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

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.

STereotactic Arrhythmia Radioablation (STAR): the Standardized Treatment and Outcome Platform for Stereotactic Therapy Of Re-entrant tachycardia by a Multidisciplinary consortium (STOPSTORM.eu) and review of current patterns of STAR practice in Europe

“…Almost all centres use a single dose of 25 Gy at the time, while some centres began looking into dose modification based on recent findings from radiation biology studies. 14 , 15 , 17 However, the methods of planning margins, dose prescription, target coverage, dose (in)homogeneity, and treatment duration vary greatly. Inconsistent documentation further complicates comparability between institutions and even systems.…”

Short-term and long-term effects of noninvasive cardiac radioablation for ventricular tachycardia: A single-center case series

“…Recent study with human cardiomyocyte showed increased conduction velocity after irradiation, which gives clue for the interpretation of our findings. 24 In contrast, a conflicting result that cardiac radioablation did not affect the conduction velocity was also reported. 3 However, we suppose that the change of coupling interval is attributable to the interaction between diseased tissue and normal adjacent cells that is yet to be identified.…”

STereotactic Arrhythmia Radioablation: current status of the art. The old world and the new world connected

“…15 Recently, Kim et al have produced a report outlining a fascinating number of possible mechanisms. 16 In this sophisticated and intricate study, human-induced pluripotent stem cell-derived cardiomyocytes were monitored with a multi-electrode array recording system to use field potential duration as a surrogate for QT interval analysis. In summary, they identified the following: 1.…”

“…Researchers in multiple sites are beginning to look at dose de-escalation, although 25 Gy may be the optimal dose based on preclinical and clinical results from two studies. In the first study by Kim et al, 16 the electrical activity of cloned human-induced pluripotent stem cell-derived cardiomyocytes was studied after exposures to multiple-dose regimen of single fraction radiotherapy. Single doses of 20,25,30,40 and 50 Gy were delivered to the cells and compared to unirradiated cells as a control.…”