Unravelling the temporal dynamics of takotsubo syndrome in an ex-vivo model: multi-parametric approach ad modum langendorff perfusion

Abstract Background Takotsubo Syndrome (TTS) is an acute, reversible cardiac failure marked by regional wall motion abnormalities. Despite its significant morbidity, the mechanisms driving TTS progression remain poorly understood. Our ex vivo TTS model offers a controlled environment to investigate TTS at a mechanistic level, providing insights into hemodynamic and biomechanical changes. However, the temporal dynamics of TTS are not fully understood. Purpose This study aims to develop an ex vivo TTS model to explore temporal changes in cardiac function using Langendorff, focusing on parameters reflecting myocardial dysfunction progression. Methods Twenty male Sprague-Dawley rats (~47 days, ~300 g) were divided into control and ex vivo TTS groups. After cardiac extraction and mounting within 75 seconds, hearts were assessed for viability (Rate Pressure Product (RPP) 26, 000, dp/dt ±2000, and heart rate 200–500). TTS was induced in the ex vivo group by infusing isoprenaline (1 mg/kg) over 15 minutes. Key parameters, including temperature, myocardial flow rate, heart rate (HR), intraventricular pressure (IVP), systolic blood pressure (SBP), diastolic pressure (DP), left ventricular developed pressure (LVDP), rate of pressure change (DPDTMAX, DPDTMIN), rate-pressure product (RPP), pH, pO2, and pCO2, were monitored over six hours. The TTS phenotype was assessed using ex vivo echocardiography. Results Echocardiography confirmed the TTS phenotype with regional wall motion abnormalities, including apical akinesia and basal hypercontractility. Significant differences in cardiac parameters between control and ex vivo TTS groups were observed, reflecting isoprenaline effects and myocardial dysfunction progression. Notably, LVDP and SBP were significantly elevated in the ex vivo TTS group early (p 0. 05). PCA revealed that the first two principal components (PC1 and PC2) explained 95. 6% of the variance, with PC1 associated with myocardial contractility and PC2 linked to cardiac output. ARIMA time-series modelling showed strong temporal dependence in HR (AR (1) = 0. 9575). Cox Proportional Hazards regression identified HR, SBP, and LVDP as independent predictors of the time to reach LVDP 4. 5 (HR: 1. 35, 1. 20, and 1. 42), with ex vivo TTS hearts reaching this threshold earlier than controls (p 0. 01). Ex vivo echocardiography, strain analysis, and physiological measurements mirrored in vivo findings, highlighting dyssynchrony in TTS hearts. Conclusion This study establishes a novel ex vivo TTS model using the Langendorff perfusion system. Multi-parametric analysis offers insights into the temporal progression of cardiac dysfunction in ex vivo TTS. Statistical modeling highlights the role of LVDP, SBP, and HR in TTS evolution, with ex vivo TTS hearts displaying an accelerated trajectory. These findings provide new insights into TTS pathophysiology and suggest potential therapeutic avenues for mitigating stress-induced myocardial dysfunction. Figure 1 figure 2