SEX Differences

European Heart Journal (2022) 00, 1–12 SPECIAL ARTICLE
https://doi.org/10.1093/eurheartj/ehac470 Hypertension
Sex differences in arterial hypertension

A scientific statement from the ESC Council on Hypertension, the
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European Association of Preventive Cardiology, Association of
Cardiovascular Nursing and Allied Professions, the ESC Council for
Cardiology Practice, and the ESC Working Group on Cardiovascular
Pharmacotherapy
Eva Gerdts 1*, Isabella Sudano 2, Sofie Brouwers 3,4, Claudio Borghi 5,
Rosa Maria Bruno 6,7, Claudio Ceconi 8, Véronique Cornelissen 9,
François Diévart 10, Marc Ferrini 11, Thomas Kahan 12, Maja-Lisa Løchen 13
,
Angela H. E. M. Maas 14, Felix Mahfoud 15, Anastasia S. Mihailidou 16,17,
Trine Moholdt 18, Gianfranco Parati 19,20, and Giovanni de Simone 21
1
Center for Research on Cardiac Disease in Women, University of Bergen, Bergen, Norway; 2University Hospital Zurich University Heart Center, Cardiology, University Hospital and
University of Zurich, Zurich, Switzerland; 3Department of Cardiology, Cardiovascular Center Aalst, OLV Clinic Aalst, Aalst, Belgium; 4Department of Experimental Pharmacology, Faculty of
Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium; 5Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; 6Université de Paris Cité, Inserm,
PARCC, Paris, France; 7Service de Pharamcologie, AP-HP, Hôpital Européen Georges Pompidou, Paris, France; 8University of Cardiologia, ASST Garda, Desenzano del Garda, Italy;
9
Department of Rehabilitation Sciences, KU Leuven, Leuven, Belgium; 10Clinique Villette, Dunkerque, France; 11Department of Cardiology and Vascular Pathology, CH Saint Joseph and
Saint Luc, Lyon, France; 12Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital, Division of Cardiovascular Medicine, Stockholm, Sweden; 13Department of Community
Medicine, UiT The Arctic University of Norway, Tromsø, Norway; 14Department of Cardiology, Radboudumc, Nijmegen, The Netherlands; 15Department of Internal Medicine III,
Cardiology, Angiology and Intensive Care Medicine, Saarland University Hospital, Homburg/Saar, Germany; 16Department of Cardiology and Kolling Institute, Royal North Shore Hospital,
St Leonards, UK; 17Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia; 18Department of Circulation and Medical Imaging, Norwegian University of Science and
Technology, Trondheim, Norway; 19Department of Cardiac, Neural and Metabolic Sciences, Instituto Auxologico Italiano, IRCCS, Milan, Italy; 20Department of Medicine and Surgery,
University of Milano-Bicocca, Milan, Italy; and 21Hypertension Research Center and Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
Received 29 March 2022; revised 17 July 2022; accepted 11 August 2022
* Corresponding author. Tel: +4792086505, Email: [email protected]

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.
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2 E. Gerdts et al.
Graphical Abstract

Sex differences in hypertension. BP, blood pressure; CV, cardiovascular; T2D, type 2 diabetes; OSAS, obstructive sleep apnoea syndrome; LVH, left
ventricular hypertrophy; LV, left ventricular; LA left atrial; HFpEF, heart failure with preserved ejection fraction; BB, beta blocker; CCB, calcium chan-
nel blocker; HFrEF, heart failure with reduced ejection fraction.
Abstract
There is strong evidence that sex chromosomes and sex hormones influence blood pressure (BP) regulation, distribution of cardiovascular (CV)
risk factors and co-morbidities differentially in females and males with essential arterial hypertension. The risk for CV disease increases at a lower
BP level in females than in males, suggesting that sex-specific thresholds for diagnosis of hypertension may be reasonable. However, due to pau-
city of data, in particularly from specifically designed clinical trials, it is not yet known whether hypertension should be differently managed in
females and males, including treatment goals and choice and dosages of antihypertensive drugs. Accordingly, this consensus document was con-
ceived to provide a comprehensive overview of current knowledge on sex differences in essential hypertension including BP development over
the life course, development of hypertension, pathophysiologic mechanisms regulating BP, interaction of BP with CV risk factors and co-morbid-
ities, hypertension-mediated organ damage in the heart and the arteries, impact on incident CV disease, and differences in the effect of antihy-
pertensive treatment. The consensus document also highlights areas where focused research is needed to advance sex-specific prevention and
management of hypertension.
.............................................................................................................................................................................................
Keywords Hypertension • Sex • Blood Pressure regulators • Hypertension-mediated organ damage • Pharmacological treatment •
Adverse events • Cardiovascular disease • Sex hormones
publications have documented important sex differences in hyperten-

