Impact of High-Dose Irradiation on Human iPSC-Derived Cardiomyocytes Using Multi-Electrode Arrays: Implications for the Antiarrhythmic Effects of Cardiac Radioablation.

Jae Sik Kim,Myung-Jin Cha,Chang Heon Choi,Ji Hyun Chang,Yun-Gwi Park,Seong Woo Choi,Sung Joon Kim

doi:10.3390/ijms23010351

Abstract

Cardiac radioablation is emerging as an alternative option for refractory ventricular arrhythmias. However, the immediate acute effect of high-dose irradiation on human cardiomyocytes remains poorly known. We measured the electrical activities of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) upon irradiation with 0, 20, 25, 30, 40, and 50 Gy using a multi-electrode array, and cardiomyocyte function gene levels were evaluated. iPSC-CMs showed to recover their electrophysiological activities (total active electrode, spike amplitude and slope, and corrected field potential duration) within 3–6 h from the acute effects of high-dose irradiation. The beat rate immediately increased until 3 h after irradiation, but it steadily decreased afterward. Conduction velocity slowed in cells irradiated with ≥25 Gy until 6–12 h and recovered within 24 h; notably, 20 and 25 Gy-treated groups showed subsequent continuous increase. At day 7 post-irradiation, except for cTnT, cardiomyocyte function gene levels increased with increasing irradiation dose, but uniquely peaked at 25–30 Gy. Altogether, high-dose irradiation immediately and reversibly modifies the electrical conduction of cardiomyocytes. Thus, compensatory mechanisms at the cellular level may be activated after the high-dose irradiation acute effects, thereby, contributing to the immediate antiarrhythmic outcome of cardiac radioablation for refractory ventricular arrhythmias.

Highlights

We first assessed the electrical activities of human iPSC-CMs using the multielectrode array (MEA) recording system for 7 days after irradiation with 0, 20, 25, 30, 40, and 50 Gy (Figure 1a)
We evaluated percent changes as the outcomes of the records, defined by differences from the baseline of each radiation dose group as all the baseline parameters on day 0 were relatively dispersed among different radiation dose groups
It takes months for fibrosis to occur, which is not enough to explain the immediate antiarrhythmic several months for fibrosis to occur, which is not enough to explain the immediate antieffect of radioablation

Summary

Introduction

Sudden cardiac death accounts for more than 60% of all cardiovascular-related deaths, raising crucial health issues individually and socioeconomically [1]. Among several risk factors of this global leading death cause, ventricular arrhythmias (VAs) are an important problem [1]. Considerable therapeutic advancement has been made for VAs, including antiarrhythmic drugs or catheter ablation that successfully manage these events, and implantable cardioverter-defibrillator that reduces sudden cardiac deaths [2,3]. Up to about 50% of treated patients experience VA recurrence [4]

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