Reviews: Lifestyle Interventions For The Prevention and Treatment of Hypertension

REvIEWS
Lifestyle interventions for the prevention

and treatment of hypertension
Pedro L. Valenzuela 1,8, Pedro Carrera-Bastos 2,8, Beatriz G. Gálvez3,
Gema Ruiz-Hurtado 4,5, José M. Ordovas 6,7, Luis M. Ruilope4,5 and Alejandro Lucia 3,4 ✉
Abstract | Hypertension affects approximately one third of the world’s adult population and is a
major cause of premature death despite considerable advances in pharmacological treatments.
Growing evidence supports the use of lifestyle interventions for the prevention and adjuvant
treatment of hypertension. In this Review, we provide a summary of the epidemiological research
supporting the preventive and antihypertensive effects of major lifestyle interventions (regular
physical exercise, body weight management and healthy dietary patterns), as well as other less
traditional recommendations such as stress management and the promotion of adequate sleep
patterns coupled with circadian entrainment. We also discuss the physiological mechanisms
underlying the beneficial effects of these lifestyle interventions on hypertension, which include
not only the prevention of traditional risk factors (such as obesity and insulin resistance) and
improvements in vascular health through an improved redox and inflammatory status, but also
reduced sympathetic overactivation and non-traditional mechanisms such as increased secretion
of myokines.
Approximately one third of the world’s adult population as resistant hypertension, should therefore be a priority.
1
Department of Systems have arterial hypertension, traditionally defined as a This approach is particularly relevant in light of the new
Biology, University of Alcalá, clinic (or office) blood pressure (BP) of ≥140/90 mmHg1. stringent cut-off values. Indeed, the aforementioned
Madrid, Spain. In the past decade, the number of deaths attributable to ACC/AHA and ESC/ESH guidelines recommend life-
2
Centre for Primary Health high BP has risen by 56.1%, and hypertension remains a style interventions for the prevention and treatment
Care Research, Lund major cause of premature death worldwide despite sub- of hypertension (Table 1). The guidelines distinguish
University/Region Skane,
stantial advances in pharmacological treatment2. The between effective lifestyle interventions for lowering
Skane University Hospital,
Malmö, Sweden. global direct medical costs associated with hyperten- BP, such as physical exercise, body weight loss, modera-
3
Faculty of Sport Sciences,
sion treatment are estimated to be US$370 billion per tion in alcohol intake and healthy dietary patterns with
Universidad Europea de year, with the health-care savings from effective man- low sodium intake and high potassium intake, and other
Madrid, Madrid, Spain. agement of this condition projected to be about $100 bil- interventions for which robust evidence of long-term
4
Research Institute of the lion per year3. However, recent changes in international BP-lowering effects is lacking, including behavioural
Hospital Universitario 12 de guidelines might actually increase the prevalence of therapies such as guided breathing, yoga, transcenden-
Octubre (imas12), Madrid,
hypertension. According to the 2017 guidelines from tal meditation or biofeedback. In this Review, we provide
Spain.
the ACC/AHA4, the threshold to define hypertension a summary of the epidemiological research supporting
5
CIBER-CV, Hospital
Universitario 12 de Octubre,
has now been established at 130/80 mmHg, with stage 1 the benefits of major lifestyle interventions for the pre-
Madrid, Spain. hypertension defined as office systolic BP (SBP) of vention and adjuvant treatment of hypertension and
6
Jean Mayer USDA Human
130–139 mmHg and stage 2 hypertension defined as describe the main physiological mechanisms underlying
Nutrition Research Center office SBP of ≥140 mmHg. The 2018 guidelines of the these benefits.
on Aging at Tufts University, ESC/ESH5 define a SBP of 130–139 mmHg as ‘high–
Boston, MA, USA. normal’. Therefore, many individuals who were not Lifestyle versus genotype
IMDEA Alimentacion,
7
previously receiving medication might now be placed Although both heritable and lifestyle risk factors
Madrid, Spain.
on treatment, leading to an increase in the number of contribute to increased BP levels, the latter can have a
8
These authors contributed individuals treated for hypertension in the near future. substantial effect on BP beyond genetic endowment.
equally: Pedro L. Valenzuela,
Pedro Carrera-Bastos.
The promotion of lifestyle interventions (notably To investigate whether lifestyle factors offset the BP
✉e-mail: alejandro.lucia@ exercise, body weight reduction and healthy diet recom effect of an adverse genetic profile, Pazoki and col-
universidadeuropea.es mendations) aimed at optimizing the prevention and leagues constructed a genetic risk score for high BP with
https://doi.org/10.1038/ management of hypertension (Fig. 1), including dis- 314 published BP loci and used it to score 277,005 indi-
s41569-020-00437-9 ease phenotypes with higher cardiovascular risk, such viduals without previous cardiovascular disease (CVD)
Nature Reviews | Cardiology

Reviews
Key points is not well controlled5. In turn, the benefits of an optimal

lifestyle should not be overlooked when considering
• Strong evidence supports the benefits of regular physical activity and exercise for the antihypertensive medical treatment, because lifestyle
prevention and management of hypertension. intervention remains a cornerstone for the manage-
• Reducing body weight to normal in individuals with overweight or obesity reduces ment of hypertension independently of the medical
the risk of hypertension, but further evidence is needed on the long-term efficacy treatment received. For instance, physical exercise has
of this strategy. been reported to improve BP in both pharmacologi-
• Sodium intake restriction reduces blood pressure, particularly in patients with cally treated and untreated individuals12. Exercise can
hypertension, and the Dietary Approaches to Stop Hypertension (DASH) diet is markedly lower BP even in association with therapy with
the most effective dietary approach to prevent hypertension and to reduce blood
three or more drugs (such as in people with resistant
pressure in individuals with pre-hypertension or hypertension.
hypertension)13.
• Shift work, short sleep duration or poor sleep and other forms of circadian disruption
Dietary modifications such as the adoption of the
might increase the risk of hypertension.
Dietary Approaches to Stop Hypertension (DASH) diet are
• Some forms of psychological stress, such as post-traumatic stress disorder, seem to
similarly effective in reducing BP in individuals with or
be associated with a higher risk of hypertension, but strong evidence on the potential
antihypertensive benefits of stress management techniques is lacking.
without hypertension, as well as in patients with or with-
out antihypertensive treatment14. Similarly, a reduction
• In contrast to common antihypertensive medications, lifestyle interventions,
especially exercise, reduce blood pressure through multisystemic and ‘non-
in sodium intake (one of the most popular recommen-
traditional’ mechanisms (for example, not only by improving vascular health or dations for the dietary management of hypertension)
reducing sympathetic overactivation). is an effective strategy for reducing BP in patients
with hypertension, and the effects might be additive to
those of pharmacological interventions15. For instance,
from the UK Biobank (age 40–69 years and median reducing sodium intake in patients aged 60–80 years
follow-up ~6 years)6. The investigators also scored par- with hypertension who were taking one antihyperten-
Clinic (or office) blood
pressure
ticipants according to lifestyle factors, including BMI, sive drug resulted in a lower BP and a lower incidence
Blood pressure (BP) measured healthy diet, sedentary behaviour, alcohol consump- of elevated BP, or resumption of medication, during a
in the clinical setting (for tion, smoking status and urinary sodium excretion 28-month follow-up after withdrawal of the antihyper-
example, an outpatient clinic). levels measured at recruitment, and assessed the asso- tensive drug16. Likewise, a reduction in excessive body
In this Review, ‘BP’ refers to
ciation between the genetic risk, lifestyle scores and BP weight has been reported to be a beneficial strategy in
‘clinic BP’ unless otherwise
stated. levels. The healthy lifestyle score was strongly inversely patients with hypertension, in both those not receiv-
associated with both SBP and diastolic BP (DBP) irre- ing medication and, particularly, in those receiving
Resistant hypertension spective of the underlying BP genetic risk. Individuals medication17.
Clinic (or office) systolic with a favourable lifestyle had lower SBP (4–5 mmHg In the next sections, we review the lifestyle inter-
blood pressure/diastolic blood
pressure ≥140/90 mmHg
lower, on average) in all genetic risk groups than those ventions that are recommended by the ACC/AHA4 and
(or ≥130/80 mmHg according with an unfavourable lifestyle. These data support ESC/ESH5 guidelines for the prevention and treatment
to the 2017 ACC/AHA population-wide efforts to lower BP through lifestyle of hypertension on the basis of robust evidence, that is
guidelines) in patients receiving modification. physical exercise, body weight management, healthy die-
at least three antihypertensive
Evidence from non-westernized populations, which tary patterns, circadian entrainment and adequate sleep
drugs (including one diuretic) at
maximally tolerated doses. have low rates of hypertension and a very low prevalence patterns, and stress management. The current evidence
of age-related increases in BP and overall CVD despite on the main lifestyle factors that can reduce BP and/or
Physical exercise receiving no pharmacological treatment, also provides the risk of hypertension is summarized in Fig. 4.
Also termed ‘exercise training’ support for the role of lifestyle factors in the prevention
or simply ‘exercise’. A subset of
physical activity that is planned,
of hypertension7–11 (Fig. 2). These low rates of hyperten- Physical exercise
structured and repetitive and sion and CVD are attributable, at least partly, to their Despite the little attention that physical exercise has
has a final or an intermediate traditional diets and lifestyles, which are similar to those received in medical practice compared with drug ther-
objective of improving or that have characterized most of human evolutionary apy, guidelines from the Seventh and Eight US Joint
maintaining physical fitness. In
history — that is, non-westernized dietary patterns, regu- National Committees, ACC, AHA, ESC, ESH, American
this Review, physical activity
and exercise are sometimes lar physical activity, ‘natural’ sleep–wake cycles, and sun College of Sports Medicine and Canadian Hypertension
used interchangeably to ease exposure, among others (Fig. 3) — all of which can influ- Education Program recommend increasing the levels
readability. ence BP levels and the risk of hypertension, as discussed of regular physical activity and exercise for the pre-
in depth in the following sections. vention and management of hypertension18. A 2019
Non-westernized
populations
umbrella review of 18 meta-analyses and systematic
Hunter–gatherers, traditional Drugs and lifestyle: interaction effects reviews including 594,129 adult participants provided
horticulturalists, pastoralists The role of lifestyle habits in the prevention and treat- strong evidence to support the role of physical activity
and farmers, and other ment of hypertension should be considered together in preventing hypertension in individuals with normal
populations minimally affected
with the potential interactions with antihypertensive BP, as well as in reducing BP among individuals with
by western habits.
medical treatments. An optimal lifestyle can be viewed pre-hypertension or hypertension19. A meta-analysis
Non-westernized dietary as the first-line treatment of hypertension in some cases. of longitudinal studies suggested that individuals who
patterns The ESC/ESH guidelines indeed consider an optimal meet the minimum physical activity levels recommended
Composed mainly of universal lifestyle as the only treatment needed for people with by international guidelines have a 6% lower risk of
fresh food sources very low in
refined oils, margarine, refined
mild hypertension during the first 3–6 months after hypertension than individuals with inactive lifestyles20.
cereal grains, added sugars diagnosis, with the recommendation that pharmacolog- Moreover, an inverse dose–response relationship seems
and ultra-processed foods. ical treatment is added after this period if hypertension to exist between the level of physical activity and the
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Visceral adiposity
↑ Release of adipocytokines
(such as leptin, resistin and TNF)
↑ Macrophage infiltration
↑ Renal sympathetic nerve activity
Physical exercise
Insulin resistance
↑ Glycaemia
↑ Insulinaemia
Body weight management RAAS

↑ Vasoconstrictor axis activity
↑ Sodium reabsorption
↓ Natriuresis
Vascular structure
Refraction and rarefaction ↑ Blood pressure
Healthy dietary pattern ↑ Arterial stiffness
↓ Vessel lumen
↑ Vascular resistance
Vascular function and oxidative status ROS

↓ NO availability
↑ ROS production
Circadian synchrony
Inflammation
↑ Pro-inflammatory cells
↑ Pro-inflammatory molecules
(such as CRP and TNF)
Stress management
Autonomic function
↓ Baroreceptor function
↑ SNS tone
Fig. 1 | Physiological mechanisms underlying the benefits of healthy lifestyle patterns on hypertension. Each lifestyle
factor can modulate one or more of the main physiological mechanisms that are involved in the development of hypertension:
visceral fat accumulation, insulin resistance, stimulation of the renin–angiotensin–aldosterone system (RAAS), alteration
of vascular structure, vascular endothelial dysfunction and oxidative stress, inflammation and autonomic dysfunction
(with increased tone of the sympathetic nervous system (SNS)). CRP, C-reactive protein; NO, nitric oxide; ROS, reactive
oxygen species; TNF, tumour necrosis factor.
risk of incident hypertension, with no cut-off to the patient population13,25. Meta-analytical evidence also
amount of physical activity that confers benefit19,20. indicates that moderate exercise during pregnancy is
A network meta-analysis of 391 randomized controlled associated with a significantly reduced risk of gestational
trials (RCTs) and 39,742 individuals found that both hypertensive disorders26,27. Nonetheless, more evidence is
exercise interventions and antihypertensive drugs were needed on the sustainability of the benefits of exercise in
similarly effective in reducing SBP in individuals with the long term (Box 1). Also, although exercise has benefi-
hypertension (SBP ≥140 mmHg)21. cial effects per se on BP and in reducing the risk of hyper-
Physical exercise has also shown remarkable benefits tension, these beneficial effects might be maximized
in patients with resistant hypertension, although more if combined with body weight reduction (Box 2).
research is needed to confirm these observations22.
Greater physical activity levels have been associated with Exercise modalities
Physical activity a lower risk of CVD in people with resistant hyperten- Different types of exercise have been shown to reduce
Any bodily movement
produced by skeletal muscles
sion23,24, and two RCTs have shown that exercise inter- BP. An umbrella review and a network meta-analysis
that requires energy ventions reduce 24-h ambulatory BP (average 20 mmHg concluded that all the main types of exercise (endurance
expenditure. decrease in SBP and 10 mmHg decrease in DBP) in this exercise (also known as aerobic exercise), resistance exercise