Introduction sion related to main BP regulators, co-morbidities, CV complications
Arterial hypertension, in particular elevated systolic blood pressure and adverse effects of antihypertensive drugs.6–8 However, there is
(BP), remains a major cause of reduced quality of life, cardiovascular paucity in reports of sex-specific effects from clinical trials in hyperten-
(CV) morbidity and mortality and all-cause mortality in the world.1,2 sion. Recent data indicate that risk for CV complications starts at lower
Both BP development and BP regulation are influenced by biological ef- BP levels in females than in males, questioning current practice of using
fects of sex chromosomes, sex hormones and reproductive events.3 In the same BP threshold for identification of hypertension in both
addition, the sex difference in hypertension prevalence has been related sexes.9,10 The scope of this collaborative document is to give a compre-
to ethnicity, co-morbidities, socio-economic status, education and en- hensive overview of current knowledge on sex differences in essential
vironmental pollution in middle-aged and older adults.4,5 Previous arterial hypertension, associated organ damage and CV disease (CVD)
Sex differences in arterial hypertension 3
and hypertension management (Graphical Abstract), as well as identify- demonstrated.17 An accelerated increase in systolic BP is observed in
ing knowledge gaps hindering the development of sex and gender in- about 35%, particularly in females with early menopause and vasomotor
formed hypertension management. symptoms,17 and in women with clustering of CV risk factors.18 In
population-based cohort studies from Italy and the Czech Republic, BP
increase during menopause transition was explained by weight gain,
BP development and hypertension obesity and aging.19,20 In a pooled analysis of longitudinal individual BP
prevalenceover the life course measures over 43 years in >32 800 individuals in four population-based
cohorts in the USA, a steeper increase in systolic, diastolic and mean BP

BP development in the young as well as in pulse pressure was observed in females compared to males
Sex differences in BP trajectories are apparent from early life and already from the third decade onwards (Figure 1).13
change across the life course, suggesting that early life factors may Globally, the age-adjusted prevalence of hypertension in adults (using
play a role in how CVD present differently in females and males.11 At systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg as definition in
age seven, both sexes have similar systolic BP, which then increases a both sexes) was 32% in females and 34% in males in 2019, unchanged
little faster in females up to age 12, and thereafter slower in females re- from 1990, as a result of a comparable decrease in hypertension in high-
sulting in a lower systolic BP in females than in males starting from 13 income countries and increase in low- and middle-income countries.21
years of age (Figure 1).11 Systolic BP is 10 mmHg higher in males com- However, due to the aging trend, the absolute number of patients with
pared with females by the age of 18 years, a difference which slightly hypertension almost doubled during this period21 (Box 1).
increases over time up to 30 years.11 Diastolic BP is higher in females
at age 7, then increases similarly in both sexes up to age 12, thereafter
slower in females. From age 16, diastolic BP decreases in both sexes, but
faster in males.11 In the National Health and Nutrition Examination
Box 1 Key messages on sex differences
Survey (NHANES), the annual net transition rate from optimal BP (sys- in BP development over the life course
tolic BP <120 mmHg and diastolic BP <80 mmHg) to prehypertension
• Healthy young females have lower BP than males at similar age
(systolic BP 120–139 mmHg or diastolic BP 80–89 mmHg) was twice
but experience a steeper increase in BP from the third decade
as high among males compared with females aged 8–30 years, and high- of life.
est for young African American males.14 However, their findings may • Better understanding of the underlying mechanisms of BP in-
have been influenced by the lower BP in healthy young females, since crease in midlife may provide targets for improved prevention
the same BP threshold was used in both sexes. of hypertension in both sexes.
BP in midlife and beyond

