A primary isolated heart model of Takotsubo syndrome for mechanistic investigation and preclinical therapeutic testing.

Aims: Current experimental models of Takotsubo syndrome (TTS) do not readily distinguish intrinsic myocardial responses from systemic neurohumoral influences. We sought to establish and comprehensively characterize a primary isolated heart TTS model, in which the complete TTS-like phenotype is induced entirely within a Langendorff-perfused rat heart, enabling mechanistic investigation and preclinical therapeutic testing under controlled conditions. Methods and results: Male Sprague-Dawley rat hearts were perfused, and TTS was induced by controlled intra-aortic isoprenaline infusion, while control hearts received vehicle alone. Haemodynamic function and coronary flow were monitored continuously for 6 h. The primary endpoint was the group-by-time interaction for left ventricular developed pressure, analysed using generalized additive mixed models. Prespecified exploratory analyses included principal component analysis, Gaussian mixture modelling, and machine-learning-based feature analysis. Echocardiography, cardiac troponin release, and representative histology were used for multimodal phenotypic validation. Primary isolated TTS hearts developed progressive systolic and diastolic dysfunction characterized by reductions in left ventricular developed pressure, rate-pressure product, and coronary flow together with prolongation of surrogate isovolumic relaxation constant (TAU) (primary endpoint: Conclusion: We describe the first primary isolated heart model reproducing the core functional phenotype of TTS entirely within an isolated heart preparation. Thus, intrinsic myocardial responses to acute catecholaminergic stress are sufficient to generate regional dysfunction of TTS in the absence of systemic neurohumoral input.