Inflammatory Forms of Cardiomyocyte Cell Death in the Rat Model of Isoprenaline-Induced Takotsubo Syndrome

Abstract

Takotsubo syndrome (TTS) is associated with inflammatory response, therefore the aim of the study was to evaluate the presence and dynamics of inflammatory-associated forms of cell death, necroptosis, and pyroptosis in the female rat model of isoprenaline (ISO)-induced TTS. TTS was induced in female Sprague Dawley rats (n = 36) by ISO 150 mg/kg intraperitoneally. Animals were divided into four groups: TTSO (TTS+ovariectomy; n = 10), TTSP (TTS+sham operation; n = 10), CO (0.9% NaCl+ovariectomy; n = 8), CP (0.9% NaCl+sham operation; n = 8). Histopathological analysis, evaluation of plasma concentration, and myocardial expression of pyroptosis- and necroptosis-associated proteins were performed. TTSO and TTSP groups had higher plasma concentrations of interleukin-1β in comparison with the controls. Low myocardial protein expression of mixed lineage kinase domain-like pseudokinase (MLKL), caspase-1 (Casp-1), and calcium/calmodulin-dependent kinase type II isoform delta (CAMKIIδ) was visible 6 and/or 12 h post-ISO. Twenty-four hours post-ISO, high myocardial and vascular protein expression of CAMKIIδ was visible in TTSO but not TTSP rats, while high myocardial expression of MLKL and Casp-1 was visible both in TTSO and TTSP rats. The course of TTS is associated with activation of inflammatory-associated programmed cell death, necroptosis, and pyroptosis, therefore inflammation may be a primary response occurring simultaneously with cardiomyocyte death in TTS.

Development of a small animal model replicating core characteristics of takotsubo syndrome in humans

“…The IP model established in 2012 by our group and histologically validated with patient samples 5 is the most reproduced model by others. 17 , 18 However, the IP model has a mortality rate of 73% at 30 days, much higher than what is reported in patients. 19 , 20 Most of the deceased animals from the IP model displayed an inability to maintain proper oxygenation and regain consciousness after anaesthesia and a rapid decline in cardiac function with a notable spasm-like dysfunction.…”