Arterial hypertension

Seminar
www.thelancet.com Published online May 18, 2021 https://doi.org/10.1016/S0140-6736(21)00221-X 1
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
remains poor. Although the diagnosis of hypertension is still based on office blood pressure, confirmation with out-
of-office blood pressure measurements (ie, ambulatory or home monitoring) is strongly recommended. The definition
of hypertension differs throughout various guidelines, but the indications for antihypertensive therapy are relatively
similar. Lifestyle adaptation is absolutely key in non-pharmacological treatment. Pharmacologically, angiotensin-
converting enzyme inhibitors or angiotensin receptor blockers, calcium channel blockers, and diuretics are the first-
line agents, with advice for the use of single-pill combination therapy by most guidelines. As a fourth-line agent,
spironolactone should be considered. The rapidly evolving field of device-based therapy, especially renal denervation,
will further broaden therapeutic options. Despite being a largely controllable condition, the actual rates of awareness,
treatment, and control of hypertension are disappointingly low. Further improvements throughout the process of
patient screening, diagnosis, treatment, and follow-up need to be urgently addressed.
Epidemiology
Hypertension is one of the most important modifiable
risk factors for cardiovascular disease and one of
the largest contributors to morbidity and mortality
worldwide. In a systematic analysis done for the Global
Burden of Disease Study 2017, high systolic blood
pressure (SBP) was the leading risk factor for mortality
(10·4 million deaths) and disability-adjusted life-years
(218 million).1
In a study including 8·69 million
participants from 154 countries, it was estimated that
between 1990 and 2015, the number of participants with
an SBP of at least 110–115 mm Hg increased from
73·1% to 81·3%, and those with an SBP of at least
140 mm Hg increased from 17·3% to 20·5%.2
Add
itionally, the estimated rate of annual deaths associated
with an SBP of at least 110–115 mm Hg increased by
7·1% from 1356 per million, and deaths associated with
an SBP of at least 140 mm Hg increased by 8·6% from
979 per million.
According to the 2019 May Measurement Month
campaign initiated by the International Society of
Hypertension (ISH), involving more than 1·5 million
individuals screened from 92 countries, 32·0% had never
had their blood pressure measured and 34·0% had been
diagnosed with hypertension, among whom 58·7% were
aware that they had hypertension and 54·7% were on
antihypertensive medications.3
In patients with hyper
tension, 31·7% had blood pressure readings below
140/90 mm Hg and 23·3% below 130/80 mm Hg. Of
patients on at least one antihypertensive, 57·8% had blood
pressure readings below 140/90 mm Hg and 28·9% below
130/80 mm Hg. Of patients taking antihypertensive
medications, half were single-drug users. Since May, 2017,
more than 4·2 million participants had their blood
pressure measured and almost 1 million adults with
hypertension were untreated or undertreated.
Globally, hypertension awareness varies, with at least
70% of people with hypertension from the Americas and
Europe being aware of their condition compared with
only up to 40% of patients from south Asia and sub-
Saharan Africa. In a sample of 1·7 million adults in
China, it was found that 44·7% of patients were
hypertensive and only 44·7% of those with hypertension
were aware of their condition.4
Even more compelling,
only 30·1% of patients were prescribed antihypertensive
agents and 7·2% had their blood pressure controlled.
When standardised for age and sex, hypertension had
rates of 37·2% for prevalence, 36·0% for awareness,
22·9% for treatment, and 5·7% for control.
In the African population, a systematic review and
meta-analysis of data from 25 studies showed a pooled
prevalence of 5·5% in children and adolescents with
elevated blood pressure (≥95th percentile) and of 12·7%
in children and adolescents with slightly elevated blood
pressure (≥90th percentile and <95th percentile).5
Increased body-mass index was largely associated with
prevalence of elevated blood pressure, which was
six times higher in children and adolescents (aged
2–19 years) with obesity than in age-matched individuals
without obesity. From a public health standpoint, it is
Published Online
May 18, 2021
https://doi.org/10.1016/
S0140-6736(21)00221-X
Department of Cardiology,
Cardiovascular Center Aalst,
OLV Hospital Aalst, Aalst,
Belgium (S Brouwers MD);
Department of Experimental
Pharmacology, Faculty of
Medicine and Pharmacy,Vrije
Universiteit Brussel, Brussels,
Belgium (S Brouwers);
University Heart Center,
Cardiology, University Hospital
Zurich, University of Zurich,
Zurich, Switzerland
(I Sudano MD); Department of
Preventive Cardiology,
National Cerebral and
Cardiovascular Center, Suita,
Japan (Y Kokubo MD); Institute
of Cardiovascular and Medical
Sciences, University of
Glasgow, Glasgow, UK
(Y Kokubo); Pharmacy Practice
andTranslational Research,
University of Houston College
of Pharmacy, Houston,TX, USA
(E M Sulaica PharmD)
Correspondence to:
Prof Sofie Brouwers, Department
of Cardiology, Cardiovascular
Center Aalst, OLV Hospital Aalst,
Aalst 9300, Belgium
sofie.brouwers@olvz-aalst.be
Search strategy and selection criteria
We searched PubMed and MEDLINE for articles published
from Jan 1, 2010, to Oct 25, 2020.We used the search terms
“blood pressure”, “hypertension”, “arterial hypertension”,
in combination with the terms “guidelines”, “chronotropy”,
“resistant hypertension”, “diabetes”, “ambulatory blood
pressure monitoring”, “home blood pressure measurement”,
“digital health”, “mobile health”, “lifetime risk”, “prospective
studies”, “epidemiology”, “population”, “lifetime blood
pressure”, “diet”, “lifestyle”, “periodontitis”, “inflammation”,
“renin-angiotensin system”, “angiotensin-(1–7)”, “novel
coronavirus disease 2019”, “genome-wide association”,
and “global”.We largely selected publications from the past
5 years, but did not exclude commonly referenced and highly
regarded older publications.We also searched the reference
lists of articles identified by this search strategy and selected
those we judged relevant. Review articles and book chapters
are cited to provide readers with more details and references
than this Seminar has room for.
Descargado para Ronald Eduardo Lozano Acosta (loacro@yahoo.com) en Cayetano Heredia Pervuvian University de ClinicalKey.es por Elsevier en mayo 22,
2021. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados.

