Novel rat model reveals important roles of β-adrenoreceptors in stress-induced cardiomyopathy ☆ Yangzhen Shao a, 1 , Bjorn Redfors a, ⁎ , 1 , Margareta Scharin Täng a , Helge Möllmann b, c , Christian Troidl b, c , Sebastian Szardien b , Christian Hamm b, c , Holger Nef b, c , Jan Borén a , Elmir Omerovic a a Wallenberg Laboratory at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden b Department of Cardiology, Kerckhoff Heart and Thorax Center, Bad Nauheim, Germany c University of Giessen, Department of Cardiology, Giessen, Germany abstract article info Article history: Received 24 May 2012 Received in revised form 6 December 2012 Accepted 27 December 2012 Available online 26 January 2013 Keywords: Takotsubo cardiomyopathy Stress-induced cardiomyopathy (SIC) β-adrenoreceptors (β-ARs) Gi-protein pathway, myocardial metabolism Rat model Background: Stress-induced cardiomyopathy (SIC), also known as Takotsubo cardiomyopathy, is an acute car- diac syndrome with substantial morbidity and mortality. The unique hallmark of SIC is extensive ventricular akinesia involving apical segments with preserved function in basal segments. Adrenergic overstimulation plays an important role in initiating SIC but the pathophysiological pathways and receptors involved are unknown. Methods: Sprague Dawley rats (~ 300 g) were injected with a single dose of the β-adrenergic agonist isopren- aline (ISO, i.p.) and echocardiography was used to study cardiac function. The akinetic part of the left ventri- cle was biopsied in six SIC patients. Amount of intracellular lipid and glycogen as well as degree of permanent cardiac damage were assessed by histology. Results: In rats, ISO at doses ≥50 mg/kg induced severe SIC-like regional akinesia that completely resolved within seven days. Intracellular lipid content was higher in akinetic, but not in normokinetic myocardium in both SIC patients and rats. β2-receptor blockade or Gi-pathway inhibition was associated with less wide- spread akinesia and low lipid accumulation but significantly increased acute mortality. Conclusions: We provide a novel rat model of SIC that supports the hypothesis of circulating catecholamines as initiators of SIC. We propose that the β-adrenoreceptor pathway is important in the setting of severe catecholamine overstimulation and that perturbations of cardiac metabolism occur in SIC. © 2013 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Stress-induced cardiomyopathy (SIC) also known as takotsubo cardiomyopathy is an increasingly recognized syndrome character- ized by severe regional left ventricular (LV) dysfunction that is not caused by the occlusion of coronary arteries. The predominant presentation of SIC is widespread akinesia in the apical segments and hyperkinesia in the basal segments. This extensive organ dys- function is reversible if the patient survives the acute phase, but may lead to lethal complications, including malignant arrhythmias, ventricular rupture and cardiogenic shock. Although, there is increas- ing evidence that short- and long-term prognosis for patients with SIC is not better than the prognosis for patients with acute myocardial infarction [1–4], we currently lack guidelines for the diagnosis, treat- ment and follow-up of SIC patients. SIC patients are often treated sim- ilar to patients with acute coronary events or heart failure, which may worsen their condition [2,5]. Our understanding of the pathomechanisms underlying SIC be- yond adrenergic overstimulation is limited [6]. Several small clinical studies have shown that SIC is associated with myocardial metabolic derangements, e.g. decreased uptake of lipid and glucose in the akinetic myocardium [7]. This “metabolic stunning” has been pro- posed to occur due to a switch in intracellular trafficking from Gs pro- tein to Gi protein signaling, mediated by β2-adrenoceptors (β2-AR) [8–10]. Such a metabolic switch may protect the myocardium against the toxic effects of intense β1-AR activation. The development of an- imal models is important to elucidate the mechanisms behind this syndrome and develop evidence-based treatment guidelines. Here, we present a novel rat model of SIC that reproduces the characteristic SIC phenomena. We then used this rat model to address whether metabolic dysfunction is associated with cardiac dysfunction of SIC through activation of the β2-AR–Gi pathway. International Journal of Cardiology 168 (2013) 1943–1950 ☆ The study was supported by the Swedish Heart and Lung Foundation, the Swedish Scientific Research Council and the University of Gothenburg, Sweden. ⁎ Corresponding author at: Bruna stråket 16, SE 413 45 Göteborg, Sweden. Tel.: + 46 31 343 7560; fax: +46 31 823 762. E-mail address: bjorn.redfors@wlab.gu.se (B. Redfors). 1 Contributed equally. 0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2012.12.092 Contents lists available at ScienceDirect International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard