The curse of the sympathetic nervous system: are men or women more unfortunate?

Decades of research suggests that the male sex is unfortunate when it comes to the development of cardiovascular disease (and potentially other things that remain unnamed!). The female sex hormones (particularly oestrogens) have long been associated with a protective effect on the cardiovascular system. Oestrogen has been demonstrated to increase endothelial nitric oxide production, reduce atherosclerotic plaque development, attenuate circulating low density lipoproteins, have anti-oxidant effects, and finally, but not least, attenuate sympathetic nerve activity. Consequently, the incidence of cardiovascular related mortalities is greater in pre-menopausal women compared to men (Burt et al. 1995).

Increased levels of sympathetic nerve activity are also associated with increased rates of cardiovascular morbidity. In men, sympathetic nerve activity is typically elevated compared to women of the same age (although this is not always the case and may depend on the phase of the menstrual cycle). Central oestrogen administration has been demonstrated to attenuate sympathetic nerve activity in female and male rats. Furthermore, sex appears to affect how the vasculature interacts with the sympathetic nerves. In young men, muscle sympathetic nerve activity (MSNA) is positively related to total peripheral resistance, whereas in women this relationship does not exist. Consequently, a high level of MSNA does not necessarily mean that there is an elevated peripheral vasoconstrictor tone in women, as it does in men (Hart et al. 2009).

In a recent issue of the Journal of Physiology, Momen et al. (2010) demonstrate that sympathetic activity directed to the coronary arteries might also interact with vasculature differently in men and women. The authors demonstrate that in men sympathetic activation induced by static hand grip exercise (70% MVC) and lower body negative pressure (−30 mmHg) caused a larger reduction in coronary blood flow velocity in men compared to women. This was reflected by a greater reduction in coronary vascular resistance in men. Consequently, Momen et al. concluded that coronary vasoconstrictor responses to elevated sympathetic activity are attenuated in young women. The authors’ data provide further evidence that women appear to be less responsive to sympathetic vasoconstrictor activity than men. This presents two questions: what are the mechanisms underlying this and are reductions in coronary vasoconstrictor responsiveness good or bad for women?

There are several possible reasons for the reduction in coronary vasoconstrictor responsiveness to sympathetic stimuli in women. First, enhanced nitric oxide bioavailability due to oestrogen, might prevent increases in coronary vasoconstrictor tone in women during periods of elevated sympathetic nerve activity. Secondly, oestrogen receptors on vascular smooth muscle cells cause vasodilatation. This might also blunt coronary vasoconstriction in response to increased sympathetic nerve activity in women. Finally, some evidence suggests that β₂-adrenergic receptor sensitivity is increased in young women compared to men (Kneale et al. 2000). Thus, increased sympathetic activity directed towards the coronary arteries might also stimulate the β₂-adrenergic receptors, offsetting α-adrenergic mediated vasoconstriction in women. Whether oestrogen increases β₂-adrenergic receptor sensitivity in humans is unknown.

So then what does the blunted coronary artery vasoconstrictor response to increased sympathetic activity mean for women? Is it good or bad? Momen et al. speculate that enhanced coronary vasoconstriction observed in men might actually help to maintain perfusion throughout the myocardial layers, especially during exercise. This suggests that because women have a blunted coronary artery vasoconstrictor response they are more at risk of developing myocardial ischaemic injury during exercise. Along these lines, data indicate that the incidence of angina during exercise is greater in women. Interestingly, over one-third of women with reported angina had normal coronary artery angiograms (Sharaf et al. 2001). However, these women were older (∼55 years) compared to the women participating in this study (∼30 years). Future studies could examine whether vasoconstrictor responsiveness is impaired in older postmenopausal women compared to men of the same age.

On the other hand, elevated coronary vasoconstrictor responsiveness might not be beneficial for young men. Increased coronary vasoconstriction has been shown to actually decrease myocardial perfusion, so that blood flow is not uniform across the myocardial layers during exercise. Additional recent evidence indicates that α-adrenergic blockade increases coronary blood flow during exercise and improves left ventricular function in dogs (Coutsos et al. 2010). Thus increased coronary vasoconstrictor responsiveness might actually put men at risk of developing ischaemic injury instead of women. Whether rates of exertional angina are greater in young men vs. women of a similar age is unknown and may be unknowable because this is a symptom usually seen in middle age and the elderly. Another negative effect of increased coronary vasoconstrictor responsiveness might actually be related to coronary vasospasm. Coronary vasospasm is related to altered sympathetic innervation of the coronary smooth muscle cells. It is possible that enhanced vasoconstrictor responses to increased sympathetic nerve activity might also put men at risk of developing coronary vasospasms. This might be especially detrimental since males have an enhanced sympathoexcitation response to external stressors (e.g. mental stress tests) compared to women. Thus enhanced coronary vasoconstriction might be another unfortunate characteristic of the male cardiovascular system. However, one has to think hard about women after menopause when rates of cardiovascular disease start to rise for women and at least some older women are at risk for acute heart failure in response to severe emotional stress. Is this caused by a loss of vasodilator mechanisms which offset increases in vasoconstrictor tone in the affected women? In this context, perhaps the most important clinical elements of this paper are the questions it raises relating to how sympathetic control of coronary circulation might change with ageing.