Seminar
2 www.thelancet.com Published online May 18, 2021 https://doi.org/10.1016/S0140-6736(21)00221-X
essential to prevent obesity to improve hypertension,
given that the factors contributing to increased body-
mass index are applicable to Africans spanning from
childhood5
to adulthood.6
The meta-analysis also found
that elevated blood pressure was more pervasive in rural
areas than in urban areas; however, no differences in
prevalence were observed between boys and girls.5
Another study showed that the prevalence of hyper
tension is higher in people of African origin than in
those of European origin.7
In a study done in the USA, the strongest increase
from ideal blood pressure to pre-hypertension occurs at
age 8 years for boys of White ethnicity, and at age
25 years for young African Americans, illustrating
how heterogeneity in blood pressure starts appearing
at a young age.8
Pre-emptive prophylaxis beginning
in early adulthood might be necessary to prevent
pre-hypertension and hyperten
sion, as well as the
development of associated racial, ethnic, and gender
disparities that could be variably interpreted.9,10
An
analysis of the original cohort in the Framingham Heart
Study showed that individuals in the community
generally maintained SBP below 120–125 mm Hg;
however, when SBP began to rise above this range, it
increased relatively rapidly towards overt hypertension.11
This tendency was consistent, regardless of whether or
not hypertension appeared early or late in life.
Interestingly, a large-scale analysis of individual patient
trajectories provided evi
dence that lifetime SBP and
diastolic blood pressure were most elevated at least
14 years before death, and subsequently decreased until
death.12
64·0% of the patients included in this analysis
had SBP decreases of at least 10 mm Hg. This reduction
was present in all individuals, including those who did
not receive anti
hypertensive treatment, and was most
pronounced in older patients and in patients treated for
hypertension, dementia, heart failure, or late-life weight
loss.
Pathophysiology
Hypertension can be classified as essential or secondary,
with most patients having essential hypertension.13
The cause of hypertension is multifactorial in nature, with
environment, genetics, and social determinants having
the potential to contribute to its development.13
A better
understanding of the interplay between these components
has continued to unfold.14
Increasing knowledge has also been gathered on the
pathophysiology of hypertension. Besides the traditional
environmental factors (eg, obesity, physical inactivity,
excessive sodium intake, and chronic stress), preterm
birth or low birthweight,15,16
and air and noise pollution,17,18
have also been shown to contribute to the development
of the condition. Additionally, immune mechanisms and
systemic inflammation have proven to be important in
the pathogenesis of hypertension.19,20
In particular, gut
microbiota21,22
and periodontitis23
seem to play a role in
systemic inflammation, leading to increased blood
pressure.
Interactions between genes and the environment
illustrate the benefit of common lifestyle modifications
based on the recommendations of hypertension guide
lines, which consist of the following elements: weight
reduction, a healthy diet, dietary sodium reduction,
increased physical activity, and the cessation of smoking
and excessive alcohol consumption.24
As well as these environmental factors, a complex genetic
background has a role, which research is continuing to
expand on.25
Data from genome-wide association studies
on blood pressure traits (systolic, diastolic, and pulse
pressure) have led to greater understanding of important
loci involved in blood pressure. The discovery of novel loci
has clarified new mechanisms of blood pressure regulation
and the association between blood pressure and lifestyle.26,27
The renin–angiotensin–aldosterone system (RAAS) and
COVID-19
Throughout the COVID-19 pandemic, a key consideration
of hypertension pathophysiology and management has
been the effect of SARS-CoV-2 on the RAAS system.
SARS-CoV-2 has been proposed to gain entry into cells
through endocytosis, by binding to angiotensin-
converting enzyme (ACE) 2.28
This theory has led to
discussion around discontinuing ACE inhibitors or
angiotensin receptor blockers (ARBs) due to concern
for ACE2 upregulation and subsequent increase in
SARS-CoV-2 virility. To our knowledge, clinical studies
in this population are observational in nature and an
association between use of ACE inhibitors or ARBs and
increased SARS-CoV-2 infection or severity of COVID-19
has not been found.29–35
Multiple prospective, ongoing,
randomised trials will evaluate the outcomes of ACE
inhibitor or ARB use or discontinuation in the setting of
COVID-19 (NCT04591210; NCT04353596). Interestingly,
SARS-CoV-2 infection has also been shown to result
in ACE2 downregulation after initial binding to recep
tors.28,36
ACE2 is important in counteracting effects of
the RAAS system and, thus, there is also discussion
around the possible benefits of RAAS attenuation in
COVID-19.37
Current recommendations are to avoid
discontinuing RAAS inhibitors when they are clinically
indicated and especially if they are the cornerstone of the
therapy, like in heart failure and ischaemic heart
disease.37–39
Diagnosis
Blood pressure measurements
Accurate and reliable blood pressure measurements
are essential for the diagnosis of hypertension. Blood
pressure changes constantly in response to endogenous
factors and exogenous stimuli; therefore, standardisation
is essential for an accurate measurement.40
Unfortunately,
the problem of unstandardised measurements has
persisted for decades, despite efforts in education and

Seminar
simplification of the measurement process. The wide
spread availability of non-validated blood pressure devices
might lead to incorrect diagnosis41
and management.42
The Lancet Commission on hypertension43,44
aimed to
identify key actions for improving global management
of blood pressure, both at population and individual
levels. To obtain correct blood pressure measurements,
trained observers using standardised methodologies are
needed.45–47
Multiple readings over time are required to
estimate blood pressure, allowing for regression to the
mean, and mitigating risk of obtaining elevated readings
secondary to white-coat hypertension.43,48
The most used
methods for measuring blood pressure in a clinical care
setting are either direct (ie, intra-arterial) or indirect (ie,
cuff-based). Indirect blood pressure measurements are
typically done via auscultation or with a semi-automated
or fully automated device, which most often uses the
oscillometric technique. Use of automated measurements
might avoid observer bias; however, there are situations
(eg, increased arterial stiffness or arrhythmias) in which
use of automated devices can lead to error. Although office
blood pressure is still the gold standard for diagnosing
arterial hypertension, contemporary guidelines recom
mend confirming the diagnosis with out-of-office mea
surements, such as ambulatory or home blood pressure
monitoring.48–51
24 h ambulatory and home blood pres
sure
monitoring were shown to be superior to office mea
surements for prediction of cardiovascular events and are
ideal for follow-up monitoring in the long term.48–50
Unattended blood pressure measurements eliminate
patient–observer interaction, minimise patient anxiety,
and reduce observer error associated with manual
measurement.52
This method was used for the first time
in the SPRINT trial.53
On average, unattended SBP is
10 mm Hg lower than the office sphygmomanometer
or oscillometric value (depending on baseline blood
pressure), and should not be used interchangeably with
other office measurements.54
Large randomised con
trolled trials exploring use of unattended blood pressure
measurements for predicting hypertension-mediated
organ damage, as well as the correlation between this
method and cardiovascular morbidity and mortality, are
still needed.
