High levels of circulating epinephrine trigger apical cardiodepression in a β2-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy

Circulation. 2012 Aug 7;126(6):697-706. doi: 10.1161/CIRCULATIONAHA.112.111591. Epub 2012 Jun 25.


Background: Takotsubo cardiomyopathy is an acute heart failure syndrome characterized by myocardial hypocontractility from the mid left ventricle to the apex. It is precipitated by extreme stress and can be triggered by intravenous catecholamine administration, particularly epinephrine. Despite its grave presentation, Takotsubo cardiomyopathy is rapidly reversible, with generally good prognosis. We hypothesized that this represents switching of epinephrine signaling through the pleiotropic β(2)-adrenergic receptor (β(2)AR) from canonical stimulatory G-protein-activated cardiostimulant to inhibitory G-protein-activated cardiodepressant pathways.

Methods and results: We describe an in vivo rat model in which a high intravenous epinephrine, but not norepinephrine, bolus produces the characteristic reversible apical depression of myocardial contraction coupled with basal hypercontractility. The effect is prevented via G(i) inactivation by pertussis toxin pretreatment. β(2)AR number and functional responses were greater in isolated apical cardiomyocytes than in basal cardiomyocytes, which confirmed the higher apical sensitivity and response to circulating epinephrine. In vitro studies demonstrated high-dose epinephrine can induce direct cardiomyocyte cardiodepression and cardioprotection in a β(2)AR-Gi-dependent manner. Preventing epinephrine-G(i) effects increased mortality in the Takotsubo model, whereas β-blockers that activate β(2)AR-G(i) exacerbated the epinephrine-dependent negative inotropic effects without further deaths. In contrast, levosimendan rescued the acute cardiac dysfunction without increased mortality.

Conclusions: We suggest that biased agonism of epinephrine for β(2)AR-G(s) at low concentrations and for G(i) at high concentrations underpins the acute apical cardiodepression observed in Takotsubo cardiomyopathy, with an apical-basal gradient in β(2)ARs explaining the differential regional responses. We suggest this epinephrine-specific β(2)AR-G(i) signaling may have evolved as a cardioprotective strategy to limit catecholamine-induced myocardial toxicity during acute stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Arrhythmia Agents / administration & dosage
  • Anti-Arrhythmia Agents / blood
  • Cells, Cultured
  • Disease Models, Animal*
  • Epinephrine / administration & dosage
  • Epinephrine / blood*
  • GTP-Binding Protein alpha Subunits, Gi-Go / agonists
  • GTP-Binding Protein alpha Subunits, Gi-Go / blood
  • GTP-Binding Protein alpha Subunits, Gi-Go / physiology*
  • Humans
  • Male
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, beta-2 / physiology*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Takotsubo Cardiomyopathy / blood*


  • Anti-Arrhythmia Agents
  • Receptors, Adrenergic, beta-2
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • Epinephrine