High levels of circulating epinephrine trigger apical cardiodepression in a β2-adrenergic receptor/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 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.


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.
Myocardial Function Section, National Heart and Lung Inst, Imperial College London, London, United kingdom.
Helen
H
Paur
Myocardial Function Section, National Heart and Lung Inst, Imperial College London, London, United kingdom.
Peter T
PT
Wright
Myocardial Function Section, National Heart and Lung Inst, Imperial College London, London, United kingdom.
Markus B
MB
Sikkel
Myocardial Function Section, National Heart and Lung Inst, Imperial College London, London, United kingdom.
Matthew H
MH
Tranter
Myocardial Function Section, National Heart and Lung Inst, Imperial College London, London, United kingdom.
Catherine
C
Mansfield
Myocardial Function Section, National Heart and Lung Inst, Imperial College London, London, United kingdom.
Peter
P
O'Gara
Myocardial Function Section, National Heart and Lung Inst, Imperial College London, London, United kingdom.
Daniel J
DJ
Stuckey
Emmy Noether Group of the DFG, Dept of Cardiology and Pneumology, Georg August Univ medical Ctr, Göttingn Germany.
Viacheslav O
VO
Nikolaev
Myocardial Function Section, National Heart and Lung Inst, Imperial College London, London, United kingdom.
Ivan
I
Diakonov
Myocardial Function Section, National Heart and Lung Inst, Imperial College London, London, United kingdom.
Laura
L
Pannell
Xuzhou Cardiovascular Disease Inst.
Haibin
H
Gong
Physiology Dept, Xuzhou Medical College, Xuzhou, China.
Hong
H
Sun
Myocardial Function Section, National Heart and Lung Inst, Imperial College London, London, United kingdom.
Nicholas S
NS
Peters
Cardiovasular Biomedical Rsrch Unit, Royal Brompton Hosp, London, United Kingdom.
Mario
M
Petrou
Cardiology Dept, UBC Hosp, Vancouver, Canada.
Zhaolun
Z
Zheng
Myocardial Function Section, National Heart and Lung Inst, Imperial College London, London, United kingdom.
Julia
J
Gorelik
Myocardial Function Section, National Heart and Lung Inst, Imperial College London, London, United kingdom.|Cardiovasular Biomedical Rsrch Unit, Royal Brompton Hosp, London, United Kingdom.
Alexander R
AR
Lyon
Myocardial Function Section, National Heart and Lung Inst, Imperial College London, London, United kingdom.
Sian E
SE
Harding
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000097:blood; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004837:Epinephrine / Q000008:administration & dosage / Q000097:blood*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000819:agonists / Q000097:blood / Q000502:physiology*; D006801:Humans; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D054549:Takotsubo Cardiomyopathy / Q000097:blood*
D000889:Anti-Arrhythmia Agents; D018343:Receptors, Adrenergic, beta-2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D004837:Epinephrine