Blood pressure variability is considered to be a potential
novel risk factor for cardiovascular disease. Blood pres
sure
is not a constant variable; rather, it shows marked
spontaneous oscillations over short-term (minutes to days)
and long-term (day-to-day, visit-to-visit, or seasonal)
periods, and studies in animal models indicate that
development of target organ damage is associated with
increased variability in blood pressure.55
Additionally,
in both the general population and patients with hyper
tension, studies have shown that the degree of short-term
andlong-termvariabilityinbloodpressureisindependently
associated with target organ damage and an increased rate
of cardiovascular events.56,57
However, many aspects related
to blood pressure variability need to be clarified, including
consensus on definitions, thresholds and targets, and
demonstration that interventions mitigating blood
pressure variability improve outcomes.
Classification
The definition of arterial hypertension is based in all
available guidelines on office blood pressure.48–50
Although
the definition of arterial hypertension differs between the
2018 European Society of Cardiology (ESC)–European
Society of Hypertension (ESH) guidelines,48
the 2017
American College of Cardiology (ACC)–American Heart
Association (AHA) guidelines,49
and the 2020 ISH
guidelines (table 1),50
the indications for antihypertensive
therapy are similar: patients with a blood pressure of
at least 140/90 mm Hg should be treated if the cardio
vascular risk is high or if signs of target organ damage are
present. In patients with grade 1 hypertension (definitions
vary depending on the guideline),48,49
at low-to-moderate
cardiovascular risk, and without evidence of hypertension-
mediated organ damage, drug treatment to lower blood
pressure is recommended if the patient remains
hypertensive after a period of lifestyle intervention.58
All guidelines agree that many blood pressure
measurements are necessary to correctly diagnose
arterial hypertension.48–50
In all patients who have an
elevated office blood pressure, diagnosis should be
confirmed by use of out-of-office blood pressure
measurements (ie, home or ambulatory blood pressure
monitoring). Out-of-office measurements are also useful
for diagnosing white coat or masked hypertension. It
should be noted that values classified as normal are
different for office and out-of-office measurements
(table 2).
Systolic and diastolic blood pressure,
mm Hg
American College of Cardiology–American Heart Association49
Normal <120 and <80
Increased 120–129 and <80
Stage 1 130–139 or 80–89
Stage 2 ≥140 or ≥90
European Society ofCardiology–European Society of Hypertension48
Optimal <120 and <80
Normal 120–129 or 80–84, or both
High-normal 130–139 or 85–89, or both
Stage 1 140–159 or 90–99, or both
Stage 2 160–179 or 100–109, or both
Stage 3 ≥180 or ≥110, or both
Isolated systolic hypertension ≥140 and <90
International Society of Hypertension50
Normal <130 and <85
High-normal 130–139 or 85–89, or both
Grade 1 hypertension 140–159 or 90–99, or both
Grade 2 hypertension ≥160 or ≥100, or both
Table 1: Classification of office blood pressure by class or grade, mm Hg

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Treatment thresholds and targets
The ESC–ESH guidelines suggest that office blood
pressure should be reduced below 140/90 mm Hg, with
an optimal range around 130/80 mm Hg.48
If tolerated,
office blood pressure could be further reduced, but
possibly not below 120/70 mm Hg. The ACC–AHA
guidelines49
suggest an office blood pressure target of
below 130/80 mm Hg for adults with confirmed
hypertension and cardiovascular disease or for those
with a 10-year event risk of atherosclerotic cardiovascular
disease of 10% or higher. An office blood pressure
target of below 130/80 mm Hg is also noted to be
reasonable in patients with hypertension but without
additional markers of increased risk of cardiovascular
disease.
Optimal blood pressure target is still a matter of debate.
The SPRINT trial53
showed a reduction in cardiovascular
outcomes (including death) with an intensive unattended
SBP target of below 120 mm Hg, compared with the
standard SBP target of below 140 mm Hg. This reduction
was counterbalanced by an increase in side-effects,
including electrolyte abnormalities, worsening of renal
function, and hypotension. This study excluded patients
with a history of diabetes or stroke, thus limiting extra
polation of these results to all patients with hypertension.
Of note, unattended blood pressure might be up to
10 mm Hg lower than blood pressure measured with a
health-care professional present;59
however, hypertensive
organ damage appears to be similar regardless of the
measurement method used.60
The ACCORD study61
and multiple meta-analyses62
have not found significant benefits with more intensive
versus less intensive blood pressure targets. Furthermore,
the results from the HOPE-3 trial58
did not reflect a
reduction in cardiovascular outcomes with blood pressure
reduction to below 140/90 mm Hg. In contrast to these
reports, a robust meta-analysis evaluated individual
participant-level data from randomised clinical trials
from the Blood Pressure Lowering Treatment Trialists
Collaboration63
and showed that a 5 mm Hg reduction in
blood pressure resulted in a decrease of major adverse
cardiovascular events by approximately 10%, regardless
of baseline blood pressure (range <120 to ≥170 mm Hg)
or history of a previous cardiovascular event. These
results suggest the consideration of blood pressure
lowering treatment to reduce elevated cardiovascular risk,
independent of thresholds or history of cardiovascular
disease.
Considering the nuances of the data, an SBP target of
below 130 mm Hg for attended blood pressure or below
120 mm Hg for unattended blood pressure might be
reasonable to target to optimise the balance of efficacy and
safety for most patients. Specific patient characteristics
should be taken into account when establishing blood
pressure targets (eg, age, comorbidities, level of cardio
vascular risk).