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Table 1 | lifestyle recommendations from major hypertension guidelines

lifestyle factor aCC/aHa4 ESC/ESH5
Physical exercise Aerobic exercise (90–150 min per week, 65–75% Aim for 300 min per week of
and physical activity of heart rate reserve) moderate-intensity or 150 min per week of
vigorous-intensity aerobic physical activity,
or an equivalent combination thereof
Dynamic resistance exercise (90–150 min Dynamic resistance exercises (2–3 days
per week, 50–80% one repetition maximum, per week)
six exercises, three sets per exercise, ten
repetitions per set)
Isometric resistance exercise (handgrip The effect of isometric exercises is less well
4 × 2 min, 1 min rest between exercises, 30–40% established
maximal voluntary contraction, three sessions
per week)
Nutrition Consume a diet rich in fruits, vegetables, whole Increased consumption of vegetables, fresh
grains and low-fat dairy products, with reduced fruits, fish, nuts and unsaturated fatty acids
content of saturated and total fat (DASH (olive oil); low consumption of red meat; and
dietary pattern) consumption of low-fat dairy products
Reduce intake of dietary sodium (optimal goal Sodium intake restriction to <2,000 mg
<1,500 mg per day) per day
Increase intake of dietary potassium (aim for
3,500–5,000 mg per day)
Body weight Best goal is ideal body weight Avoid obesity (BMI >30 kg/m2 or waist
management circumference >102 cm in men and >88 cm
in women), and aim for healthy BMI (about
20–25 kg/m2) and waist circumference values
Alcohol Two or fewer drinks per day for men and one or Drink <14 units per week for men and <8 units
fewer drinks per day for women per week for women, and avoid binge drinking
Smoking Not specified Smoking cessation, supportive care and
referral to smoking-cessation programmes
DASH, Dietary Approaches to Stop Hypertension.
(also known as strength exercise) or a combina- Exercise intensity

tion thereof ) are similarly effective in reducing Moderate-intensity and high-intensity exercise have
BP in individuals with hypertension19,21. Although similar beneficial effects on BP21, although the latter has
endurance exercise is probably the most commonly been suggested to be more effective in downregulating
prescribed exercise modality for patients with hyper- the pathophysiological mechanisms that contribute
Dietary Approaches to Stop
Hypertension tension, the benefits of resistance exercise (such as to the development of hypertension (such as arterial
(DASH). A lifelong approach to weight lifting) or the combination of endurance and stiffness)32. However, according to a 2019 systematic
healthy eating that is designed resistance exercise remain largely unknown in the clin- umbrella review, insufficient evidence is available to
to help treat or prevent ical setting, despite eliciting similar (or even greater) determine the relationship between exercise intensity
hypertension without
medication, sponsored by the
reductions in BP to those achieved with endurance and BP19.
NIH. This diet is rich in fruits, exercise in patients with hypertension (SBP 8.7 mmHg
vegetables, whole grains and for endurance exercise, 7.2 mmHg for resistance exer- Mechanisms
low-fat dairy products, includes cise and 13.5 mmHg for combined exercise) 21,28,29. Adiposity. Obesity per se (that is, without other cardio
poultry, fish and nuts, contains
Moreover, growing evidence suggests that a specific metabolic conditions) is associated with a higher
small amounts of red meat,
sweets and sugar-containing type of resistance exercise, isometric exercise (such risk of hypertension33, with the two main causative
beverages, and results in a as handgrip), which has previously been associated mechanisms being compression of the kidneys by
sodium intake within normal with acute, potentially harmful hypertensive responses, visceral, perirenal and renal sinus fat, and increased
limits. might be effective in reducing BP (6–8 mmHg decrease renal sympathetic nerve activity with subsequent
Minimum physical activity

in SBP and 3–4 mmHg decrease in DBP)30,31. A 2019 renin–angiotensin–aldosterone system (RAAS) activation34
levels meta-analysis showed that the effects of isometric resist- (Fig. 1). In addition, obese adipose tissue (particularly the
WHO recommends that adults ance exercise on BP reduction are significant and indeed visceral depot) is characterized by an increase in the pro-
engage in ≥150 min per week similar to those provided by other exercise modali- duction and secretion of cytokines and other peptides
of moderate-intensity physical
ties (endurance, resistance or a combination thereof) — the so-called adipocytokines (or adipokines), such
activity (such as brisk walking)
or ≥75 min per week of when analysing individuals with or without hyper- as tumour necrosis factor (TNF), resistin and espe-
vigorous physical activity (such tension together (mean 5.7 mmHg decrease in SBP)21. cially leptin — that have several negative multisystemic
as very brisk walking or However, the BP changes did not reach statistical signif- effects including increased inflammation, and contrib-
jogging), or a combination icance when analysing only patients with hypertension ute to a higher risk of hypertension35. Furthermore, lep-
thereof, as well as in
muscle-strengthening activities
(4.9 mmHg decrease). Nonetheless, a potential matter tin increases renal sympathetic nerve activity through
involving major muscle groups of concern is the ‘hypertensive response to exercise’ stimulation of the melanocortin 4 receptor (MC4R)
on ≥2 days per week. phenomenon (Box 3). pathway in the central nervous system34. Patients with
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24-h ambulatory BP
loss-of-function mutations in MC4R have diminished and hyperinsulinaemia being significant contributors to
Also termed ‘24-h BP’. The adrenergic activity and are less likely to develop hyper- the risk of hypertension, at least in the early stages of
mean result of blood pressure tension than control individuals36. Exercise interven- impaired glucose metabolism43. However, the potential
(BP) levels measured with a tions, even without a concomitant hypocaloric diet37 or association between plasma insulin levels or insulin
portable automated device at
regular intervals during normal
body weight loss38, are particularly effective in reducing resistance and incident hypertension is much weaker in
daily life over 24 h. visceral fat mass, which is more prone to induce insu- the absence of obesity (at least in men)44, suggesting that
lin resistance than subcutaneous fat39 and has a unique obesity, especially when associated with excess visceral
Endurance exercise pro-inflammatory profile40,41. adiposity, is a confounder and that hyperinsulinaemia
Also termed ‘aerobic exercise’.
per se is not a primary cause of the development of
A type of exercise that is
performed for more than a few
Insulin resistance. Insulin resistance and compensatory hypertension45.
minutes and preferentially hyperinsulinaemia are traditionally associated with an Although compensatory hyperinsulinaemia owing
involves aerobic metabolism increased risk of hypertension, as revealed in popula- to insulin resistance can acutely increase renal tubular
for energy production (for tion studies showing correlations between these metab sodium reabsorption and sympathetic nervous system
example, brisk walking, jogging,
bicycling and swimming).
olic alterations and elevated BP in people with obesity (SNS) activity, these effects do not actually translate into
and metabolic syndrome (so-called syndrome X)42. increases in BP in humans or in animal models other
For instance, the prevalence of hypertension increased than rodents and, therefore, do not increase the risk of
with worsening stages of impaired glucose metabolism hypertension in the absence of coexistent obesity and/or
in a cohort of Japanese individuals, with hyperglycaemia metabolic syndrome42. Nevertheless, the metabolic
Yanomani
Amazon rainforest,
Venezuela and Brazil
Forager–horticulturalists
Kitava
Papua New Guinea
Shuar Horticulturalists
Amazon rainforest,
Ecuador
Forager–horticulturalists
Tsimané
Amazon rainforest, Bolivia
Forager–horticulturalists Hadza
Serengeti National Park,
Tanzania
Hunter–gatherers
b
6 3
40
0
,39 99 ,39
95 95 –3 92 11
de 4,3 8,3 97 1,3 i
an
,3
wi
9 9
7,3 é 95 9,3
an
3
ld za ar va om
or d im u ta n
W Ha Ts Sh Ki Ya
140
120
Blood pressure (mmHg)
100
80
60
40
20 SBP
DBP
0
9 4 9 4 9 4 9 4 9 4 9 4 9 4 5 9 9 0 4 4 4 4 5 8 9 9 6 5
– 1 – 2 – 2 – 3 – 3 – 4 – 4 – 5 – 5 – 6 – 6 – 7 – 7 – 8 > 8 8 – 3 0 – 5 +6 0 – 4 5 – 5 5 – 6 5 – 7 > 7 ~3 0 – 3 0 – 5 0 – 8 2 ± 1
18 20 25 30 35 40 45 50 55 60 65 70 75 80 1 4 4 4 5 6 2 4 6 2
Age (years)
Fig. 2 | Blood pressure profile of non-westernized populations. The figure shows the geographical distribution (panel a)
and blood pressure profiles (panel b) of representative non-westernized populations (Hadza, Kitava, Shuar, Tsimané and
Yanomani) compared with the mean blood pressure values for the worldwide population. Non-westernized populations
have low rates of hypertension and do not seem to show the typical age-related increase in blood pressure. Data from
non-westernised populations were obtained from refs7–9,11,391–399. World mean blood pressure levels were obtained
from ref.400. DBP, diastolic blood pressure; SBP, systolic blood pressure.

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Non-westernized populations Westernized populations
Sedentary lifestyle
• Low energy expenditure
Regular physical activity
• High energy expenditure Westernized dietary patterns
• Hypercaloric diet
• High intake of processed meat,
Non-westernized dietary patterns Effect on health parameters alcohol, sugar, refined grains and
• High intake of fruits, tubers, • Hypertension rates ultra-processed foods
roots and vegetables • Adiposity levels • High sodium-to-potassium ratio
• Low intake of processed foods • Glucose and insulin levels
in blood Circadian disruption
• Blood lipids
Circadian synchrony • Inflammation • Irregular sleep–wake cycle
• Regular sleep–wake cycle • SNS activity • Irregular eating pattern
• Eating during daytime • Physical inactivity
• Sunlight exposure • High screen use at night
• Daytime physical activity
Psychosocial behaviour
• Chronic psychosocial stress
Fig. 3 | Characteristic lifestyle factors in non-westernized and westernized populations. The lifestyle pattern of
westernized populations (frequently associated with a sedentary lifestyle, unhealthy diets, circadian disruption and high
levels of chronic psychosocial stress) is likely to contribute to the high rates of hypertension and other associated risk factors
commonly observed in these populations. By contrast, non-westernized populations usually have an opposite lifestyle (high
physical activity levels, healthy diets and circadian synchrony) and, therefore, have a heathier cardiometabolic profile and
lower rates of hypertension. SNS, sympathetic nervous system.
effects of insulin resistance (notably, hyperglycaemia exercise has the opposite effect on artery remodel-
and dyslipidaemia) can interact synergistically with ling to that associated with hypertension, eliciting an
pre-existing high BP to aggravate vascular and kid- increase in the luminal diameter of conduit arteries and
ney injury and therefore exacerbate hypertension and resistance arteries and in capillary density in skeletal
its consequences42. Physical exercise per se has been muscles55. Exercise training can also reduce the carotid
reported to improve insulin sensitivity, at least when intima–media thickness in patients with hypertension56.
Resistance exercise associated with some modest body weight reduction46,
Also termed ‘strength exercise’.
A type of exercise that is
and exercise alone has been shown to improve glucose Vascular function and oxidative status. Vascular
performed against a load or control in healthy adults47 and in patients with diabetes endothelial dysfunction (VED) is a reversible func-
resistance (for example, weight mellitus48. tional condition57, as opposed to the vascular damage
lifting and leg press). or ‘destruction’ that occurs in hypertension-associated
Renin–angiotensin–aldosterone system. The RAAS has target-o rgan damage, and encompasses not only
Isometric exercise
A type of exercise that usually a central role in regulating BP and is an important tar- blunted endothelium-dependent vasodilatation but also
involves small muscle groups get in the treatment of hypertension49. The RAAS has endothelial inflammatory activation58. VED might con-
and results in no displacement two main axes, which counteract each other in terms of tribute to hypertension, albeit with a less clear influence
or joint movement (such as vascular control: the classic vasoconstrictive axis (renin– compared with its role in atherosclerosis development58.
handgrip).
angiotensin-converting enzyme (ACE)–angiotensin II Reduced nitric oxide (NO) bioavailability seems to be an
Renal sympathetic nerve (Ang II)–type 1 Ang II receptor) and the opposing vas- important characteristic of VED in hypertension57, and
activity orelaxant axis (ACE2–Ang 1–7–Mas receptor)50. An might impair the inhibitory effect of NO on another
An important nerve regulator abnormally high RAAS activity (for example, because endothelium-derived vasoactive molecule, endothe-
of the function of the renal
of an imbalance between the two axes) can contribute lin 1 (ref.59). Endothelin 1 is a potent vasoconstrictor,
vasculature, tubules and
juxtaglomerular granular cells to the development of hypertension50. Evidence from a meaning that the resulting imbalance between NO and
and, therefore, of renal meta-analysis does not support a clear role of physical endothelin 1 can result in increased vasoconstriction. An
haemodynamics, tubular exercise for targeting the RAAS51. Exercise interventions increased production of reactive oxygen species and a
reabsorption and renin (≥4 weeks) reduced plasma renin activity concomitant heightened inflammatory status also contribute to VED
secretion rate.
with a reduction in BP, but with no significant relation- in patients with hypertension60. Oxidative stress causes
Renin–angiotensin– ship between the magnitude of improvements in both NO inactivation61 and might oxidize LDL particles
aldosterone system markers and no effect on plasma levels of Ang II or thereby affecting their function, with resulting toxicity
(RAAS). A hormonal system aldosterone. to endothelial cells and adhesion and migration of
that is a critical regulator of
leukocytes to the arterial wall62.
blood volume and systemic
vascular resistance. Vascular structure. Structural changes in microcircula- Meta-analytical evidence indicates that exercise
tory beds are responsible for the elevation in vascular improves endothelial function (typically assessed by
Adipocytokines resistance in hypertension, mediated mainly by a reduc- flow-mediated dilatation of the brachial artery) and arte-
From the Greek adipo (fat), tion in vessel lumen (remodelling) and in the number or rial stiffness (measured as pulse wave velocity and aug-
cytos (cell) and kinos
(movement); also termed
length of small vessels (rarefaction)52,53. Hypertension is mentation index), with a dose–response relationship
adipokines. Cytokines secreted also associated with a reduced diameter and an increased between exercise intensity, at least in the case of aero-
by adipose tissue. wall thickness of large peripheral arteries54. Regular bic exercise, and the benefits obtained63,64. Of note, the
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Sympathetic nervous system beneficial effects of exercise on endothelial function and/or associated with a higher prevalence of hypertension in a
(SNS). One of the two main arterial stiffness have been confirmed in individuals number of observational studies, which was confirmed
divisions of the autonomic with pre-hypertension and those with hypertension65–67. in a 2019 meta-analysis showing that higher levels of cir-
nervous system, the other By contrast, aerobic exercise training for 8 months was culating C-reactive protein (CRP), high-sensitivity CRP
being the parasympathetic
nervous system. Although its
not sufficient to reduce arterial stiffness in children (hsCRP) and IL-6 are associated with the risk of devel-
primary function is to stimulate with excess body weight, suggesting that longer inter- oping hypertension75. Notably, a link between inflamma-
the ‘fight, flight or freeze’ ventions or concomitant body weight reduction might tion and increased activity of the RAAS vasoconstrictor
response, the SNS is constantly be required to improve arterial stiffness68. Physical exer- axis has been reported, with high circulating levels of
active at a basal level to
cise increases NO bioavailability69, possibly owing to the pleiotropic cytokine IL-6 having a pathogenic role
maintain homeostasis in
haemodynamics by inducing a
the beneficial effects of exercise on redox homeostasis in Ang II-mediated hypertension76.
vasoconstrictor effect in most and inflammation, mediated by the downregulation of In addition to clinical data, mechanistic evidence
vessels. nuclear factor-κB (NF-κB) signalling70. Physical exer- supports a causal role for inflammation in hyperten-
cise also stimulates the production of vasodilatory (NO sion. Indeed, activation of the innate immune system
Conduit arteries
Also known as conducting
and prostacyclin) and angiogenic (for example, vascular after arterial wall injury might be an initial pathogenic
arteries or elastic arteries. endothelial growth factor (VEGF)) agents by increas- event in hypertension, in which tissue injury leads to
Arteries with many collagen ing shear stress71. Meta-analytical evidence supports the activation of Toll-like receptors (TLRs; notably TLR4) in
and elastin filaments in the role of exercise training for the improvement of redox endothelial cells and leukocytes, with subsequent secre-
tunica media, which provides
status in various populations72, including women aged tion of various inflammatory cytokines and increased
the capacity to stretch in
response to each pulse.
60–75 years with hypertension73. production of reactive oxygen species77. Among the
Conduit arteries include the known causes of chronic systemic inflammation is
largest arteries in the body Inflammation. Chronic systemic inflammation is involved physical inactivity 78, whereas regular exercise has
(pulmonary arteries, the aorta in the pathophysiology of hypertension74. Elevated anti-inflammatory effects. For instance, a meta-analysis
and its branches).
concentrations of inflammatory biomarkers have been indicates that engaging in exercise training is associated
with a decrease in circulating CRP levels regardless of age
or sex79. At the mechanistic level, the anti-inflammatory
milieu created by exercise training is largely mediated
by myokines.
Myokines and adipokines. Working muscles act as

