There is a pervasive idea of a ‘gender gap’ in hypertension and cardiovascular disease, with the general perception being that women are less likely to experience these problems than men. On the face of it, women do tend to have lower blood pressure and less cardiovascular disease than men of equivalent age.
Despite this, women are just as likely as men to die from cardiovascular causes. Cardiovascular disease is the number one killer of both men and women across the world.
Under the cardiovascular disease umbrella, select pathologies have a gender preference; it is well known that men are more likely to develop atherosclerosis and severe hypertension. On the other hand, women present with more severe initial myocardial infarctions than men, are nearly twice as likely to die in the 28 days following the event, and have worse prognoses following a diagnosis of hypertrophic cardiomyopathy than men.
These statistics are undoubtedly partially reflective of social factors, including lack of patient awareness and clinician bias, leading to underdiagnosis or preference for less aggressive treatment in women. But even taking those factors into consideration, it is likely that endocrine and genetic factors also contribute to physiological sex differences in cardiovascular disease epidemiology.
Oestrogen has long been thought of as a major contributing factor to the sex differences in cardiovascular disease. The cardiovascular effects of oestrogen include vasodilation, reduction of vascular inflammation and inhibition of vascular smooth muscle cell proliferation, all of which are beneficial to cardiovascular health. However, clinical trials investigating hormone replacement (oestrogen plus or minus progestin) in postmenopausal women have shown either no benefit to cardiovascular disease incidence, or that hormone replacement actually increased it. Clearly, it is not as simple as equating oestrogen with cardioprotection.
Androgens aren’t exactly the villain in this story either; they’re important for local production of oestrogen in arteries and androgen suppression therapy in men increases the incidence of myocardial infarction.
So, where does this leave us?
The renin–angiotensin system (RAS) is a key regulator of blood-pressure homeostasis and is often dysfunctional in cardiovascular disease states. This receptor system exemplifies some of the complexities in how sex-dependent factors (hormones, sex chromosomes, gonadal status) drive sexually dimorphic cardiovascular phenotypes. As the RAS is the most-studied receptor system in relation to sex differences in the cardiovascular system, many of these effects may also be applicable to other receptors that have not yet been examined.
Sex hormones themselves play a key role in regulation of the RAS. Oestrogen reduces expression of the pro-hypertensive AT1R receptors, an effect that seems to be dependent on the G protein-coupled receptor for oestrogen, GPER (formerly known as orphan receptor GPR30). In the opposite direction, testosterone exposure in early life increases the concentration of AT1R in the aorta of female mice, which also increases the incidence of aortic aneurysms in females to the level of males, indicating that developmental exposure is also important for ‘programming’ sex differences in the cardiovascular system in later life.
The male predisposition to develop aortic aneurysms has an additional genetic component, with XY females (generated using the ‘four core genotypes’ mouse model) developing more severe aortic aneurysms than XX females. One possible explanation for a sex-chromosome-dependent effect in this case is that the cardioprotective AT2R receptor is encoded on the X chromosome. Since approximately 15% of the X chromosome escapes X inactivation, this may result in genomic cardioprotection in XX females.
The RAS is just the tip of the iceberg – there are sex differences in receptor systems for endothelin, the most potent endogenous vasoconstrictor, and for prostanoid receptors including thromboxane. What hasn’t even been touched on here are the sex differences that exist in CYP450 enzymes, which may additionally contribute to differences in the metabolism of cardiovascular therapeutic agents.
The evidence is mounting for sex differences in the cardiovascular system. Though it has been done in the past, it is generally not appropriate to infer effects in females from studies conducted in males, nor is it rigorous to conduct a study in a singular sex. Thankfully, many journals and funding bodies are now acknowledging this issue and expect that both sexes should be studied in animal work and should be considered as a biological variable. When examining cardiovascular phenotypes, it is important to deliberate – does this phenomenon also occur in females?
NB - Based on definitions recommended by the Institute of Medicine, the term ‘gender’ (woman/man) as used here refers to differences between people based on self-identity, while ‘sex’ (female/male) is used to describe differences in animals as a function of sex chromosomal complement and gonadal/hormonal status.
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