Review Article | Published:

Sex-specific differences in hypertension and associated cardiovascular disease

Nature Reviews Nephrology volume 14, pages 185201 (2018) | Download Citation

Abstract

Although intrinsic mechanisms that regulate arterial blood pressure (BP) are similar in men and women, marked variations exist at the molecular, cellular and tissue levels. These physiological disparities between the sexes likely contribute to differences in disease onset, susceptibility, prevalence and treatment responses. Key systems that are important in the development of hypertension and cardiovascular disease (CVD), including the sympathetic nervous system, the renin–angiotensin–aldosterone system and the immune system, are differentially activated in males and females. Biological age also contributes to sexual dimorphism, as premenopausal women experience a higher degree of cardioprotection than men of similar age. Furthermore, sex hormones such as oestrogen and testosterone as well as sex chromosome complement likely contribute to sex differences in BP and CVD. At the cellular level, differences in cell senescence pathways may contribute to increased longevity in women and may also limit organ damage caused by hypertension. In addition, many lifestyle and environmental factors — such as smoking, alcohol consumption and diet — may influence BP and CVD in a sex-specific manner. Evidence suggests that cardioprotection in women is lost under conditions of obesity and type 2 diabetes mellitus. Treatment strategies for hypertension and CVD that are tailored according to sex could lead to improved outcomes for affected patients.

Key points

  • Although blood pressure (BP) is lower in women than in men during the reproductive years, 50% of all cardiovascular disease (CVD)-related deaths occur in women, resulting in a greater incidence of CVD in older women than in age-matched men.

  • The same mechanisms that regulate BP and cardiovascular function are present in both men and women, but these systems are shifted towards cardioprotective pathways in women between puberty and menopause.

  • Sex hormones such as oestrogen and testosterone have a role in cardioprotection by modulating vasodilator and vasoconstrictor pathways, including the renin–angiotensin–aldosterone system (RAAS) and the endothelin system.

  • The sex chromosome complement can act independently of sex hormone effects, which results in sex-specific, age-specific and tissue-specific differences in gene transcription.

  • Obesity affects more women than men; as obesity is associated with a loss of cardioprotection, CVD occurs at an earlier age in obese women than in lean women.

  • Women have a longer lifespan than men and develop age-related and CVD-related pathologies later in life; these beneficial outcomes might be due in part to sex differences in cell injury and repair pathways that delay the chronic accumulation of senescent cells, end-organ damage and the progression of CVD.

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Acknowledgements

K.M.M.C is supported by an Australian National Health and Medical Research Council (NHMRC) CJ Martin Research Fellowship (1112125), and K.M.D is supported by an NHMRC Senior Research Fellowship (1041844).

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Affiliations

  1. Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University Wellington Road, Clayton, Victoria 3800, Australia.

    • Katrina M. Mirabito Colafella
    •  & Kate M. Denton
  2. Department of Physiology, Monash University, 26 Innovation Walk, Clayton, Victoria 3800, Australia.

    • Katrina M. Mirabito Colafella
    •  & Kate M. Denton
  3. Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, Netherlands.

    • Katrina M. Mirabito Colafella

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K.M.M.C. and K.M.D. researched the data, discussed the article's content, wrote the text and reviewed or edited the article before submission.

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The authors declare no competing financial interests.

Corresponding authors

Correspondence to Katrina M. Mirabito Colafella or Kate M. Denton.

Glossary

Hypertensive disorders of pregnancy

Hypertension that develops during pregnancy and is resolved following delivery of the offspring.

Polycystic ovary syndrome

(PCOS). A hormonal condition in which testosterone levels are elevated that is associated with irregular menstrual cycles, excessive facial and body hair, obesity, reduced fertility and increased risk of diabetes.

Hypothalamic hypoestrogenaemia

A condition in which plasma oestrogen levels are low owing to abnormal pituitary regulation of oestrogen.

Senescence-associated secretory phenotype

(SASP). A phenotype of senescent cells in which there is a high production of cytokines (IL-β1, tumour necrosis factor), chemokines (monocyte chemoattractant proteins), reactive oxygen species (superoxide) and remodelling factors (transforming growth factor–β), which results in recruitment of immune cells to the site of injury.

Cellular senescence

A process that results in permanent cellular proliferative arrest.

Sirtuins

NAD+-dependent deacetylases that act on forkhead homeobox transcription factors, peroxisome proliferator-activated receptor-α and nuclear factor-κB.

Telomere uncapping

Telomere ends form a loop structure, known as a cap, which prevents the chromosome ends from being recognized as double-stranded DNA breaks and initiating a DNA damage response. Telomere uncapping increases with advancing age and is associated with hypertension.

Oestrogenic compound

A compound with oestrogen-like activity. In women, there are three major endogenous oestrogenic compounds: estrone, oestradiol and estriol. In rodents, 17β-oestradiol is the major oestrogenic compound.

Radiotelemetry

The use of radio-waves to transmit information from a device to a remote receiver. This is the gold-standard method used to measure blood pressure (BP) in rodents, as BP can be measured continuously in unrestrained animals.

Tail-cuff plethysmography

A non-invasive method that uses plethysmography (volume displacement) to measure blood pressure (BP) in rodents via a cuff placed around the tail. This method is associated with stress and results in underestimation or overestimation of BP, but it is an inexpensive method that lends itself to long-term tracking of BP.

Sympathetic nervous system

(SNS). The part of the autonomic nervous system that serves to increase heart rate, constrict blood vessels and raise blood pressure when activated. Overactivity of the sympathetic nerves, particularly in the kidney, drives the development of hypertension.

Hyperandrogenaemia

A state characterized by androgen excess in females, for example, as seen in polycystic ovary syndrome.

Sex chromosome complement

The number and type of sex chromosomes present in an organism, with XY being usual in males and XX in females.

Four core genotype model

In the four core genotype (FCG) model, Sry, the testis-determining gene, is deleted from the Y chromosome and inserted into chromosome 3. In XY-male males (gonadal and chromosomal male), the autosome becomes male-determining instead of the Y chromosome. The FCGs are generated by crossing this XY-male (Sry on chromosome 3) with a wild-type XX-female, which gives XX-males (gonadal males with XX chromosomal complement), XY-males (gonadal males with XY chromosomal complement), XX-females (gonadal females with XX chromosomal complement) and XY-females (gonadal females with XY chromosomal complement).

Adoptive T cell transfer

The transfer of T cells into an individual; the cells may originate from the same subject or from another individual.

'Fat-but-fit' hypothesis

The hypothesis that cardiovascular fitness (and muscle mass) ameliorates the adverse impact of obesity on cardiometabolic health.

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