endocrine organs that can produce and secrete small
peptides (including cytokines) known as myokines,
Reg
u which can provide direct and indirect beneficial
Eat lar s
nd es Reg ing lee effects on cardiovascular phenotypes, including those
ula du p–
n a qu related to BP80. Notably, muscle-released IL-6 — as
it o chni r p rin
hy g
wa ay ctivi
a te si opposed to that released from other sources in a non-

ke time ty
at t
n
ax di
d
ca
exercise milieu — exerts anti-inflammatory effects

cy
rel Me
ss
io
stre C
la
syn ircad
cle
ial t
soc emen ch ia
ro
by promoting the production of other cytokines with
o ag n
n anti-inflammatory properties (such as IL-1 receptor
n y
ma h
c
Psy
antagonist and IL-10), while decreasing the circulating

levels of pro-inflammatory factors (such as TNF)81,82.
ei g h t in p e o p le
Exercise-i nduced myokines might also reduce BP

Endurance and res
age m e nt
Blood pressure through more direct mechanisms not necessarily

o r o b e sity
P h y si c al e x
management linked to anti-inflammatory effects. In particular, iri-

sin has been shown to reduce BP (with attenuation of
t man
VED mediated by the AMP-activated protein kinase

o ve b o d y w
ig ht
ig h
erc
(AMPK)–AKT–endothelial NO synthase (eNOS)–NO

is t a
we
is e
rw e
pathway) and stimulate vasorelaxation in hypertensive

dy
nce
Bo
wi on o
rats83. Muscle-released irisin might also prevent the ele-

tra
He s
th
ti
al t h t er n vation of BP induced by SNS outflow via activation of

i ni
uc
y dietary p at
ed
ng
R ATP-sensitive potassium channels in smooth muscle84.

Di
et io These preclinical findings are consistent with the
H ig w i t h rat
h a lo w a s s i u m bles reported inverse association between baseline plasma
Lo i n s p o t a
w i t a k e o f o d i u m - t o - d v e g et ai n s, levels of irisin and SBP and DBP in women with pre-
n ta
k e o f f rui ts, t u b ers a n n ed gr eclampsia85. However, other researchers have found a
r efi
proc ed meat, sugar, r hol
e s s e d f o o d s a n d a lc o positive association between irisin and DBP in patients
with renal disease86, or between irisin, SBP and the risk
of hypertension in a cohort comprising both individuals
Fig. 4 | lifestyle factors with blood pressure-reducing effects. Summary of the major,
evidence-based lifestyle factors that reduce blood pressure levels and the risk of
with normal BP and patients with hypertension87, or no
hypertension. A variety of lifestyle factors, including regular physical exercise, body significant association between irisin and BP in individ-
weight management and adhering to a healthy diet, along with other potentially uals with central obesity88. Because irisin, and indeed
influencing factors, such as circadian entrainment and avoiding psychosocial stress, most myokines, can also originate from tissues other
contribute to the adequate management of blood pressure. than working muscles (such as adipose tissue) under

Reviews
Box 1 | are the beneficial effects of exercise on blood pressure sustainable? 1 mmHg in individuals with or without hypertension17.
A prospective study (including ~14,000 individuals)
Some research suggests that the beneficial effects of exercise on blood pressure found that body weight loss reduced the risk of uncon-
might still be observed with long-term interventions (≥12 months)401–403. However, trolled hypertension in individuals with hypertension
a meta-analysis indicated that exercise interventions reduce systolic blood pressure and overweight or obesity101.
(4.4 mmHg) and diastolic blood pressure (4.2 mmHg) in the short-to-medium term
Body weight-r educing strategies, particularly
(3–6 months) in young adults with pre-hypertension or hypertension, but the benefits
are lost at ≥12 months (systolic blood pressure −1.0 mmHg and diastolic blood pressure energy-restricted diets and physical exercise, have tra-
−0.9 mmHg)404. Therefore, further research is needed to confirm the long-term ditionally been considered major lifestyle interventions
effectiveness of exercise interventions. for the prevention and management of hypertension.
In this regard, a meta-analysis concluded that interven-
tions to reduce body weight, including energy-restrictive
resting conditions89, the beneficial effects of this and diets, induced greater reductions in both SBP (5 mmHg)
other myokines (such as IL-6) on BP might be specific and DBP (4 mmHg) than those including exercise
to the exercise milieu. interventions alone (2 mmHg)17. However, the oppo-
Evidence from a meta-analysis suggests that reg- site trend was observed, at least for DBP, when results
Resistance arteries ular exercise, even without major body weight reduc- were standardized for the amount of body weight lost17.
Small-diameter blood vessels in tions, decreases leptin levels90. Similarly, an acute bout More evidence is needed on the strength of the effect of
the microcirculation with thick of intense exercise reduces the circulating levels of body weight loss on BP reduction. A Cochrane review
muscular walls and narrow
pro-inflammatory adipokines linked to insulin resist- and meta-analysis of eight studies involving a total of
lumen (usually arterioles and
end point arteries) that ance and obesity, such as omentin and resistin (with the 2,100 participants with high BP found significant and
contribute the most to the reduction below baseline levels lasting up to 48–72 h moderate-quality evidence for the body weight reduc-
resistance to blood flow. after exertion)91. Therefore, regular exercise could pro- tion effects of hypocaloric dietary interventions com-
vide benefits in individuals with hypertension, as in pared with no dietary intervention (mean difference of
Nitric oxide
(NO). A volatile gas produced
those with other chronic diseases92, through the cumula- −4.0 kg)102. Nevertheless, the evidence for a BP reduction
by endothelial cells that acts tive effects of acute increases in myokines and decreases in the participants assigned to body weight-reducing
to relax vascular tone. in pro-inflammatory adipokines during and after each diets, although significant compared with controls (SBP
bout of exercise93,94. However, more research is needed 4.5 mmHg and DBP 3.2 mmHg), was of low quality.
Oxidative stress
in this area. The authors concluded that body weight-reducing diets
A process of cellular damage
related to uncontrolled action reduce body weight and BP in people with primary
of reactive oxygen species, a Autonomic function. The autonomic nervous system hypertension but the magnitude of the effects is uncer-
group of molecules, including modulates BP by increasing SNS or parasympathetic tain because of the small number of participants and
oxygen and its derivatives, nervous system (vagal) activity, with the former trigger- studies included in the analyses. As for exercise interven-
produced by the normal
process of aerobic metabolism.
ing systemic vasoconstriction. Patients with hyperten- tions, controversy exists on the long-term sustainability
sion tend to present with chronic SNS activation95, and of body weight reduction strategies (Box 4).
Chronic systemic the impaired function of carotid baroreceptors has been
inflammation suggested to contribute to this neurogenic component Mechanisms
Usually referred to as simply
of hypertension96. Evidence supports a role of exercise Adiposity. A high BMI, particularly if associated with
‘inflammation’. A state of
low-grade, non-infective training in counteracting autonomic dysfunction, specif- excessive visceral fat103, has been identified as a major
(‘sterile’) inflammation at ically in increasing vagal tone and decreasing SNS tone97. risk factor for hypertension35,104, and the role of adiposity
the systemic level that is Exercise training improves arterial baroreflex control in the pathophysiology of hypertension is described ear-
characterized by activation and therefore reduces BP in healthy individuals98 and lier in this Review. Beyond its obvious effects in reduc-
of immune components that
are often distinct from those
in patients with hypertension99. The benefits of exercise ing adiposity, the beneficial effects of intentional body
engaged during an acute could result from both mechanical (reduced vascular weight reduction on hypertension can be mediated, at
immune response and that stiffness and consequent increased barosensory vessel least partly, by additional mechanisms, as discussed in
can lead to major alterations distensibility) and neural (adaptations in the afferent– the sections below.
in all cells, tissues and organs.
efferent baroreflex control of cardiac vagal outflow)
This state is reflected by high
baseline levels of specific mechanisms related to baroreflex control53. Insulin resistance. A strong correlation exists between
biomarkers such as insulin resistance (as determined by homeostatic model
high-sensitive C-reactive Body weight management assessment of insulin resistance (HOMA-IR)) and most
protein. Overweight and obesity are associated with an increased indicators of adiposity and obesity (total fat, visceral fat
Myokines
risk of hypertension. A meta-analysis of prospective mass, BMI and waist circumference), with the strongest
From the Greek myo (muscle) studies including a total of 173,828 participants found association for visceral fat mass105. Furthermore, mod-
and kinos (movement). that the risk ratios (RR) of incident hypertension were erate body weight reductions (average 9%) are accom-
Molecules (mostly, but not 1.52 (95% CI 1.37–1.67) and 2.17 (95% CI 1.84–2.50) panied by remarkable decreases in both HOMAR-IR
only, small peptides such
for individuals with overweight or obesity, respectively, (26%) and SBP and DBP (7 mmHg and 6 mmHg,
as cytokines) released from
muscles, usually during compared with individuals with normal body weight. respectively)106. In patients with obesity and diabetes, a
exercise. A reduction in body weight to normal in individuals 10% reduction in BMI attenuates insulin resistance and
with overweight or obesity has indeed been reported adipokine dysregulation (for example, with reductions
Baroreceptors to reduce the risk of incident hypertension by 24–40% in the circulating levels of leptin and resistin)107. Long-
Mechanical receptors that
sense blood pressure changes
and 40–54%, respectively100. Similarly, a meta-analysis term (33-week) body weight reduction altered cytokine
in both carotid sinuses and the of 25 RCTs concluded that for each 1 kg of body weight gene expression in peripheral immune blood cells of
aortic arch. lost, both SBP and DBP were reduced by approximately individuals with obesity (for example, reductions in IL6
Reviews
Arterial baroreflex and IL1B mRNA levels) that correlated with improve- reduce obesity-associated oxidative stress, typically
Also known as the baroreceptor ments in insulin sensitivity, although BP changes were assessed through determination of lipid oxidation prod-
reflex. A rapid negative not recorded68. The effects of body weight reduction ucts (such as 8-isoprostane)115. Whether the potential
feedback loop in which on glucose homeostasis are associated with changes in beneficial effects of body weight reduction on oxidative
elevated blood pressure is
sensed by baroreceptors, with
the expression of many (80–100) genes in macrophages stress translate into a healthier BP profile also needs
their subsequent activation and adipocytes108. The changes induced by body weight further investigation.
leading to rapid increases in reduction in the expression of genes associated with
parasympathetic outflow and improved insulin sensitivity also involve downregulation Pro-inflammatory adipokines. The involvement of obe-
decreases in sympathetic
of genes related to NF-κB activation109. sity and adipose tissue-released adipokines in systemic
outflow and therefore to
restoration of blood pressure
inflammation is well documented116. In older individ-
levels. Renin–angiotensin–aldosterone system. Body weight uals with obesity, higher adiposity is associated with
reduction, even of moderate magnitude (<10%) can higher blood levels of inflammatory markers such as
Peripheral chemoreceptors reduce both RAAS activity and BP in individuals with CRP117. A meta‐analysis has suggested a positive corre-
Located in the carotid and
aortic bodies. Sensory
obesity110. Notably, moderate body weight mass reduc- lation between circulating leptin and inflammatory bio-
extensions of the peripheral tions (5%) can have an inhibitory effect on several markers (CRP, IL-6 and TNF)118. Obesity also results in
nervous system into blood RAAS components, such as reduced levels of plasma dysfunction of the perivascular adipose tissue (PVAT),
vessels that detect changes in angiotensinogen (27%) and adipose tissue-derived angio which in lean individuals has beneficial vasodilatory and
chemical homeostasis
tensinogen (20%), renin (43%) and aldosterone (31%) anti-inflammatory functions116. Indeed, in obesity, the
(hypoxaemia, hypercapnia and
acidosis), which increases their
and reduced ACE activity (12%), that in turn is coupled PVAT has an increased production of adipokines (IL-6,
firing with a subsequent with decreases in SBP (7 mmHg)111. In addition, reduc- leptin, resistin and TNF) and chemokines that orches-
increase in ventilation and tions in waist circumference significantly correlate trate inflammatory cell infiltration (mainly T cells) into
sympathetic nervous system with reductions in plasma levels of angiotensinogen111. PVAT and result in eNOS dysfunction119.
outflow.
Reductions in plasma levels of angiotensinogen, Ang II, Body weight reduction improves the inflamma-
Obstructive sleep apnoea renin and the vasoconstrictor molecule endothelin 1 tory profile in individuals with obesity through a
(OSA). A sleep-related have been reported 6 months after bariatric surgery decrease in pro-inflammatory factors and an increase
breathing disorder inducing an average reduction in BMI from 52.1 kg/m2 in anti-inflammatory molecules in subcutaneous adi-
characterized by repeated
to 40.4 kg/m2, although changes in adiposity or RAAS pose tissue120. Therefore, even modest body weight
episodes of complete or partial
upper-airway occlusion (and
components did not correlate with BP reductions112. reductions (average 1.1 kg per month) in adults with
subsequent arterial overweight or obesity can reduce the plasma levels of
hypoxaemia) during sleep. Vascular function and oxidative status. Meta-analytical inflammatory molecules (mainly CRP, IL-6 and TNF)121.
evidence suggests that obesity is associated with poorer In women with obesity, decreases in circulating CRP
arterial endothelial function (as assessed by flow- levels induced by a rapid body weight reduction inter-
mediated dilatation of the brachial artery)113, whereas vention (4–6 weeks) are proportional to the magnitude
body weight reduction has the opposite effect, with of the body weight reduction122. The beneficial effects of
each 10-kg decrease in body weight being associated on body weight reduction on inflammation seem to be
average with a 1.1% increase in fasting flow-mediated maintained in the long term: substantial body weight
dilatation 114. However, whether improvements in loss (average 15%) over 1 year inhibited the expres-
endothelial function induced by body weight reduction sion of genes related to vascular inflammation123, and
translate into reductions in BP, as well as the potential in people with morbid obesity, surgically induced body
mechanisms, remain to be elucidated. The overall evi- weight reduction was associated with marked decreases
dence indicates that intentional body weight loss can in renal and systemic inflammation as well as in SBP
and DBP 1 year after surgery124. In addition, preclinical
evidence shows that body weight reduction can reverse
Box 2 | Can exercise without weight loss lower blood pressure? obesity-induced PVAT damage through a mechanism
A classic study showed a decrease in blood pressure (6.4 mmHg in systolic blood pressure involving reduced inflammation and increased eNOS
(SBP), 5.2 mmHg in diastolic blood pressure (DBP)) after an exercise intervention in men activity within the PVAT125.
with or without hypertension even without changes in body weight405. However, a
reduction in body weight led to a greater reduction in blood pressure even with no Autonomic function. Increased activity of the SNS has
exercise (8.8 kg reduction in body weight: 9.2 mmHg reduction in SBP, 6.2 mmHg an important role in the development of obesity-related
reduction in DBP)405. Other investigators have reported marked reductions in SBP and hypertension126, with pharmacological α-/β-adrenergic
DBP (4.4 mmHg and 4.3 mmHg, respectively) in individuals with hypertension after an receptor blockade resulting in a greater reduction in SBP
exercise intervention despite only a small reduction in body weight (1.8 kg)406. In turn,
in patients with hypertension who are obese than in those
if exercise was combined with a body weight management programme and a dietary
intervention that resulted in much greater body weight reductions (7.8 kg), the intervention
who are lean127. Causative mechanisms of SNS overac-
induced greater reductions in SBP and DBP (7.4 mmHg and 5.6 mmHg, respectively)406. tivation in obesity, especially central obesity, include
A meta-analysis found similar reductions in SBP and DBP (approximately 5 mmHg and abnormal adipokine secretion from adipose tissue (such
3 mmHg, respectively) with endurance exercise across different body weight reductions as the role of leptin in stimulating the brain melano-
(≥1.5 kg reductions, or −1.5 kg to +0.2 kg), with SBP and DBP significantly reduced cortin system, as explained above), stimulation via the
(by approximately 3 mmHg and 2 mmHg, respectively) even in those trials investigating RAAS (with an existing reciprocal SNS–RAAS activa-
exercise interventions in which body weight actually increased (by >0.2 kg)407. Therefore, tion)128, insulin resistance129, baroreceptor dysfunction130
the beneficial effects of exercise on blood pressure seem to occur independently of body and sustained activation of peripheral chemoreceptors131.
weight reduction but the magnitude of the blood pressure reduction might increase, at Regarding the activation of peripheral chemoreceptors,
least slightly, when both factors are combined.
obesity frequently coexists with obstructive sleep apnoea

