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

SNT Gatchaman · Apr 2, 2023

Understanding Takotsubo syndrome: first evaluate your mouse model
John D. Horowitz; Sven Y. Surikow

Editorial. No abstract.

Link | Paywalled (American Journal of Physiology-Heart and Circulatory Physiology)

SNT Gatchaman · Apr 2, 2023

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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SNT Gatchaman · Apr 2, 2023

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.

SNT Gatchaman · Aug 22, 2023

See also Pivotal role of early coronary microvascular dysfunction in Takotsubo Syndrome (2023, Preprint: MedRxiv)

RedFox · Aug 22, 2023

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.

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

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

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