Key result
High concentration epinephrine induced arrhythmic events and prolonged action potential duration in hiPSC-CMs, effects that were attenuated by alpha-adrenoceptor blockade.
Why the study?
This study aimed to investigate the possible roles and underlying mechanisms of alpha-adrenoceptor-coupled signalling in the pathogenesis of Takotsubo syndrome.
Alpha 1-adrenoceptor signaling contributes to catecholamine-induced arrhythmogenesis in a cellular model of Takotsubo syndrome, highlighting a potential therapeutic role for alpha-blockers.
Alpha1 signaling contributes to catecholamine arrhythmogenesis in Takotsubo models; leaves open therapeutic translation of alpha-blockade.
AIMS: This study aimed to investigate possible roles and underlying mechanisms of alpha-adrenoceptor coupled signalling for the pathogenesis of Takotsubo syndrome (TTS). METHODS AND RESULTS: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were treated with a toxic concentration of epinephrine (Epi, 0.5 mM for 1 h) to mimic the setting of TTS. Patch-clamp technique, polymerase chain reaction (PCR) and Fluorescence-activated cell sorting (FACS) were employed for the study. High concentration Epi suppressed the depolarization velocity, prolonged duration of action potentials and induced arrhythmic events in hiPSC-CMs. The Epi effects were attenuated by an alpha-adrenoceptor blocker (phentolamine), suggesting involvement of alpha-adrenoceptor signalling in arrhythmogenesis related to QT interval prolongation in the setting of TTS. An alpha 1-adrenoceptor agonist (phenylephrine) but not an alpha 2-adrenoceptor agonist (clonidine) mimicked Epi effects. Epi enhanced ROS production, which could be attenuated by the alpha- adrenoceptor blocker. Treatment of cells with H2O2 (100 µM) mimicked the effects of Epi on action potentials and a reactive oxygen species (ROS)-blocker (N-acetyl-I-cysteine, 1 mM) prevented the Epi effects, indicating that the ROS signalling is involved in the alpha-adrenoceptor actions. Nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidases were involved in alpha 1-adrenoceptor signalling. A protein kinase C (PKC) blocker suppressed the effects of Epi, phenylephrine and ROS as well, implying that PKC participated in alpha 1-adrenoceptor signalling and acted as a downstream factor of ROS. The abnormal action potentials resulted from alpha 1-adrenoceptor activation-induced dysfunctions of ion channels including the voltage-dependent Na+ and L-type Ca2+ channels. CONCLUSIONS: Alpha 1-adrenoceptor signalling plays important roles for arrhythmogenesis of TTS. Alpha-adrenoceptor blockers might be clinically helpful for treating arrhythmias in patients with TTS.
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Huang et al. (2021) studied Takotsubo syndrome. Epinephrine was evaluated on Depolarization velocity, action potential duration, and arrhythmic events. High concentration epinephrine induced arrhythmic events and prolonged action potential duration in hiPSC-CMs, effects that were attenuated by alpha-adrenoceptor blockade.
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