Screening for hypertension-mediated organ damage
All guidelines agree that assessment of hypertension-
mediated organ damage is needed to estimate the
cardiovascular risk of a patient with hypertension.48–50
Assessment of hypertension-mediated organ damage is
summarised in panel 1.
Secondary hypertension
Secondary hypertension is a type of hypertension with
a potentially correctable underlying cause. Secondary
hypertension should be considered in young patients
without a family history of arterial hypertension, in
patients with resistant hypertension, and in patients with
American College of Cardiology–
American Heart Association49
European Society ofCardiology–
European Society of
Hypertension48
and International
Society of Hypertension50
Office BPM, mm Hg <130/80 <140/90
Home BPM, mm Hg <130/80 <135/85
24 h ambulatory BPM, mm Hg <125/75 <130/80
Awake ambulatory BPM, mm Hg <130/80 <135/85
Sleep ambulatory BPM, mm Hg <110/65 <120/70
BPM=blood pressure monitoring.
Table 2: Normal values of blood pressure according to the methods used for screening
Panel 1: Assessment of hypertension-mediated organ damage
Asymptomatic hypertension-mediated organ damage
• Arterial stiffening
• Pulse pressure >60 mm Hg (in older people aged >65years)
• Carotid–femoral pulse wave velocity >10 m/s
• Electrocardiogram LV hypertrophy (Sokolow-Lyon index >35 mm or R in augmented
Vector Left ≥11 mm; Cornell voltage-duration product >2440 mm ms, or Cornell
voltage >28 mm in men or >20 mm in women)
• Echocardiographic LV hypertrophy (LV mass index >50 g/m²·
⁷ in men and >47 g/m²·
⁷ in
women [height in m²·
⁷]; indexation for BSA [LV mass/BSA] might be used in patients
with healthy weight: >115 g/m² in men and >95 g/m² in women)
• Microalbuminuria (30–300 mg/24 h) or elevated albumin–creatinine ratio
(30–300 mg/g; 3·4–34·0 mg/mmol), preferentially on morning spot urine
• Moderate CKD with eGFR >30–59 mL/min/1·73 m² (BSA) or severe CKD with
eGFR <30 mL/min/1·73 m²
• Ankle-brachial index <0·9
• Advanced retinopathy: haemorrhages or exudates, papilloedema
Established cardiovascular or renal disease
• Cerebrovascular disease—eg, ischaemic stroke, cerebral haemorrhage, transient
ischaemic attack
• Coronary artery disease—eg, myocardial infarction, angina, myocardial revascularisation
• Presence of atheromatous plaque on imaging
• Heart failure, including heart failure with preserved ejection fraction
• Peripheral artery disease
• Atrial fibrillation
LV=left ventricular. BSA=body surface area.CKD=chronic kidney disease. eGFR=estimated glomerular filtration rate.

Seminar
a late sudden onset of hypertension.64
In addition to
medical history, a secondary cause might be suggested by
symptoms (eg, flushing and sweating, suggestive of
pheochromocytoma), examination findings (eg, a renal
bruit, suggestive of renal artery stenosis), or laboratory
abnormalities (eg, low or low-to-normal kalaemia, sug
gestive of aldosteronism). Approximately 5–10% of adults
with hypertension have a secondary cause. The prevalence
of secondary hypertension and the most common causes
vary by age group. Whenever a patient is diagnosed with
hypertension, the aim of the initial assessment must be
to rule in or out possible secondary causes (table 3).
Additionally, adherence to therapy and use of substances
and drugs, which can increase blood pressure, should be
considered (panel 2).
Treatment
Non-pharmacological and pharmacological
management of hypertension
Within the past 4 years, four major guideline writing
entities have published updates regarding hypertension
management: the ACC–AHA, the ESC–ESH, the
National Institute for Health and Care Excellence
(NICE), and, most recently, the ISH guidelines. The
intent of the ISH guideline was to be written in a manner
that would be easy to use and apply in low-income,
middle-income, and high-income countries.50
Each set of guidelines notes that sodium restriction in
patients with hypertension is needed as there is a linear
relationship between reduction in sodium intake and
subsequent reduction in blood pressure in patients with
hypertension. Recommendations for sodium intake
range from up to 1·5–2·0 g/day to a general reduction
in sodium intake.48–50
In conjunction with sodium
Possible diagnosis Diagnostic tests
Different blood pressure (≥20/10 mm Hg) between upper and lower
extremities, right and left arms, or both; delayed femoral pulsations,
interscapular ejection murmur, rib notching on chest radiograph
Coarctation of the aorta Echocardiography, chest radiograph, MRI
Peripheral oedema, pallor, loss of muscle mass Renal parenchymal disease Creatinine, ultrasound of the kidney
Abdominal bruits, peripheral vascular disease Renal artery stenosis Duplex, CT, MRI, angiography
Fatigue, constipation, polyuria, polydipsia, muscle weakness Primary aldosteronism Aldosterone–renin ratio
Weight gain, impotence, fatigue, psychological changes, polydipsia and
polyuria, obesity, hirsutism, skin atrophy, striae rubrae, muscle
weakness, osteopenia
Cushing’s syndrome 24 h urinary cortisol, dexamethasone
testing
Headache, palpitations, flushing, anxiety, paroxysmal hypertension,
pounding, headache, perspiration, palpitations, pallor
Pheochromocytoma Plasma or 24 h urinary metanephrines,
24 h urinary catecholamine
Palpitations, weight loss, anxiety, heat intolerance, tachycardia, atrial
fibrillation, accentuated heart sounds, exophthalmos
Hyperthyroidism (thyroid disease) Thyroid stimulating hormone,
tri-iodothyronine, thyroxine
Weight gain, fatigue, obstipation, bradycardia, muscle weakness,
myxoedema
Hypothyroidism (thyroid disease) Thyroid stimulating hormone,
tri-iodothyronine, thyroxine
Snoring, daytime sleepiness, morning headache, irritability, increase in
neck circumference, obesity, peripheral oedema
Obstructive sleep apnoea Screening questionnaire,
polysomnography
Modified from Sudano and colleagues.64
Table 3: Signs and symptoms suggesting specific causes of secondary hypertension
Panel 2: Examples of selective drugs that can elevate blood
pressure
Oestrogen
• Oral contraceptives
Herbal
• Ephedra (Ma huang)
• Ginseng
Illicit
• Amphetamines
• Cocaine
Non-steroidal anti-inflammatory
• COX-2 inhibitors
• Ibuprofen
• Naproxen
Psychiatric
• Buspirone
• Carbamazepine
• Clozapine
• Fluoxetine
• Lithium
• Tricyclic antidepressants
Steroid
• Methylprednisolone
• Prednisone
Sympathomimetic
• Decongestants
• Diet pills
Modified from Sudano and colleagues.64

Seminar
reduction, diet is also important. Intake should be high
in fruits, vegetables, fish, and whole grains, and low in
processed foods, saturated fat, and red meat. Low-fat
dairy products should replace dairy high in saturated
fats. Plant-based diets have shown benefits, with a meta-
analysis finding a reduction in SBP of –5·53 mm Hg in
participants following the DASH diet (Dietary Approach
to Stop Hypertension), –0·95 mm Hg in those on a
Mediterranean diet, and –5·47 mm Hg in those on a
lacto-ovo-vegetarian diet.65
Diet, physical activity, and
weight reduction work to address obesity and subse
quently reduce blood pressure. There is a complex
interplay between hypertension and risk factors for
cardiovascular disease that stems from mechanisms
such as insulin resistance, dysregulation of the RAAS
system, and endothelial dysfunction.66
Addressing
modifiable risk factors (eg, tobacco use, diabetes,
dyslipidaemia, etc) might result in blood pressure
reduction and mitigation of overall progression of
cardiovascular disease. Key lifestyle recommendations
are summarised in table 4.