Reviews
Box 3 | Hypertensive response to acute exercise salt restriction and cardiovascular benefits and therefore
reinforcing salt reduction as a public health preventive
Although long-term physical exercise interventions are associated with blood pressure measure against CVD15. However, further evidence on
reductions, blood pressure normally rises acutely during exercise as a result of increases the effects of strict salt restriction in individuals without
in cardiac output in response to the higher demands for oxygen from working muscles.
hypertension is warranted145. Furthermore, the effects of
This response is usually physiological and is not associated with adverse events. However,
salt intake on BP must be considered together with the
some individuals have an exaggerated increase in systolic blood pressure during exercise,
a condition known as a hypertensive response to exercise (HRE; usually defined as an concomitant water load (Box 5).
increase in systolic blood pressure during exercise of ≥60 mmHg in men and ≥50 mmHg in The ACC/AHA guidelines also recommend increas-
women, or a systolic blood pressure of >210 mmHg in men and >190 mmHg in women)408. ing potassium intake4. Potassium is an essential nutrient
In individuals with normal blood pressure, a HRE might be a prognostic marker of the that is required for the maintenance of total body fluid
future development of hypertension and a greater incidence of cardiovascular disease408. volume, acid and electrolyte balance, and normal cell
Importantly, lifestyle interventions, including a healthy diet and regular exercise, have function. In pre-industrial era diets, potassium intake
been reported to reduce the HRE13,409. was very high, often exceeding 200 mmol per day146.
However, in westernized societies, potassium intake
(OSA), the most common condition associated with is markedly lower. Food processing reduces the potas-
resistant hypertension, which is indeed observed in sium content of food, and a diet high in processed foods
30−40% of all patients with hypertension132. OSA leads and low in fresh fruits and vegetables is often lacking
to chronic intermittent hypoxia and sustained activation in potassium146. Global data suggest that the average
of carotid body chemoreceptors that reflexively upregu- potassium consumption in many countries is clearly
late SNS activity133. Body weight reduction per se (with below the values recommended by the European Union
or without a concomitant exercise intervention) has (90 mmol per day)147 and WHO (≥90 mmol per day)148
proven sympathoinhibitory benefits in individuals with and in the USA (60–90 mmol per day)149. This obser-
obesity134–136, which in turn are associated with improve- vation is concerning, especially when considering the
ments in baroreflex sensitivity and BP136, with the oppo- role of potassium in BP regulation, which has been
site effects (increased parasympathetic and decreased demonstrated in multiple studies. A meta-analysis of
SNS activity) observed with body weight increase137. 15 RCTs involving a total of 917 patients showed that
However, some of the hypotensive effects of body weight potassium supplementation (particularly with intakes
reduction in individuals with severe obesity might be of 75–125 mmol per day) is associated with a decrease
independent of the accompanying changes in the SNS135. in BP in individuals who are not receiving antihy-
pertensive medication, especially in patients with
Healthy dietary patterns hypertension (mean 6.8 mmHg decrease in SBP and
Sodium and potassium intake 4.6 mmHg decrease in DBP) 150. A meta-regression
Sodium restriction has been the most popular recom- analysis showed that both increased daily potassium
mendation for the dietary prevention of hypertension excretion and decreased sodium-to-potassium ratio are
and for BP reduction in general, and current dietary associated with BP reduction150. These results overall
guidelines recommend reducing sodium (or salt) confirm those of a previous meta-analysis reporting
intake4,5. A 2020 meta-analysis showed that the magni- high-quality evidence that increased potassium intake
tude of the BP decrease achieved with sodium reduction reduces BP in patients with hypertension and has no
follows a dose–response relationship, being greater in adverse effect on blood lipid concentrations, catecho-
older populations, non-white populations and those with lamine concentrations or renal function151. Similarly, a
higher BP138. A meta-regression analysis of 133 RCTs study showed that the population-wide (2,376 partici-
found strong evidence for a linear dose–response rela- pants from six different villages in Peru) implementation
tionship between sodium restriction and BP (7.7 mmHg of a salt-substitution programme (replacing regular salt
decrease in SBP and 3.0 mmHg decrease in DBP per with potassium-enriched substitutes (75% NaCl and
100 mmol sodium restriction)139. However, the rela- 25% KCl)) resulted in an average 1.3 mmHg decrease
tionship was weaker in the groups with mean SBP/DBP in SBP and 0.8 mmHg decrease in DBP in individuals
≤131/78 mmHg, possibly because dramatically reducing with or without hypertension (albeit of greater mag-
sodium intake leads to compensatory increases in circu- nitude in those with hypertension)152. Moreover, salt
lating aldosterone, renin and noradrenaline levels, with substitution reduced the incidence of hypertension by
the magnitude of this effect being more pronounced in 51% in participants without hypertension at baseline
individuals with SBP <140 mmHg140. Moreover, differ- compared with a control group, which occurred along
ent meta-analyses have suggested that the association with increased urine levels of potassium but with no
between sodium intake and mortality might follow a differences in urine sodium levels. However, the evi-
U-shaped or J-shaped curve141,142, which would be in dence from RCTs does not allow the identification of a
accordance with the observation that the plasma levels precise optimal level of potassium intake for maximum
of renin and aldosterone increase exponentially when health benefits. Nevertheless, if a person consumes
sodium is restricted to <100 mmol per day140. However, both ≥90 mmol per day of potassium and the WHO-
these conclusions have been questioned because of recommended sodium intake (<90 mmol per day)153, their
methodological limitations (such as the use of unreli- diet would have a molar ratio of sodium to potassium of
able methods for the assessment of sodium intake and approximately one-to-one, which is considered benefi-
confounding effects of comorbidities)15,143,144, providing cial for health, particularly for individuals with sodium
support for a linear dose–response relationship between sensitivity147.
Reviews
Mediterranean diet Diets diet significantly decreased SBP (3.2 mmHg) and DBP
A diet abundant in fruits, A number of dietary approaches have gained popularity (2.5 mmHg) in adults with or without hypertension14.
vegetables, legumes, whole owing to their purported beneficial effects not only on Moreover, a long-term analysis of the ENCORE study
grains, olives, nuts and seeds, body weight, but also on overall cardiovascular health showed that some beneficial effects of the 4-month
and containing extra-virgin olive
oil associated with frequent
and hypertension in particular. Of note, the interven- DASH diet intervention on SBP were still present at
consumption of fish, moderate tions described below have been typically compared 12 months (9.5 mmHg versus 3.9 mmHg decrease
consumption of dairy products with isocaloric control diets. compared with baseline for the DASH diet and usual
and red wine, and low diet, respectively), although no significant differences
consumption of red meat and
DASH diet. The first multicentre clinical trial of the between the groups were observed for DBP158.
isolated sugars.
DASH diet154, published in 1997, showed that this diet
can be effective in the prevention and management of Mediterranean diet. Several studies have found that
hypertension. Subsequent evidence provided further consuming foods typical of the Mediterranean diet
support for the benefits of this diet. In the PREMIER might reduce the risk of hypertension, whereas food
trial155, the DASH diet induced significant reductions in not typical of this dietary pattern, such as red meat,
BP after 6 months in non-medicated individuals with processed meat and poultry, has an unfavourable effect
above-optimal BP levels compared with an interven- (reviewed previously159). A prospective study including
tion consisting only of advice about lifestyle factors that 9,408 Spanish individuals without hypertension con-
affect BP (body weight reduction, sodium reduction, cluded that a high adherence to a Mediterranean diet
increased physical activity and limited alcohol intake). did not reduce the risk of incident hypertension, but
Of note, however, the DASH diet did not provide addi- was associated with decreases in mean SBP (3.1 mmHg)
tional beneficial effects on BP compared with a third, and DBP (1.9 mmHg) from baseline to 6 years of
behavioural 6-month intervention consisting of estab- follow-up compared with individuals with low adher-
lished lifestyle recommendations (body weight reduc- ence to the diet160. In the PREDIMED RCT161 including
tion, sodium restriction, increased physical activity and 7,447 Spanish men and women (aged 55–80 years, >80%
limited alcohol intake) but with no control or advice on with hypertension), a Mediterranean diet that involved
the intake of fruits, vegetables or fat155. In the ENCORE increasing the consumption of either extra-v irgin
trial156, the DASH diet alone induced significant reduc- olive oil or nuts led to decreases in SBP (5.9 mmHg
tions in BP compared with usual diet in individuals with and 7.1 mmHg, respectively) and DBP (1.6 mmHg and
pre-hypertension or stage 1 hypertension (11.2 mmHg 2.6 mmHg, respectively) at 3 months compared with a
versus 3.4 mmHg for SBP, and 7.5 mmHg versus low-fat control diet. After a follow-up of 4 years, SBP
3.8 mmHg for DBP). had not changed in either group, whereas DBP had
The evidence accumulated over the years indi- decreased substantially and moderately in the extra-
cates that the DASH diet is one of the most effective virgin olive oil group (15 mmHg) and the mixed nuts
approaches for the management of hypertension, group (0.7 mmHg), respectively162. An RCT in Australian
especially if combined with calorie restriction 157. individuals aged >64 years showed that those who con-
A meta-analysis of 30 RCTs found that the DASH sumed a Mediterranean diet had a small but significant
decrease in SBP and an improved endothelial function
Box 4 | Sustainability of weight reduction strategies after either 3 or 6 months compared with individuals
who maintained their habitual diet163. Similarly, a trial
Less than 20% of individuals who achieve a 10% reduction in body weight maintain that found that individuals aged >64 years who had adhered
weight loss for more than 1 year410. A network meta-analysis found that different diets to a Mediterranean diet for 1 year showed a significant
resulted in significant reductions in body weight at 6 months (4.6 kg, 4.4 kg and 3.1 kg
decrease in SBP (5.5 mmHg) but not in DBP compared
for low-carbohydrate and low-fat diets and moderate intake of all macronutrients,
respectively) together with significant decreases in systolic blood pressure (5.1 mmHg,
with a control group that received standardized die-
5.1 mmHg and 3.5 mmHg, respectively) and diastolic blood pressure (3.2 mmHg, 2.9 mmHg tary advice164. However, the effect was significant only
and 1.9 mmHg, respectively)166. However, the effects on weight loss (−3.2 kg, −3.3 kg and in male participants in separate analyses. Although the
−1.9 kg), systolic blood pressure (−1.3 mmHg, 0.3 mmHg and −0.5 mmHg) and diastolic Mediterranean diet has a potentially favourable effect
blood pressure (−0.8 mmHg, −0.2 mmHg and −0.1 mmHg) were reduced at 12 months in reducing BP in healthy people and in patients with
with all diets. Evidence for the long-term sustainability of physical exercise interventions hypertension, data are lacking to determine how strong
for promoting body weight reduction is also unclear. Body weight management this effect is, and more studies are required159.
programmes, including both exercise and diet, are more effective in reducing body
weight mass in the short-to-medium term (3–6 months, mean difference −5.3 kg) and long Vegan diets. These diets are increasing in popularity
term (12–18 months, mean difference −6.3 kg) than exercise interventions alone411.
and have beneficial effects on glycaemia and blood lipid
Moreover, although combined interventions seem similarly effective to diet alone for
reducing body weight in the short-to-medium term (3–6 months, mean difference
profiles. Although the evidence on BP is less conclusive,
−0.6 kg), diet-only interventions seemed to be more effective in the long term (mean preliminary evidence suggests that vegan diets could also
difference −1.7 kg)411. A meta-analysis of studies in individuals with obesity who had lost have a beneficial effect in reducing high SBP. A meta-
>5% of body weight concluded that lifestyle interventions focusing on both exercise and analysis including 983 individuals showed that a vegan
diet result in significant, albeit small, beneficial effects on body weight after 12 months diet without calorie restrictions did not significantly
(−1.6 kg)412. However, no evidence for efficacy was found when considering diet-only or change SBP (1.3 mmHg decrease) or DBP (1.2 mmHg
physical activity-only interventions412. The evidence on the actual long-term sustainability decrease) compared with less-restrictive diets (such
of lifestyle interventions aimed at promoting body weight reduction is therefore unclear, as lacto-ovo-vegetarian diets or omnivorous diets)165.
although combining energy-restrictive diets and physical exercise interventions seems to However, a subgroup analysis of studies including par-
maximize the likelihood of maintaining body weight reduction.
ticipants with a baseline SBP of ≥130 mmHg showed that

