Takotsubo syndrome-like model in rats with high reproducibility and low mortality
Authors: Zulfaj E , Redfors B , Nejat A , Shekka Espinosa A , Hussain S , Haamid A , Elmahdy A , Kakei Y , Omerovic E 
Published: October 2022

Abstract

Background/Purpose
Takotsubo syndrome (TS) is an acute form of heart failure with similar mortality and clinical presentation as myocardial infarction. The pathophysiology of the potentially life-threatening syndrome is only partially understood. This experimental study aimed to produce a human-like TS model with high reproducibility and low mortality. Rats have been the small-animal model of choice for preclinical studies within the cardiovascular field, successfully translating gained knowledge to humans. A relevant animal model can aid in elucidating mechanisms behind TS and serve as a platform for developing evidence-based treatment guidelines specific for the disease, which are currently missing.

Methods
190 Sprague Dawley rats (male, ∼300 g, ∼47 d) were infused i.v. with a single dose of the β-adrenergic agonist isoprenaline. The first study group was randomized by infusion time (ranging from 1 min to 60 min) while maintaining a fixed total dose (6.25 mg/kg), and the second group by total dose (0.1–50 mg/kg) with specified infusion time. The studies were replicated with saline infusion as a control. This study looked at mortality, the incidence of apical akinesia, the extent of apical akinesia, and recovery time. ECG, HR, SpO2, and temperature were monitored during the induction phase (&lt;60 min) and at time points for imaging. High-resolution speckle-tracking echocardiography was used to study heart function for up to 30 days. The study followed the principles of laboratory animal care and was approved by our institution's Animal Ethics Committee.

Results
Mechanical dyssynchrony preceded global contractile dysfunction and development of transient apical akinesia. LV function and contractility normalised after 1 to 7 days. All surviving rats showed normal behaviour, ECG, and imaging at 30 days. TS-like phenotype was achieved in 92.9% of survivors. Mortality at 30-day was 6.7%. The deceased animals developed complications like TS patients including heart failure, malignant arrhythmias, LV mural thrombus formation, cardiogenic shock. Longer infusion time was associated with increased mortality (p=0.002), but not with the incidence of akinesia (p=0.818). The extent of apical akinesia decreased at the shortest infusion time (1 min) while at 7.5 minutes and above, it did not differ. The replication study validated these findings, although variability in incidence and mortality was seen across the groups.

Conclusions
This study provides a highly reproducible TS-like model with low mortality and excellent translational potential. High-resolution imaging and the natural course demonstrated the presence of the most critical characteristics of TS-like phenotype as in humans. The model also validates other findings related to TS including variability in the susceptibility to develop TS-like phenotype and complications. Our model provides a solid experimental platform for future preclinical studies of TS.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): ALF - Swedish Research Council