Sex-specific effects of oestrogen in Takotsubo syndrome: protective in females, detrimental in males

Abstract Introduction Takotsubo syndrome (TS) is characterized by transient regional wall motion abnormalities, manifesting as apical ballooning on imaging, following acute stress. Sex differences in TS prevalence are well-documented, with a marked preponderance among post-menopausal women. Oestrogen deprivation is believed to play a facilitating role. Using a high-fidelity rat model of TS, we aimed to investigate the relationship between oestrogen and stress-induced apical ballooning in female and male rats. Methods Study 1 examined 24 oophorectomized female rats receiving daily subcutaneous 17β-oestradiol injections (0-72.9 µg) for three weeks before TS induction. Study 2 randomized 32 orchiectomized male rats to receive oestrogen supplementation (54.3 µg daily for 3 weeks) or vehicle (Miglyol 812N). TS was induced in all animals via isoprenaline infusion, 1 mg/kg over 15 minutes, and blood samples were taken prior induction for analysis of sex hormones using high-sensitive gas chromatography-tandem mass spectrometry. Using high-resolution echocardiography, left ventricular akinesia index (LVAI) was measured to quantify the extent of regional wall-motion abnormalities. Results In Study 1, oestrogen demonstrated an exponential dose-dependent protective effect against TS in females, with higher plasma levels correlating with reduced LVAI (correlation coefficient = -0.564, p = 0.006). In contrast, Study 2 demonstrated that oestrogen supplementation in males significantly increased TS severity (p = 0.022), incidence of apical thrombus formation (22% vs. 0% in controls, p = 0.002), and showed a trend toward increased mortality (p = 0.1) due to early-phase arrhythmias. Combined analysis revealed an increased TS susceptibility in female rats after adjusting for sex hormone differences (coefficient for male sex: -7.85, p = 0.022), and a significant sex-specific effect of oestrogen supplementation (interaction p < 0.001), with protective effects in females but detrimental effects in males. Conclusion TS has long been described as a 'woman's disease' and differences in sex hormones, mainly oestrogen, have been considered the main cause. Our investigations reveal that oestrogen's role is more complex than previously thought. Our findings provide strong evidence for the protective role of oestrogen in females, however, it paradoxically increases TS severity in male rats. This distinct sex-specific response to oestrogen suggests that additional mechanisms beyond simple hormone levels contribute to the sex differences observed in TS patients. This sex-specific response to oestrogen helps explain why, despite men having lower oestrogen levels throughout life, they don't show the same TS susceptibility as postmenopausal women.Figure 1