Oestrogen and the post-myocardial infarction heart: benefit or detriment?

Abstract

Oestrogen (E) is thought to be protective within the cardiovascular system. Pre-menopausal women have a lower risk of developing cardiovascular disease than age-matched men but this difference is lost at the menopause. E initially protects the myocardium following myocardial infarction (MI), yet there is evidence that pre-menopausal women have a higher acute mortality rate following MI, an effect that is also seen in experimental MI. Recent clinical trials show that hormonal replacement therapy is not effective for prevention of cardiovascular disease in post-menopausal women.This thesis aimed firstly to investigate the effects of E on the myocardium during healing after MI. In ovariectomised female mice, E treatment results in an increase in acute mortality due to cardiac rupture following induction of MI by coronary artery ligation. We hypothesised that E modifies the remodelling process, particularly through regulation of matrix metalloproteinase (MMP) enzyme activity. After MI, there was a reduction in necrotic myocardial tissue and inflammatory response in E treated compared to placebo treated mice. However there was no concomitant reduction in MMP-2 and MMP-9 activity. E treatment was also associated with a reduction in MMP-13 expression and an increase in tissue inhibitor of metalloproteinase type 2 activity. These data show that E disrupts matrix degradation during infarct healing after MI. In the mouse this results in an increased incidence of cardiac rupture.A second aim of the thesis was to determine the roles of the E receptor (ER) α and ERß in mediating the initial cardioprotective effects of E following MI. E reduced infarct size, neutrophil infiltration and generation of oxidant stress following myocardial ischaemia with reperfusion in rats. This effect was not blocked by a novel ERß antagonist but was mimicked by a novel ERα agonist. The ERα agonist also protected the isolated buffer perfused heart from reperfusion injury showing that it has both neutrophil dependent and independent effects.A third aim of the thesis was to determine whether inclusion of a progesterone analogue in hormone replacement therapy (HRT) regimes modifies the cardioprotective effects of E. In ovariectomised female rats, E supplementation reduced infarct size and neutrophil infiltration following ishaemia and reperfusion compared to placebo treated animals. This protection was lost in animals receiving the progesterone analogue medroxyprogesterone acetate (MPA) in addition to E. Co-administration of MPA therefore negates the beneficial effects of E in myocardial reperfusion injury.In conclusion, the data confirm the initial cardioprotective effects of E following myocardial infarction with or without reperfusion. At least in the rat, this protection is mediated through stimulation of the ERa, through direct effects on the heart and additional effects on neutrophils. This protective influence of E is lost if E is co-administered with MPA, as it frequently is in HRT regimes. In addition, despite the initial cardioprotection E can influence subsequent matrix remodelling during healing of the myocardial infarct through modification of MMP activity. In the mouse this destabilises the infarct and results in an increased incidence of cardiac rupture. E therefore has both beneficial and detrimental effects in the post-MI heart.