide.44 treatment and follow-up were written by EMS and SB, and the subsection
Medications available for hypertension management on device-based treatment was written by IS, SB, and EMS. The section
on future perspectives was written by SB and EMS. All authors
have not changed profoundly throughout previous participated in the literature search. SB and EMS produced the figures
decades. Excitingly, as more has been learned about the and entirely revised all versions of the manuscript. All authors approved
central regulation of blood pressure, a first-in-class the final version for publication.
Declaration of interests 19 Drummond GR, Vinh A, Guzik TJ, Sobey CG. Immune
IS reports consulting fees, speaker fees, and travel grants from Amgen, mechanisms of hypertension. Nat Rev Immunol 2019; 19: 517–32.
AstraZeneca, Boston Scientific, Daiichi Sankyo, Medtronic, Novartis, 20 Rodriguez-Iturbe B, Pons H, Johnson RJ. Role of the immune
Recordati, Sanofi, and Servier. All other authors declare no competing system in hypertension. Physiol Rev 2017; 97: 1127–64.
interests. 21 Marques FZ, Mackay CR, Kaye DM. Beyond gut feelings: how the gut
microbiota regulates blood pressure. Nat Rev Cardiol 2018; 15: 20–32.
Acknowledgments
22 Vallianou NG, Geladari E, Kounatidis D. Microbiome and
We thank H Zekollari for the fruitful discussions and help with the hypertension: where are we now? J Cardiovasc Med (Hagerstown)
design of figure 2. YK is supported by the Intramural Research Fund for 2020; 21: 83–88.
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