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New Discovery Puts Endothelial Dysfunction at the Heart of Broken Heart (Takotsubo) Syndrome

Free Radic Biol Med 2021 Apr 14 Special issue “Implications of oxidative stress and redox biochemistry for heart disease and cardioprotection” Takotsubo Syndrome: Impact of Endothelial Dysfunction and Oxidative Stress Thomas Münzel 1, Christian Templin 2, Victoria Lucia Cammann 2, Omar Hahad 3 Affiliations collapse Affiliations

  • 1 Department of Cardiology, University Medical Center of Johannes Gutenberg University Mainz, Mainz, Germany. Electronic address:

  • 2 Heart Center, University of Zürich, Switzerland.

  • 3 Department of Cardiology, University Medical Center of Johannes Gutenberg University Mainz, Mainz, Germany.

Abstract Takotsubo Syndrome (TTS) is characterized by a transient left ventricular dysfunction recovering spontaneously within days or weeks. Although the pathophysiology of TTS remains obscure, there is growing evidence suggesting TTS to be associated with increased production of reactive oxygen species (ROS), which may be involved in causing transient coronary and peripheral endothelial dysfunction leading to a transient impairment of myocardial contraction due to stunning (apical ballooning). Endothelial dysfunction is mainly caused by decreased vascular and myocardial nitric oxide bioavailability in response to increased ROS production. Accordingly, studies in humans and animal models demonstrated increased myocardial dihydroethidium staining of the myocardium in endomyocardial biopsy specimens, increased levels of hydrogen peroxide and malondialdehyde as well as reduced glutathione levels compatible with increased oxidative stress. As significant superoxide sources the mitochondria and the NADPH oxidase isoform NOX-4 and the NOX-2 regulating cytosolic subunit p67phox have been identified. Treatment with antioxidants such as sodium hydrosulfide reduced superoxide production in mitochondria and reduced expression of NOX-4 and p67phox, respectively. The presence of superoxide and nitric oxide also provides the basis for the concept of nitro-oxidative as well as nitrosative stress in TTS. Keywords: Takotsubo Syndrome; microvascular dysfunction; nitrosative and nitro-oxidative stress; oxidative stress.

Figure 1. Different methodologies to assess endothelial dysfunction in the setting of Takotsubo Syndrome (TTS). A: Flow-mediated dilation (FMD) of the brachial artery. TTS shows a decrease in FMD but not in nitroglycerin (GTN)-mediated vasodilation [18]. With permission. B: Change in coronary blood flow (CBF) in response to intracoronary acetylcholine. TTS patients had a clearly diminished increase in CBF pointing to coronary microvascular dysfunction [17]. With permission. C: Peripheral arterial tonometry (PAT) score in response to mental stress test in patients with TTS/apical ballooning syndrome (ABS), acute myocardial infarction (MI) and postmenopausal controls [16]. With permission. The images in the left panel were adopted from [28].


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