Impact of biological sex on presentation and mortality in Takotsubo syndrome

Background A striking female predominance characterizes Takotsubo syndrome (TTS), yet the impact of biological sex on clinical outcomes remains debated. While women constitute the majority of cases, some evidence suggests that males may experience a more severe clinical course. We wanted to explore how men and women differ in their symptoms, including heart function and cardiogenic shock, and how these differences relate to short- and long-term survival rates. Methods We analyzed data from 5,431 patients from the SWEDEHEART registry. To address missingness in baseline variables, random forest-based imputation was employed. Multivariable Cox regression was used for mortality, adjusting for age, traditional risk factors, socioeconomic status, and comorbidities. Secondary analyses included ordinal logistic regression for LV function categories and logistic regression for cardiogenic shock. Results Population characteristics: Of the 5,431 patients (77.9% female, 22.1% male), the mean age was 69±11 years. Males were significantly younger than females (66±12 vs. 70±11 years; SMD: -0.299). Baseline cardiovascular risk factors were more prevalent in males, including diabetes (23% vs. 12%), hypertension (58% vs. 53%), smoking (49% vs. 41%), and hyperlipidemia (47% vs. 29%). Clinical presentation: At admission, males presented with significantly more severe LV dysfunction than females (OR for a worse LV category: 0.60; 95% CI: 0.51–0.72; P < 0.001). While the incidence of cardiogenic shock was numerically higher in males, the difference was not statistically significant after adjustment (1.98% vs. 1.77%; aOR: 0.71; 95% CI: 0.38–1.39; P = 0.33). Mortality: Female sex was associated with a robust survival advantage. At 30 days post-admission, females exhibited a 45% lower risk of death (aHR: 0.55; 95% CI: 0.39–0.77; P < 0.001, Fig. 1). This survival benefit persisted throughout the first year, with an adjusted hazard ratio of 0.60 (95% CI: 0.47–0.76; P < 0.001, Fig. 2). The increased mortality risk in males remained independent of age, socioeconomic status, baseline comorbidities, and initial clinical severity. Conclusion In this nationwide registry analysis, biological sex emerged as a critical determinant of both presentation and survival in TTS. Male patients present with significantly worse LV function and face a substantially higher risk of death in both the acute phase (30-day mortality) and during the first year of follow-up. These findings suggest that the poorer prognosis in men is not fully explained by traditional risk factors or acute clinical markers, which points to the importance of intensified monitoring and sex-specific risk stratification for male patients.Figure 1Figure 2