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

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)

 

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

 

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.

 

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

 

See also —

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

Spoiler: Abstract

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)

 

Some more recent major papers on TTS —

Machine learning-based prediction of in-hospital death for patients with takotsubo syndrome: The InterTAK-ML model (2023, European Journal of Heart Failure)

Cardiac biomarkers for diagnosing Takotsubo syndrome (2024, European Heart Journal)

Temporal Trends in Takotsubo Syndrome: Results From the International Takotsubo Registry (2024, Journal of the American College of Cardiology)