Hipertension

PRIMER
Hypertension
Suzanne Oparil1, Maria Czarina Acelajado2, George L. Bakris3, Dan R. Berlowitz4,5,
Renata Cífková6, Anna F. Dominiczak7, Guido Grassi8,9, Jens Jordan10, Neil R. Poulter11,
Anthony Rodgers12 and Paul K. Whelton13
Abstract | Systemic arterial hypertension is the most important modifiable risk factor for all-cause
morbidity and mortality worldwide and is associated with an increased risk of cardiovascular disease
(CVD). Fewer than half of those with hypertension are aware of their condition, and many others are
aware but not treated or inadequately treated, although successful treatment of hypertension reduces
the global burden of disease and mortality. The aetiology of hypertension involves the complex interplay
of environmental and pathophysiological factors that affect multiple systems, as well as genetic
predisposition. The evaluation of patients with hypertension includes accurate standardized blood
pressure (BP) measurement, assessment of the patients’ predicted risk of atherosclerotic CVD and
evidence of target-organ damage, and detection of secondary causes of hypertension and presence
of comorbidities (such as CVD and kidney disease). Lifestyle changes, including dietary modifications
and increased physical activity, are effective in lowering BP and preventing hypertension and its CVD
sequelae. Pharmacological therapy is very effective in lowering BP and in preventing CVD outcomes in
most patients; first-line antihypertensive medications include angiotensin-converting enzyme inhibitors,
angiotensin II receptor blockers, dihydropyridine calcium-channel blockers and thiazide diuretics.
Systemic arterial hypertension (hereafter referred to excess state) and conditions due to mutations in PDE3A
as hypertension) is characterized by persistently high (which encodes cGMP-inhibited 3ʹ,5ʹ-cyclic phospho-
blood pressure (BP) in the systemic arteries. BP is com- diesterase A)), in which a single gene mutation fully
monly expressed as the ratio of the systolic BP (that is, explains the pathogenesis of hypertension and indi-
the pressure that the blood exerts on the arterial walls cates the best treatment modality 7–9. If hypertension
when the heart contracts) and the diastolic BP (the is caused by another condition (for example, primary
pressure when the heart relaxes). The BP thresholds aldosteronism, pheochromocytoma (a neuroendo-
that define hypertension depend on the measurement crine tumour of the adrenal glands or other neuro-
method (TABLE 1). Several aetiologies can underlie hyper- endocrine tissues) or renal artery stenosis), it is referred
tension. The majority (90–95%) of patients have a highly to as secondary hypertension.
heterogeneous essential, or primary, hypertension with Hypertension is the most common preventable risk
a multifactorial gene–environment aetiology. A positive factor for cardiovascular disease (CVD; including coro-
family history is a frequent occurrence in patients with nary heart disease, heart failure, stroke, myocardial
hypertension, with the heritability (a measure of how infarction, atrial fibrillation and peripheral artery dis-
Correspondence to S.O. much of the variation in a trait is due to variation in ease), chronic kidney disease (CKD) and cognitive
Vascular Biology and genetic factors) estimated to be between 35% and 50% impairment and is the leading single contributor to all-
Hypertension in the majority of studies1,2. Genome-wide association cause mortality and disability worldwide10. The relation-
Program, Division of
studies (GWAS) have identified ~120 loci that are associ- ship between BP and the increased risk of CVD is graded
Cardiovascular Disease,
Department of Medicine,
ated with BP regulation and together explain 3.5% of the and continuous, starting at BPs as low as 115/75 mmHg,
School of Medicine, The trait variance3–5. These findings are becoming increas- well within what is considered to be the normotensive
University of Alabama at ingly important as we search for new pathways and new range. Successful prevention and treatment of hyperten-
Birmingham (UAB), 1720 2nd biomarkers to develop more-modern omics-driven diag- sion are key to reducing disease burden and promoting
Avenue South, Birmingham,
nostic and therapeutic modalities for hypertension in the longevity in the world’s population. In treating hyper-
AL, 35294–0007, USA.
soparil@uabmc.edu era of precision medicine6. tension, it is important to consider a person’s predicted
Several rare, monogenic forms of hypertension have atherosclerotic CVD (ASCVD) risk more than the level
Article number: 18014
doi:10.1038/nrdp.2018.14 been described (for example, Liddle syndrome, glucocorti- of BP alone, as persons with high ASCVD risk derive the
Published online 22 Mar 2018 coid-remediable aldosteronism (a mineralocorticoid greatest benefit from BP-lowering treatment 11.
NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18014 | 1
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ɥ ɥ ɥ ɥ ɥ ɥ ɥ ɥ ɥ ɥ ɥ
PRIMER
Author addresses Disease burden

Globally, 3.5 billion adults have non-optimal systolic BP
1
Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, levels (that is, >110–115 mmHg), and 874 million adults
Department of Medicine, School of Medicine, The University of Alabama at Birmingham have a systolic BP of ≥140 mmHg. Thus, approximately
(UAB), 1720 2nd Avenue South, Birmingham, AL, 35294–0007, USA. one in four adults has hypertension16. Between 1990
2
Athens-Limestone Hospital, Athens, AL, USA.
and 2015, there was a 43% increase in the total global
3
The University of Chicago Medicine, Chicago, IL, USA.
4
Center for Healthcare Organization and Implementation Research, Bedford Veteran number of healthy life years lost to nonoptimal BP, driven
Affairs Medical Center, Bedford, MA, USA. by population increase, population ageing and a 10%
5
Schools of Medicine and Public Health, Boston University, Boston, MA, USA. increase in the age-standardized prevalence of hyperten-
6
Center for Cardiovascular Prevention, Charles University in Prague, First Faculty sion16. The Global Burden of Disease study has shown
of Medicine and Thomayer Hospital, Prague, Czech Republic. that nonoptimal BP continues to be the largest single risk
7
Institute of Cardiovascular and Medical Science, College of Medical, Veterinary factor contributing to the global burden of disease and to
and Life Sciences, University of Glasgow, Glasgow, UK. global all-cause mortality, leading to 9.4 million deaths
8
Clinica Medica, University of Milano-Bicocca, Milan, Italy. and 212 million lost healthy life years (8.5% of the global
9
IRCCS Multimedica, Sesto San Giovanni, Milan, Italy. total) each year 10.
10
Institute of Aerospace Medicine, German Aerospace Center (DLR), University
of Cologne, Cologne, Germany.
11
Imperial Clinical Trials Unit, School of Public Health, Imperial College London, London, UK. Cardiovascular disease risk
12
The George Institute for Global Health, Sydney, New South Wales, Australia. Prospective observational studies have repeatedly
13
Department of Epidemiology, Tulane University School of Public Health and Tropical demonstrated a strong, continuous, positive relationship
Medicine, New Orleans, LA, USA. between BP and CVD, with no evidence of a threshold for
risk throughout the usual range of BP observed in clin-
ical practice17–19. The relationship between BP and CVD
This Primer discusses the epidemiology and patho- applies to both systolic BP and diastolic BP but is some-
physiology of primary hypertension, prevention strategies what more-robust for systolic BP in adults19. It is noted
for slowing the progression of BP elevation, management in both sexes, at all ages throughout adulthood and for all
strategies (including optimal BP targets) for lowering BP major manifestations of CVD, including stroke (ischae-
and preventing CVD outcomes in patients with estab- mic and haemorrhagic), coronary artery disease, heart
lished hypertension and the effects of antihypertensive failure, peripheral artery disease and end-stage renal dis-
treatment on quality of life; finally, we explore knowledge ease (although there are variations in the strength of the
gaps, future trends and the outlook for hypertension associations and the slopes of the curves)17–20 (FIG. 1). The
research and treatment over the next decade. relationship is independent of other CVD risk factors,
and the level of BP has proved to be a major component
Epidemiology of CVD risk in all prediction models21. Approximately
In pre-industrial societies, BP levels had narrow distrib- two-thirds of all adults who have hypertension or receive
utions with mean values that changed little with age treatment with BP-lowering medication at 30 years of age
and averaged around 115/75 mmHg (REF. 12), a value have a ~40% higher risk of experiencing a CVD event
that probably represents the normal (or ideal) BP for than their age-matched and sex-matched counterparts
humans. However, in most contemporary societies, sys- with a lower level of BP18. In addition, CVD events in
tolic BP levels rise steadily and continuously with age in individuals with hypertension tend to manifest about
both men and women. This ubiquitous finding could be 5 years earlier than in individuals with a lower level
explained by the fact that age is a proxy for the probabil- of BP18.
ity and duration of exposure to the numerous environ- In individuals of 40–69 years of age, a 20 mmHg
mental factors that increase BP gradually over time, such increase in systolic BP or a 10 mmHg increase in dias-
as excessive sodium consumption, insufficient intake of tolic BP regardless of baseline values is associated with
dietary potassium, overweight and obesity, alcohol intake more than a doubling of the risk of stroke or ischaemic
and physical inactivity. Other factors, such as genetic pre- heart disease mortality 17, whereas a systolic BP reduc-
disposition or adverse intrauterine environment (such as tion of 5 mmHg can decrease stroke mortality by 14%
in gestational hypertension or pre-eclampsia), have small and CVD mortality by 9%. At older ages (≥80 years), the
but definite associations with high BP levels in adult- corresponding relative risk is slightly lower, but the abso-
hood13. Even modest rises in the mean population BP lute risk is far greater than earlier in life17. For example,
lead to large increases in the absolute number of people a 20 mmHg difference in systolic BP between 120 mmHg
with hypertension14. and 140 mmHg is associated with an annual difference
As economic development progresses, hypertension in absolute risk that is nearly ten times larger at ages of
initially affects those with a high socio-economic status, 80–89 years than at ages of 50–59 years17.
but at later stages of economic development, the preva-
lence of hypertension and its consequences is greatest in Mechanisms/pathophysiology
those with lower socio-economic status; this phenom- Blood pressure regulation
enon is seen both within and between countries. Further, BP is determined by several parameters of the cardiovas-
the speed of change in the prevalence of hypertension cular system, including blood volume and cardiac output
from 2000 to 2010 has been much more rapid than in (the amount of blood pumped by the heart per minute),
previous epidemiological transitions15. as well as the balance of arterial tone, which is affected by
2 | ARTICLE NUMBER 18014 | VOLUME 4 www.nature.com/nrdp
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PRIMER
both intravascular volume and neurohumoral systems Salt sensitivity is defined as a marked elevation in BP
(discussed in the following sections). The maintenance following a sodium load of ≥5 g and is characterized by
of physiological BP levels involves a complex interplay of an elevation of systolic BP of at least 10 mmHg within a
various elements of an integrated neurohumoral system few hours of ingestion. Individuals who are salt-sensitive
that includes the renin–angiotensin–aldosterone sys- have underlying endothelial dysfunction due to genetic
tem (RAAS), the roles of natriuretic peptides and the or environmental influences. In response to a high salt
endothelium, the sympathetic nervous system (SNS) and load, these individuals generally manifest overproduction
the immune system (FIG. 2). Malfunction or disruption of transforming growth factor-β (TGFβ), which increases
of factors involved in BP control in any component of the risk of fibrosis, and oxidative stress and have limited
this integrated neurohumoral system can directly or bioavailable NO. Chronic high salt ingestion can result
indirectly lead to increases in mean BP, BP variability in endothelial dysfunction, even in individuals who are
or both, over time resulting in target-organ damage (for not salt-sensitive30, and also affects the gut microbiota,
example, left ventricular hypertrophy and CKD) and with resultant changes that contribute to increased salt
CVD outcomes22. sensitivity and the development of hypertension31. High
The pathophysiological mechanisms responsible salt intake also seems to drive autoimmunity by inducing
for hypertension are complex and act on a genetic T helper 17 (TH17) cells31. High salt intake in mice has
background. Primary hypertension involves multiple been shown to deplete Lactobacillus murinus in the gut
types of genes; some allelic variants of several genes are microbiota. Treatment of mice with L. murinus prevented
associated with an increased risk of developing primary salt-induced exacerbation of salt-sensitive hypertension
hypertension and are linked in almost all cases to a pos- by modulating TH17 cells31. In line with these findings,
itive family history (BOX 1). This genetic predisposition, a moderate high-salt challenge in a pilot study in humans
along with a host of environmental factors, such as high reduced intestinal survival of Lactobacillus spp., increased
sodium intake, poor sleep quality or sleep apnoea, excess the number of TH17 cells and increased BP31. Thus, the
alcohol intake and high mental stress, contributes to the gut microbiota seems to contribute to salt sensitivity of
development of hypertension22–24. Finally, the probabil- BP and the pathogenesis of hypertension.
ity of developing hypertension increases with ageing,
owing to progressive stiffening of the arterial vascula- Renin–angiotensin–aldosterone system
ture caused by, among other factors, slowly developing The RAAS has wide-ranging effects on BP regula-
changes in vascular collagen and increases in athero- tion, mediating sodium retention, pressure natriuresis
sclerosis25–27. Immunological factors can also play a (that is, the mechanism whereby increases in renal
major part, especially in the background of infectious perfusion pressure (the gradient between renal arterial
or rheumatological diseases such as rheumatoid arthri- and venous BP) lead to decreased sodium reabsorp-
tis. The mosaic theory of hypertension describes its tion and increased sodium excretion), salt sensitivity,
multifaceted pathophysiology 28,29. vasoconstriction, endothelial dysfunction and vascular
injury and plays an important part in the pathogenesis of
Sodium homeostasis regulation hypertension22 (FIG. 2). The RAAS is present at the cellular
Sodium is a crucial regulator of blood volume: high level in many organs, but its most crucial role is to help
serum sodium concentration promotes fluid (water) regulate pressure–volume homeostasis in the kidney,
retention, thereby increasing blood volume and BP. where it maintains perfusion in volume-depleted states
When dietary sodium increases in normotensive (that is, when there is a reduction in extracellular fluid
individuals, compensatory haemodynamic changes volume as a result of sodium and fluid loss) and is sup-
occur to maintain constant BP. These changes include pressed in volume-expanded (fluid overload) conditions.
reduction in renal and peripheral vascular resistance Renin and its precursor, prorenin, are synthesized and
and increased production of nitric oxide (NO, a vaso- stored in the juxtaglomerular cells of the kidney and are
dilator) from the endothelium. However, if the effect released in response to various stimuli (FIG. 3). The main
of NO is impaired or absent, an increase in BP occurs. function of renin is to cleave angiotensinogen to form
Endothelial dysfunction is a risk factor for the develop- angiotensin I. Angiotensin-converting enzyme (ACE)
ment of salt sensitivity and subsequent hypertension. cleaves angiotensin I to form angiotensin II, which is
at the centre of the pathogenetic role of the RAAS in
hypertension32 (FIG. 3).
Table 1 | Definitions of hypertension based on the 2013 ESH/ESC guidelines Angiotensin II enhances sodium reabsorption in the
Category Subtype Systolic BP (mmHg) Diastolic BP (mmHg) proximal tubule by increasing the activity of the sodium/
Office BP NA ≥140 ≥90 hydrogen exchanger 3, electrogenic sodium bicarbo-
nate cotransporter 1 and Na+/K+-ATPase and by induc-
Ambulatory BP Daytime (awake) ≥135 ≥85
ing aldosterone synthesis and release from the adrenal
Night-time (asleep) ≥120 ≥70 glomerulosa22. Angiotensin II is also associated with
24 h ≥130 ≥80 endothelial dysfunction and has profibrotic and pro-
Home BP NA ≥135 ≥85
inflammatory effects, mediated in large part by increased
oxidative stress, resulting in renal, cardiac and vascular
For the diagnosis of hypertension, systolic blood pressure (BP), diastolic BP or both have to
exceed the reported values. ESC, European Society of Cardiology; ESH, European Society of injury. Angiotensin II is tightly linked to target-organ
Hypertension; NA, not applicable. Modified from REF. 77. damage in hypertension via these mechanisms22.
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PRIMER
ACE2 has emerged as an important modulator in (phosphoinositide 3-kinase–RAC serine/threonine-

