Development of a Small Animal Model Replicating Core Characteristics of Takotsubo Syndrome in Humans

Abstract

Adequate animal models are necessary to understand human conditions such as Takotsubo syndrome (TS), characterized by the heart's transient regional wall motion abnormalities. This study aims to develop a reproducible, low-mortality TS model that closely mimics the human condition and addresses the limitations of existing models. We conducted six experiments using 309 Sprague Dawley rats, each approximately 300 grams and aged 7-8 weeks. Initially, we replicated an established model using intraperitoneal isoprenaline injections. Subsequent experiments varied the doses and infusion durations of intravenous isoprenaline and assessed the effects of sex, strain, and breeder on the development of reversible akinetic segments. High-resolution echocardiography monitored regional wall motion over 30 days to correlate with histological changes. Increasing isoprenaline dose and infusion time significantly enhanced akinesia (p < 0.01), resulting in pronounced apical ballooning observed in 3D imaging. Akinesia peaked at 6 hours post-infusion, with recovery observed at 24 hours; most rats recovered from akinetic segments within 48-72 hours. Optimizing the mode of administration, dose, and duration achieved a TS-like phenotype in 90% of cases with a 16.7% mortality rate. Histological examinations confirmed myocardial injury occurred independently of apical ballooning. This study presents a refined TS model that reliably replicates the syndrome's key features, including morphological and electrocardiographic changes, demonstrating its transient nature with high fidelity and reduced mortality. The model’s reproducibility, evidenced by consistent results across trials, suggests its potential for broader application pending further validation.