Abstract
Takotsubo syndrome (TTS) is identified as an acute severe ventricular systolic dysfunction, which is usually characterized by reversible and transient akinesia of walls of the ventricle in the absence of a significant obstructive coronary artery disease (CAD). Patients present with chest pain, ST-segment elevation or ischemia signs on ECG and increased troponin, similar to myocardial infarction. Currently, the known mechanisms associated with the development of TTS include elevated levels of circulating plasma catecholamines and their metabolites, coronary microvascular dysfunction, sympathetic hyperexcitability, inflammation, estrogen deficiency, spasm of the epicardial coronary vessels, genetic predisposition and thyroidal dysfunction. However, the real etiologic link remains unclear and seems to be multifactorial. Currently, the elusive pathogenesis of TTS and the lack of optimal treatment leads to the necessity of the application of experimental models or platforms for studying TTS. Excessive catecholamines can cause weakened ventricular wall motion at the apex and increased basal motion due to the apicobasal adrenoceptor gradient. The use of beta-blockers does not seem to impact the outcome of TTS patients, suggesting that signaling other than the beta-adrenoceptor-associated pathway is also involved and that the pathogenesis may be more complex than it was expected. Herein, we review the pathophysiological mechanisms related to TTS; preclinical TTS models and platforms such as animal models, human-induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) models and their usefulness for TTS studies, including exploring and improving the understanding of the pathomechanism of the disease. This might be helpful to provide novel insights on the exact pathophysiological mechanisms and may offer more information for experimental and clinical research on TTS.
Highlights
Takotsubo syndrome (TTS), known as Takotsubo cardiomyopathy (TTC) or broken heart syndrome or stress-induced cardiomyopathy, is a type of acute heart failure syndrome characterized by an acute, transient and reversible left ventricular (LV) systolic dysfunction with apical ballooning and ST-segment elevation or T-wave inversion in the absence of obstructive coronary artery disease (CAD), which is often associated with emotional or physical stress [1,2]
TTS was first described in Japan in 1990, in five cases of typical cardiac arrest patients suffering from chest pain with abnormal electrocardiogram, similar to acute myocardial infarction (AMI), but without evidence of coronary artery stenosis on angiography (CAG) [4]
Our group found that a high concentration of isoprenaline prolonged action potential duration (APD) via increasing reactive oxygen species (ROS) production, enhancing the late sodium channel current and suppressing the transient outward potassium current (Ito) [14]. These results suggest that ROS participates in beta and alpha 1-adrenoceptor signaling at high concentrations of catecholamines, which may contribute to the pathogenesis of TTS
Summary
Takotsubo syndrome (TTS), known as Takotsubo cardiomyopathy (TTC) or broken heart syndrome or stress-induced cardiomyopathy, is a type of acute heart failure syndrome characterized by an acute, transient and reversible left ventricular (LV) systolic dysfunction with apical ballooning and ST-segment elevation or T-wave inversion in the absence of obstructive coronary artery disease (CAD), which is often associated with emotional or physical stress [1,2]. The development of neurogenic cardiomyopathy (NC) is mainly associated with an elevated plasma norepinephrine (NE) level, which is mediated by neuronal NE rather than adrenal epinephrine (EPI) [10]. Both a surge in catecholamine secretion in the first hour of brain death and a deficiency in the following hours are causes of cardiac stunning and altered vascular reactivity in NS [11]. The suggested mechanisms associated with the development of TTS include elevated levels of circulating plasma catecholamines and its metabolites, coronary microvascular dysfunction, sympathetic hyperexcitability, inflammation, estrogen deficiency, basal hypercontractility with left ventricular outflow tract obstruction and signal trafficking/biased agonism, spasm of the epicardial coronary vessels, genetic predisposition and thyroidal dysfunction [12–17]. We focus on reviewing the existing TTS models and pathogenesis of TTS to gain a better understanding of the underlying mechanism of this disease
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