the pathophysiology of hypertension, CVD and renal protein kinase), NADPH oxidase, TGFβ1, the epider-
disease, owing to its role in metabolizing angiotensin II mal growth factor (EGF) receptor and nuclear factor-κB
into angiotensin (1–7)33. Angiotensin (1–7) induces (NF-κB) activity 33–35.
systemic and regional vasodilation, diuresis and natri- Aldosterone plays a crucial part in hypertension.
uresis and exerts antiproliferative and antigrowth effects By binding to the mineralocorticoid receptor, it induces
on vascular smooth muscle cells, cardiac myocytes and nongenomic effects (that is, without directly modify-
fibroblasts as well as on glomerular and proximal tubu- ing gene expression) that include activation of the
lar cells33. Angiotensin (1–7) also has cardiorenal pro- amiloride-sensitive sodium channel, commonly known
tective effects that are mediated by the proto-oncogene as the epithelial sodium channel (ENaC), and result in
Mas receptor through signalling pathways that include the stimulation of renal sodium reabsorption in the
mitogen-activated protein kinases (MAPKs), PI3K–AKT cortical collecting duct 36. Aldosterone also has many
nonepithelial effects that contribute to endothelial dys-
function, vasoconstriction and hypertension36,37. These
a
60 include vascular smooth muscle cell proliferation, vascu-
Incidence (per 10,000 person-years)
lar extracellular matrix deposition, vascular remodelling,

50 fibrosis and increased oxidative stress36,37.
40
Natriuretic peptides
30 Atrial natriuretic peptide (ANP) and brain natriuretic
peptide (BNP) play an important part in salt sensitivity
20 and hypertension (FIG. 2). They have important natriuretic
and vasodilator properties that enable the maintenance
10 of sodium balance and BP during sodium loading 38,39.
Upon administration of a sodium load, atrial and ven-
0
tricular stretch leads to the release of ANP and BNP,
b respectively, which leads to systemic vasodilation and
30
decreased plasma volume (owing to fluid shifts from the
Prevalence (%)
20 intravascular to the interstitial compartment) and results

in BP lowering 40. Natriuretic peptides increase glo-
10 merular filtration rate via an increase in efferent arterio-
lar tone in volume-expanded states and inhibit renal
0
sodium reabsorption through both direct and indirect
c effects. Direct effects include decreased activity of
30
Excess mortality (%)
Na+/K+-ATPase and the sodium-glucose cotransporter

20 in the proximal tubule and inhibition of the ENaC in
the distal nephron. Indirect effects include inhibition of
10 renin and aldosterone release39.
Natriuretic peptide deficiency promotes hyperten-
0
<110 110–119 120–129 130–139 140–149 150–159 160–169 170–179 ≥180 sion. Corin (also known as atrial natriuretic peptide-
Systolic blood pressure (mmHg) converting enzyme) is a serine protease that is largely
Sample expressed in the heart and converts the ANP and BNP
distribution 75 20 5 precursors pro-ANP and pro-BNP to their active forms.
(%)
Corin deficiency has been associated with volume over-
Figure 1 | Association between systolic blood pressure Nature Reviews |heart
and coronary Disease Primers
disease load, heart failure and salt-sensitive hypertension41.
mortality. The relationship of systolic blood pressure (BP) to subsequent risk of coronary
Natriuretic peptide deficiency also predisposes to
heart disease mortality was evaluated in >340,000 US men of 35–57 years of age at the
beginning of the study and followed up for an average of 11.6 years. a | Distribution of insulin resistance and type 2 diabetes mellitus. Obesity
the incidence of coronary heart disease mortality, adjusted for age, race, total serum is associated with natriuretic peptide deficiency, prob-
cholesterol level, cigarettes smoked per day, use of medication for diabetes mellitus and ably through upregulation of the atrial natriuretic pep-
income. Individuals with the highest levels of BP were at greatest risk of cardiovascular tide receptor 3 in adipose tissue42. Natriuretic peptides
disease (CVD) mortality. b | Prevalence of coronary heart disease mortality. Only a have therapeutic potential for the metabolic syndrome
minority of the men examined were exposed to the high risk associated with — a cluster of conditions (including high BP, high fasting
hypertension (≥140 mmHg for systolic BP, as per office BP measurement). However, glucose levels, abdominal obesity, high triglycerides and
a much larger number of individuals, who had BP in the nonhypertensive range, were microalbuminuria) that occur together, increasing the
exposed to the more-modest but still important increases in CVD risk. c | Estimation risk of CVD and diabetes mellitus42.
of the per cent of excess coronary heart disease mortality occurring in each category of
systolic BP using individuals with a systolic BP of <110 mmHg as the reference group.
About two-thirds of the overall burden of BP-related coronary heart disease mortality Endothelium
occurred in men who had a systolic BP of ≥140 mmHg (25% of the sample). However, The endothelium is a major regulator of vascular tone
about two-thirds of the remaining disease burden could be attributed to the and a major contributor to salt sensitivity through NO
approximately 20% of adults who had a systolic BP in the high-normal range (FIG. 2). Endothelial cells produce a host of vasoactive
(systolic BP 130–139 mmHg)203. Data from (REF. 19). substances, of which NO is the most important in BP
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PRIMER
RAAS Natriuretic peptides Endothelium SNS Immune

system
• Endothelial • Maintenance • Other vasoactive Activation of the SNS ↑ acrophage in ltration