Both the ESC–ESH and ACC–AHA guidelines
recommend ACE inhibitors, ARBs, calcium channel
blockers, and thiazide or thiazide-like diuretics as first-
line agents (figure 1).48,49
It should be noted that first-line
pharmacological therapy should always be accompanied
by non-pharmacological education and reinforcement at
follow-up visits. Additionally, although lifestyle modifica
tions can delay hypertension or allow patients to meet
their blood pressure targets, initiation of first-line phar
macological therapy should not be delayed in patients
with hypertension who qualify.
The ESC–ESH guidelines only recommend β blockers as
first-linetherapyinthesettingofacompellingcomorbidity.48
Both the 2020 ISH and 2019 NICE guide
lines provide
stepwise algorithms for management of antihypertensive
therapy.50,67
Table 5 provides an overview of guideline
recommendations for therapy initiation.
Figure 1: Mechanisms of action for first-line antihypertensive medications
ACE=angiotensin-converting enzyme. ARB=angiotensin receptor blocker. Ca²⁺=calcium ion. Na⁺=sodium ion.
Cl⁻=chloride ion. *Decreased heart rate associated with non-dihydropyridine calcium channel blocker use.
Angiotensinogen
Outside cell
Angiotensin 1
Angiotensin 2
Angiotensin receptor
ARB
ACE inhibitor
Renin
ACE
Ca2+
Inside cell
Vasoconstriction • Myocardial contraction
• Increased heart rate*
Calcium channel blocker
Thiazide-type
diuretic
Na+
Na+
Cl –
Cl –
K+
Lumen Blood
American College of Cardiology–
American Heart Association
201749
European Society of Cardiology–
European Society of
Hypertension 201848
National Institute for
Health and Care
Excellence 201967
International Society of
Hypertension 202050
Sodium
consumption
<1500 mg/day (ideal) Limit to up to 2000 mg/day Encourage a reduction
in sodium intake
Avoid foods with high salt content
Diet DASH High in fruits and vegetables,
low-fat dairy, fish, whole grains;
low in red meat and saturated fats
Encourage a healthy
diet
DASH diet; high in fruits and vegetables,
polyunsaturated fats, anddairy; low in foods
high in sugar, saturated fats, and trans fats
Alcohol
consumption
≤2 standard drinks* per day for
men; ≤1 standard drinks* per day
for women
<14 units/week for men†;
<8 units/week for women†
Encourage a reduction
in intake if excessive
≤2 standard drinks‡ per day for men;
≤1·5 standard drinks‡ per day for women
Physical
activity
Aerobic exercise: 90–150 mins/
week; dynamic resistance training:
90–150 mins/week
Aerobic exercise for ≥30 mins/day
≥5 days/week
Encourage regular
exercise
Moderate aerobic activity for 30 mins/day
≥5 days/week or high-intensity interval
training; resistance or strength exercises
2–3 days/week
Weight
reduction
Target ideal bodyweight Avoid BMI >30 kg/m² or waist
circumference >102 cm in men or
>88 cm in women
NA Ethnic-specific BMI and waist
circumference cutoffs to avoid obesity
DASH=dietary approachto stop hypertension. NA=not applicable. BMI=body-mass index. *One standard drink contains roughly 14 g of pure alcohol, which istypically 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 equalto 125 mL of
wine or 250 mL of beer. ‡One standard drink is equivalentto 10 g of alcohol.
Table 4: Key lifestyle recommendations

Seminar
The NICE guidelines recommend initiation with one
agent for most patients.67
The authors provide rationale
that there is no new or compelling evidence to recom
mend dual therapy upfront in most cases. By contrast, the
ESC–ESH guidelines recommend upfront dual therapy
because patients are less likely to reach blood pressure
targets with monotherapy and are likely to benefit with
multimodal pharmacological approaches.48
Guideline writing entities are still divided over
thiazide versus thiazide-like diuretics for hypertension
manage
ment. Current NICE and ISH guidelines recom
mend initiation of thiazide-like diuretics (eg, indapamide
or chlorthalidone) over thiazide diuretics (eg, hydro
chlorothiazide or bendroflumethiazide), and ACC–AHA
guidelines note that chlorthalidone is preferred.49,50,67
By
contrast, ESC–ESH guidelines state that either thiazide-
like or thiazide diuretics are reasonable to use for blood
pressure management.48
The conflict between guidelines
stems from an absence of large, prospective, head-to-head
trials comparing thiazide with thiazide-like diuretics in
patients with hyper
tension. A multicentre cohort study
comparing chlor
thalidone with hydrochlorothiazide found
no difference between the two treatment groups with
regard to cardiovascular outcomes (eg, acute myocardial
infarction, heart failure hospitalisation, or stroke); however,
there were more adverse effects, including electrolyte
abnor
malities, syncope, and acute renal failure, in
patients taking chlorthalidone.6
An ongoing, open-label,
randomised trial comparing chlorthalidone with hydro
chlorothiazide in veterans aged 65 years and older and
assessing time to a major cardiovascular event will
hopefully provide more clarity when deciding between
these agents (NCT021854).68
Single-pill combination therapy, a combination of two
or more antihypertensive agents, is a way to decrease pill
burden and improve patient adherence.48
Quad therapy
(ie, four antihypertensive medications in one) was
evaluated in the Quadpill trial.69
This trial assessed a
quarter dose of four medications (irbesartan, amlodipine,
hydrochlorothiazide, and atenolol) in a single pill versus
placebo in patients with hypertension, and found a
greater reduction in blood pressure in the group receiving
a single-pill combination at 4 weeks. Although the sample
size was small and an assessment of cardiovascular
outcomes is still needed, these results are promising and
highlight the efficacy of a multimodal agent approach to
hypertension management. Nevertheless, the potential
for adverse effects with a polypill (eg, dizziness or hypo
tension in sensitive patients) should be carefully weighed,
especially in older patients or in patients prone to falls.
