High Levels of Circulating Epinephrine Trigger Apical Cardiodepression in a β2-Adrenoceptor/Gi-Dependent Manner: A New Model of Takotsubo Cardiomyopathy
Background—Takotsubo cardiomyopathy is an acute heart failure syndrome characterized by myocardial hypocontractility from the mid left ventricle to 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 hypothesised that this represents switching of epinephrine signalling through the pleiotropic β2-adrenoceptor (β2AR) from canonical Gs-activated cardiostimulant to Gi-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 Gi inactivation by pertussis toxin pretreatment. β2AR number and functional responses were greater in isolated apical cardiomyocytes compared to basal cardiomyocytes, confirming higher apical sensitivity and response to circulating epinephrine. In vitro studies demonstrated high dose epinephrine can induce direct cardiomyocyte cardiodepression and cardioprotection in a β2AR-Gi dependent manner. Preventing epinephrine-Gi effects increased mortality in the Takotsubo model, while β-blockers which activate β2AR-Gi 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 β2AR-Gs at low and Gi at high concentrations underpins the acute apical cardiodepression observed in Takotsubo cardiomyopathy, with an apical-basal gradient in β2ARs explaining the differential regional responses. We suggest this epinephrine-specific β2-Gi signalling may have evolved as a cardioprotective strategy to limit catecholamine-induced myocardial toxicity during acute stress.
- Received April 10, 2012.
- Accepted June 19, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited