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Stress (Takotsubo) cardiomyopathy—a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning

Abstract

Stress cardiomyopathy, also referred to as Takotsubo cardiomyopathy, is an increasingly recognized clinical syndrome characterized by acute reversible apical ventricular dysfunction. We hypothesize that stress cardiomyopathy is a form of myocardial stunning, but with different cellular mechanisms to those seen during transient episodes of ischemia secondary to coronary stenoses. In this syndrome, we believe that high levels of circulating epinephrine trigger a switch in intracellular signal trafficking in ventricular cardiomyocytes, from Gs protein to Gi protein signaling via the β2-adrenoceptor. Although this switch to β2-adrenoceptor–Gi protein signaling protects against the proapoptotic effects of intense activation of β1-adrenoceptors, it is also negatively inotropic. This effect is greatest at the apical myocardium, in which the β-adrenoceptor density is greatest. Our hypothesis has implications for the use of drugs or devices in the treatment of patients with stress cardiomyopathy.

Key Points

  • Stress cardiomyopathy is the result of the direct effects of high levels of epinephrine on the ventricular myocardium

  • High levels of epinephrine are negatively inotropic; they switch β2-adrenoceptor coupling in ventricular cardiomyocytes, from the Gs protein to the Gi protein signaling pathway

  • The density of β-adrenoceptors is greatest at the apical myocardium of the mammalian heart, which explains the regional nature of the stunning in response to high levels of circulating epinephrine after stressful stimuli

  • This effect is reversible after the epinephrine levels return to normal, which explains why left ventricular function and apical wall motion return to normal within days to weeks of the acute insult

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Figure 1: Left ventricular end systolic cardiac MRI.
Figure 2: Inotropic effects of epinephrine and norepinephrine.
Figure 3: Schematic representation of the regional differences in response to high catecholamine levels, explaining stress cardiomyopathy.

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Acknowledgements

Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Correspondence to Alexander R Lyon.

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Lyon, A., Rees, P., Prasad, S. et al. Stress (Takotsubo) cardiomyopathy—a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. Nat Rev Cardiol 5, 22–29 (2008). https://doi.org/10.1038/ncpcardio1066

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