The sex-specific BP trajectories from puberty to adulthood continue Sex differences in regulators of BP
with different patterns during young and middle-aged adulthood.12,15
From late adolescence, males have higher levels and steeper slopes of The regulation of vascular function and BP differs between females and
both systolic and diastolic BP than females until early midlife, at which males, in particular due to sex differences related to the autonomic ner-
there is a crossover, and females have a steeper rise in BP thereafter vous system, the renin-angiotensin-aldosterone system (RAAS), brady-
throughout their life course (Figure 1).12,16 In subjects older than 40 years, kinin, nitric oxide, brain natriuretic peptides and humoral mechanisms
transition from optimal BP to prehypertension was stable or decreased related to sex chromosomes, sex hormones and other hormones.7,22,23
among males, but rapidly increased among females in NHANES.14
Diversity in the BP development during menopause transition is well The autonomic nervous system
The autonomic nervous system plays an important role in BP regulation
and contributes to modulate CVD.24 Although normotensive adult fe-
males and males share the same CV autonomic regulation, they exhibit
differences in the sympatho-vagal balance and central and reflex neuron-
al influence on the CV system.25 Sex-dependent physiological changes
related to age, menopause, obesity and physical activity might also influ-
ence neuronal hemodynamic regulation. Females have a larger increase
in sympathetic nervous activity with age and obesity than males.
Compared to healthy males, healthy females are characterized by lower
baroreceptor reflex sensitivity and lower heart rate variability.26,27
BP effects of sex hormones

Ovarian hormones have a major role in BP regulation, endogenous oes-
trogen being associated with the lower BP in premenopausal fe-
males.28,29 Oestrogens modulate BP directly through non-genomic
effects on vascular, renal and cardiac cells, by reducing calcium pathways
Figure 1 Blood pressure development in females and males during and indirectly through genomic actions, controlling expression of po-
childhood, adolescence, and early adulthood. Based upon O’Keeffe tent vasoconstrictors, such as angiotensin II, endothelin 1 and catecho-
et al.,11 Shen et al.,12 and Ji et al.13. lamines, and controlling the RAAS and endothelin pathway.28,30 On the
contrary, testosterone is pro-hypertensive and likely contributes to the
4 E. Gerdts et al.
increase in CV risk observed with ageing in males and after menopause Traditional CV risk factors in hypertension
in females.28,29,31 Androgens increase BP by activating the RAAS.29 Important sex differences in conventional CV risk factors have been re-
Oestrogens reduce plasma renin and angiotensin-converting enzyme ported in hypertension, particularly related to smoking and metabolic
(ACE) activity, and up-regulate angiotensinogen expression, leading risk factors [obesity, type 2 diabetes (T2D) and dyslipidaemia], and to
to increased levels of angiotensin and aldosterone, and sodium reten- co-morbidities (obstructive sleep apnoea, renal dysfunction, and auto-
tion.32 Progesterone is a potent aldosterone antagonist, which acts immune disorders) (Table 1). Clustering of more than two metabolic
on the mineralocorticoid receptor to prevent sodium retention and risk factors is often referred to as the metabolic syndrome.60 Glucose
counteracts the sodium-retaining effect of oestrogen.33 When becom- and lipid metabolism are directly modulated by oestrogen and testoster-

ing hypertensive, females tend to have lower plasma renin activity than one. Oestrogen deficiency or a relative increase in testosterone pro-
males.34 The premenopausal cardioprotective effects of oestrogens motes insulin resistance and a pro-atherogenic lipid profile.54
may in part result from RAAS inhibition.35 After menopause, increased Consequently, the prevalence of the metabolic syndrome is higher in
salt sensitivity is observed in females.28,36 Thus, lower oestrogen level males in a young hypertensive population, but higher in females in older
after menopause is related to both upregulation of hormonal systems hypertensive population.54 Dyslipidaemia is highly prevalent in hyperten-
such as the RAAS and sympathetic nervous system, and to reduced vas- sion, particularly among white males.56 In females, serum levels of total
cular nitric oxide bioavailability.23 As a consequence, the synthesis of cholesterol, low-density lipoprotein cholesterol and apolipoprotein B
potent vasoconstrictors such as angiotensin II, endothelin-1, and cate- increase substantially in the perimenopausal period.61 In the Women’s
cholamines rises after menopause.37,38 Antihypertensive drug therapy Health Study, the association of higher serum triglycerides with in-
in postmenopausal women may improve endothelial dysfunction creased CVD risk attenuated with increasing age of onset.62
caused by decreased vascular nitric oxide bioavailability and thereby re- Obesity is present in at least 50% of individuals with hypertension,51
duce CV risk.39 The roles of relaxin, oxytocin, prolactin and vasopressin and is more common in females.52 The higher fat mass in females and
in the regulation of BP are less well characterized than for oestrogen, sex differences in adipose tissue distribution are well documented.
progesterone and testosterone (Box 2). Higher abdominal visceral adipose mass has been more strongly asso-
ciated with risk of hypertension in females, and with risk of metabolic
syndrome in males.53 Obesity and hypertension are both strongly asso-
Box 2 Key messages on sex-differences ciated with insulin resistance and development of T2D. The prevalence
of T2D is age-dependent and higher in males than in females.55 Presence
in BP regulators, CV risk factors and of T2D in females reduces their innate CV risk advantage, and females
co-morbidities with T2D have a comparable risk as males for CVD.63,64 The relatively
worse prognostic impact of T2D in females may be associated with dif-
• The activity of autonomic and endocrine BP regulators differs be-
ferent hormonal modulation of insulin sensitivity,65 sex disparities in dia-
tween sexes and may influence drug efficacy and adverse effects.
• The prevalence and influence of traditional risk factors on CVD betes care and greater risk factor clustering among females with T2D.66
vary between females and males. Sex-specific CV risk factors
are documented in both sexes. Better integration of these differ-
ences in risk assessment tools will improve CVD prevention.
Table 1 Sex differences in conventional CV risk factors
and co-morbidities in hypertension
Factor Females Males Relevant