Black patients have a higher prevalence of hypertension
diagnosesandaremorelikelytohavepoorercardiovascular
outcomes associated with the condition than non-Black
patients.49,70
ACE inhibitors or ARB monotherapy have
been found to be less effective at controlling blood
pressure in Black patients than has monotherapy with
agents such as thiazide or thiazide-like diuretics and
calcium channel blockers.71,72
A 2019 study compared
between amlodipine–hydrochlorothiazide, amlodipine–
perindopril, and perindopril–hydrochloro
thiazide in
African men and women with elevated blood pressure in
six sub-Saharan African countries.73
These patients were
either on no antihypertensive therapy or on mono
therapy and had no history of cardiovascular disease. At
6 months, SBP was significantly lower in the amlodipine–
hydrochlorothiazide group and amlodipine–perindopril
group than in the perindopril–hydrochlorothiazide group.
A significant difference in SBP was not found between
the amlodipine–hydrochlorothiazide and amlodipine–
perindopril groups. Antihypertensive management for
most Black patients can include a combination of calcium
channel blocker plus RAAS inhibitor, calcium channel
blocker plus thiazide or thiazide-like diuretic, or RAAS
inhibitor plus thiazide or thiazide-like diuretic to reach
blood pressure targets. Of note, various guidelines
recommend ARBs over ACE inhibitors in this population
due to the increased risk of angioedema observed in Black
patients.50,74
Although there are some data (albeit scarce) in
the Black population, more evidence is needed in these
patients and in the Asian population to better tailor
therapy. The consensus statement for hypertension
management in Asian patients recommends upfront
initiation with a calcium channel blocker and RAAS
inhibitor.75
Resistant hypertension is defined as inadequate blood
pressure control with adherence to three antihypertensive
agents (calcium channel blocker, ACE inhibitor or ARB,
Therapy recommendations
National Institute for Health and Care Excellence67
Patients with hypertension and diabetes or aged <55 years and not of Black African or African-Caribbean
family origin (without diabetes)
Step 1 A
Step 2 A plus C or D
Patients with hypertension without diabetes and either aged ≥55 years or of Black African or African-
Caribbean family origin
Step 1 C
Step 2 C plus A or D
European Society of Cardiology–European Society of Hypertension48
Step 1 A plus C or D
Step 2 A plus C plus D
International Society of Hypertension50
Step 1 A plus C*† (low dose)
Step 2 A plus C* (full dose)
Step 3 A plus C* plus D
American College of Cardiology–American Heart Association49
Step 1 A or C or D‡
A is angiotensin-converting enzyme inhibitor or angiotensin receptor blocker; C is calcium channel blocker; and D is
thiazide-like or thiazide diuretic. *Dihydropyridine calcium channel blocker. †Angiotensin receptor blocker preferred in
Black patients. ‡Dual therapy upfront for patients with stage 2 hypertension and blood pressure ≥20/10 mm Hg above
target.
Table 5: Guideline recommendations for therapy initiation

Seminar
or thiazide or thiazide-like diuretic) at maximally tolerated
doses.48–50,67
Options for add-on therapy include miner
alocorticoid receptor antagonists, β blockers, and
α1 blockers. A meta-analysis found mineralocorticoid
receptor antagonists to be the most effective add-on
therapy for resistant hypertension. Compared with
doxazosin and bisoprolol, a significantly greater reduction
in SBP was achieved with spironolactone in a double-
blind,placebo-controlled,crossovertrial.76,77
Spironolactone
should be considered as a fourth-line agent for hyper
tension in the absence of contraindications.
Theremightbeinstancesinwhichreducingamedication
dose or even discontinuing medication altogether could be
considered in patients with blood pressures below the
optimal target, or in the case of adverse events. A systematic
review found that factors such as monotherapy and lower
blood pressure before withdrawal were both predictors of
success with regard to blood pressure control.78
The blood
pressure of approximately 40% of patients was found to
still be controlled 1 year after medication withdrawal.
Regardless of why medications are reduced in dose or are
discontinued, continual follow-up and monitoring for
return of hypertension is paramount. Additionally, abrupt
withdrawal of medications, particularly β blockers or
clonidine, should be avoided due to risk of deleterious
effects. Further research is needed to identify ideal patients
for whom to consider withdrawal, and to assess the long-
term outcomes.
A 2020 publication longitudinally evaluating blood
pressure differences between sexes found that women
had a more precipitous increase in blood pressure than
men, starting in early adulthood.79
These results warrant
further exploration; however, they have not yet led to
changes in hypertension management between sexes. In
general, sex-specific management should be considered,
especially in pregnant women. ACE inhibitors, ARBs,
and direct renin inhibitors are contraindicated due to
risk of foetal injury and death. Appropriate agents for
hypertensive management include methyldopa, labetalol,
or nifedipine.48,49
Despite how women aged 65 years and
older are more likely to have higher blood pressure later
in life than are men, there is currently no distinction in
pharmacological management between the two sexes.70
It is well known that hypertension prevalence increases
with age. It was found that more than 50% of patients with
hypertension aged 80 years and older in the USA have
uncontrolled hypertension.80
Elevated blood pressure has
been associated with poor cardiovascular outcomes in
older patients, yet questions of how much to lower SBP by
in this population continue to arise.81
In a subgroup
analysis from the SPRINT trial, patients aged 75 years and
older were found to benefit more from intensive blood
pressure treatment (SBP <120 mm Hg) than from stan
dard treatment (SBP <140 mm Hg). Current guidelines
recommend that providers work with patients to reach
blood pressure targets in patients aged 65 years and older,
given that data indicate benefits from blood pressure
control in this age group. Decisions for antihypertensive
management should be all encom
passing, not solely based
on age, and take into account considerations such as
patient comorbidities, other medications that can affect
blood pressure, and level of frailty.