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Box 5 | Salt intake effects on blood pressure depend on concomitant water intake low-s odium, Nordic, Tibetan, and control) involv-
ing 17,230 participants (including individuals with
The association between salt intake and blood pressure has been known for at least pre-hypertension or hypertension)168. The network
a century, and low-salt diets were one of the first lifestyle interventions to prevent meta-analysis showed that the DASH, Mediterranean,
hypertension. Although the traditional thought is that the amount of salt is a critical
low-c arbohydrate, Palaeolithic, high-protein, low-
factor driving acute blood pressure responses, the proposed mechanisms by which salt
glycaemic index, low-sodium, and low-fat diets were
intake influences blood pressure have been evolving and, indeed, acute blood pressure
responses to salt intake can be prevented by concomitant water loading413. Therefore, significantly more effective in reducing SBP (−8.7 to
the capacity of salt intake to acutely increase blood pressure depends on the changes −2.3 mmHg) and DBP (−4.9 to −1.3 mmHg) than the
in plasma osmolality more than on the amount of salt intake per se. control diet. The DASH diet was ranked the most effec-
Although the mechanisms involved in blood pressure elevation induced by salt- tive dietary approach for reducing SBP and DBP, followed
associated hyperosmolarity remain to be fully elucidated, they include: activation of by the Palaeolithic, low-carbohydrate and Mediterranean
osmosensitive neurons located in the subfornical organ, which sense osmotic changes diets168. Overall, the DASH diet seems to be the most
in the plasma and stimulate the activity of the sympathetic nervous system414; activation of effective dietary approach to manage BP in patients with
T cells by osmolarity-mediated pathways, which might have a role in the development pre-hypertension or hypertension.
of T cell-mediated autoimmune inflammation in the kidney and arterial walls415; increased
vasopressin release and vasopressin V2 receptor activation416; and stimulation of the
Dietary compounds
secretion of endogenous cardiotonic steroids (such as ouabain and marinobufagenin)417
and the aldose reductase–fructokinase pathway in the hypothalamus, which might Food groups. Current dietary guidelines for the preven-
mediate blood pressure responses418. tion of hypertension recommend high intake of specific
food groups such as whole grains, fresh fruits, vegetables,
nuts and legumes, and low intake of red and processed
vegan diets significantly reduced both SBP (4.1 mmHg) meats and sugar-sweetened beverages (SSBs)4,5. The
and DBP (4.0 mmHg) in these individuals165. overall available evidence supports these recommenda-
tions. A meta-analysis to assess the relationship between
Diet comparisons the risk of hypertension and the intake of 12 major food
Numerous dietary approaches have a lowering effect groups (whole grains, refined grains, vegetables, fruits,
on SBP and DBP compared with a control intervention. nuts, legumes, eggs, dairy products, fish, red meat, pro-
A network meta-analysis concluded that both low-fat cessed meat and SSBs) showed an inverse association for
(such as the Ornish diet) and low-carbohydrate (such 30 g of whole grains per day, 100 g of fruit per day, 28 g of
as the Atkins, South Beach or Zone diets) diets and nuts per day and 200 g of dairy products per day169. By
to a lesser extent those consisting of a moderate intake of contrast, a positive association with the risk of hyper-
all macronutrients (such as the DASH or Mediterranean tension was observed for 100 g of red meat per day, 50 g
diets) decrease SBP (5.1, 5.1 and 3.5 mmHg, respec- of processed meat per day and 250 ml of SSB per day.
tively) and DBP (3.2, 2.9 and 1.9 mmHg, respectively) However, the quality of the evidence was very low or
in the medium term (6 months) compared with a con- low. A meta-analysis with a more focused approach of
trol intervention, although the effects attenuate in the selecting a few food items and including 351,819 indi-
long term (12 months)166. When separately analysing viduals (5,000 with hypertension) showed that red meat
each individual diet, the Palaeolithic and Atkins diets (both processed and unprocessed) and poultry con-
were the most effective in decreasing SBP (14.6 mmHg sumption were associated with a higher risk of hyper-
with the Palaeolithic diet) and DBP (3.3 mmHg with tension, whereas egg consumption was associated with
the Atkins diet), although other popular diets such a lower risk170. A meta-analysis of eight RCTs found
as the DASH diet were also among the most effective no differences in the effects on BP of consuming more
(4.7 mmHg decrease in SBP and 2.8 mmHg decrease than four whole eggs per week or four or fewer whole
in DBP)166. eggs per week171. A meta-analysis of 14 RCTs including
A systematic review and meta-analysis of studies 980 participants found that isocaloric substitution of a
including a total of 23,858 individuals of the effects of high-carbohydrate diet for a diet high in monounsatu-
dietary pattern interventions (low-sodium, low-sodium– rated fatty acids (both in the context of low saturated
high-potassium, low-sodium–low-calorie, low-calorie, fatty acids) did not affect BP levels in individuals with
low-c arbohydrate, Palaeolithic, high-protein, low- or without hypertension172.
glycaemic index, and low-fat) on BP showed that the An increased sugar intake, particularly when main-
dietary interventions led to overall pooled decreases of tained for >8 weeks, has been reported to increase BP173.
3.1 mmHg in SBP and 1.8 mmHg in DBP167. The DASH A high fructose intake might lead to increased sodium
diet had the greatest effects, with a 7.6 mmHg decrease absorption, as well as activation of renal sympathetic
in SBP and 4.2 mmHg decrease in DBP. Low-sodium, nerve activity and the RAAS174. However, whether an
low-sodium–high-potassium, low-sodium–low-calorie, association exists between fructose (or raw fruit or fruit
and low-calorie diets also led to significant reductions juice175) intake and the risk of hypertension is so far
in SBP and DBP. By contrast, the Mediterranean diet unclear176,177. Evidence from a meta-analysis supports
was associated with a significant reduction in DBP but an association between SSB consumption and hyper-
not in SBP167. Another systematic review and network tension, with each additional serving of SSB per day
meta-analysis included 67 trials comparing 13 dietary increasing the risk of hypertension by 8%178, and with
approaches (DASH, low-fat, moderate-carbohydrate, reductions in SSB consumption associated with a lower
high- p rotein, low- c arbohydrate, Mediterranean, BP in the long term (1.8 mmHg for SBP and 1.1 mmHg
Palaeolithic, vegetarian, low-glycaemic index or load, for DBP per daily serving)179. The consumption of
Reviews
artificially sweetened beverages has also been linked carbohydrate-rich foods such as vegetables, fruits and
to an increased risk of hypertension (9% increase per whole grains) can improve insulin sensitivity194,195, albeit
additional serving per day)178. with no significant beneficial effects on BP195. However,
in an animal model of hypertension associated with
Alcohol. Strong evidence supports the detrimental metabolic syndrome, pharmacological reduction of
effects of excessive alcohol intake on BP. A meta-analysis 24-h BP levels was associated with a decrease in the
of longitudinal studies including a total of 361,254 par- circulating levels of AGEs196.
ticipants concluded that alcohol intake beyond two
drinks per day (12 g of pure ethanol per drink) was Renin–angiotensin–aldosterone system. Extreme reduc-
consistently associated with an increased incidence of tions in sodium intake have been shown to activate the
hypertension in both men and women, although for RAAS (by increasing renin and Ang II levels) in short-
lower intakes the results were significant only for men180. term studies15. This observation has been used as a
However, even low alcohol intakes (around one drink counter-argument to salt reduction recommendations
per day) are associated with a higher prevalence of CVD for the prevention and treatment of hypertension15.
(including hypertension) and death, as supported by a However, patients with hypertension seem to have
combined analysis of 83 prospective studies including a more sudden decrease in BP after acute reduction
599,912 current drinkers181. in salt intake than individuals with normal BP levels,
Both the ACC/AHA4 and the ESC/ESH5 guidelines which is, at least partly, attributable to a less responsive
recommend reducing alcohol intake for the man- RAAS197. Conversely, a meta-analysis has suggested that
agement of hypertension. A meta-analysis including a modest reduction in salt intake for ≥4 weeks causes
36 trials and 2,865 participants concluded that alcohol significant and clinically important reductions in BP in
intake reduction was not associated with BP reductions individuals with or without hypertension, irrespective
in individuals with moderate alcohol consumption (two of sex and ethnic group, with a concomitant, small (or
or fewer drinks per day) but resulted in a significant BP ‘physiological’) increase in plasma renin activity and
reduction in those who consumed larger quantities aldosterone and noradrenaline levels198. This observa-
(1.2 mmHg decrease in SBP and 1.1 mmHg decrease in tion is in line with the finding that combining moderate
DBP in those who consumed three drinks per day, and salt restriction and RAAS blockers seems to work better
5.5 mmHg and 4.0 mmHg, respectively, in those who than either strategy alone199. Notably, the DASH diet
consumed more than six drinks per day)182. Therefore, seems to have a priming effect on pathways affected by
reducing alcohol intake might be an effective strategy the RAAS (resulting in a natriuretic and diuretic effect)
for the management of hypertension in individuals who and results in a greater physiological response when
consume more than two drinks per day. combined with ACE inhibitors200. Chronic high alcohol
intake induces increases in plasma renin concentration
Mechanisms and BP201. Moderate alcohol intake also stimulates renin
Adiposity. Westernized dietary patterns are charac- release202, but repeated RAAS activation is not likely to
terized by hyperpalatable processed foods with a high mediate the pressor effect of regular moderate alcohol
content of fat, sugar, salt and flavour additives that consumption202.
increase energy intake183, thereby contributing to obesity,
which, as previously discussed, can lead to hypertension. Potassium. The effects of sodium intake on BP should
be considered together with those of potassium. A low
Insulin resistance. Among the possible environmen- intake of dietary potassium (such as in westernized
tal causes of insulin resistance is the chronic adoption diets) reduces extracellular potassium content, which
of westernized diets with a high energy content, as hyperpolarizes the plasma membrane and, at the kid-
shown in short-term overfeeding studies in healthy ney level, causes a reduction in intracellular chloride in
individuals184,185. Despite the high energy content of the distal convoluted tubule. Low intracellular chloride
westernized diets, these diets are high in ultra-processed concentration in turn activates the renal sodium chlo-
foods and can be deficient in several micronutrients, ride cotransporter (NCC), via WNK serine/threonine
such as magnesium186. Meta-analytical evidence supports protein kinases, with subsequent extracellular retention
an inverse association between magnesium intake and of sodium and an increase in BP, even in the setting of
metabolic syndrome187, and a beneficial effect of mag- high salt intake203,204. Conversely, high potassium intake
nesium supplementation on glucose homeostasis188,189. (such as from diets rich in fruits, vegetables, tubers and
Magnesium supplementation also reduces BP190, includ- legumes, such as the DASH and Mediterranean diets)
ing in patients with type 2 diabetes and independent suppresses the NCC, resulting in a positive sodium bal-
of body weight status191. For instance, at a median dose of ance owing to pronounced natriuresis, with subsequent
368 mg per day for a median duration of 3 months, mag- benefits for BP control203.
nesium supplementation can reduce SBP by 2.0 mmHg
and DBP by 1.8 mmHg190. Owing to their usual high con- Vascular function and oxidative status. High dietary
Advanced glycation tent in processed foods or animal-derived foods high salt intake can impair vascular endothelial function205,206,
end-products in fat and protein and cooked at high temperature and although this effect can occur independent of changes
(AGEs). Proteins or lipids that
become non-enzymatically
low humidity, western diets can be a substantial source in BP206,207. A potential mechanism for sodium-induced
glycated as a result of exposure of advanced glycation end-products (AGEs)192. AGEs can VED is oxidative stress in the microvasculature207. A diet
to sugars. impair insulin sensitivity193. Diets low in AGEs (typically rich in AGEs208 and hypercaloric meals rich in trans-fatty