Sex differences in risk factors and references
....................................................................................
13,50
co-morbidities Age ++ +
8,51,52
Obesity ++ +
Sex-specific CV risk factors Visceral obesity + ++ 8,53
Important sex-specific CV risk factors have been identified.40 In males,
8,54
erectile dysfunction and androgenic alopecia are associated with in- Metabolic + (++ after ++
creased risk for hypertension as well as for CVD.41,42 Females undergo syndrome menopause)
important changes in sex hormones throughout their life course that Type 2 diabetes + +(+) 55
impact CV risk.18 Pregnancy-related hypertensive disorders increase 56

Dyslipidaemia + ++
the risk for chronic hypertension and CVD, even before menopause
57
transition.43–45 Detailed European recommendations on management Smoking + ++
of peripartum hypertension were recently published.46 Women with Obstructive sleep + ++ 58,59
polycystic ovary syndrome have a higher risk of hypertension, including apnoea

hypertensive disorders in pregnancy.47 In transgender populations, in- 49
Autoimmune +++ +
sufficient data have been reported on the effects of gender-affirming
disorders
hormone therapy on the incidence of hypertension.48
57
Inflammatory and autoimmune disorders are associated with in- Reduced eGFR ++ +
creased risk for hypertension and CVD, and both the innate and adap- Albuminuria + ++ 57
tive immune systems are influenced by sex hormones.49 While 7,32

Gout + +++
progesterone and androgens are considered immunosuppressive, oes-
trogens are considered immune-stimulatory, contributing to the ob- +Common; ++more common; +++much more common vs. other sex.
served preponderance of most autoimmune diseases in females.49
Obstructive sleep apnoea is more prevalent in males.58 It is an inde- hypertension, females exhibit higher LV myocardial function and ejec-
pendent risk factor for hypertension in both sexes, but the risk for tion fraction than males, independent of LV geometry.83
hypertension is evident at lower sleep apnoea severity in females
than in males.59 Females with hypertension more often have reduced
glomerular filtration rate than males. In contrast, males with hyperten- Dilated left atrium
sion more often exhibit albuminuria, possibly due to sex differences in A dilated left atrium (LA) is another common sign of hypertensive heart
protein handling.57 disease. LA dilatation is associated with increased CVD, in particular atrial
fibrillation, heart failure (HF) and ischaemic stroke.84–86 In healthy sub-