dysfunction of Na+ balance substances
• Salt sensitivity and BP during • Salt sensitivity
• Vascular tone Catecholamine ↑ Na+ sensitivity
• Vascular injury Na+ loading
• Natriuresis release
• Vasodilation ↑ BP
Pressure natriuresis
Nitric oxide
↑ Renal sympathetic
activity Anti‑in ammatory Treg cell
↓ BP
↓ BP
+ ↑ Na+ avidity ↓ BP
• Na retention
• Vasoconstriction Endothelin 1 Pro‑in ammatory TH1 cells
↑ BP ↓ BP ↑ BP ↑ BP ↑ BP
Figure 2 | The major neuroendocrine systems involved in the regulation of blood pressure. Neurohumoral, immune
Nature Reviews | Disease Primers
and organ systems involved in the maintenance of blood pressure (BP). Na+, sodium; RAAS, renin–angiotensin–aldosterone
system; SNS, sympathetic nervous system; Treg, regulatory T.
regulation43,44. NO is continuously released by endothe- Endothelial dysfunction plays a seminal part in the
lial cells in response to flow-induced shear stress, leading pathogenesis of hypertension. Normotensive offspring
to vascular smooth muscle relaxation through activation of parents with hypertension often have impaired
of guanylate cyclase and generation of intracellular cyclic endothelium-dependent vasodilation, which implies a
GMP45. Interruption of NO production via inhibition genetic component in the development of endothelial
of constitutively expressed endothelial NO synthase dysfunction47. Endothelial dysfunction in the setting
(eNOS) causes BP elevation and development of hyper- of chronic hypertension is related to a combination of
tension in animals and humans46. Studies to evaluate NO direct pressure-induced injury and increased oxidative
activity in humans have demonstrated decreased whole- stress. Several enzyme systems, including NADPH
body production of NO in patients with hypertension oxidase, xanthine oxidase and cyclooxygenase, as well
compared with normotensive controls46,47. as decreased activity of superoxide dismutase, generate
Endothelial cells also secrete a variety of other vaso- reactive oxygen species47,54. Excess superoxide anions
regulatory substances, including vasodilators, such as bind to NO, decreasing NO bioavailability and generating
prostacyclin and endothelium-derived hyperpolariz- the pro-inflammatory oxidant peroxynitrite. Decreased
ing factors, and vasoconstrictors, such as endothelin 1 NO bioavailability is the central factor that links oxidative
(ET1), locally generated angiotensin II and the prosta- stress to endothelial dysfunction and hypertension47.
noids thromboxane A2 and prostaglandin A2. ET1 is Individuals who are salt-sensitive might be very sensi-
a potent vasoconstrictor that activates ET1 receptor tive to the haemodynamic stress of increased blood vol-
(ETA) in vascular smooth muscle48. Other vasodilating ume, leading to overproduction of TGFβ and oxidative
substances secreted by a variety of cell types, such as stress and limiting bioavailable NO30. Angiotensin II,
calcitonin gene-related peptides, adrenomedullin and along with other factors, including cyclic vascular
substance P, act primarily through increases in NO stretch as a result of BP changes, ET1, uric acid, sys-
release from endothelial cells49,50. The glucose-regulating temic inflammation, noradrenaline, free fatty acids and
gut hormone glucagon-like peptide 1 also has vaso- tobacco smoking, increases NADPH oxidase activity and
dilating properties51. The balance between these factors, plays a central part in the generation of oxidative stress
along with NO and ET1, determines the final effect of in hypertension52.
the endothelium on vascular tone48,51–53. Circulating ET1
levels are not consistently increased in hypertension, but Sympathetic nervous system
there is a trend towards increased sensitivity to the vaso- Baroreceptors, mechanoreceptors that sense pressure
constrictor and hypertensive effects of ET1 in individ- changes in the circulatory system, are housed in various
uals with hypertension53. ETA antagonists attenuate or locations in the arterial tree, a key place being the caro-
abolish hypertension in a variety of experimental models tid sinus, a dilated area at the base of the internal carotid
and are effective in lowering BP in humans48,53. artery just superior to the bifurcation of the common
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PRIMER
Box 1 | Genetic predisposition to hypertension sustained hypertension62. In another animal model, rats
that received daily infusions of phenylephrine for 8 weeks
A large genome-wide association study of 2.5 million genotyped single nucleotide developed hypertension during the infusions; their BP
polymorphisms (SNPs) in >69,000 individuals of European ancestry from 29 studies normalized under a low-salt diet after discontinuation
demonstrated that most SNPs related to blood pressure (BP) regulation and of phenylephrine, but once rechallenged with a high-
cardiovascular disease (CVD) risk involved natriuretic peptides196. SNPs in genes that
salt diet, the animals became hypertensive again30. The
encode precursors for atrial natriuretic peptide (ANP) and brain natriuretic peptide
(BNP) had been previously identified197, and two other loci containing genes involved degree of BP elevation on the high-salt diet was directly
in natriuretic peptides and nitric oxide (NO) signalling pathways were identified in this related to the degree of renal tubulo-interstitial fibrosis
study. Both of these pathways regulate cyclic GMP, which promotes vasodilation. and decrease in glomerular filtration rate, suggesting
A 2016 study identified 66 BP-associated loci, which were enriched for cis-regulatory that catecholamine-induced hypertension causes renal
elements in vascular endothelial cells, consistent with a role in BP control through interstitial injury and a salt-sensitive phenotype that
modulation of vascular tone. This information prompted the development of a genetic persists even after sympathetic overactivity is no longer
risk score to predict target-organ damage4. present. In addition, increased SNS activity results in α-1
Gene deletion studies in rodent models have evaluated cardiac ANP and BNP as adrenergic receptor-mediated endothelial dysfunction,
paracrine regulators of vascular regeneration. Deletion of the genes encoding ANP vasoconstriction, vascular smooth muscle proliferation
and BNP exaggerates cardiac fibrosis and increases adverse left ventricular (LV)
and increased arterial stiffness, which contribute to the
remodelling38, and atrial natriuretic peptide receptor 1 (NPR1) deficiency leads to
increased BP, cardiac fibrosis and LV dysfunction. Further, deletion of the gene encoding development and maintenance of hypertension66. Finally,
the endothelial guanylyl cyclase-A receptor, a cell surface receptor for natriuretic there is evidence that sympathetic overactivity enhances
peptides, leads to diminished vascular regeneration and angiogenesis in response to salt sensitivity owing to a reduction in activity of WNK4,
critical hindlimb ischaemia, as well as cardiac fibrosis and diastolic dysfunction. encoding serine/threonine kinase WNK4, which inhib-
Finally, clinical studies have observed an association between certain CORIN its the thiazide-sensitive Na-Cl cotransporter, resulting
polymorphisms and risk of pre-eclampsia and hypertension, particularly among in increased distal tubular sodium retention67. These
African-American populations but not among Chinese populations198. mechanisms have been reviewed recently 66.
Inflammation and the immune system

carotid artery. When this artery is stretched by elevated Inflammation makes an important contribution to
BP, nerve bundles projecting from the baroreceptors in the genesis of hypertension and related target-organ
the carotid sinus send messages to the brain to reduce damage. Inflammation is associated with increased vas-
sympathetic outflow of nerve impulses (nerve traffic) cular permeability and release of potent mediators, such
and, thereby, BP55–57. The SNS is generally more activ- as reactive oxygen species, NO, cytokines and metallo-
ated in persons with hypertension than in normotensive proteinases. Cytokines mediate the formation of neo-
individuals58,59. SNS activity is also greater in individuals intima (a new or thickened layer of arterial intima),
with obesity, in men than in women, in younger than in thereby decreasing the lumen diameter of resistance
older persons and in those with advanced kidney dis- vessels (small arteries and arterioles that are highly
ease60,61. Many patients with hypertension are in a state innervated by autonomic nerves and the primary vessels
of autonomic imbalance with increased sympathetic involved in the regulation of BP) and promoting vascu-
activity and decreased parasympathetic activity 59,62. lar fibrosis, leading to increased vascular resistance and
SNS hyperactivity is relevant to both the generation and stiffness. Cytokines also affect renal tubular function
maintenance of hypertension (FIG. 2). Studies in humans by increasing local synthesis of angiotensinogen and
have also identified markers (such as increased systemic angiotensin II, as well as promoting sodium and volume
catecholamine spillover (the amount of catecholamines retention in hypertension68. Matrix metalloproteinases
released from sympathetic nerves innervating blood stimulate the degradation of the extracellular matrix,
vessels that enter the bloodstream) and sural nerve enabling infiltration of immune cells through the vessel
activity assessed by microneurography) of sympathetic wall into the interstitium of the affected organs, pro-
overactivity in normotensive individuals with a family moting apoptosis and enhancing collagen synthesis and
history of hypertension63. Among patients with hyper- matrix deposition, leading to target-organ damage68.
tension, increasing severity of hypertension is associated Whereas animal data are clear about the relation-
with increasing levels of sympathetic activity measured ship between inflammation and hypertension, the data
by microneurography 64,65. Plasma catecholamine levels, in humans are limited. There are associations between
microneurographic recordings and systemic catecho- C-reactive protein, tumour necrosis factor and various
lamine spillover studies have provided evidence of interleukins and hypertension, but no direct link68. GWAS
increased sympathetic activity in patients with hyperten- have identified a single nucleotide polymorphism (SNP)
sion who have obesity, in those with the metabolic syn- of SH2B3 (SNP rs3184504), which results in an amino
drome and in those whose hypertension is complicated acid substitution in SH2B adaptor protein 3 (a protein
by heart failure or kidney disease65. involved in T cell receptor activation and signalling) that
The importance of the SNS in the pathogenesis of is associated with many autoimmune and cardiovascular
hypertension has been defined in a variety of experi- disorders, including hypertension69. Further, drugs that
mental models. Models of obesity-related hypertension are used to treat inflammation, such as NSAIDs and
demonstrate that increased renal sympathetic nerve cyclosporine, raise rather than lower BP in individuals
activity and its attendant increase in renal sodium with hypertension, highlighting the complex nature of the
reabsorption are key factors in the maintenance of relationship between inflammation and hypertension69.
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PRIMER
Both innate and adaptive immune responses partici- target-organ damage, as these cells regulate the inflam-
pate in the generation of reactive oxygen species and matory processes in the kidney and vasculature that
inflammatory changes in the kidneys, blood vessels underlie hypertension-induced kidney disease68,70,71.
and brain in hypertension68,70 (FIG. 2). Innate immune
responses, especially those mediated by macrophages, Diagnosis, screening and prevention
have been linked to hypertension induced by angio- Diagnosis and screening
tensin II, aldosterone and NO antagonism68,70. Reductions Primary hypertension is usually asymptomatic; thus,
in macrophage infiltration of the kidney or the peri- in clinical practice, all adults should have their BP meas-
adventitial space of the aorta and medium-sized arteries ured at regular office visits. Hypertension is most com-
lead to reductions in BP and salt sensitivity 68. Adaptive monly diagnosed based on repeated BP measurements
immune responses via T cells have also been linked to in a clinical office setting. Accurate measurement and
the genesis of hypertension and its target-organ damage. recording of BP are essential to categorize the level of
T cells express type 1 angiotensin II receptor (AT1) BP, ascertain BP-related CVD risk and guide manage-
and mediate angiotensin II-dependent hypertension70; ment. Since 2010, methods to measure out-of-office
of note, depletion of mature lymphocytes ameliorated BP have been increasingly introduced to guide diagno-
hypertension and kidney injury resulting from a high- sis and treatment of hypertension72,73 (TABLE 1). These
salt diet in the Dahl Salt Sensitive rat model71. Thus, include home BP monitoring (HBPM) and ambulatory
a balance between pro-inflammatory T cell reactivity and BP monitoring (ABPM). HBPM refers to the measure-
inflammatory suppression induced by regulatory T cells ment of BP at regular intervals by an individual at their
determines the development of hypertension, as demon- home or elsewhere outside the clinic setting. ABPM
strated by the amelioration of hypertension with the consists of measuring and recording the BP at regular
adoptive transfer of regulatory T cells in several animal intervals (usually every 20–30 minutes), typically for
models of hypertension68–70. Abnormalities in both a 24-hour period and while individuals go about their
pro-inflammatory T cells and anti-inflammatory regu- daily activities. The ability to measure out-of-office BP
latory T cells are implicated in hypertension-induced has enabled the identification of distinct BP phenotypes,
including white-coat or isolated clinic hypertension and
masked or isolated ambulatory hypertension74,75. White-
• ↓ Na+ delivery • ↑ Renal sympathetic coat hypertension is characterized by elevated office
• ↓ Renal a erent activity BP but normal ABPM or HBPM readings. By contrast,
perfusion pressure • ↑ Vasodilation masked hypertension is characterized by normal office
readings but elevated out-of-office readings (ABPM
Renin ACE ACE2 and HBPM)74,75.
Angiotensinogen Angiotensin I Angiotensin II Angiotensin (1–7) Diagnosis. The evaluation of a patient with elevated
BP requires more than the diagnosis of hypertension.
It should also include the assessment of the CVD risk,
AT1 AT2 target-organ damage and concomitant clinical condi-
tions that could affect the BP or related target-organ
• Smooth muscle cell • Aldosterone release • Antiproliferative
damage, as well as recognition of features suggestive of
contraction • Na+ reabsorption e ects secondary hypertension. Some of these investigations
• Systemic vasoconstriction • ↓ Renal medullary • Natriuresis are routine tests necessary in all patients, but others are
• ↑ Vascular resistance blood ow • Vasodilation necessary only in specific patient groups identified by
history, clinical examination and routine tests. In rare,
↑ BP ↓ BP inherited forms of hypertension, a single gene muta-
tion explains the pathogenesis of hypertension7–9 (FIG. 4).
Figure 3 | Role of the renin–angiotensin–aldosterone NaturesystemReviews
in the regulation of
| Disease Primers
A small proportion of patients have a potentially revers-
blood pressure. Decreased renal afferent arteriolar perfusion pressure, reduced sodium
(Na+) delivery to the macula densa (an area lining the wall of the distal convoluted tubule ible cause of hypertension, and a correct diagnosis might
in contact with the glomerulus), activation of renal sympathetic nerves (via β1 adrenergic lead to a cure or a substantial improvement in BP control
receptor stimulation) and a variety of vasodilators, including prostaglandin E2, stimulate with a reduction of CVD risk. Thus, it is appropriate to
the release of renin. Angiotensin II activates the type 1 angiotensin II receptor (AT1), implement a simple screening for secondary hyperten-
triggering smooth muscle cell contraction, systemic vasoconstriction, increased sion in all patients. The screening is based on clinical
renovascular resistance and decreased renal medullary blood flow, a mediator of salt history, physical examination and routine laboratory
sensitivity. Stimulation of the AT2 has opposite effects, resulting in vasodilation, investigations (BOXES 2,3). Secondary hypertension
natriuresis and antiproliferative actions. Cross-transplantation studies using wild-type should also be considered in cases of a sudden worsening
mice and mice lacking the AT1 have shown that both systemic and renal actions of of hypertension, poor BP response to drug treatment or
angiotensin II are relevant to physiological blood pressure (BP) regulation but that the
severe target-organ damage that is out of proportion to
detrimental effects of angiotensin II in hypertension are mediated mainly via the
kidneys204,205. Angiotensin-converting enzyme (ACE) inhibitors and AT1 antagonists have the duration and severity of hypertension. In these cases,
been shown to increase angiotensin (1–7) levels in the plasma and urine of normotensive specific diagnostic tests are indicated (TABLE 2).
animals and to enhance renal ACE2 activity33. Studies in rodents and humans with The medical history has to address the time of the first
diabetic kidney disease suggest that upregulation of ACE2 delays progression of diagnosis of hypertension, current and past BP measure-
kidney disease206. ments and antihypertensive medications. A history
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PRIMER
of pregnancy-related hypertension is an important The physical examination aims to establish the

