Pathophysiology of Takotsubo Syndrome - Insights from preclinical studies

Abstract

Takotsubo syndrome (TS) is an acute, stress-associated cardiac syndrome characterized by transient regional wall motion abnormalities (RWMA), most commonly presenting as apical ballooning on imaging. TS can occur in both sexes and across ages, but is most common in postmenopausal women. It often mimics acute myocardial infarction in its clinical presentation, yet typically occurs without culprit coronary occlusion. Although TS is associated with substantial morbidity and mortality, the mechanisms that initiate RWMA, shape susceptibility, and determine recovery remain incompletely understood. This thesis integrates six studies that critically appraise TS animal models, develop and validate a reproducible small-animal model, and use that platform together with human registry data to explore modulatory factors and downstream molecular responses. Paper I systematically reviewed published TS animal models, focusing on their ability to reproduce essential clinical characteristics and identifying key limitations. Papers II and III aimed to develop and validate a new TS model using intravenous isoprenaline infusion in rats. Using this established model, Paper IV performed the first analysis of the extracellular vesicle (EV) proteome from TS-affected hearts. Paper V quantified age- and sex-specific TS incidence in the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) and tested sex-steroid effects on RWMA in the TS model. Paper VI examined whether the TS phenotype confers protection against subsequent myocardial ischemia–reperfusion injury. Paper I highlighted key clinical features, identified inconsistent preclinical definitions of TS, and noted a lack of adequate validation across available models. Many models reproduced catecholamine cardiotoxicity changes without demonstrating the transient RWMA that distinguishes clinical TS from other catecholamine-induced injuries. To address these gaps, Paper I proposed updated criteria for preclinical TS, introduced an assessment tool for evaluating TS animal models aligned with the clinical context, and emphasized the need for a refined experimental model. Paper II and III established a TS model that reproduced core features of the clinical syndrome and several additional characteristics. Body temperature and catecholamine kinetics influenced the development of post-catecholamine RWMA. Catecholamines induced both RWMA and structural myocardial changes, but these did not consistently co-occur, suggesting partially overlapping mechanisms rather than a direct causal relationship between the two. Paper IV identified a distinct EV molecular signature in the RWMA-affected myocardial region, with protein content indicating potential involvement in inflammatory responses, tissue repair mechanisms, mitochondrial function and metabolic remodelling, and cell survival pathways. Paper V showed that TS incidence increased with age in both sexes, with a significant sex×age interaction reflecting a greater age-associated increase in females. Experimentally, estrous cycle-phase was associated with TS susceptibility and estradiol exerted sex-dependent effects, attenuating TS occurrence in females yet increasing it in males, whereas testosterone loss had limited impact in males. Paper VI demonstrated a TS-phenotype-dependent reduction in ischemia–reperfusion injury that was independent of catecholamine-induced damage. Collectively, this work supports TS as a syndrome defined by transient RWMA that can occur independently of the severity of structural myocardial injury. It provides a more standardized experimental platform and supports a framework in which TS-like wall motion abnormalities emerge from catecholamine-triggered, regionally heterogeneous myocardial responses, modulated by catecholamine kinetics, temperature, and sex-steroid milieu, and accompanied by EV-mediated molecular signalling. The observed cardioprotection provides further evidence consistent with TS as an endogenous, injury-limiting programme.