jects, the LA is normally larger in males than in females,87 but in hyperten-
Environmental risk factors sion LA dilatation is more common in females.88,89 In older subjects with
Air pollution contributes to risk for CVD through a number of mechan- hypertension and LVH, LA dilatation was significantly more prevalent in
isms, including oxidative stress, systemic inflammation and vascular dys- females.88 Similarly, also in middle-aged subjects with obesity without
function that all promote hypertension.67,68 Sex differences in these known CVD, LA dilatation was significantly more prevalent in females
relations have been little studied, but fine particulate matter (PM2.5) than in males, and particularly associated with co-presence of hyperten-
and sulphur dioxide have been suggested as stronger risk factors for sion and increased arterial stiffness90 (Box 3).
hypertension in females and nitric dioxide and carbon monoxide stron-
ger in males in studies from China.69,70 A post-hoc analysis within the
Systolic Blood Pressure Intervention Trial (SPRINT) trial demonstrated Box 3 Key messages about
that the effect of intensive antihypertensive drug treatment (systolic BP
<120 mmHg) was greater in participants exposed to higher PM2.5 sex-differences in hypertension
levels.71 mediated organ damage
Studies on noise around major European airports have reported air-
craft noise to be associated with incident hypertension in males.72 In the • Hypertension mediated organ damage like hypertensive heart
disease and arterial dysfunction show sex specific incidence,
UK Biobank cohort, exposure to road traffic noise above 60 dB was as-
threshold values and treatment success and may develop despite
sociated with higher systolic and diastolic BP, irrespective of antihyper- treatment.
tensive drug treatment73 (Box 2). • Identification of the underlying mechanisms for such develop-
ment in females and males may provide targets to reduce high-
risk phenotypes and progression to CVD.
Sex differences in hypertensive
heart disease
Arterial hypertension causes structural and functional changes in the Sex differences in arterial
heart, collectively named hypertensive heart disease.50 The heart is nor-
mally smaller in females than in males from puberty onwards,74 largely dysfunction
due to differences in body size and composition.75 Current guidelines
therefore recommend sex-specific threshold values for optimal detec-
Arterial structure and function
tion of hypertensive heart disease by echocardiography.50,76 Sex differences both in micro- and macrovascular structure and function
have been documented.91 Sex- and age-specific threshold values for diag-
nosis of arterial dysfunction in large arteries by arterial stiffness and intima-
Left ventricular hypertrophy media thickness, and in small arteries by lumen media ratio and flow-
Left ventricular (LV) hypertrophy (LVH) is the hallmark of hypertensive mediated vasodilatation have been published.91–94 Females have smaller
heart disease and a powerful prognostic marker in hypertension. aortic root dimensions than males, even after adjusting for body size.95
Hypertensive LVH is more prevalent and less modifiable by antihyper- Sex differences in ventricular-arterial coupling and higher arterial stiffness
tensive treatment in females than in males.8,77,78 Persistent LVH is par- in females, particularly in the ascending aorta, have been documented in
ticularly associated with increased arterial stiffness, and higher risk of several studies.96,97 Augmentation pressure and augmentation index are
CV events and mortality during follow-up, independent of achieved both higher in females at all ages, while carotid-femoral pulse wave vel-
BP values.79 ocity (PWV) does not differ by sex.94,98 Steeper increases in carotid-
In the Strong Heart Study, LVH was found in 36% of middle-aged fe- femoral PWV and peripheral vascular resistance are observed with aging
males and in 23% of middle-aged males.80 During 4 years of follow-up, and hypertension in females compared to males.97,98
LVH prevalence increased despite good BP control. The lack of LVH
regression was attributed to obesity and a progressive decline in renal
function. The prospective Italian Campania Salute Network registry of Arterial stiffness
subjects treated for hypertension demonstrated that presence of LVH Arterial stiffness can be estimated from the ratio of pulse pressure to
off-sets the innate lower CV risk in females, and females and males with stroke volume index (PP/SVi) or more directly measured by carotid-
hypertension and LVH had comparable risk of CVD.81 Furthermore, femoral PWV. In addition to being a predictor of CVD, independent
during follow-up, 21% of subjects with hypertension and initial normal of other hypertension-mediated organ damage like LVH,99 increased
LV mass developed LVH, particularly females and those with obesity.82 PP/SVi is also an independent predictor of the transition from diastolic
Presence of LVH in hypertension is associated with reduced myocar- to isolated systolic hypertension, with a risk for transition being 30%
dial function in both sexes, whether assessed by midwall shortening or higher in females than in males.100 This finding has been confirmed by
global longitudinal strain, while LV ejection fraction is usually normal. In analyzing sex differences in PWV trajectories over time, demonstrating
6 E. Gerdts et al.