Reviews
acids and/or certain saturated fatty acids can trigger or those providing adequate amounts of micronutrients,
endothelial dysfunction209. Conversely, dietary AGE such as zinc232, magnesium233 and potassium. Potassium
restriction might attenuate oxidative stress210, and some supplementation could counteract the pro-inflammatory
dietary interventions can improve endothelial function effects of sodium on T cells that are mediated through
through NO-related mechanisms. Indeed, the ingestion activation of the p38–MAPK–SGK1 pathway235.
of foods rich in inorganic nitrite and/or nitrate, such as
spinach, beetroot and other plants, improve endothelial Autonomic function. Alcohol intake diminishes barore-
function and reduce arterial stiffness and BP, because flex sensitivity239,240, and is associated with a higher SNS
nitrites and nitrates can potentially be converted to tone241.
NO211. Dietary nitrate is sequentially reduced to NO
through an enterosalivary nitrate–nitrite–NO path- Gut microbiota. The gut microbiota has essential func-
way that involves the oral microbiota212. The use of an tions that are conserved from worms to humans, includ-
Polyphenols antibacterial mouth rinse reduces the saliva and plasma ing regulation of nutrition, protection from pathogens
A main class of plant secondary concentrations of nitrate and nitrite, with a concomitant and production of metabolites. Metabolites from the
metabolite, existing in a wide
variety of foods, typically
increase in BP213. gut microbiota also signal to distant organs, contrib-
divided into flavonoids and Certain dietary components, most of which are char- uting to the maintenance of host physiology242. In this
non-flavonoid polyphenols. acteristic of the Mediterranean diet, can also improve context, alterations (dysbiosis) of the gut microbiota
endothelial function, such as magnesium214, fish-derived are associated with a higher risk of inflammation and
Anthocyanins
omega-3 fatty acids215, olive oil216 (with extra-virgin oil CVD. A meta-analysis showed an association between
A type of flavonoid with
antioxidant and colouring being associated with many of the cardiovascular bene- the gut microbiota-derived metabolite trimethylamine
effects that give certain plants fits of the Mediterranean diet217 and olive oil polyphenols N-oxide (TMAO) — which has been shown to be a
that are rich in these with improvements in both VED and BP218), cocoa biomarker for CVD events and death — and the risk of
compounds (blueberry, flavanols219, anthocyanins (mainly berries, red grapes and hypertension243. Preclinical evidence suggests an asso-
raspberry, red and black grapes
and black soybean, among
red wine, with concomitant beneficial effects on VED ciation between higher salt intake and gut microbiota
many others) a red, blue, purple and BP)220, flavan-3-ols (also with beneficial effects on dysbiosis244,245. Probiotics can reduce BP in patients with
or black colour. VED and BP)221 and nuts222. type 2 diabetes246, as well as in healthy individuals and
Alcohol consumption might promote the release of patients with hypercholesterolaemia, hypertension,
Flavan-3-ols
endogenous vasoconstrictor substances such as Ang II, obesity or metabolic syndrome, albeit with a modest
Sometimes referred to as
‘flavanols’, not to be confused endothelin 1 and endothelin 2 (refs202,223,224), which can effect247.
with flavonols. Derivatives of increase oxidative stress and cause VED224. Preclinical
flavans that include catechin, evidence indicates that chronic alcohol ingestion Xenobiotics. With a high prevalence of fast-food
epicatechin gallate, induces VED by promoting inflammation and reducing meals, westernized diets can increase exposure to
epigallocatechin,
epigallocatechin gallate,
the levels of NO, eNOS and vascular VEGFA, thereby xenobiotics such as bisphenol A248. Bisphenol A expo-
proanthocyanidins, theaflavins hindering vasorelaxation225. sure is associated with an increase in BP and a higher
and thearubigins. risk of hypertension249–252 in observational studies,
Inflammation. High-glycaemic foods (containing added independent of race, ethnicity, smoking status, BMI
Gut microbiota
sugars and/or refined grains) can cause inflammation or diabetes252. Furthermore, one RCT showed that a
The collective microorganisms
(bacteria, archaea, fungi and through increases in NF-κB activation in blood mononu- high exposure to bisphenol A (through consumption
viruses) that reside in the clear cells226. Diets high in saturated fatty acids227, meals of beverages in cans instead of glass bottles) increased
gastrointestinal tract. rich in trans-fatty acids228 and dietary AGEs (through SBP by ~4.5 mmHg253. If combined with a high-fat
the activation of the receptor for AGEs expressed on intake, bisphenol A can induce hypertension in pre-
Probiotics
Live microorganisms with
various cells including leukocytes) can also have a pro- clinical models through decreased NO bioavailability,
purported health benefits when inflammatory effect229. However, more evidence based increased oxidative stress and activation of the aryl
consumed, mainly as a result of on high-quality RCTs is needed before recommend- hydrocarbon receptor signalling pathway254 (a nuclear
improving or restoring the gut ing dietary AGE restriction for the alleviation of the receptor with a primary function in mediating xenobi-
microbiota.
pro-inflammatory milieu210. otic metabolism through transcriptional activation of
Xenobiotics Westernized diets are usually high in sodium, which drug-metabolizing enzymes). Other mechanisms for
Chemical substances found can alter the composition of the gut microbiota and is the association between bisphenol A exposure and risk
within an organism that are not associated with a pro-inflammatory phenotype in CD4+ of hypertension include endocrinal disturbance, inflam-
naturally produced or expected T cells and macrophages230. The pro-inflammatory mation and epigenetic changes255 and Ang II–calcium/
to be present within the
organism.
effects of sodium are especially marked in the context calmodulin-dependent protein kinase IIα-mediated
of resistant hypertension, in which sodium accumula- uncoupling of eNOS256. Finally, bisphenol A exposure
Bisphenol A tion together with a dysfunctional endothelial glycocalix affects autonomic function (as reflected by a decreased
A ubiquitous plasticizing agent causes microcirculation impairment, characterized by heart rate variability), but this effect does not seem to be
used in the manufacture of
macrophage infiltration and vascular inflammation231. linked to increases in BP250.
polycarbonate plastics and
epoxy resins, found in food and Westernized diets also tend to be low in nutrients and
beverage cans as well as in bioactive compounds involved in the regulation and res- Circadian entrainment and sleep
thermal receipt paper. Owing olution of inflammation, such as zinc232, magnesium233,234, Circadian entrainment
to a structural similarity to potassium235 or omega-3 fatty acids236. Most bodily functions and responses, including BP,
oestrogen, bisphenol affects
various phenotypes that are
Some dietary interventions have been reported to vary over the course of a day257. Rhythmicity of biolog-
regulated by the natural inhibit or decrease inflammation, such as those high in ical activities is a crucial factor for survival, and the cir-
hormone oestrogen. fruits and vegetables237, with a reduced glycaemic load238, cadian rhythm is the most influential. In humans and
Reviews
other mammals, the circadian rhythm is controlled by summer results in a higher average 24-h BP and also
the central biological clock in the suprachiasmatic nucleus extends the exposure to elevated SNS activity and to
(SCN) of the hypothalamus and by peripheral clocks waking physical and psychosocial stressors. The effects
located in various cells throughout the body. The SCN of seasonally shortened sleep on BP were brief for our
evolved to synchronize activity, rest and energy intake to ancestors. However, today, short sleep durations and
the circadian and circannual cycles using the autonomic sleep disruptions are common throughout the year.
nervous system. To entrain autonomic rhythms to the For instance, >57% of participants in a 2013 study
external environment, the SCN requires repeated cues reported getting less sleep than needed on workdays276.
from light exposure, sleep, activity and nutrient intake, Indeed, humans are now chronically exposed to many
at certain times. potential sleep disruptors, including shift work, multi-
Circadian rhythmicity is especially relevant to the ple jobs, 24-h access to shopping, Internet, television,
cardiovascular system. Therefore, BP, cardiac output smart phones and travel across time zones, which can
and heart rate have a marked circadian pattern, and the compete with sleep time and interrupt sleep schedules.
dysregulation of this circadian pattern, especially for Moreover, exposure to artificial light (especially in the
BP, is associated with increased risk of CVD257. In this blue spectrum) at night disturbs sleep quality and leads
context, 24-h ambulatory BP monitoring provides clin- to irregular sleep schedules277. These alterations in sleep
ically useful information and is a stronger prognostic patterns can contribute to sleep-maintenance insomnia
factor for CVD and mortality than clinic BP258–261. The and disrupt circadian rhythmicity and autonomic bal-
influence of circadian entrainment on hypertension risk ance. Even if individuals with insomnia can achieve
is particularly relevant in light of the clinical importance adequate sleep durations by compensating for noc-
of night-time ambulatory BP, which has been identified turnal awakenings by sleeping during the day, chronic
as a better predictor of adverse events than daytime insomnia has been found to be associated with a higher
ambulatory BP262, and from which different risk levels night-time SBP and blunted day-to-night decreases
can be identified. In patients with a good control of BP, a in SBP278.
drop in BP of >10% is usually observed from daytime to Other sleep-related variables can also negatively
night-time (known as the ‘dipping pattern’)263. However, affect BP. Evidence from longitudinal and cross-sectional
other BP patterns such as ‘extreme dipping’ (drop in BP studies in young and middle-aged individuals of various
from daytime to night-time of >25%), ‘non-dipping’ ethnicities suggest an association between sleep dura-
Suprachiasmatic nucleus (<10%) and ‘riser’ (increase in BP from daytime to tion and hypertension and/or higher BP. A meta-analysis
(SCN). A small region of the night-time) are all characterized by an increased risk including 1,074,207 individuals found that both short
brain in the hypothalamus, of CVD264,265. Therefore, an elevation in night-time BP (≤5 h) and long (≥9 h) sleep durations were associ-
situated directly above the regardless of the pattern, which can be exacerbated by ated with increased BP levels279. A significant asso-
optic chiasm, that is
responsible for controlling
an impaired circadian rhythm, along with an increased ciation between short sleep duration and the risk of
circadian rhythms. 24-h BP would be associated with a higher risk of CVD hypertension was found in a large meta-analysis with
morbidity and death266. 5,172,710 adults280 and in another including adoles-
Sleep quality Disruption (misalignment) of the circadian rhythm cents only281. Sleep quality is another important aspect
The self-reported, retrospective
(inverting behavioural and environmental cycles) is a that can be associated with the risk of hypertension.
appraisal of the sleep
experience. A good sleep common feature in individuals engaged in shift work. A meta-analysis suggests that self-assessed poor sleep
quality typically means falling Evidence from a meta-analysis supports an association quality is associated with a greater likelihood of hyper-
asleep in ≤30 min and sleeping between shift work, particularly rotational shifts, and tension (OR 1.48, 95% CI 1.13–1.95)282. Variations in
soundly through the night (one the risk of hypertension267. A non-dipper pattern can be sleep architecture, such as decreased percentage of time
or no awakenings and drifting
back to sleep within 20 min of
observed from the first night shift, which recovers after in slow-wave sleep and low non-rapid eye movement sleep
waking up). 4 days of continuous shift work268. Circadian misalign- have also been shown to increase the risk of hypertension
ment for 3 days can increase 24-h BP owing to a rise in in older men283 and middle-aged women284.
Sleep-maintenance insomnia night-time BP (5.6 mmHg for SBP and 1.9 mmHg for The influence of sleep on hypertension risk is par-
A condition characterized by
DBP)269. Exercise and eating schedules can also affect ticularly relevant given the clinical importance of the
difficulty staying asleep,
nocturnal awakenings and, in circadian entrainment. Therefore, aligning meals night-time ambulatory BP as a predictor of adverse
particular, waking too early and with circadian rhythms by restricting eating to early events262. In this regard, the presence of OSA or insom-
struggling to get back to sleep. hours results in lower BP levels, along with other cardio nia and a low number of sleeping hours in patients
metabolic benefits such as improved insulin sensitivity, with hypertension can negatively affect the control of
Slow-wave sleep
The phase of sleep that is
lipid profile and redox status, in individuals with night-t ime BP and, consequently, increase the risk
considered to be restorative metabolic syndrome or pre-diabetes270–272. of CVD285–287.
and is associated with the The observed association between sleep dura-
highest arousal threshold. Sleep tion and hypertension has raised the hypothesis that
The total daily sleep duration in the first humans was interventions aimed at extending sleep duration and
Low non-rapid eye
movement sleep likely to have been >8 h during most of the year273. improving sleep quality could be effective measures
The phase of sleep associated Those individuals living away from the equator were for the prevention of hypertension274. Adequate treat-
with better performance and exposed seasonally to shortened (in winter) and ment of OSA and the use of sleeping pills can improve
learning as well as with lengthened (in summer) photoperiods that induced the control of night-time ambulatory BP288. A RCT in
decreased sympathetic nervous
system activity and increased
shorter sleep durations in summer and longer sleep patients with pre-hypertension or stage 1 hyperten-
parasympathetic nervous durations in winter274. BP decreases by an average of sion and with habitual sleep durations of ≤7 h showed
system activity during the night. 10–20% during sleep275, meaning that less sleep in the that a 6-week sleep extension intervention (resulting