factor in the assessment of women with hypertension. diagnosis of hypertension and screen for target-organ
Hypertension results in an increased risk of CVD com- damage and secondary causes (BOX 2). The patient should
plications and CKD. Thus, a careful medical history sit quietly for 5 minutes before a BP reading is taken, and
should be taken in all patients to enable assessment the BP cuff should be at heart level. An average of 2–3 BP
of global CVD risk, with special emphasis on current measurements obtained on 2–3 separate occasions prov-
and past smoking habits and evidence of dyslipidae- ides an accurate basis for estimation of BP77,78. At least
mia and diabetes mellitus. CVD risk should be esti- once, BP should be measured on both arms, and dif-
mated using an established calculator (for example, ferences in systolic BP of >20 mmHg and/or in dias-
the American College of Cardiology ASCVD Risk tolic BP of >10 mmHg should initiate investigations of
Estimator). Adults at high risk of CVD have a high prob- vascular abnormalities77. Careful attention should be
ability to benefit from antihypertensive drug therapy in paid to choosing an appropriately sized cuff, particu-
addition to lifestyle changes76. larly for the increasing number of patients with obesity.
Glomerulus
Proximal convoluted
Distal
tubule Gitelman Gordon
convoluted tubule
syndrome syndrome
β
Thick Na+
ascending WNK4 Cl–
limb Cl– CLCNKB
Juxtaglomerular SLC12A3 WNK1
cells Na+
ATP
Mg2+ K+
TRPM6
Loop of Cortical ECaC

Henle collecting Ca2+
duct Urine Blood
Urine Blood Adrenal gland

Bartter Aldosterone
syndrome Recessive synthase
type 1 PHA1 GRA ci c
Dominant
PHA1 Aldosterone
SLC12A1 β ENaC
Na+
2Cl– Cl– Na+ MR
K+ CLCNKB
Liddle AME Cortisol Deoxycorticosterone
Bartter syndrome
KCNJ HSD11B2
syndrome CYP21A2
K+ type 3 K +
Cortisone ci c
KCNJ
CYP17A1
Ca2+ ci c
Mg2+
Bartter CYP11B1
syndrome ci c
type 2
Urine Blood
Figure 4 | Pathways affected in single gene, Mendelian hypertension GRA, glucocorticoid‑remediable aldosteronism; HSD11B2, corticosteroid
and hypotension syndromes. Some inherited diseases can affect the 11-β‑dehydrogenase isozyme 2; K+, potassium; KCNJ, inward rectifier
renal–angiotensin–aldosterone system pathways and, therefore, blood potassium channel; Mg2+, magnesium; MR, mineralocorticoid receptor;
pressure (BP); hypertensive disorders are listed in orange boxes and Na+, sodium; PHA1, pseudohypoaldosteronism, type 1; SLC12A1, solute
hypotensive disorders in green boxes. AME, apparent mineralocorticoid carrier family 12 member 1; SLC12A3, solute carrier family 12 member 3;
excess; Ca2+, calcium; Cl−, chloride; CLCNKB, chloride channel protein TRPM6, transient receptor potential cation channel subfamily M
ClC‑Kb; CYP11B1, cytochrome P450 11B1, mitochondrial; CYP17A1, member 6; WNK1, serine/threonine‑protein kinase WNK1; WNK4,
steroid 17-α‑hydroxylase/17,20 lyase; CYP21A2, steroid 21‑hydroxylase; serine/threonine‑protein kinase WNK4. Adapted with permission from
ECaC, epithelial calcium channel; ENaC; epithelial sodium channel; REF. 7, LWW.
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PRIMER
Box 2 | Physical examination for patients with hypertension by screening for hypertension in public places over
the entire month of May 2017, might have better and
Signs suggestive of secondary hypertension more-sustained results83.
• Features of Cushing syndrome
• Neurofibromatosis (pheochromocytoma) Prevention
• Enlarged kidneys (polycystic kidney) The association between BP and CVD risk highlights
• Abdominal bruits (abnormal sound) (renovascular hypertension) the importance of treating hypertension, especially when
• Precordial murmurs (sounds audible via the stethoscope) (aortic coarctation and severe. Further, it also underscores the importance of
aortic disease) strategies to reduce BP-related CVD risk in those whose
BP level is higher than normal (average systolic BP
Signs of target-organ damage
120–129 mmHg) but below the hypertension threshold.
• Brain: motor or sensory deficit Reducing BP in adults with a high normal BP (referred
• Retina: hypertensive retinopathy to as elevated BP in the 2017 ACC/AHA BP Guideline)
• Heart: atrial fibrillation, arrhythmias, pulmonary congestion and peripheral oedema provides the potential to directly reduce CVD risk and
• Peripheral arteries: absent, reduced or asymmetrical pulses and ischaemic skin lesions to prevent or at least slow the age-related tendency for
• Carotid arteries: murmurs individuals to develop hypertension.
Evidence of obesity In most countries, there is a strong tendency for BP,
especially systolic BP, and the prevalence of hyperten-
• BMI (body weight/height2) of >30 kg/m2
sion to increase progressively from childhood until
• Waist circumference* of >102 cm in men and of >88 cm in women
late in life79. However, studies in isolated societies that
BMI, body mass index. *Values might need to be adjusted on the basis of ethnicity or other factors. have limited contact with the outside world84,85 indi-
cate that high BP is not an inevitable consequence of
ageing and that the rise in BP associated with local
Further, BP should be measured in both sitting and migration by members of isolated societies is related
standing positions to rule out orthostatic hypotension to changes in diet, decreased physical activity and con-
(a sudden drop in the BP when a person stands up from sumption of alcohol84,86,87. These reports underscore the
a lying or sitting position). This is particularly important logic of efforts to prevent high BP in settings where an
in elderly individuals. age-related increase in BP is common.
All patients should undergo auscultation of the
carotid arteries, heart and renal arteries. Detection of Lifestyle changes. A variety of nonpharmacological
murmurs (sounds audible via the stethoscope) should interventions are effective in lowering BP and prevent-
lead to further investigations, including carotid ultra- ing hypertension. The most effective interventions are
sonography, echocardiography and renal ultrasono- weight loss88–90, reduced sodium intake88–91, increased
graphy. An irregular pulse frequently indicates atrial potassium intake 92,93, increased physical activity 94,
fibrillation, which should be confirmed by an electro- reduced consumption of alcohol95,96 and diets, such as
cardiogram (EKG). Laboratory investigations are used the dietary approaches to stop hypertension (DASH)
to detect additional risk factors, to confirm or exclude diet 97, that combine several elements that favourably
secondary hypertension, to detect clinical or subclinical affect BP98,99 (TABLE 3). The DASH diet is especially
target-organ damage and to estimate global CVD risk successful when combined with other effective BP-
(BOX 3). lowering interventions, such as a reduced intake of
dietary sodium91. Lifestyle changes are the best way for
Screening. Despite overwhelming evidence that hyper- the individual to implement these interventions. Even
tension is a major treatable CVD risk factor, studies small improvements in an individual’s lifestyle can be
across the world show that a large proportion of individ- valuable. The websites of several government agencies
uals with hypertension are either unaware of their high and professional societies provide helpful tips for life-
BP or aware but not treated or inadequately treated15,79. style changes and monitoring of BP. Careful monitor-
Thus, there is a strong indication to screen middle-aged ing of BP is essential because the beneficial effects
or younger persons to detect and treat more patients with of lifestyle changes are predicated on maintenance of
hypertension. The most serious attempt by a health care the intervention100.
system to improve the diagnostic aspects of hyperten- Two complementary strategies aimed at achieving
sion has been done in the United Kingdom, based on the a small population-wide reduction in BP or a larger
pay-for-performance principle, that is, to give incentives reduction in those who are at higher risk of developing
to general practitioners (primary care physicians) for the hypertension can be employed to implement hyperten-
appropriate diagnosis and treatment of chronic diseases, sion prevention interventions98,99,101. Modelling studies
including hypertension. Early reports80,81 showed that suggest that a downward shift of as little as 2 mmHg
this initiative was associated with an increased rate of in the population distribution of diastolic BP would
BP monitoring and better BP control, but a later report result in a 17% reduction in the incidence of hyper-
suggested that this was not a sustained improvement 82. tension, a 14% reduction in the risk of stroke and tran-
It is possible that the initiative championed by the sient ischaemic attacks and a 6% reduction in the risk
International Society of Hypertension (ISH) and many of coronary heart disease102. Public health interven-
national societies, which targeted entire populations tions focused on dietary improvements and increases
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PRIMER
Box 3 | Laboratory investigations in the diagnosis of hypertension low-dose pharmacotherapy should be restricted to those
who are at high risk of developing hypertension despite
Routine tests energetic efforts to lower BP by means of one or more
• Haemoglobin and haematocrit nonpharmacological interventions105.
• Fasting plasma glucose
• Serum total cholesterol, low-density lipoprotein cholesterol and high-density Management
lipoprotein cholesterol BP treatment thresholds and targets
• Fasting serum triglycerides Until 2015, most guidelines recommended a target BP of
• Serum potassium and sodium <140/90 mmHg for most patients and of <150/90 mmHg
• Serum uric acid for elderly patients (defined as of >60 years of age or
of >80 years of age)77,106 (TABLE 4). However, after the
• Serum creatinine
publication of the results of the Systolic Blood Pressure
• Estimated glomerular filtration rate (eGFR)
Intervention Trial (SPRINT) 107, target systolic BP
• Urine analysis including a test for microalbuminuria values have been frequently debated. SPRINT was a
• 12-lead electrocardiogram (EKG) randomized, open-label, controlled trial that enrolled
Additional tests based on history, clinical examination and routine tests 9,361 participants without diabetes mellitus but with
• Haemoglobin A1c increased CVD risk. Patients with a history of stroke
• Quantitative proteinuria were excluded. Participants were randomized to a stan-
• Out-of-office BP measurements* dard systolic BP target of <140 mmHg or intensive sys-
tolic BP target of <120 mmHg. Intensive BP treatment in
• Echocardiography
SPRINT resulted in a significantly greater (25%) reduc-
• Holter monitoring
tion in the primary end point (first occurrence of myo-
• Carotid ultrasonography cardial infarction, acute coronary syndrome, stroke or
• Abdominal ultrasonography heart failure or death from cardiovascular causes) com-
• Pulse wave velocity pared with standard treatment. Office BP measurement
• Ankle-brachial index in SPRINT was performed with an automated device
• Further specialist tests for secondary hypertension (renin, aldosterone, timed to start measurement after 5 minutes of rest in
catecholamines and their metabolites) an effort to standardize measurements in the various
*Ambulatory blood pressure (BP) monitoring (ABPM) is the preferred method for measurement clinics and to minimize the white-coat effect108. Because
of out-of-office BP to confirm high BP and to diagnose masked hypertension. Careful home BP large differences had been observed between automated
monitoring (HBPM) is acceptable when ABPM is not feasible. office BP measurement and conventional auscultatory
measurements (with the automated technique show-
ing lower values)109, some groups have questioned the
in physical activity that are known to lower BP provide applicability of the SPRINT intensive systolic BP target
the basis for population-wide strategies. Diet in the gen- of <120 mmHg to ordinary office practice110. Both the
eral population can be favourably influenced by means appropriate methods of measuring office BP (automated
of public health education campaigns, food products versus manual; unattended versus attended) and the
labelling and collaborations with food manufacturers appropriate BP targets for antihypertensive treatment
to reduce the calorie and sodium content of their prod- are currently topics of vigorous debate. In summary,
ucts, as well as with fast-food companies and restaurants newer guidelines published after SPRINT generally
to reduce portion size and to promote healthier food have more-aggressive goals, at least for individuals at
preparation and promotion practices. Physical activity high CVD risk (TABLE 4).
can be increased by making it easier for members of the The patient’s global CVD risk and comorbidi-
community to engage in exercise on a routine basis. ties should be considered in determining the need
for pharmacological antihypertensive treatment. The
Pharmacological interventions. Low-dose pharmaco- 2017 US ACC/AHA BP Guideline for the Prevention,
logical therapy has also been effective in lowering BP Detection, Evaluation and Management of High Blood
and preventing hypertension in three randomized Pressure in Adults111 recommends the use of antihyper-
controlled trials conducted in adults with high normal tensive medication in patients with pre-existing CVD
BP103–105. The Brazilian multicentre PREVER-Prevention and those without a CVD event but an estimated 10-year
Trial compared treatment with the low-dose, long- ASCVD risk of ≥10% at BP levels of ≥130/80 mmHg.
acting, thiazide-like diuretic chlorthalidone in combin- In individuals without CVD and with 10-year ASCVD
ation with the potassium-sparing agent amiloride with risk of <10%, antihypertensive medication should be
placebo treatment 105. Treatment with the low-dose initiated at BP of ≥140/90 mmHg. (FIG. 5; TABLE 4).
chlorthalidone and amiloride combination resulted in
both a decrement in BP and prevention of hypertension Nonpharmacological management
and a reduction in left ventricular mass. Although a drug Lifestyle advice is recommended for all patients with
intervention is easier to implement and to maintain than hypertension. The most effective interventions are the
a lifestyle change intervention, there is a natural reluc- same as those used for the prevention of hypertension.
tance to recommend a lifetime of pharmaceutical ther- Targeted dietary approaches can reduce the systolic BP
apy for the prevention of hypertension. Consideration of in individuals with hypertension. For example, reducing
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PRIMER
sodium intake (ideally to <2.3 g per day or <1.5 g per Randomized controlled trials carried out in persons
day in those most susceptible to the effects of sodium with hypertension have consistently shown that redu-
on BP, but reduction by at least 1.0 g per day is desirable) ced sodium intake is associated with BP reduction116.
can lower the systolic BP by 2–4 mmHg (REFS 111–113). The most convincing evidence is provided by the
A similar reduction can be expected by increasing DASH-sodium trial91, in which the effects of three
potassium intake to 3.5–5.0 g per day 92. different sodium intakes were tested separately in
combination with two diets: the DASH diet, which is
Reduced salt intake. For metabolic balance, the amount rich in fruit, vegetables and low-fat dairy products and
of salt consumed must be equal to that lost. Thus, under reduced in saturated fat and cholesterol, and a control
normal living conditions and physical activity levels, diet consisting of what many people in the United States
an intake of 5 g of salt per day is considered sufficient, typically eat. Reduction of sodium intake by ~0.9 g per
in line with the WHO recommendation (<5 g per day)114. day induced a greater BP reduction when the starting
By contrast, the currently estimated dietary intake of salt sodium intake was <2.3 g per day, which corresponds
is about 9–12 g per day in most countries. The current to ~6.0 g of salt per day. Of note, sodium reduction
recommendations of the American Heart Association reduced BP in individuals without hypertension on
(AHA)115 are stricter than the European guidelines, both diets. Reduced sodium intake can also prevent
recommending lowering salt intake to 2.3 g per day, hypertension (relative risk reduction of ~20% with or
whereas the 2013 European Society of Hypertension/ without concomitant weight loss)90, improve hyperten-
European Society of Cardiology (ESH/ESC) guidelines sion control117 and, therefore, possibly reduce the need
recommend 5–6 g of salt per day 77. for antihypertensive medication100. In the Intersalt
Table 2 | Diagnostics of secondary hypertension