Figure 2 Sex differences in development of arterial dysfunction and related complications. Red arrows indicate mechanisms that are enhanced in
females. MBP, mean arterial blood pressure; PP, pulse pressure; DBP, diastolic blood pressure; LVH, left ventricular hypertrophy; HFpEF, heart failure
with preserved ejection fraction; AMI, acute myocardial infarction; AF, atrial fibrillation; RAAS, renin-angiotensin-aldosterone system; NO, nitric oxide;
SNS, sympathetic nervous system.
a more rapid increase in systolic BP and higher prevalence of HF with time to night-time (dipping) and prevalence of non-dipping in both
preserved ejection fraction (HFpEF) in females than in males.13 sexes.106 Asleep systolic BP is a stronger predictor of all-cause mortality
Increased arterial stiffness augments systolic BP and pulse pressure, and CVD in females than males.106 In a study in the Italian Umbria dis-
worsening hypertension through hemodynamic load-induced elastic fi- trict, non-dipping in hypertension was associated with increased risk of
bre degradation and collagen deposition in the arterial wall. Higher aor- CVD only in females.107
tic stiffness and pressure and flow pulsatility increases the pulsatile load Several studies have now documented that the CVD risk increases at
on the heart, promoting LVH and reduction in global longitudinal strain a lower BP level in females than in males, including risk for myocardial
in the LV.101 Excessive stiffness and flow pulsatility have also been asso- infarction, HF and stroke.9,10,103 A case-control study of risk factors as-
ciated with microvascular lesions in high-flow organs like the brain and sociated with myocardial infarction in 52 countries showed that hyper-
the kidneys, suggesting that pulsatile flow damages small arteries in tension was associated with greater risk of myocardial infarction in
these organs (Figure 2).101 Arterial stiffness is less modifiable by antihy- older females than males.108 Also the community based Tromso
pertensive therapy in females than in males.99 Greater prognostic sig- Study found higher BP a stronger risk factor for myocardial infarction
nificance of arterial stiffness in females than in males was suggested in females than males.109
by a study in patients with coronary artery disease,102 but this finding
needs confirmation in patients without coronary artery disease (Box 3). HF and atrial fibrillation
Females with hypertension develop more vascular and myocardial stiff-
ness than their male counterparts at old age, contributing to their high-
Sex differences in the association of er risk for atrial fibrillation, HFpEF and stroke.110–113 Among patients
hypertension with CVD with atrial fibrillation, females have higher prevalence of hypertension
than males.114,115 While some reviews have suggested that hyperten-
The association of BP with CVD sion confers similar risk of atrial fibrillation in both sexes,116,117 the
The 2019 Global Burden of Disease study report confirmed that ele- Tromso Study reported a stronger association of elevated systolic BP
vated systolic BP was the most important risk factor for mortality in fe- with incident atrial fibrillation in females than in males.118 In the same
males worldwide and only second to smoking in males.2 The majority of cohort, increased systolic BP was associated with higher risk for both
these deaths are caused by CVD. Hypertension in midlife seems to be paroxysmal/persistent and permanent atrial fibrillation in females, but
more harmful in females than in similarly aged males, with hypertension only for paroxysmal/persistent atrial fibrillation in males.119
being a stronger risk factor for myocardial infarction, cognitive decline Hypertension is associated with high risk for HF in both sexes.120–122
and dementia.9,103–105 Hypertension is more prevalent among female than male HF patients
Ambulatory BP recording have documented higher asleep BP in (50% vs. 40%) and increases the risk for HF in females by 3-fold, com-
males in population-based studies, but a similar decline in BP from day- pared to 2-fold in males.121 Males constitute about 30% of patients with
HFpEF, and females about 40% of patients with HF with reduced ejec-
tion fraction (HFrEF) by current definitions.122 Sex differences in arter-
Sex differences in the effects of
ial, LA and LV adaptation to pressure overload, and in micro- and antihypertensive treatment
macrovascular coronary disease may contribute to the higher preva-
lence of HFpEF in women.123 Furthermore, iron deficiency, T2D, obes- Adverse effects of antihypertensive drugs
ity, preeclampsia, and autoimmune diseases, all common co-morbidities Sex differences in pharmacokinetics and pharmacodynamics are well
in females with hypertension, may contribute to higher risk of HFpEF described and mostly due to differences in either drug transporters af-
through amplification of cardiac dysfunction and systemic inflamma- fecting absorption (i.e. P-glycoprotein) or enzymes affecting metabol-
ism and/or clearance (i.e. cytochrome P450 activity).35 Interaction of