Reviews
in average sleep extensions of 35 min) significantly insulin resistance independently of loss of total sleeping
decreased beat-t o-b eat SBP (14 mmHg) and DBP hours304.
(8 mmHg) averaged across a 24-h recording period com-
pared with maintenance of habitual sleep duration289. Renin–angiotensin–aldosterone system. The RAAS is
However, a more recent RCT in individuals with mild closely related to sleep regulation, with an increase in
sleep impairment did not find a beneficial effect of activity during slow-wave sleep305. However, whether
a sleep intervention on BP despite finding a beneficial circadian alterations or sleep deprivation can medi-
effect on sleep quality290. Improvements in sleep could ate potential increases in BP through a RAAS-related
positively influence other common hypertension-related mechanism remains to be elucidated. Nevertheless, OSA
markers. Indeed, sleep deprivation is positively associ- might cause hypertension, at least in part, by stimulat-
ated with the incidence of obesity, which is a risk factor ing RAAS activity306. Mechanistically, this effect might
for hypertension291, and with deregulated fasting leptin involve the intermittent hypoxia caused by upper air-
levels and increased hunger292. Accordingly, adequate way collapse. Preclinical evidence shows that recurrent
sleep might help with adherence to dietary interventions hypoxia increases BP in part through increases in renal
and body weight reductions292 and might also help to sympathetic nerve activity that increase RAAS activity
achieve the necessary energy to engage in regular physi by upregulation of Ang II receptors307,308 and activates the
cal activity274. Shift work and the attendant changes in RAAS in the carotid bodies309. In turn, continuous posi-
the sleep timing and circadian reversal is a risk factor tive airway pressure therapy to treat OSA downregulates
for hypertension267, particularly when coupled with RAAS components and reduces BP310.
short sleep duration293. Therefore, the promotion of
adequate sleep should be coupled with circadian syn Vascular function and oxidative status. Even short-term
chronization, such as maintaining regular sleep–wake (5 days) partial sleep deprivation (<5 h) is sufficient
times, adhering to time-restricted eating patterns, to impair endothelial function, but with no apparent
promoting the exposure to bright light during the day changes in BP311. However, OSA is associated with an
and minimizing exposure to bright light in the evening. increased risk of VED312 and arterial stiffness313, which
is caused by oxidative stress and systemic inflamma-
Mechanisms tion (resulting in reduced NO availability)314, increased
Adiposity. Shift work is associated with altered eating levels of adhesion molecules315 and leukocyte-derived
patterns across the 24-h period (above the usual three microparticles316, and disorders of coagulation and lipid
meals every 24 h) including at night294,295. Circadian metabolism315.
disruption or sleep deprivation can also impair the
homeostatic control of food intake. For instance, par- Inflammation. Shift work is associated with systemic
tial sleep deprivation increases ghrelin levels and sub- inflammation (reflected by increased levels of hsCRP)
jective appetite296,297. A meta-analysis of RCTs suggests and with higher SBP and DBP317. Circadian misalign-
that sleep restriction (to a total sleep time of 3.5–5.5 h) ment (independently of sleep loss) increases inflamma-
increases subjective hunger, calorie intake (average tion, as determined by circulating levels of hsCRP304 or
increase of 253 kcal per day) and body weight gain (albeit CRP317. This pro-inflammatory pattern can be accompa-
with modest average increases of 0.34 kg)298. However, nied by an increase in SBP and DBP317. A meta-analysis
whether these changes are associated with concomitant suggested that sleep disturbance and longer sleep dura-
increases in BP is unknown. In addition, although long tion (>8 h), but not sleep restriction or deprivation, are
sleep duration (>9 h) is associated with a higher risk of associated with inflammation (higher circulating levels
obesity in adults299,300, evidence to date does not support of CRP and IL-6)318.
an association with incident hypertension300.
Autonomic function. Partial sleep deprivation causes a
Insulin resistance. Partial sleep deprivation can mod- significant increase in SNS activity, but does not neces-
erately decrease insulin sensitivity298, but whether this sarily translate into higher SBP and DBP, at least in the
concurrently affects BP remains to be determined. short term (within days)311. However, total sleep dep-
One potential mechanism is the generation of an rivation has rapid effects on BP, with increases in both
insulin-resistant state in peripheral adipocytes, reflected SNS activity and BP observed within only 24 h (ref.319)
by an impairment in the capacity of insulin to trigger an or 40 h (ref.320) of continuous non-sleep. These effects
increase in the levels of phosphorylated AKT, a crucial are mediated by a stress-induced resetting of arterial
step in the insulin signalling pathway301. Restructuring of baroreceptors towards higher BP levels and a decrease
the morning-to-evening transcriptome profile in white in baroreflex sensitivity319.
adipose tissue can also be involved, with uncoupling
from the local clock machinery and a resulting increase Stress management
in carbohydrate turnover and impairment in glucose A growing number of people in western countries are
homeostasis302. The adverse effects of sleep depriva- experiencing increased anxiety, depression and chronic
Psychosocial stress tion seem to be reversible, with two nights of recovery psychosocial stress (herein mostly referred to as ‘stress’
Also frequently referred to as sleep (approximately 10 h per night) after four nights for simplicity) brought about by globalization, cultural
‘mental stress’. The feeling of
being overwhelmed or unable
of sleep restriction restoring insulin sensitivity to base- and socioeconomic changes, and stress in the work
to cope as a result of pressures line levels303. The circadian misalignment that occurs in place321,322. Strong evidence indicates that stress and/or
that are unmanageable. individuals engaged in shift work might also increase anxiety can transiently increase BP, being a prominent
Reviews
component of white-c oat syndrome 323. Robust evi- Mechanisms

dence also links the exposure to intensely traumatic Adiposity. In the past four decades, the prevalence of
life events with an increased risk of hypertension. For stress has increased in parallel with that of obesity in
instance, an increased prevalence of hypertension has industrialized societies334. Indeed, the presence of psy-
been reported in a large cohort of US veterans with chosocial stress has been associated with an increased
post-t raumatic stress disorder (PTSD) who had been adiposity335, especially abdominal adiposity334. Obesity
deployed in Afghanistan or Iraq324. An increased risk is itself a stress situation336 that can undermine self-
of incident hypertension during a 22-year follow-up regulatory cognitive processes such as executive
was also observed among civilian women with PTSD325. functioning337, and interfere with the brain areas respon-
Similarly, PTSD was the main predictor of incident sible for self-regulation338. Stress can affect behaviour by
hypertension in a 2.4-year follow-up study in US vet- inducing over-eating and consumption of high-calorie
erans, whereas treatment for PTSD (with individual foods339–341. In addition, a stress-induced, prolonged acti-
psychotherapy sessions or prescription of selective ser- vation of the hypothalamic–pituitary–adrenal (HPA)
otonin reuptake inhibitors) significantly reduced the risk axis might promote abdominal fat accumulation medi-
of hypertension326. ated by increases in cortisol secretion334. Greater stress is
Whether chronic exposure to psychosocial stress usually linked to lower physical activity342 and disrupts
can lead to an increased risk of hypertension is more sleep343. In turn, shorter sleep duration is associated
controversial327. A meta-analysis showed that psy- with an increased subjective hunger and body weight298,
chosocial stress is associated with an increased risk of and poorer sleep quality is linked to a higher risk of
hypertension (OR 2.40, 95% CI 1.65–3.49) and that obesity344. The evidence on the effects of stress manage-
patients with hypertension have a higher incidence of ment on body weight reduction is promising345,346 but
psychosocial stress than individuals without hyperten- scarce, and whether it translates into clinical benefits for
sion (OR 2.69, 95% CI 2.32–3.11)321. However, because BP management remains to be determined.
of the heterogeneity between studies (particularly in the
definition of stressors), more evidence (based on addi- Insulin resistance. Stress-induced chronic glucocor-
tional case–control and cohort studies) is needed to con- ticoid exposure owing to the prolonged activation of
firm that chronic psychosocial stress is a risk factor for the HPA axis can provoke insulin resistance through
hypertension. specific activation of glucocorticoid receptors in the
Controversy also exists as to the effectiveness of hypothalamic arcuate nucleus, which stimulates neuro
stress management techniques for the prevention and peptide Y (NPY) release347. In turn, increased NPY
treatment of hypertension327. A meta-analysis includ- release from sympathetic nerves upregulates the produc-
ing 17 RCTs found no consistent benefits of different tion of NPY and its receptors in the abdominal fat in a
stress-reduction techniques, such as biofeedback or glucocorticoid-dependent manner, leading to fat accu-
relaxation, on BP in patients with hypertension328. mulation and a metabolic syndrome-like condition with
Another meta-analysis found decreases in both SBP reduced insulin sensitivity347,348. Glucocorticoids reduce
(5.5 mmHg) and DBP (3.5 mmHg) with relaxation insulin-mediated glucose uptake at the muscle tissue
techniques in patients with hypertension, although level via stimulation of serine kinases349,350, resulting in
the effects were not significant when the studies that phosphorylation and inactivation of the insulin receptor
included a sham therapy were analysed separately329. and insulin receptor substrate molecules349. In patients
Some investigators argue that the 2017 ACC/AHA with coronary heart disease, a 16-week transcendental
hypertension guidelines should have included medita- meditation intervention improved insulin resistance as
tion in the list of effective non-pharmacological interven- well as BP levels, and the beneficial effects on the former
tions for the prevention and treatment of hypertension330. were independent of potential confounders such as BMI,
A 2019 meta-analysis including 851 adults with hyper- diabetes at baseline or physical activity351.
tension or CVD found no significant effects of transcen-
dental meditation on SBP or DBP compared with their Renin–angiotensin–aldosterone system. Acute stress
White-coat syndrome
Also known as ‘white-coat peers doing no transcendal meditation, but significant stimulates the RAAS through SNS activation, but the
hypertension’. A phenomenon within-group (BP change from baseline) reductions in evidence for chronic stress is not so clear. Nevertheless,
in which people exhibit a blood SBP and DBP were observed in the transcendental medi- data indicate that chronic stress increases plasma renin
pressure above the normal tation group331. A RCT not included in this meta-analysis activity in humans (such as in people living alone)352 and
range in a clinical setting but
not in other settings (at home
showed a significant effect of mindfulness meditation rats (such as after forced immobilization)353.
or with 24-h ambulatory on lowering clinically measured SBP, 24-h SBP, at-rest
assessments). SBP and DBP in individuals with high-normal BP or Vascular function and oxidative status. Recurrent
stage 1 hypertension compared with a control interven- mental stress in mice (such as tail suspension) impairs
Post-traumatic stress
tion involving health education talks332. The benefits endothelial function, with markedly reduced aor-
disorder
(PTSD). A mental health seem to be greater if meditation or mental relaxation tic mRNA levels of Nos3 (which encodes eNOS) and
condition triggered by a are combined with breathing techniques in yoga ses- increases in vascular oxidative stress, mediated by heart
terrifying event, either sions (average 11 mmHg decrease in SBP and 6 mmHg rate increases and reverted by adrenergic blockade354.
experiencing it or witnessing it, decrease in DBP)333. Further evidence is needed to draw In patients with major depressive disorder, exposure
with symptoms including
flashbacks, nightmares, severe
strong conclusions on the benefits of stress management to everyday psychosocial stressors is associated with
anxiety or uncontrollable techniques, including meditation, in the prevention or greater impairment of endothelial function (as assessed
thoughts about the event. management of hypertension. by acetylcholine-induced dilatation in cutaneous

