A Primary Isolated Heart Model of Takotsubo Syndrome for Mechanistic Investigation and Preclinical Therapeutic Testing

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Abstract Aims Current experimental models of Takotsubo syndrome 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. Hemodynamic function and coronary flow were monitored continuously for 6 hours. The primary endpoint was the group-by-time interaction for LVDP, analyzed using GAMM. Prespecified exploratory analyses included PCA, 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 LVDP, RPP, and coronary flow together with prolongation of surrogate TAU (primary endpoint: P<0.001; q = 0.002). Temporal modeling identified three reproducible physiological phases: hyperactivation, transition, and functional nadir. Echocardiography demonstrated characteristic apical ballooning, reduced ejection fraction, impaired global longitudinal strain, and increased left ventricular akinesia index. Progressive cardiac troponin release and representative histological alterations provided supportive biochemical and structural corroboration of the functional phenotype. Conclusions We describe the first Primary isolated heart model reproducing the core functional phenotype of Takotsubo syndrome 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.

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