Editorial — Understanding Takotsubo syndrome: first evaluate your mouse model, 2023, Horowitz et al.

Takotsubo syndrome has been mentioned a couple of times on the forum. Some quotes from the editorial —

It is barely 30 years since Japanese investigators first described a syndrome that clinically resembled acute myocardial infarction, but which occurred irrespective of the presence or absence of epicardial coronary artery stenoses or occlusions. Although initially named “Takotsubo” and widely regarded as a cardiomyopathy, the newly identified condition had a number of unique features, including predominant occurrence in aging women, the induction of left and sometimes right ventricular systolic dysfunction that is usually, but not always apical, a high incidence of early, potentially life-threatening hypotension, and in many cases precipitation either by sudden severe emotional or physical stress or by administration of agents which increase plasma catecholamine concentrations.
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Finally, many patients eventually develop some degree of myocardial fibrosis. Furthermore, there is evidence that the spectrum of “Takotsubo” is not limited to this acute myocarditis but also involves an early arteritis, evidenced by retardation of coronary flow rates and release into plasma not only of myocardial proteins such as troponin and B-type natriuretic peptide (BNP) but also syndecan-1, the latter indicative of damage to the vascular glycocalyx (5), potentially contributing to vascular permeabilization, impaired vascular rheology, and hypotension.
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It is now appreciated that Takotsubo is in no way rare and is associated with considerable short- and long-term morbidity and mortality. Therefore, it is a considerable priority to develop effective treatments
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In a recent issue of the American Journal of Physiology-Heart and Circulatory Physiology, Hayashi et al. have used a mouse model where inferoapical hypokinesis of the left ventricle was induced by single intraperitoneal injection of isoproterenol into 10-wk-old male and female mice.
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Serial changes in behavior of the mice postinjection included an immobile period from 10 min postisoproterenol injection, lasting at least 60 min. Female mice recovered more rapidly than males, with complete recovery of spontaneous movement within 6 h, whereas some males had not recovered full locomotor activity within 3 days. There was also more prolonged and marked troponin I release in male mice, but mortality rates did not vary significantly according to sex. Cellular infiltration of left ventricular myocardium also differed according to sex, with more pronounced accumulation of neutrophils, monocytes, and macrophages in the hearts of male than female mice. Thus, the investigation revealed that many aspects of hemodynamic and cellular infiltrative changes postisoproterenol were more marked in male than in female mice.
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Of course, as the authors acknowledge, the study evaluated only some of the important parameters now recognized as components of Takotsubo syndrome, as summarized in Fig. 1. Specifically, there was no evaluation of extent of coronary circulatory impairment, including hyperresponsiveness to nitric oxide and inflammatory glycocalyx shedding, which together may predispose to development of severe and global myocardial edema, as well as facilitating transmigration of leukocytes from the circulation into the myocardium.
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Furthermore, it would have theoretically been desirable to assess the extent of biased post-β2-adrenoceptor signaling, since this appears to represent a pivotal aspect of the pathophysiology of Takotsubo syndrome.
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Referenced paper is —

Refining the reproducibility of a murine model of stress-induced reversible cardiomyopathy (2023, American Journal of Physiology-Heart and Circulatory Physiology)

Abstract
Despite the many advantages of isoproterenol (Iso)-induced models of cardiomyopathy, the extant literature suggests that the reproducibility of the Iso-induced stress cardiomyopathy phenotype varies considerably depending on the dose of Iso used, the mode of administration of Iso (subcutaneous vs. intraperitoneal), and the species of the animal that is being studied.

Recently, we have shown that a single injection of Iso into female C57BL/6J mice provokes transient myocardial injury that is characterized by a brisk release of troponin I within 1 h, as well as a self-limited myocardial inflammatory response that is associated with increased myocardial tissue edema, inferoapical regional left ventricular (LV) wall motion abnormalities, and a transient decrease in global LV function, which were completely recovered by day 7 after the Iso injection (i.e., stress-induced reversible cardiomyopathy).

Here we expand upon this initial report in this model by demonstrating important sexually dimorphic differences in the response to Iso-induced tissue injury, the ensuing myocardial inflammatory response, and changes in LV structure and function. We also provide information with respect to enhancing the reproducibility in this model by optimizing animal welfare during the procedure. The acute Iso-induced myocardial injury model provides a low-cost, relatively high-throughput small-animal model that mimics human disease (e.g., Takotsubo cardiomyopathy).

Given that the model can be performed in different genetic backgrounds, as well as different experimental conditions, the acute Iso injury model should provide the cardiovascular community with a valuable nonsurgical animal model for understanding the myocardial response to tissue injury.
 
The heart problems some people with LC experience might be similar. Many have various heart issues, including chest pain or other heart-attack-like symptoms without obvious damage to the heart.
 
See also —

Orexin/hypocretin system dysfunction in patients with Takotsubo syndrome: A novel pathophysiological explanation (2022)
Knez, Rajna; Niksic, Milan; Omerovic, Elmir

Takotsubo syndrome (TTS) is an acute heart failure syndrome. Emotional or physical stressors are believed to precipitate TTS, while the pathophysiological mechanism is not yet completely understood. During the coronavirus disease (COVID-19) pandemic, an increased incidence of TTS has been reported in some countries; however, the precise pathophysiological mechanism for developing TTS with acute COVID-19 infection is unknown. Nevertheless, observing the symptoms of COVID-19 might lead to new perspectives in understanding TTS pathophysiology, as some of the symptoms of the COVID-19 infection could be assessed in the context of an orexin/hypocretin-system dysfunction.

Orexin/hypocretin is a cardiorespiratory neuromodulator that acts on two orexin receptors widely distributed in the brain and peripheral tissues. In COVID-19 patients, autoantibodies against one of these orexin receptors have been reported. Orexin-system dysfunction affects a variety of systems in an organism.

Here, we review the influence of orexin-system dysfunction on the cardiovascular system to propose its connection with TTS. We propose that orexin-system dysfunction is a potential novel explanation for the pathophysiology of TTS due to direct or indirect dynamics of orexin signaling, which could influence cardiac contractility. This is in line with the conceptualization of TTS as a cardiovascular syndrome rather than merely a cardiac abnormality or cardiomyopathy.

To the best of our knowledge, this is the first publication to present a plausible connection between TTS and orexin-system dysfunction. We hope that this novel hypothesis will inspire comprehensive studies regarding orexin's role in TTS pathophysiology. Furthermore, confirmation of this plausible pathophysiological mechanism could contribute to the development of orexin-based therapeutics in the treatment and prevention of TTS.


Link | PDF (Frontiers in Cardiovascular Medicine) [Open Access]

Referenced in The Orexin System and Its Impact on the Autonomic Nervous and Cardiometabolic System in Post-Acute Sequelae of COVID-19 (2025, Biomedicines)
 
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