Although not approved for hypertension, SGLT2
inhibitors have been found to decrease SBP by around
4 mm Hg.82
The mechanism for this reduction is thought
to be secondary to inhibition of sodium reuptake and
subsequent sodium excretion.83
This effect of SGLT2
inhibitors is something to consider when managing
patients with diabetes and hypertension; although not an
antihypertensive agent, its antihypertensive effects could
allow for maximisation of blood pressure control in
conjunction with diabetes management.
Device-based treatment
Various device-based therapies have emerged, such as
renal denervation, carotid baroreceptor stimulation,
creation of an arteriovenous fistula, or endovascular
carotid body modification, and principally target the
treatment of resistant or difficult-to-treat hypertension.
Renal denervation is the treatment modality with the
most available data to date. The principle of this therapy
is to eliminate sympathetic nerves around the renal
artery, resulting in lower renal efferent and afferent
sympathetic nervous activity and ultimately lower blood
pressure. The first results of renal denervation were
obtained with devices that used radiofrequency appli
cation in the open-label SYMPLICITY HTN-184
and
SYMPLICITY HTN-285
trials, along with several case
series and observational studies. Despite showing
safety, the SYMPLICITY HTN-386
trial was unable
to show efficacy of renal denervation with a radio
frequency catheter over sham treatment in patients with
severe resistant hypertension on multiple medications.48
However, post-hoc analyses of the SYMPLICITY HTN-3
trial underlined important trial limitations to consider,
including trial patient selection, differences in adherence
to antihypertensive medications between the treatment
groups, a higher use of anti
hypertensive drugs in the
sham group, and technical failure in carrying out renal
denervation in the intervention group (eg, an insufficient
number of ablations, ablation in the distal part of the
artery and limited to the main renal artery, and first-time
performance of renal denervation for some operators).
These limitations led to a revision of renal denervation
technology and technique. Since SYMPLICITY HTN-3,
several novel, sham-controlled studies have been done or
are underway. The SPYRAL HTN-OFF MED,87,88
SPYRAL
HTN-ON MED,89
and RADIANCE-HTN SOLO90
trials
showed signifi
cant and consistent reductions in blood
pressure (both office and ambulatory) in patients with
and without concomitant antihypertensive use. The
SPYRAL HTN-OFF MED trial showed catheter-based
renal denervation to be superior to a sham procedure,
with the intervention safely lowering blood pressure in

Seminar
the absence of antihyper
tensive medications.88
Possible
response indicators to renal denervation therapy can be
divided into patients with increased arterial stiffness and
those with increased neurogenic activity.91
Consideration
of these factors and use of the revised techniques will
considerably improve future studies and ultimately
expand our knowledge on renal denervation. Data
showing efficacy of renal denervation for hypertension
in patients without pharmacological therapy led to
discussion about device treatment of hypertension as a
possible area of a shared decision making approach.
Less evidence is available on the effect of carotid
baroreceptor stimulation and endovascular carotid body
modification. Both techniques aim to reduce blood
pressure through reduction of sympathetic tone. The
first-generation carotid baroreceptor stimulation device
reduced blood pressure in controlled and uncontrolled
clinical trials. Currently, there are no controlled clinical
trials proving efficacy in blood pressure reduction for the
second-generation carotid sinus stimulator.92
Some (mostly
uncontrolled) studies suggest that other techniques, such
as baroreflex amplification and carotid body modulation,
might lead to blood pressure reduc
tion in patients with
difficult-to-treat hypertension. However, more evidence
regarding the safety and efficacy of these techniques from
large, randomised, sham-controlled trials is needed before
implementing baroreflex amplification and carotid body
modulation into routine clinical practice.93
Furthermore, the creation of an iliac arteriovenous
anastomosis to safely reduce blood pressure in patients
with uncontrolled hypertension was assessed.94
The
ROX CONTROL HTN study95
evaluated this intervention
with the novel arteriovenous ROX Coupler (ROX
Medical; San Clemente, CA, USA). This small study,
involving 44 patients in the treatment group and
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
adverse events, including the development of venous
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
hypertension, unless in the context of clinical studies
and randomised controlled trials.48
Nevertheless, device-
based therapy for hypertension is a fast-moving field and
newly emerging data are now becoming available, which
could change this recommendation.
Timescales of treatment and follow-up
A short-term, medium-term, and long-term timescale
can be distinguished in the course, challenges, and
treatment of arterial hypertension. A timely diagnosis,
which can only be obtained by regular blood pressure
measurements throughout an individual’s lifetime, is
crucial in the management of hypertension. Additionally,
timely initiation of therapy is essential. Unfortunately, an
important issue in improving population-wide blood
pressure control is therapeutic inertia, which includes
failure to start or intensify antihypertensive therapy,
despite not having blood pressure under control. This
conundrum can consequently lead to additional years of
exposure to high blood pressure. When the decision is
made to start antihypertensive treatment, the patient
should have regularly scheduled follow-ups in the early
phase that continue until blood pressure is controlled
under stable treatment. Another major concern in
unsuccessful treatment is non-adherence. This common
and persistent problem should be addressed from the
start of treatment and throughout its course. From early
on, it is important to extensively counsel the patient and
their support system about the clinical reasoning for
treatment and the long-term risk of elevated blood
pressure. The sharing of responsibility for a patient’s
cardiovascular health is pivotal to improve patient
investment in their health, diet, lifestyle, and medication
compliance. In addition, obtaining blood pressure targets
in the short term will reinforce the patient’s confidence
in their treatment and promote persistent blood pressure
control to increase the likelihood of cardiovascular
benefit. Simplified and tailored treatment regimens (eg,
considering costs, use of single-pill combinations, etc)
will be of great impor
tance for treatment success.96,97
The greatest challenge beyond the short-term manage
ment of hypertension is maintaining therapy adherence.
