Glucose Counteracts Isoprenaline Effects on Ion Channel Functions in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Lin Qiao,Ibrahim Akin,Ibrahim El-Battrawy,Xuehui Fan,Xiaobo Zhou,Zhen Yang

doi:10.3390/jcdd9030076

Abstract

Recent studies indicate that the disorder of glucose metabolism in myocardial tissue is involved in the development of Takotsubo syndrome (TTS). This study investigated the effects of a high level of glucose on the pathogenesis of TTS, focusing on the electrophysiological mechanisms. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were treated with toxic concentration of isoprenaline (Iso, 1 mM) and a high level of glucose (22 mM) to mimic the setting of TTS and diabetes mellitus (DM). Iso prolonged action potential duration (APD) through enhancing the late sodium channel current and suppressing the transient outward potassium current (Ito). However, a high level of glucose prevented the APD prolongation and the change in Ito. High-level glucose reduced the expression levels of PI3K/Akt, β1-adrenoceptors, Gs-protein, and PKA, suggesting their involvement in the protective effects of high-level glucose against toxic effects of catecholamine. High glucose level did not influence Iso-induced ROS-generation, suggesting that the protective effects of high-level glucose against Iso did not result from changes in ROS generation. High-level glucose may protect cardiomyocytes from the toxic effects of catecholamine excess through suppressing β1-adrenoceptor-Gs-PKA signaling. DM may reduce the risk for occurrence of arrhythmias due to QT prolongation in TTS patients.

Highlights

Takotsubo syndrome (TTS), which is known as “stress induced cardiomyopathy”, was first described in Japan in 1990
To examine the influences of high level of blood sugar in diabetes on phenotypic feature of TTS, the hiPSC-CMs were pre-treated with a high level of glucose (22 mM) for 14 days to mimic the setting of diabetes and treated with a high concentration of Iso (1 mM) for 1 h to mimic the setting of TTS with catecholamine excess
Given that all the results shown above were obtained from experiments in hiPSC-CMs from only one healthy donor (D1), some key experiments were repeated in hiPSC-CMs from the other two healthy subjects—donor 2 (D2) and donor 3 (D3)

Summary

Introduction

Takotsubo syndrome (TTS), which is known as “stress induced cardiomyopathy”, was first described in Japan in 1990. It is characterized by transient systolic dysfunction of the apical and middle segments of the left ventricle, with clinical features of myocardial infarction but without obstructive coronary artery disease (CAD) [1]. About 20% of TTS patients have severe cardiac complications in the acute phase, which is comparable with acute coronary syndrome (ACS) [2]. The critical complications associated with TTS include atrial fibrillation, ventricular arrhythmias, thrombus formation, and heart failure (HF) [3–9]. Acquired long QT syndrome (LQTs) was described in almost 50% of TTS patients and can lead to life-threatening arrhythmias (ACS) [2]. The exact mechanism of TTS is still unknown, it is generally accepted that the development of the disease is associated with catecholamine excess

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