Reviews
microvessels)355. However, more evidence of the ben- Dietary fibre. An increased intake of dietary fibre
eficial effects of stress management interventions on could be one of the mechanisms underlying the ben-
BP management is needed. The BP-reducing effects of eficial effects on hypertension of fruit and vegetable
a 16-week transcendental meditation programme in consumption. A meta-analysis of 21 RCTs including
patients with coronary heart disease were not accom- 1,343 participants showed that viscous soluble fibre
panied by improvements in endothelial function supplementation (β-glucan from oats and barley, guar
(as assessed by flow-mediated dilatation)351. gum, konjac, pectin and psyllium) at a median dose of
8.7 g per day for ≥4 weeks reduced SBP (1.6 mmHg) and
Inflammation. Acute stress increases the production DBP (0.4 mmHg) over a median follow-up of 7 weeks366.
of pro-inflammatory molecules (IL-1β, IL-6, IL-10 and Therefore, inclusion of viscous soluble fibre in habitual
TNF)356, and several forms of chronic stress (such as diets might be beneficial.
job stress or poverty) are associated with chronic sys-
temic low-grade inflammation (as shown by increases in Polyphenols. In the past decade, dietary polyphenols
hsCRP or CRP)357,358. Mindfulness-based interventions have been under the spotlight because of evidence
have shown modest but significant effects in reducing of their association with positive health outcomes in
the levels of biomarkers of low-grade inflammation numerous studies and their wide availability in a variety
(hsCRP, IL-6, NF-κB and TNF)359. The potential link of commonly consumed foods. Among the most studied
between reduced inflammation and the beneficial effects polyphenols are flavonoids. A meta-analysis of 15 cross-
on BP remains to be determined. sectional studies and seven prospective cohorts, com-
prising 200,256 individuals (45,732 with hypertension),
Autonomic function. Stress in adulthood can lead to found no significant association between extreme quan-
pathophysiological changes including increased SNS tiles of flavonoid intake and the risk of hypertension (RR
activity with subsequent increases in BP322. In this 0.96, 95% CI 0.89–1.03)367. Although dietary intake of
context, a single session of mindfulness meditation anthocyanins (a flavonoid subclass) was associated with a
can acutely decrease SNS activity and SBP and DBP in significant, albeit modest, reduction in the risk of hyper-
patients with hypertension and chronic kidney disease360. tension when comparing highest versus lowest exposure
These findings are consistent with the benefits of regular (RR 0.92, 95% CI 0.88–0.97)367. Another meta-analysis
meditation (up to 16 weeks) for improving autonomic of RCTs found significant effects of quercetin (a dietary
balance (as assessed with heart rate variability)351 and BP flavonol) in reducing SBP and DBP at doses of ≥500 mg
in patients with pre-hypertension or hypertension361,362 per day368. Evidence suggests that certain polyphenol-
or with coronary heart disease351, and even for decreas- containing herbs and spices, notably ginger, can reduce
ing mortality (over a mean follow-up of 7.6 years) in BP in patients with pre-hypertension or hypertension369.
patients aged ≥55 years with hypertension363. A meta-analysis of six RCTs including 345 participants
suggested that ginger supplementation reduces SBP
Unproven lifestyle interventions (6.4 mmHg) and DBP (2.1 mmHg)370. Nevertheless, in
Dietary acid load This section summarizes lifestyle interventions that are separate subgroup analyses, SBP and DBP were signifi-
The balance of net acid-yielding
increasingly gaining attention but for which conclusive cantly reduced only in the subset of studies that included
food items (meats, fish,
shellfish, eggs, cheese, cereal evidence of efficacy for BP management is lacking. participants with a mean age of ≤50 years, with a follow-up
grains and salt) and net of ≤8 weeks and with ginger doses of ≥3 g per day.
base-producing food items Dietary components Further evidence supporting the BP-lowering effects
(fruits, tubers, roots and Dietary acid load. When the dietary acid load is positive, of polyphenols comes from studies on beetroot. This
vegetables).
excess acids must be excreted by the kidney to main- root vegetable has been postulated as a complementary
Flavonoids tain the acid–base balance146. Therefore, in the setting treatment for hypertension because of its high content
A type of polyphenol whose of chronic kidney disease, a high dietary acid load of inorganic nitrate, which has vasodilatory effects371.
subclasses (for example, invokes adaptive mechanisms to increase acid excretion A systematic review and meta-analysis of 22 RCTs found
flavanols, flavonones and
despite a reduced number of nephrons, such as increased lower SBP (3.6 mmHg) and DBP (1.3 mmHg) in groups
isoflavones) are present mostly
in fruits, certain vegetables, ammoniagenesis per nephron and augmented distal receiving beetroot juice supplementation than in con-
seeds (such as flax), soy, whole acid excretion mediated by the RAAS and endothelin 1, trol groups371. However, the benefits were independent of
grains, honey, tea, coffee, which might induce renal injury. In this context, a high nitrate content and, according to the investigators, other
cocoa, some alcoholic acid load might increase the risk of hypertension. Meta- bioactive compounds in beetroot, such as polyphenols,
beverages (such as wine) and a
few spices.
analytical evidence suggests a dose–response association might explain the observed BP-lowering effects.
between acid load (as determined by potential renal acid The flavan-3-ols found in cocoa, particularly epi-
Quercetin load), the risk of hypertension364 and the risk of higher catechin, might increase the formation of endothelial
The most abundant dietary values of both SBP and DBP364,365. Therefore, consuming NO, promoting vasodilatation and consequently BP
flavonol, mainly found in
a net base-yielding diet could be expected to decrease reduction372. Indeed, the high intake of flavanol-rich
onions, apples and berries.
BP, especially when characterized by a reduction in salt cocoa in the non-westernized Kuna Indians has been
Ginger intake and an increase in the consumption of fruits, suggested as one of the underlying causes of their low
A flowering plant whose tubers, roots and vegetables, because it will also lead to prevalence of high BP373. A Cochrane review including
rhizome is frequently used as a an increase in magnesium content and a decrease in the 35 trials concluded that cocoa consumption resulted in
spice, containing several
bioactive compounds (such as
sodium-to-potassium ratio. More evidence is needed a small but significant reduction in SBP (1.8 mmHg) and
gingerols) with the potential to on the potential BP-lowering effects of reducing dietary DBP (1.8 mmHg), with stronger effects in patients with
affect human health. acid load. hypertension (SBP 4 mmHg, DBP 2.0 mmHg)374.
Reviews
Flaxseed Flaxseed. The potential BP-lowering effects of flaxseed between the use of multivitamin supplements and the
A seed from the flax plant with are probably related to its content of α-linolenic acid (an risk of incident hypertension383. Regarding the effect of
moderate-to-high contents of omega-3 fatty acid), fibre and lignans. A meta-analysis specific vitamin supplements, a meta-analysis of 29 RCTs
α-linolenic acid (an omega-3 of 15 RCTs including 1,302 participants indicated that concluded that vitamin C supplementation reduces BP,
fatty acid), lignans (a group of
polyphenols), and soluble and
supplementation with flaxseed products significantly with the benefit remaining significant when analysing
insoluble fibre. reduced SBP (2.9 mmHg) and DBP (2.4 mmHg) 375. Of only patients with hypertension384. Greater controversy
note, supplementation with flaxseed powder signifi- exists about the efficacy of vitamin D supplementation
cantly reduced SBP but supplementation with oil prepa- on BP, with meta-analytical evidence showing no or
rations or lignan extract did not, and supplementation inconsistent benefits385,386.
with flaxseed powder and oil preparations significantly
reduced DBP, but supplementation with lignan extract Smoking cessation
did not. Cigarette smoking increases the risk of CVD through
several mechanisms, including oxidative stress, impair-
Coffee and tea. Given that caffeine is widely consumed ment of endothelial function, arterial stiffness and
in coffee and other items, defining the possible BP inflammation, among others387. Cigarette smoking also
effects associated with caffeine intake is important. has an acute hypertensive effect, principally through
Coffee consumption is associated with an acute (~3 h) SNS stimulation388. The ESC/ESH guidelines5, but not
increase in BP in both healthy individuals and patients the ACC/AHA guidelines4, recommend smoking ces-
with hypertension. For this reason, coffee consumption sation to prevent and manage hypertension. However,
has traditionally been believed to increase the risk of no clear evidence exists for a direct causal relationship
hypertension, but this notion does not seem to be sup- between cigarette smoking and the risk of hyperten-
ported by scientific evidence. A meta-analysis (including sion. A Mendelian randomization meta-analysis with
196,256 participants, 41,184 with hypertension) found 141,317 participants from 23 population-based studies
that habitual drinking of one or two cups of coffee per found no strong association between smoking and SBP
day was not associated with an increased risk of hyper- and DBP levels or the risk of hypertension389. Further
tension compared with non-drinking376. Indeed, a small research is warranted, because physiological mechanisms
but significant protective effect of coffee consumption suggest that cigarette smoking can increase BP. Indeed,
was found starting from the consumption of three several meta-analyses have confirmed the deleterious
cups of coffee per day (RR 0.97, 95% CI 0.94–0.99)376. effects of smoking on overall cardiovascular health390.
A meta-analysis suggested that black or green tea can
significantly reduce SBP and DBP in individuals with Conclusions
pre-hypertension or hypertension377. Green tea has also The lifestyle changes brought by the westernized way
been shown to reduce SBP and DBP in individuals with of life (including, among others, a high prevalence of
overweight or obesity378. physical inactivity, unhealthy dietary patterns, disrupted
circadian rhythms and high levels of psychosocial stress)
Vitamins. A poor vitamin status has been suggested to contribute to increasing the risk of hypertension. This
increase the risk of hypertension. A prospective study contribution is important because hypertension remains
including 20,926 participants concluded that those with a major cause of premature death worldwide despite
the highest plasma vitamin C concentrations at base- considerable advances in pharmacological treatments.
line had a 22% lower risk of high BP than those with As summarized in this Review, growing evidence sup-
vitamin C levels in the bottom quartiles379. This finding ports the role of lifestyle interventions (mainly regular
might be related to the role of vitamin C in the synthesis physical exercise and nutritional interventions, but
and bioavailability of NO380. A meta-analysis of 35 stud- also other less traditional approaches such as promo-
ies including 108,173 participants concluded that high tion of adequate sleep patterns coupled with circadian
plasma 25-hydroxyvitamin D concentrations are asso- entrainment) for the prevention and adjuvant treatment
ciated with a reduced risk of hypertension381. A meta- of hypertension. These strategies act over a variety of
analysis of 12 RCTs concluded that multivitamin and physiological mechanisms at the multisystem level and
multimineral supplementation has a lowering effect on have beneficial effects on BP and overall cardiovascular
BP (SBP 1.3 mmHg, DBP 0.7 mmHg), with the effect health. An optimal lifestyle should be the first-line strat-
on SBP being much larger in patients with hypertension egy to prevent hypertension and an established adjuvant
(8.0 mmHg)382. However, the low number of partici- treatment in patients with hypertension.
pants analysed precluded strong conclusions from being
drawn. Indeed, a prospective study found no association Published online xx xx xxxx
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REvIEWS

Lifestyle interventions for the prevention

Nature Reviews | Cardiology

Key points is not well controlled5. In turn, the benefits of an optimal

Body weight management RAAS

Vascular function and oxidative status ROS

Nature Reviews | Cardiology

Table 1 | lifestyle recommendations from major hypertension guidelines

(also known as strength exercise) or a combina- Exercise intensity

Minimum physical activity

Nature Reviews | Cardiology

Non-westernized populations Westernized populations

Myokines and adipokines. Working muscles act as

a te si opposed to that released from other sources in a non-​

exercise milieu — exerts anti-​inflammatory effects

antagonist and IL-10), while decreasing the circulating

Exercise-​i nduced myokines might also reduce BP

Blood pressure through more direct mechanisms not necessarily

management linked to anti-​inflammatory effects. In particular, iri-

VED mediated by the AMP-​activated protein kinase

(AMPK)–AKT–endothelial NO synthase (eNOS)–NO

pathway) and stimulate vasorelaxation in hypertensive

rats83. Muscle-​released irisin might also prevent the ele-

al t h t er n vation of BP induced by SNS outflow via activation of

R ATP-​sensitive potassium channels in smooth muscle84.

Nature Reviews | Cardiology

Nature Reviews | Cardiology

Nature Reviews | Cardiology

Nature Reviews | Cardiology

Nature Reviews | Cardiology

component of white-​c oat syndrome 323. Robust evi- Mechanisms

Nature Reviews | Cardiology

Nature Reviews | Cardiology

Nature Reviews | Cardiology

Nature Reviews | Cardiology

Nature Reviews | Cardiology

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a te si opposed to that released from other sources in a non-

exercise milieu — exerts anti-inflammatory effects

Exercise-i nduced myokines might also reduce BP

management linked to anti-inflammatory effects. In particular, iri-

VED mediated by the AMP-activated protein kinase

rats83. Muscle-released irisin might also prevent the ele-

R ATP-sensitive potassium channels in smooth muscle84.

component of white-c oat syndrome 323. Robust evi- Mechanisms