tion.123 Hypertension may contribute to the observed higher risk of
stroke in female HFrEF patients.124 In a post-hoc analysis of data sex hormones with enzymes involved in drug absorption and metabol-
from two large trials in patients with HFrEF, female patients had lower ism influences drug pharmacokinetics and pharmacodynamics, efficacy
mortality despite suboptimal treatment with diuretics, anticoagulants and adverse effects.143 Overall, females more often report adverse ef-
and device therapy compared to male patients.124 fects from antihypertensive drugs than males, except for mineralocor-
ticoid receptor antagonists. In particular, females more often
experience hyponatremia, hypokalemia and arrhythmia during treat-
Aortic valve stenosis ment with diuretics, oedema with dihydropyridine calcium channel
Both systolic and diastolic hypertension are associated with increased risk blockers (CCBs) and cough with ACE inhibitors (ACEI), while males
for degenerative aortic valve stenosis (AS) among older subjects.125 In AS, more often experience gout during treatment with diuretics.7,144–147
hypertension is particularly common in older females,126 and associated Sexual dysfunction is almost uniquely reported in males, and particularly
with impaired LV function and outcome in both sexes.127 In a Danish during beta blocker (BB) treatment.148
population-based study, progression of aortic valve calcification by cardiac
computed tomography was particularly associated with hypertension in Efficacy of antihypertensive treatment
females, and with dyslipidaemia in males.128 The ESC recently published
In the Dietary Approaches to Stop Hypertension trial, dietary sodium
a consensus document on how to manage hypertension in AS.129
restriction induced a pronounced BP reduction only in females.149
Structured aerobic exercise therapy reduced BP more in males than
Stroke in females in a meta-analysis of 93 trials.150
Stroke is a major complication in hypertension.130 Sex differences in Sex differences in drug effects on BP are well described.35 In particu-
stroke incidence, presentation, and outcome are well documen- lar, females have enhanced BP reduction from treatment with BB and
ted.131,132 Females with acute stroke often report non-conventional CCB.35 Studies on prescription of antihypertensive drugs have docu-
symptoms, which may contribute to delay in diagnosis and treatment, mented that females are more often prescribed diuretics and males
and subsequent increased mortality and disability.133 Males have higher more often ACEI.151,152 The Stockholm regional database including
stroke incidence up to 85 years of age.134 However, stroke risk in- prescriptions to 292 428 subjects, found that prescription of diuretics
creases at a lower BP level in females than in males.10 A recent and BB increased while prescription of ACEI, angiotensin receptors
meta-analysis demonstrated that young women may be disproportion- blockers (ARBs) and CCB decreased with aging in both sexes.153 In par-
ately at risk for ischaemic stroke.135 Among patients with ischaemic ticular, treatment with BB was more common in females than males
stroke, females more often present with atrial fibrillation, hypertension, among subjects without known CVD, while treatment with ACEI or
obesity and T2D than males.136,137 ARB was more common in males than females with HF or diabetes.153
Few ancillary analyses in clinical trials of antihypertensive drug treat-
Peripheral artery disease ment have reported sex-specific treatment results. Comparable bene-
fits were demonstrated for females and males in the Nordic Diltiazem
Hypertension is a major risk factor for peripheral artery disease in both
Study, the Treatment of Mild Hypertension Study and the Losartan
sexes.138 Females are usually older and more obese at the time of diag-
Intervention For Endpoint Reduction in Hypertension
nosis. Claudication is more often reported in males than females during
Study.,144,154,155 However, sex differences in antihypertensive drug ef-
middle age, but this sex difference is not observed at older age.139
fects were reported in the Hypertension Optimal Treatment study,156
Among patients with critical limb ischaemia, female sex is an independ-
the Second Australian National BP Study,157 and in the Valsartan
ent predictor for pronounced femoral-popliteal involvement and more
Antihypertensive Long-term Use Evaluation trial (Table 2).158 In the
severe and diffuse atherosclerotic disease.140 Several studies have
SPRINT trial, the number of females included was too low to draw con-
noted sex differences in ankle-brachial index with lower values in
clusions on the benefit of intensive BP control in elderly females,159 and
healthy women141,142 (Box 4).
two subgroup analyses reported contrasting results.160,161 Still, SPRINT
changed the American definition of hypertension and recommenda-
Box 4 Key messages on sex differences tions for BP management in both sexes.162
A meta-analysis by the BP Lowering Treatment Trialists’
in BP association with CVD Collaboration including 31 randomized trials published before 2006,
• Females with hypertension more often develop atrial fibrillation and a total of 103 268 men and 87 349 women, found comparable re-
and HFpEF, while males more often develop AMI and HFrEF. ductions in BP and incidence of CV events in both sexes for treatments
• CV risk increases at a lower BP level in females than in males. based on ACEI, ARB, CCB, diuretics or BB.163 Similarly, another net-
Future research should explore whether different diagnostic BP work meta-analysis based on 40 trials and 152 379 patents documented
threshold values or treatment targets in females and males with that no class of medication (ACEI, ARB, CCB or BB) was significantly
hypertension may improve CVD prevention. better than thiazides as first-line therapy for any outcome (all-cause
mortality, CV mortality, HF or stroke) in females or males analyzed
8 E. Gerdts et al.
Table 2 Overview of clinical trials in hypertension reporting results stratified by sex
Paper Trial name Number of % Results stratified by sex

(Reference) participants Females
......................................................................................................................................................................................
Studies that documented comparable benefits of study treatment in both sexes
Kjeldsen et al. Influence of age, sex and blood The Nordic Diltiazem 10 876 51 Similar treatment effect in both sexes.
pressure on the principal endpoints of the Study154