Possible causes Clinical indications Diagnostics
Clinical history Physical Laboratory First-line tests Additional
examination investigations confirmatory tests
Common causes
Renal parenchymal • History of urinary tract Abdominal • Presence of protein, Renal Detailed workup for
disease infection or obstruction, masses (in case of erythrocytes or ultrasonography kidney disease
haematuria (blood in the polycystic kidney leukocytes in the
urine) or analgesic abuse disease) urine
• Family history of • Decreased GFR
polycystic kidney disease
Renal artery • Fibromuscular dysplasia: Abdominal bruit • Difference of >1.5 cm Renal duplex • Magnetic resonance
stenosis early-onset hypertension (abnormal sound) in length between Doppler angiography
(especially in women) the two kidneys (renal ultrasonography • Spiral CT
• Atherosclerotic stenosis: ultrasonography) • Intra-arterial
hypertension of abrupt • Rapid deterioration digital subtraction
onset, worsening or in renal function angiography
increasingly difficult to (spontaneous or in
treat or flash pulmonary response to RAAS
oedema blockers)
Primary • Muscle weakness Arrhythmias • Hypokalaemia Aldosterone:renin • Confirmatory tests
aldosteronism • Family history of (in case of severe (spontaneous or ratio under (oral sodium loading,
early-onset hypertension hypokalaemia) diuretic-induced) standardized saline infusion,
and cerebrovascular • Incidental discovery conditions fludrocortisone
events at <40 years of age of adrenal masses (corrected suppression or
hypokalaemia and captopril test)
withdrawal of drugs • Adrenal CT scan
affecting the RAAS) • Adrenal vein sampling
Uncommon causes
Pheochromocytoma • Paroxysmal hypertension Skin stigmata of Incidental discovery Measurement • CT or MRI of the
or a crisis superimposed neurofibromatosis of adrenal (or, in some of urinary abdomen and pelvis
to sustained hypertension (café-au-lait spots cases, extra-adrenal) fractionated • 123I-labelled meta-
• Headache, sweating, and neurofibromas) masses metanephrines iodobenzyl-guanidine
palpitations and pallor or plasma-free scanning
• Positive family history metanephrines • Genetic screening for
of pheochromocytoma pathogenetic mutations
Cushing syndrome • Rapid weight gain Typical body habitus Hyperglycaemia 24 h urinary cortisol Dexamethasone-
• Polyuria (excessive (central obesity, excretion suppression test
production of urine) moon-face, buffalo
• Polydipsia (excessive thirst) hump, red striae
• Psychological (stretch marks) and
disturbances hirsutism)
GFR, glomerular filtration rate; RAAS, renin–angiotensin–aldosterone system. Modified from REF. 77.
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PRIMER
Table 3 | Dietary approaches to stop hypertension (DASH) eating plan review of 27 randomized clinical trials in individuals with
hypertension showed that regular medium-intensity to
Food group Servings* Examples of a serving high-intensity aerobic activity reduced BP by a mean of
Whole grains 6–8 per day 1 slice of whole grain bread 11/5 mmHg (REF. 125). Sessions lasting 40–60 minutes
Vegetables 4–5 per day 1 cup of raw leafy vegetables performed at least three times a week had the greatest
effect on BP. Three randomized controlled trials of iso-
Fruits 4–5 per day 1 medium-sized fruit
metric exercise (strength training) showed a BP reduction
Dairy products 2–3 per day 1 cup of milk or yogurt of similar magnitude to that induced by aerobic exercise
(low-fat or fat-free)
in individuals with hypertension125. A meta-analysis of
Fats and oils 2–3 per day • 1 teaspoon of margarine or vegetable oil or 64 controlled studies of the efficacy of dynamic resist-
• 1 tablespoon of mayonnaise or
• 2 tablespoons of salad dressing
ance training (strength training) as stand-alone anti-
hypertensive therapy showed BP reductions comparable
Lean meat, poultry and fish 2–3 per day 2 ounces of cooked meats, chicken or fish to or greater than those achieved with aerobic exercise
Nuts, seeds and legumes 4–5 per • 1/3 cup of nuts or training 126. Greater BP reductions occurred in individ-
week • 2 tablespoons of peanut butter or uals with higher resting BP (~6/5 mmHg for individuals
• 2 tablespoons of seeds or
• 1/2 cup of cooked peas or beans with hypertension and 3/3 mmHg for individuals with
prehypertension) and in non-white individuals126.
Candy and added sugars ≤5 per • 1 tablespoon of sugar, jelly or jam or
week • 1 cup of lemonade
Weight loss. Excess adiposity generally raises BP in
*Recommended frequency of servings for a 2,000-calorie-per-day diet.
susceptible individuals, and patients with hypertension
who also have obesity require more antihypertensive
study 118, lower sodium intake was associated with a medications to control their BP and are more likely to
blunted age-related rise in systolic BP. be resistant to treatment127. A meta-analysis showed that
There is strong evidence to support population-wide any reduction in body weight lowered systolic BP by an
recommendations to lower salt intake119,120. As more than average of 2.7 mmHg and diastolic BP by an average
75% of dietary salt comes from processed foods (in West- of 1.3 mmHg (REF. 128). However, the response varies
ern countries), any population strategy to reduce salt substantially between individuals. Lifestyle interven-
intake must involve food manufacturers and restaurants tions, including hypocaloric diets and physical exercise,
to progressively reduce salt added to foods. So far, only are commonly recommended for patients with obesity
three countries (Japan, Finland and the United Kingdom) and hypertension; however, the average weight loss is
have successfully reduced population salt intake121. modest, and most patients regain weight 129 (BOX 4).
Increased potassium intake. Healthy individuals with Antihypertensive pharmacotherapy

