Isoprenaline induced Takotsubo syndrome: Histopathological analyses of female rat hearts

Abstract

Background: Takotsubo syndrome (TTS) is a stress-induced disorder affecting mostly postmenopausal women. The aim of the study was to evaluate isoprenaline (ISO) dependent female rat model and histopathological characteristics in TTS. Methods: Forty-nine Sprague Dawley female rats, 12 weeks old, were injected intraperitoneally with a single dose of ISO at doses 50 (n = 8), 75 (n = 6), 100 (n = 3), 150 (n = 27) and 200 (n = 5) mg/kg body weight (bw). The control group (n = 6) was injected with physiological saline. The echocardiographic examination to assess wall motion abnormalities took place 24, 48, 72 h, and 7 days post-ISO. Histopathological analysis was performed on the basis of hematoxylin-eosin staining. Results: The total mortality rate was 3/49 (6.12%). The optimum dose of ISO to induce TTS was 150 mg/kg bw and 21/27 (77.77%) rats showed apical ballooning. Histopathological analysis revealed focal necrosis/apoptosis of cardiomyocytes with inflammatory and fibroblast-like cell infiltration. Foci were the most numerous in the central muscle layer with apical-basal gradient 24,48,72 h post-ISO (p < 0.05). Significant differences were noted 48 h post-ISO in the central layer in apical vs basal segments (p = 0.0032), in the endocardial layer in apical vs basal segments (0.00024) and in mid-cavital vs. basal segments (p = 0.0483). The number of foci in endocardium of apical region differ 48 h post-ISO in rats with a dose of 150 vs. 200 mg/kg bw (p = 0.0084). Conclusions: The ISO female rat model of TTS is associated with higher optimum dose and lower mortality in comparison with the male TTS model. TTS presents as a singles cardiomyocyte disorder, foci concerned mainly central muscle layer with apical-basal gradient.

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

“…We have also observed relatively lower plasma concentrations of TnI when compared with other studies of ISO-induced myocardial injury. Our histopathological analysis, in agreement with other studies of experimental animal models and clinical cases of TTS, showed only the presence of focal injury of cardiomyocytes scattered between normal cardiomyocytes, therefore the area of myocardial necrosis was relatively small [21,26,63]. A hypothetical mechanism that may be responsible for the lower plasma concentration of TnI in TTS is the dominance of the programmed type of cardiomyocyte cell death.…”

“…The current study is a continuation of our previous reports regarding a female rat model of TTS, where we observed apoptosis in cardiomyocytes 24 h after ISO administration and presence of mild fibrosis, a characteristic feature of TTS, during both the acute and recovery phases [13,26]. To the best of our knowledge, this is the first study showing the activation of necroptosis and pyroptosis pathways in the rat model of ISO-induced TTS.…”

“…Trichrome blue staining also showed mild fibrosis, which is characteristic of TTS, during both the acute and recovery phases. As a result, our research aimed to explore the presence of other forms of cell death throughout the course of TTS [13,26]. The aim of the current study was to evaluate the presence and dynamics of inflammatory-related types of cell death, namely necroptosis and pyroptosis, in the experimental menopause female rat model of isoprenaline (ISO)-induced Takotsubo syndrome.…”

Takotsubo Syndrome: Translational Implications and Pathomechanisms

“…Of note, the isoprenaline (ISO)-induced female TTS rat model needs a higher triggering dose and has a lower mortality than that of male TTS rats [190]. This may be related to the fact that estrogen has a vasodilator effect through the induction and activation of endothelial nitric oxide synthase, and the reduction of estrogen may interfere with coronary microcirculation by indirect action on the nervous system and by direct action on the heart vessels [119,187].…”

“…The animal models of TTS are mainly based on monkeys, rabbits, rats and mice, which can be used to simulate TTS to a certain extent through immobilization, repeated intravenous infusion of an epinephrine overdose, vagal stimulation, intraperitoneally isoprenaline and other methods [152][153][154][182][183][184][185][186][187][188][190][191][192][193][194][195][197][198][199][200][201][202][203][204][205][206]. Many live-stranded cetaceans and terrestrial wildlife experienced capture myopathy, which was similar to TTS [207,208].…”