Nordic Diltiazem Study
Lewis et al. Efficacy and tolerance of Treatment of Mild 902 38 Similar treatment effect in both sexes.
antihypertensive treatment in men and Hypertension Study144
women with stage 1 diastolic hypertension.
Results of the Treatment of Mild
Hypertension Study
Os et al. Effects of losartan in women with Losartan Intervention For 9193 54 Similar treatment effect in both sexes. In the
hypertension and left ventricular Endpoint reduction in losartan group, females had better
hypertrophy: results from the Losartan hypertension155 reduction in the primary endpoint,
Intervention for Endpoint Reduction in all-cause mortality and new-onset
Hypertension Study diabetes.
Studies that documented sex differences in benefits of study treatment
Kjeldsen et al. Influence of gender on Hypertension Optimal 18 790 47 Achieving target diastolic BP <80 mmHg
prevention of myocardial infarction by Treatment156 reduced myocardial infarction in women
antihypertensives and acetylsalicylic acid: but not in men. Acetylsalicylic acid reduced
the HOT study incident myocardial infarction in men, but
not in women.
Wing et al. A comparison of outcomes with Second Australian 6083 51 The benefit of ACEI treatment was only
angiotensin converting enzyme inhibitors National Blood demonstrated in males.
and diuretics for hypertension in the Pressure Study157
elderly
Zanchetti et al. Outcomes in subgroups of Valsartan 15 245 42 Amlodipine lowered BP and reduced the
hypertensive patients treated with Antihypertensive primary endpoint (composite of cardiac
regimens based on valsartan and Long-term Use mortality and morbidity) better in females
amlodipine: An analysis of findings from the Evaluation trial158 than in males. Valsartan reduced the
VALUE trial secondary endpoint of hospitalization for
heart failure better in males.
BP, blood pressure; ACEI, angiotensin-converting enzyme inhibitor.
separately.164 No interaction analyses between sex and drug class ef- period 2007–17.170 Typically, these females had lower socioeconomic sta-
fects were presented. tus and used more than three antihypertensive drugs, both factors asso-
ciated with drug non-adherence in previous research.171 In the Swedish
Primary Care CV Database, BP control was not achieved to the same
BP awareness and control
BP control is necessary for optimal CV prevention in hypertension.
Awareness of hypertension has traditionally been higher in females Box 5 Key messages on sex-differences
than in males.165–167 in the effect of antihypertensive
Studies suggest that males treated for hypertension achieve better BP treatment
control than females. In the Multi-Ethnic Study of Atherosclerosis these
sex disparities increased with age and were largest in participants older • Sex-differences in efficacy and adverse effects of antihypertensive
than 75 years.168 Elderly females also have lower BP control rates vs. drugs are well described. These differences should be better
middle-aged and young females.7 Whether this is due to biological factors, communicated to health care providers to promote optimal anti-
inadequate treatment (physicians inertia, patient non-adherence, inappro- hypertensive drug treatment.
• In general, males treated for hypertension achieve better BP con-
priate drug choice), higher prevalence of CV organ damage or other co- trol than females. Future research should target underlying causes
morbidities is unknown.7 Depression and dis-satisfaction with the health for this difference, including patient related factors, health care
care provider are known factors particularly associated with non- related factors, socio-demographic factors and drug related fac-
adherence in older females, but not in males.169 A recent data analysis tors to provide sex-specific advice for optimalization of antihy-
from the Canadian Health Measures Survey demonstrated a particular de- pertensive drug therapy.
cline in hypertension treatment and control rates in females over the
extent in females as in males with hypertension managed in primary health 5. Yang BY, Qian Z, Howard SW, Vaughn MG, Fan SJ, Liu KK, et al. Global association
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care, independent of co-morbidities.152
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European Heart Journal (2022) 00, 1–12 SPECIAL ARTICLE

Sex differences in arterial hypertension

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Received 29 March 2022; revised 17 July 2022; accepted 11 August 2022

* Corresponding author. Tel: +4792086505, Email: [email protected]

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publications have documented important sex differences in hyperten-

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BP in midlife and beyond

BP effects of sex hormones

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Factor Females Males Relevant

impact CV risk.18 Pregnancy-related hypertensive disorders increase 56

polycystic ovary syndrome have a higher risk of hypertension, including apnoea

tive immune systems are inﬂuenced by sex hormones.49 While 7,32

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Table 2 Overview of clinical trials in hypertension reporting results stratiﬁed by sex

Paper Trial name Number of % Results stratiﬁed by sex

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BP, blood pressure; ACEI, angiotensin-converting enzyme inhibitor.

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