normal kidney function usually have a potassium intake Antihypertensive pharmacotherapy has evolved over
of 4.7 g per day; a higher intake is not associated with several decades, driven by the development of various
increased risk because potassium is readily excreted in antihypertensive medication classes and large-scale
persons who do not have CKD. Increased potassium outcome trials proving their benefits on CVD morbid-
intake is associated with reduced BP in individuals with ity and mortality 130. Clinicians are now faced with a
low as well as high baseline potassium intake92,93. Of note, plethora of antihypertensive medications of different
potassium reduces BP to a greater extent in black individ- drug classes and a variety of fixed-dose combinations.
uals than in white individuals122. The effect of potassium Typically, antihypertensive pharmacotherapy begins
on BP is dependent on salt intake. There is a greater BP with first-line antihypertensive medications either in
reduction with increased potassium intake in the context monotherapy or in combination131. Combination ther-
of lower salt intake123. Thus, the best strategy is to increase apy might be preferable in patients with higher levels
potassium intake and reduce sodium intake at the same of pretreatment BP. First-line antihypertensive medica-
time. The preferred strategy to increase potassium intake tions include ACE inhibitors, angiotensin II receptor
is to increase consumption of fruits and vegetables that blockers (also known as sartans), dihydropyridine
are rich in potassium rather than using supplements. calcium-channel blockers and thiazide diuretics106.
In individuals with impaired urinary potassium excretion, β-Adrenoreceptor blockers are also indicated in patients
a potassium intake of <4.7 g per day is recommended124. with heart failure with reduced left ventricular ejec-
tion fraction or post-myocardial infarction, and some
Moderate alcohol consumption. Keeping alcohol guidelines recommend β-adrenoreceptor blockers as
intake ≤2 standard drinks (~3.5 alcohol units) per day first-line antihypertensive medications77,132. The choice
for men and ≤1 standard drink (~1.75 alcohol units) should be based on individual efficacy and tolerabil-
per day for women can also contribute to a 2–4 mmHg ity. Ethnicity affects the response to antihypertensive
BP reduction95,96. medications, and it has been suggested that calcium-
channel blockers and diuretics are the first choice in
Physical activity. Regular physical activity reduces BP in black individuals106,133. Further, in specific clinical situ-
individuals with hypertension. Endurance training (aero- ations, for example, hypertension in pregnant women,
bic exercise) reduces BP more in persons with hyperten- other medications such as α-methyldopa (an agonist
sion than in individuals with normal BP. A narrative of α-adrenoreceptors in the central nervous system
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PRIMER
that inhibits the SNS) or labetalol (an α-β-adrenergic BP cannot be controlled with monotherapy in many
antagonist) are preferable, whereas some first-line patients, particularly those with severe hypertension.
antihypertensives, for example, ACE inhibitors and When combining antihypertensive medications, it is
angiotensin II receptor blockers, are contraindicated important to consider whether the drugs have addi-
because of increased risk of renal teratogenicity. Divided tive effects on BP or adverse effects and whether the
dosing of antihypertensive drugs tends to decrease patient has comorbidities that mandate particular drug
adherence and should be avoided when possible134. choices77. ACE inhibitors or angiotensin II receptor
Table 4 | Blood pressure targets recommended by various guidelines

Guideline Population Goal BP (mmHg)
2010 Chinese Adults <65 years <140/90
guidelines207
Adults ≥65 years <150/90 (<140/90 if tolerated)
Adults with diabetes mellitus, CHD or renal disease <130/80
2013 ESH/ Non‑frail adults <80 years <140/90
ESC77
Adults >80 years <150/90
Adults with diabetes mellitus <140/85
Adults with CKD without proteinuria <140/90
Adults with CKD with overt proteinuria <130/90
Adults with CHD <140/90
2013 ASH Adults 55–80 years <140/90
and ISH*208
Young adults <130/80
Adults >80 years <150/90
2014 Adults <60 years <140/90
Hypertension
guideline106 Adults ≥60 years <150/90
(formerly Adults with diabetes mellitus <140/90
known as
JNC 8) Adults with CKD <140/90
2014 South Most adults <140/90
African
guidelines209 Adults >80 years 140–150‡
2014 JSH210 Most adults <140/90

Patients 75–89 years <150/90 (<140/90 if tolerated)
Adults with diabetes mellitus or CKD <130/80
Adults with CHD or CVD <140/90
2016 CHEP 211
Adults <80 years <140/90
Adults ≥80 years <150‡
High-risk adults ≥50 years ≤120‡§
2016 Adults at high CVD risk without diabetes mellitus, including patients <120‡
Australian with CKD and those >75 years
guidelines212
Adults with diabetes mellitus in whom prevention of stroke is a priority <120‡
2017 ADA213 Adults with diabetes mellitus <140/90
Adults with diabetes mellitus and high CVD risk <130/80
2017 ACC/ Adults with known CVD or 10-year ASCVD event risk of ≥10% <130/80
AHA BP
Guideline111 Adults with no clinical CVD and 10-year ASCVD risk of < 10% <130/80
Adults of ≥65 years of age, noninstitutionalized and ambulatory <130‡
Adults of ≥65 years of age, with comorbidities and limited life Individualized goal based
expectancy on clinical judgement and
patient preference
ACC, American College of Cardiology; ADA, American Diabetes Association; AHA, American Heart Association; ASCVD,
atherosclerotic cardiovascular disease; ASH, American Society of Hypertension; BP, blood pressure; CHD, coronary heart disease;
CHEP, Canadian Hypertension Education Program; CKD, chronic kidney disease; CVD, cardiovascular disease; ESC, European
Society of Cardiology; ESH, European Society of Hypertension; ISH, International Society of Hypertension; JNC 8, Eighth Joint
National Committee; JSH, Japanese Society of Hypertension. *The 2013 ASH and ISH guidelines were written to provide
information for practitioners in low-income and middle-income countries as well as in developed countries. ‡Systolic blood
pressure. §Should be guided by automated office BP measurement.
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PRIMER
blockers, thiazide diuretics and dihydropyridine fraction or with diabetic nephropathy, both drug
calcium-channel blockers are additive in lowering BP classes improved outcomes, making them particularly
and can be combined as double or triple combination good choices in these populations. Both classes seem
therapies. By contrast, combining ACE inhibitors and to be comparable in reducing CVD risk136 and tend to
angiotensin II receptor blockers adds little BP-lowering improve glucose metabolism and, therefore, could be
effects while increasing the risk of renal dysfunction preferable in younger patients and in patients with
and hyperkalaemia (high blood potassium levels, which conditions predisposing to type 2 diabetes mellitus,
can lead to cardiac arrhythmias). Similarly, combining including obesity and the metabolic syndrome137. ACE
RAAS inhibitors with β-adrenoreceptor blockers adds inhibitors are generally well tolerated, but reductions
little BP reduction, but this combination is indicated in in kidney function, hyperkalaemia, cough and — less
patients following acute myocardial infarction or heart commonly — angioedema (swelling caused by fluid
failure with reduced left ventricular ejection fraction for accumulation) could occur with their use. The risk
reasons beyond BP reduction. of angioedema, which can be life threatening, is sub-
stantially increased in black individuals138 as well as in
ACE inhibitors and angiotensin II receptor blockers. patients treated with both ACE inhibitors and dipep-
Among medications that inhibit components of the tidyl peptidase 4 inhibitors (used in the treatment
RAAS, ACE inhibitors and angiotensin II receptor of diabetes mellitus, examples of which include sita-
blockers are considered first-line antihypertensives, gliptin, vildagliptin, saxagliptin and linagliptin)139. ACE
whereas other antihypertensive medications target- inhibitors that can be dosed once daily are preferred.
ing the RAAS, including direct renin inhibitors and Angiotensin II receptor blockers can also elicit hyper-
mineralo corticoid receptor antagonists, are usually kalaemia and worsening of kidney function but do not
considered reserve medications because there is less usually cause cough or angioedema136.
clinical trial evidence supporting their use as first-line
antihypertensive therapy. ACE inhibitors and angio- Dihydropyridine calcium-channel blockers. Dihydro-
tensin II receptor blockers have been tested extensively pyridine calcium-channel blockers elicit vasodilation
in large-scale hypertension trials135. In patients with by blocking vascular smooth muscle L-type calcium
heart failure with reduced left ventricular ejection channels. They are effective antihypertensive drugs with
BP t s ol s a comm atio s o t atm ta ollo
Normal BP Elevated BP Stage 1 hypertension Stage 2 hypertension

(BP <120/80 mmHg) (BP <120–129/<80 mmHg) (BP <130–139/80–89 mmHg) (BP ≥140/90 mmHg)
Promote optimal Nonpharmacological Clinical ASCVD or estimated 10‑year CVD risk ≥10 *
lifestyle habits therapy (Class I)
No Yes
Nonpharmacological Nonpharmacological therapy Nonpharmacological therapy

therapy (Class I) and BP-lowering medication and BP-lowering medication‡
(Class I) (Class I)
Reassess in 3–6 months Reassess in 1 month

(Class I) (Class I)
BP goal met
No Yes
Assess and optimize adherence to therapy

Reassess in 1 year Reassess in 3–6 months Reassess in 3–6 months
(Class IIa) (Class I) o si i t si catio o t a (Class I)
Figure 5 | Algorithm for the management of hypertension. Guidelines of ≥160/100 mmHg should be promptlyNaturetreated, carefully
Reviews monitored
| Disease and
Primers
for the treatment of hypertension. ASCVD, atherosclerotic cardiovascular receive upward medication dose adjustment as necessary to control BP.
disease; BP, blood pressure; CVD, cardiovascular disease. *Using the Reassessment includes BP measurement, detection of orthostatic
American College of Cardiology–American Heart Association Pooled hypotension in selected patients (for example, elderly individuals or those
Cohort Equations. Note that patients with diabetes mellitus or chronic with postural symptoms), identification of white-coat hypertension or a
kidney disease are automatically placed in the high-risk category. For the white-coat effect, documentation of adherence, monitoring of the response
initiation of renin–angiotensin–aldosterone system inhibitor or diuretic to therapy, reinforcement of the importance of adherence, reinforcement
therapy, assess blood tests for electrolytes and renal function 2–4 weeks of the importance of treatment and assistance with treatment to achieve
after initiating therapy. ‡Consider initiation of pharmacological therapy for BP target. Class of recommendation: Class I, strong; Class IIa, moderate.
stage 2 hypertension with two antihypertensive agents of different Reprinted with permission Hypertension. 2017;HYP.0000000000000065
classes. Patients with stage 2 hypertension and blood pressure (BP) © 2017 American Heart Association, Inc. (REF. 111).
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PRIMER
extensive experience in large clinical trials135. A practi-

