The role of sex hormones in Takotsubo syndrome: a preclinical investigation

Abstract Introduction Takotsubo syndrome (TS) is characterized by transient regional wall motion abnormalities, manifesting as apical ballooning on imaging, following acute stress. Sex and age differences in TS prevalence are well-documented, where TS incidence increases with age in both sexes and with a marked preponderance observed among post-menopausal women. Age-related changes in sex hormones have been suggested to play a facilitating role. Using a high-fidelity rat model of TS, we investigated the relationship between sex hormones and stress-induced apical ballooning through three complementary studies. Methods Study 1 investigated TS susceptibility in 32 female rats during different oestrous cycle phases (diestrus vs. proestrus), which demonstrate significant fluctuations in sex hormones. Study 2 examined the effect of ovariectomy, to simulate age-related hypogonadism, and the effects of oestrogen supplementation using 12 ovariectomized female rats receiving daily subcutaneous 17β-oestradiol injections (24.3 - 72.9 µg) or vehicle (Miglyol 812N) for three weeks before TS induction. Study 3 utilized 32 male rats to evaluate the effects of androgens. Rats were randomized to orchiectomy or sham to simulate age-related hypogonadism, and sex hormones were analysed after 3 weeks just prior TS induction. TS was induced in all animals via isoprenaline infusion of 1 mg/kg. Using high-resolution echocardiography, left ventricular akinesia index (LVAI) was measured to quantify the extent of regional wall-motion abnormalities and fraction area change (FAC) to measure global systolic function. Results In study 1 we observed a significant effect of oestrus cycle phase on LVAI (p = 0.003) with increased TS severity during diestrus (low oestrogen phase) compared to proestrus (high oestrogen phase). Study 2 corroborated these findings showing a similar increase in LVAI following ovariectomy, while oestrogen supplementation attenuated this effect (p = 0.003). Orchiectomy had no effect on extent of RWMA post-stress (p = 0.54). The plasma concentration of testosterone hormone levels failed to predict LVAI or FAC in a linear regression analysis (p = 0.96 and p = 0.47 respectively). Conclusion Our findings demonstrate that oestrogen protects female rats against stress-induced apical ballooning, with minimal androgen influence in males. The lack of testosterone-mediated effects suggests that the lower TS prevalence in men is unlikely due to protective androgen activity. These results provide mechanistic insight into the clinical predominance of TS among postmenopausal women, highlighting oestrogen status as a key determinant of susceptibility. Furthermore, our study emphasizes the necessity of accounting for oestrous cycle phase in preclinical research, as hormonal fluctuations may explain inconsistencies in prior studies lacking cycle phase controls.Figure 1