Figure 2: Key contributors in the process of blood pressure control and therapy adherence
The patient is an integral part of their environment, and all interactions between the patient and various actors
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,
containing many factors involved in therapy adherence.Treatment and follow-up are inseparably linked.The role
of the pharmacist and hypertension clinic can vary widely among different health-care settings. *General
practitioner or community health worker.
Hypertension
clinic
Primary
care*
Pharmacist
Awareness
Patient
environment
Patient
Sex, age, ethnicity, and
concomitant disease
Socioeconomic
status, lifestyle,
and behaviour
Diagnosis
Screening
Education
Follow-up
• Blood pressure monitoring,
compliance, treatment
• Strongly supported by
digital health
Treatment
Simplified and
tailored
Health-care system

Seminar
Non-adherence is particularly frequent in patients with
apparently resistant hypertension and contributes to
poor cardiovascular prognosis. Monitoring of adherence
should be done routinely through open and non-
accusatory communication between the clinician and
patient. Furthermore, indirect methods (eg, pill counts,
tracking prescription refills, and self-reports) and direct
methods (eg, detection of drugs or their metabolites in
urine or plasma) have been developed.98
A continuous
effort between patients and their health-care team needs
to be made to maintain, improve, and regain therapy
adherence.
Arterial hypertension is a chronic disease that requires
regular follow-up in the long term. Management is a
multidisciplinary matter that should involve the primary
health-care physician, hypertension specialist, and phar
macist, among other caregivers of the patient (figure 2).
Treatment plans should be made in conjunction with the
most important member of the team—the patient—and
their support system. By effectively educating patients
and their family, long-term compliance and adherence,
as well as early detection of changes in blood pressure,
are likely to be more successful.
The efforts of controlling blood pressure, along with the
other modifiable cardiovascular risk factors, ultimately
serve to reduce cardiovascular risk by preventing the
progression of vascular damage. Conventional 10-year
risk prediction models identify individuals who would
benefit from therapy over the relative short term, whereas
cardiovascular risk estimations over a lifetime might be
better suited to younger individuals who have a longer
cumulative exposure to elevated blood pressure but a low
10-year cardiovascular risk. While awaiting evidence to
establish the role of lifetime risk in treat
ment decisions, it
is important to recognise that early implementation of
preventative measures in younger patients might be
delayed with use of conventional 10-year risk prediction
models. However, this subset of the population is likely to
have the most success in maintaining a low-risk status
and having a life free from cardiovascular disease,
by reducing cumulative exposure to elevated blood
pressure.99–102
Older individuals, who are already at an
elevated risk, are more likely to receive treatment but are
less likely to capture long-term benefits due to their age.
Future perspectives
For a largely controllable condition, the rates of awareness,
treatment, and control of hypertension are disappointingly
low. There is room for improvement among the various
levels of health care and throughout the process of patient
screening, diagnosis, treatment, and follow-up. Previous
initiatives have reviewed the necessary actions to improve
management of blood pressure worldwide.44
Medications available for hypertension management
have not changed profoundly throughout previous
decades. Excitingly, as more has been learned about the
central regulation of blood pressure, a first-in-class
brain aminopeptidase A inhibitor, firibastat, is currently
undergoing phase 2 (NCT03715998), and will soon
begin phase 3 (NCT04277884) trials.103
Upcoming trials
will evaluate firibastat versus ramipril after myocardial
infarction (NCT03715998), and firibastat versus placebo
in patients with uncontrolled primary hypertension.
Another promising pathway for new treatment targets
is the protective arm of the RAAS (eg, ACE2, angiotensin
[1–7], AT2 receptor, Mas receptor axis), which has a
counter-regulatory role in opposing AT1 receptor-
mediated actions by mediating tissue protective and
regenerative actions (eg, vasodilation, natriuresis, and
anti-inflammatory, antiproliferative, and antifibrotic
responses).104
Sex differences have been established in
the different mechanisms of action of the RAAS.105
However, there are still important gaps in the scientific
knowledge on the preclinical and clinical level of sex
differences in the pathogenesis and treatment of
hypertension.
A challenge in the management of hypertension is the
follow-up of numerous patients. The field of digital
health, combining digital technologies and health care, is
expanding rapidly and can improve different aspects of
blood pressure management. The use of mobile health
applications are especially promising self-management
tools, although not yet fully developed for hypertension.
This technology not only provides information on home
blood pressure measurements but also promotes lifestyle
changes by giving advice on physical activity and healthy
diet, and sending medication reminders.106–108
By actively
involving the patient, improved detection and manage
ment of hypertension can be obtained, with promising
opportunities for resource-limited settings.109
However,
further research is needed to identify effective strategies
for the wide implementation of evidence-based digital
health in this field.110
Machine learning and deep learning, two components
of artificial intelligence, are being increasingly used in
the management of chronic diseases; however, they
remain underexplored in the field of hypertension. More
knowledge is needed on how to implement artificial
intelligence in risk prediction, accuracy of blood pressure
measurement, treatment decisions, and management of
patients with hypertension. Artificial intelligence will
also become an important tool for guiding clinical trials,
contributing to further development and implementation
of precision medicine.
Contributors
SB designed the Seminar and coordinated the writing process, with input
from EMS. The epidemiology and pathophysiology sections were written
by YK, EMS, and SB. The diagnosis section was written by IS, EMS, and
SB. In the treatment section, the subsections on non-pharmacological
and pharmacological management of hypertension and timescales of
treatment and follow-up were written by EMS and SB, and the subsection
on device-based treatment was written by IS, SB, and EMS. The section
on future perspectives was written by SB and EMS. All authors
participated in the literature search. SB and EMS produced the figures
and entirely revised all versions of the manuscript. All authors approved
the final version for publication.

Seminar
Declaration of interests
IS reports consulting fees, speaker fees, and travel grants from Amgen,
AstraZeneca, Boston Scientific, Daiichi Sankyo, Medtronic, Novartis,
Recordati, Sanofi, and Servier. All other authors declare no competing
interests.
Acknowledgments
We thank H Zekollari for the fruitful discussions and help with the
design of figure 2. YK is supported by the Intramural Research Fund for
the National Cerebral and Cardiovascular Center (20–4–9), Osaka, Japan.
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