Box 4 | Hypertension and obesity
cal advantage of this drug class is that it can be com-
bined with all other first-line antihypertensive drugs. Weight loss is recommended for individuals with obesity
Peripheral oedema, which is explained by peripheral and can be particularly important if these patients also
arterial vasodilation rather than worsening heart have hypertension. Medications have been developed
for the treatment of obesity, but their approval status
failure or kidney dysfunction, is a common adverse
differs between the United States and Europe: some
effect, particularly in individuals with obesity. Non- drugs are only approved in the United States (for
dihydropyridine calcium-channel blockers, especially example, lorcaserin and phentermine/topiramate),
verapamil, also inhibit cardiac calcium channels, whereas others are approved only in Europe. Blood
an effect that can reduce heart rate and cardiac con- pressure (BP) reductions in patients with hypertension
tractility 140. Calcium-channel blockers can induce or have been reported for some weight loss medications199,
worsen constipation, especially in institutionalized but their specific pharmacological actions might
older persons141. All calcium-channel blockers modestly attenuate the positive influences of weight loss on BP
inhibit the drug metabolizing enzyme cytochrome and cardiovascular disease outcomes200. Bariatric surgery
P450 3A4 and, therefore, could elicit important is very effective in reducing body weight, and the risk of
hypertension is substantially reduced up to 5 years
drug–drug interactions142.
following bariatric surgery201. However, large and
sustained body weight reductions are needed to
Thiazide-type and thiazide-like diuretics. Thiazide- substantially reduce BP following bariatric surgery202,
type diuretics (for example, hydrochlorothiazide) have and there are no large clinical trials specifically testing
a benzothiadiazine ring, whereas thiazide-like diur- the effects of weight loss medications or bariatric
etics (for example, chlorthalidone, metolazone and surgery on hypertension control.
indapamide) lack the benzothiadiazine structure. Both
subclasses of thiazide diuretics inhibit sodium and
chloride co-transporters in renal tubules, thereby pro- effects on body weight 150 and on glucose metabolism
moting natriuresis, and have been an important com- with β-adrenoreceptor blockade. Some of these dis-
ponent of pharmacological hypertension management advantages might be mitigated with newer vasodilator
ever since the first trials showing morbidity benefits of β-adrenoreceptor blockers, such as nebivolol and
antihypertensive therapy 143. Over the years, diuretic carvedilol151. However, there are no large-scale anti-
doses have been substantially reduced to attain better hypertensive trials demonstrating that this difference
risk–benefit profiles. Thiazide-type and thiazide-like translates into better clinical outcomes. β-Adreno-
diuretics can worsen glucose metabolism, increasing receptor blockers might promote bronchial obstruction
the risk of new-onset diabetes mellitus, but whether in patients with asthma and should not be combined
or not this metabolic action translates into long-term with non-dihydropyridine calcium-channel blockers
increases in CVD risk has been called into question144. (such as verapamil) that also lower sinus node rate or
Hydrochlorothiazide, the most commonly prescribed atrioventricular conduction.
thiazide-type diuretic worldwide, might be less effective
in mitigating CVD risk compared with chlorthalidone Newer pharmacological agents. Overall, the inter-
or indapamide145,146. Drug-related electrolyte disturb- est of the pharmaceutical industry in developing new
ances, including hypokalaemia and hyponatraemia anti hypertensive medications has been limited in
(low blood potassium and sodium levels, respectively), recent years. Moreover, most antihypertensive drugs
are particularly important adverse effects; hypo- are out of patent and, therefore, available as relatively
kalaemia can lead to cardiac arrhythmias and muscle inexpensive generics. Further, some of the currently
weakness, and hyponatraemia can cause confusion, approved drugs, such as angiotensin II receptor block-
seizures and coma. The risk of hypokalaemia is reduced ers, have placebo-like tolerability. Newer pharmaco-
when thiazide- type and thiazide-like diuretics are logical agents approved for other indications, including
combined with potassium supplements or potassium- combined angio tensin II receptor and neprilysin
sparing agents, such as ACE inhibitors, angiotensin II inhibitors152 (for heart failure), soluble guanylyl cyclase
receptor blockers or potassium-sparing diuretics. modulating drugs153 (for pulmonary hypertension) and
Hyponatraemia is a potentially life-threatening adverse sodium-glucose cotransporter 2 (encoded by SLC5A2,
effect, particularly in elderly persons. also known as SGLT2) inhibitors154 (for type 2 diabe-
tes mellitus), could also be useful in treating hyper-
β-Adrenoreceptor blockers. β-Adrenoreceptor block- tension. Other pharmacological agents, such as newer
ers lower BP by reducing cardiac output, heart rate, mineralocorticoid receptor antagonists, aldosterone
renin release and SNS activity 147. They improve out- synthase inhibitors, activators of the ACE2–angiotensin
comes following acute myocardial infarction and in (1–7)–MAS receptor axis and natriuretic peptide recep-
patients with heart failure with reduced left ventricu- tor agonists, are in various stages of preclinical or clinical
lar ejection fraction; however, in the absence of these development 155, often for indications other than hyper-
comorbidities, β-adrenoreceptor blockers are inferior tension. Drugs addressing novel pressor mechanisms
to other first-line antihypertensives in reducing CVD could be useful in patients with treatment-resistant
morbidity and mortality 148. This effect has been attrib- hypertension, particularly those not responding to or
uted to lesser reductions in aortic BP149 and adverse not tolerating mineralocorticoid receptor antagonists.
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PRIMER
Moreover, drugs with actions in addition to BP reduc- Quality of life

tion could prove clinically useful. For example, com- Health-related quality of life (HRQOL) is a multidimen-
bined angiotensin II receptor blockade and neprilysin sional concept that includes domains related to physi-
inhibition has been shown to ameliorate insulin resist- cal, mental, emotional and social functioning; studies
ance in patients with obesity and hypertension156 and demonstrate that each additional disease, as well as the
decrease the progression to type 2 diabetes mellitus in severity of these diseases, is associated with declines
patients with heart failure157. in HRQOL171. Population-based studies have consist-
ently shown that being diagnosed with hypertension
Treatment-resistant hypertension is associated with worsening of HRQOL even after
Treatment-resistant hypertension is commonly diag- adjusting for other comorbidities172,173. Altered HRQOL
nosed when office BP is >140/90 mmHg, despite treat- in persons with hypertension has been attributed to a
ment with ≥3 properly dosed antihypertensive drugs, variety of factors, including the diagnosis, treatment and
including a diuretic, and secondary hypertension has effects of alterations (both elevations and reductions)
been ruled out 158. Poor treatment adherence is a com- in BP172.
mon cause of apparent treatment-resistant hyperten- Labelling someone as having hypertension can result
sion. The true prevalence of treatment-resistant in worsening of self-perceived health status 174. This
hypertension is unknown, but an estimated 12.8% of was well demonstrated in a classic study of otherwise
all individuals with hypertension in the United States healthy Canadian steelworkers identified as having
and 15.3% of those treated with antihypertensive drugs hypertension as part of a screening programme. In the
fulfil the criteria for treatment-resistant hyperten- year following diagnosis, absenteeism from work owing
sion159. Adding a fourth or fifth drug to the treatment to illness more than tripled in those made newly aware
regimen could lead to satisfactory BP control in these of their hypertension, whereas it increased only slightly
patients. The PATHWAY trial rotated patients with in those previously aware of their hypertension175. This
treatment-resistant hypertension through different finding could not be explained by hypertension treat-
add-on drugs or placebo in a randomized fashion160. ment or BP level and was believed to be a direct conse-
All patients received a standardized antihypertensive quence of people adopting a ‘sick role’. These findings
regimen comprising three drugs, including a diuretic. have been replicated in studies carried out in diverse
Compared with α-adrenoreceptor or β-adrenoreceptor settings and using different measures of physical and
blockade, the mineralocorticoid receptor antagonist mental health174.
spironolactone was the most effective fourth anti- Antihypertensive medication use is associated with
hypertensive drug. In another study in patients whose a variety of symptoms that could lower HRQOL 176.
BP was uncontrolled despite receiving three drugs, Observational studies showed an association between
sequential addition of a mineralocorticoid receptor the number of antihypertensive medications pre-
antagonist followed by a loop diuretic (which acts at the scribed and worsening of HRQOL177. Some classes of
ascending limb of the loop of Henle in the kidney) was antihypertensive medications (for example, ACE inhib-
more effective than adding an ACE inhibitor followed itors) are better tolerated than others (for example,
by a β-adrenoreceptor blocker 161. Overall, mineralo- β-adrenoreceptor blockers and centrally acting agents,
corticoid receptor antagonism is a reasonable choice in such as α-methyldopa) and result in significantly better
patients with difficult-to-control hypertension. Given scores on measures of general well-being 178. Further,
the risk of inducing hyperkalaemia162, serum potassium small differences in HRQOL have even been reported
concentrations should be monitored. among medications of the same class, for example,
between enalapril and captopril179. However, clinical
Device-based treatments. Device-based treatments trials with newer antihypertensive agents have gener-
have been primarily developed for patients with severe ally indicated that they are extremely well tolerated
resistant hypertension whose BP cannot be controlled and can enhance the effects of nonpharmacological
with antihypertensive drugs155. Catheter-based renal treatment on HRQOL176,180. In the Treatment of Mild
nerve ablation163,164, electrical carotid sinus stimula- Hypertension Study (TOMHS), the combination of
tion165,166, modulation of baroreflex transduction with lifestyle modifications with any of five different anti-
a dedicated carotid stent 167, carotid body denervation168 hypertensive medication classes resulted in greater
and deep-brain stimulation169 are thought to lower BP improvements in HRQOL than lifestyle modifications
through SNS inhibition. Creation of a defined arterio- plus placebo180.
venous stent with a coupler device lowers BP by redu- Treatment-related reductions in BP could have a
cing peripheral vascular resistance170. These treatments negative effect on HRQOL, particularly in older and
are in various stages of clinical development, with the more-frail patients at high risk of hypotension. Clinical
most extensive data available on renal nerve ablation and trials performed in the 1990s that evaluated patients
electrical carotid sinus stimulation. No treatment has yet with very high baseline BP, for example, the Systolic
been proved efficacious in lowering BP in randomized Hypertension in the Elderly Program Trial (SHEP)
sham-controlled clinical trials164,166, because either the and the Systolic Hypertension in Europe Trial (Syst-
primary end point was not achieved or no trials have Eur), generally found minimal effects of BP reduc-
been conducted. Finally, trials with hard clinical end tions on HRQOL181,182. Two more-recent clinical trials
points do not exist. have targeted lower BPs (intensive systolic BP target
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PRIMER
Outlook
Box 5 | Outstanding research questions
Although there is regional variability in the outlook for
Measurement issues hypertension over the next 5 to 10 years, it is clear over-
• Is hypertension management improved by basing treatment strategies on unattended all that the prevalence of hypertension and, therefore,
office blood pressure (BP) measurements, out-of-office (home or ambulatory) the associated global burden attributable to hyperten-
BP measurements or central BP measurements? sion will increase186. Global population growth and age-
• How should BP be measured in patients with atrial fibrillation? ing will largely contribute to this increase — 1.5 billion
Treatment issues people are expected to be affected by 2025 (REF. 187)
• Should salt restriction at the population level continue to be recommended at — which will be focused in low-income and middle-
current targets? income countries186. However, these adverse trends in
• To what extent should age, estimated cardiovascular disease (CVD) risk and disease burden will be variably offset by improvements
concomitant conditions influence treatment thresholds? in prevention, awareness and treatment. The size of
• Should white-coat hypertension be treated? improvements in each of these three areas will vary
• If management strategy is to be influenced by central or out-of-office BP levels,
from nonexistent (hypertension prevention could even
what treatment thresholds and targets should be used? worsen in some parts of the world, as exposure to factors
that promote raised BP increases) to substantially large
• Should reducing 24-hour and long-term BP variability be a consideration in the
selection of drug treatment for optimal CVD protection? and important elsewhere in the world.
Overall, prevention will probably contribute least
• What combinations of antihypertensive agents give optimal CVD protection,
stratified by age and ethnicity? to any improvement in BP-associated disease burden.
This is because 80% of the world is in the process of
• What is the optimal BP treatment target stratified by age, CVD risk and concomitant
disease status? developing, which hitherto has inevitably been associ-
ated with increased exposure to the main environmen-
• What is the optimal management of treatment-resistant hypertension that is resistant
to four agents, including spironolactone? tal determinants of raised BP, such as excess intake of
calories, alcohol and salt. Food and drink industries,
• If treatment thresholds are to be driven by estimated CVD risk, at what level should
antihypertensive drug treatment be initiated and what other CVD protective agents
governments and education systems would be required
should be considered? to cooperate to reverse this pattern.
• Is initiating drug therapy with two hypertensive agents more effective than initiating
Implementation of preventive strategies has largely
with monotherapy for optimal CVD prevention? been limited to high-income countries. Despite reason-
ably compelling evidence to the contrary 112, recommen-
dations that the general population should restrict salt
of <120 mmHg versus standard systolic BP target of intake have been questioned on the basis of largely sub-
<140 mmHg). It had been postulated that this lower BP optimal observational data188. Such confusion worsens
might be expected to cause cerebral hypoperfusion, result- an already very difficult public health challenge. Data
ing in falls, dizziness and cognitive impairment183,184,107. show that only approximately half of people with hyper-
In a substudy of the Action to Control Cardiovascular tension are aware of their condition189, and the Lancet
Risk in Diabetes (ACCORD) study, HRQOL was evalu- Commission on hypertension identified that improving
ated in 1,028 participants randomized to either intensive awareness of hypertension is a crucial action needed
or standard therapy. No differences in mental func- to improve the current disease burden190,191. The global
tion were noted between treatment groups, but inten- BP awareness campaign promoted by the ISH, whereby
sive therapy was associated with a small, not clinically World Hypertension Day was extended to become May
significant, decrease in physical function184. In SPRINT, Measurement Month (MMM) in 2017, could contribute
targeting systolic BP of <120 mmHg required one addi- substantially to improving rates of routine BP screening
tional antihypertensive medication compared with stan- around the world83. Over 1.2 million adults (of ≥18 years
dard treatment to target systolic BP of <140 mmHg and of age) from >100 countries were screened as part of
was generally safe and well tolerated107,185. Compared MMM, and the ensuing data allied to health-economic
with standard treatment, intensive treatment did not analyses will be used to persuade policymakers in each
affect the perceived HRQOL of SPRINT participants, country that improved local BP screening and treatment
measured by patient-reported outcomes of physi- facilities are wise financial investments.
cal and mental health, self-reported satisfaction with Improving the efficacy of drug treatment also holds
care and medication adherence, even when stratifying great promise for reducing hypertension-associated
by age and comorbidities185. Almost 90% of partici- disease burden. Rather than focusing on rare second-
pants in both treatment groups reported satisfaction ary causes of hypertension or on the optimal manage-
with their BP care, and more than one-third described ment of treatment-resistant hypertension164, the greatest
improvement in satisfaction over baseline levels. effect could be achieved by the delivery and distrib-
Quality of life concerns remain an important aspect ution of affordable, effective single-pill combinations of
of hypertension management. SPRINT has demon- two or three drugs to low-income and middle-income
strated that with careful clinical management, lower BP countries where the burden of hypertension is consid-
can be targeted without concern of worsening physical erable and where any such therapies are currently either
and mental function. Clinicians must seek the optimal largely unavailable or unaffordable192. Unfortunately,
balance of reducing CVD morbidity and mortality while optimal combinations of two antihypertensive agents
maximizing well-being for each individual patient. have not been identified for the majority of the world’s
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PRIMER
hypertensive population: no such data are available for Antihypertensive medications are prescribed by
black, South Asian or East Asian patients193. However, the different health professionals in different countries.
first in a series of trials in these ethnic groups is underway However, even in high-income countries, much of the
in sub-Saharan Africa (N.R.P. et al., unpublished data). routine uncomplicated hypertension management
Meanwhile, single-pill formulations of the drug could, and probably should, be carried out by nurse
combinations most commonly recommended in current practitioners or other nonphysician health workers.
guidelines (calcium-channel blocker plus a diuretic, In more-remote parts of the world, the use of e-health-
calcium-channel blocker plus an RAAS-blocker or care techniques194 should be increased to facilitate task
diuretic plus an RAAS-blocker) are readily available shifting or task sharing by nonphysician health workers
and have low production costs. In addition, a three-drug where doctors are unavailable195.
combination of a calcium-channel blocker, a diuretic and In summary, although there are many interesting
an RAAS blocker 132 should also be produced for more- unanswered scientific research questions in the field of
severe hypertension, with low-dose spironolactone avail- hypertension (BOX 5), perhaps the most pressing need to
able as a fourth-line agent 160. Hence, one or two tablets reduce the disease burden is to evaluate the best ways,
will be able to control BP in all but a small proportion of at a local level, to screen routinely for raised BP and then
patients with hypertension. to deliver the best, most affordable, evidence-based com-
These formulations should be made available and bination of antihypertensive agents. Meanwhile, efforts
affordable in all countries of the world190. Additional to drive public health policy towards encouraging more-
local obstacles to the distribution and delivery of these healthy diets and lifestyles from a BP and CVD view-
agents to patients with hypertension within each country point should be encouraged, and basic scientific research
will also have to be overcome — among which the lack of that might allow precision medicine to be applied to
effective screening programmes is crucial190. patients with hypertension must also continue.
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K/DOQI clinical practice guidelines on hypertension This systematic review shows that indapamide lowers blood pressure in patients with resistant
and antihypertensive agents in chronic kidney disease. and chlorthalidone were more effective in hypertension. J. Am. Coll. Cardiol. 58, 765–773
Am. J. Kidney Dis. 43, S1–S290 (2004). lowering BP than hydrochlorothiazide at (2011).
125. Börjesson, M., Onerup, A., Lundqvist, S. & Dahlöf, B. commonly prescribed doses without increasing 167. Spiering, W. et al. LB02.05: Controlling and lowering
Physical activity and exercise lower blood pressure the risk of adverse metabolic effects, including blood pressure with the Mobiushd device: first in-man
in individuals with hypertension: narrative review of hypokalaemia, hyponatraemia and elevated results (CALM-FIM study). J. Hypertens. 33, e86
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PRIMER
169. O’Callaghan, E. L. et al. Chronic deep brain communities in high-, middle-, and low-income 211. Leung, A. A. et al. Hypertension Canada’s 2016
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170. Lobo, M. D. et al. Central arteriovenous anastomosis 191. Olsen, M. H. et al. A call to action and a lifecourse 212. National Heart Foundation of Australia. Guideline for
for the treatment of patients with uncontrolled strategy to address the global burden of raised blood the Diagnosis and Management of Hypertension in
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a randomised controlled trial. Lancet 385, Lancet Commission on hypertension. Lancet 388, 213. American Diabetes Association. Standards of
1634–1641 (2015). 2665–2712 (2016). medical care in diabetes — 2017. Diabetes Care
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& Fuchs, F. D. Health-related quality of life and 193. Park, I. U. & Taylor, A. L. Race and ethnicity in trials Clinical and Translational Research in Cardiometabolic
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shows that HRQOL was lower in persons with system (DSS) in prevention of cardiovascular disease: Introduction (M.C.A. and S.O.); Epidemiology (A.R. and
hypertension than in those with normal BP in a systematic review and meta-analysis. PLoS ONE 7, P.K.W.); Mechanisms/pathophysiology (G.L.B. and G.G.);
the domains of physical and functional functioning, e47064 (2012). Diagnosis, screening and prevention (A.F.D. and P.K.W.);
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health but that the magnitude of difference Recommendations and Guidelines (WHO, Geneva, (N.R.P.); Overview of Primer (S.O.).
was small. 2008).
173. Bardage, C. & Isacson, D. G. Hypertension and health- 196. Ehret, G. B. et al. Genetic variants in novel pathways Competing interests
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J. Clin. Epidemiol. 54, 172–181 (2001). risk. Nature 478, 103–109 (2011). support or reimbursement for travel to meetings or other
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PRIMER

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18014 | 1

Author addresses Disease burden

2 | ARTICLE NUMBER 18014 | VOLUME 4 www.nature.com/nrdp

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18014 | 3

ACE2 has emerged as an important modulator in (phosphoinositide 3-kinase–RAC serine/threonine-

lar extracellular matrix deposition, vascular remodelling,

20 intravascular to the interstitial compartment) and results

Na+/K+-ATPase and the sodium-glucose cotransporter

4 | ARTICLE NUMBER 18014 | VOLUME 4 www.nature.com/nrdp

RAAS Natriuretic peptides Endothelium SNS Immune

• Endothelial • Maintenance • Other vasoactive Activation of the SNS ↑ acrophage in ltration

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18014 | 5

Inflammation and the immune system

6 | ARTICLE NUMBER 18014 | VOLUME 4 www.nature.com/nrdp

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18014 | 7

of pregnancy-related hypertension is an important The physical examination aims to establish the

Loop of Cortical ECaC

Urine Blood Adrenal gland

8 | ARTICLE NUMBER 18014 | VOLUME 4 www.nature.com/nrdp

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18014 | 9

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Table 2 | Diagnostics of secondary hypertension

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18014 | 11

Increased potassium intake. Healthy individuals with Antihypertensive pharmacotherapy

12 | ARTICLE NUMBER 18014 | VOLUME 4 www.nature.com/nrdp

Table 4 | Blood pressure targets recommended by various guidelines

2014 JSH210 Most adults <140/90

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18014 | 13

BP t s ol s a comm atio s o t atm ta ollo

Normal BP Elevated BP Stage 1 hypertension Stage 2 hypertension

Nonpharmacological Nonpharmacological therapy Nonpharmacological therapy

Reassess in 3–6 months Reassess in 1 month

Assess and optimize adherence to therapy

14 | ARTICLE NUMBER 18014 | VOLUME 4 www.nature.com/nrdp

extensive experience in large clinical trials135. A practi-

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18014 | 15

Moreover, drugs with actions in addition to BP reduc- Quality of life

16 | ARTICLE NUMBER 18014 | VOLUME 4 www.nature.com/nrdp

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18014 | 17

18 | ARTICLE NUMBER 18014 | VOLUME 4 www.nature.com/nrdp

NATURE REVIEWS | DISEASE PRIMERS VOLUME 4 | ARTICLE NUMBER 18014 | 19

20 | ARTICLE NUMBER 18014 | VOLUME 4 www.nature.com/nrdp

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