TY - JOUR
T1 - Utilizing Human-Induced Pluripotent Stem Cells to Study Cardiac Electroporation Pulsed-Field Ablation
AU - Maizels, Leonid
AU - Heller, Eyal
AU - Landesberg, Michal
AU - Glatstein, Shany
AU - Huber, Irit
AU - Arbel, Gil
AU - Gepstein, Amira
AU - Aronson, Doron
AU - Sharabi, Shirley
AU - Beinart, Roy
AU - Segev, Amit
AU - Maor, Elad
AU - Gepstein, Lior
N1 - Publisher Copyright:
© 2024 Lippincott Williams and Wilkins. All rights reserved.
PY - 2024/3/1
Y1 - 2024/3/1
N2 - BACKGROUND: Electroporation is a promising nonthermal ablation method for cardiac arrhythmia treatment. Although initial clinical studies found electroporation pulsed-field ablation (PFA) both safe and efficacious, there are significant knowledge gaps concerning the mechanistic nature and electrophysiological consequences of cardiomyocyte electroporation, contributed by the paucity of suitable human in vitro models. Here, we aimed to establish and characterize a functional in vitro model based on human-induced pluripotent stem cells (hiPSCs)-derived cardiac tissue, and to study the fundamentals of cardiac PFA. METHODS: hiPSC-derived cardiomyocytes were seeded as circular cell sheets and subjected to different PFA protocols. Detailed optical mapping, cellular, and molecular characterizations were performed to study PFA mechanisms and electrophysiological outcomes. RESULTS: PFA generated electrically silenced lesions within the hiPSC-derived cardiac circular cell sheets, resulting in areas of conduction block. Both reversible and irreversible electroporation components were identified. Significant electroporation reversibility was documented within 5 to 15-minutes post-PFA. Irreversibly electroporated regions persisted at 24-hours post-PFA. Per single pulse, high-frequency PFA was less efficacious than standard (monophasic) PFA, whereas increasing pulse-number augmented lesion size and diminished reversible electroporation. PFA augmentation could also be achieved by increasing extracellular Ca2+levels. Flow-cytometry experiments revealed that regulated cell death played an important role following PFA. Assessing for PFA antiarrhythmic properties, sustainable lines of conduction block could be generated using PFA, which could either terminate or isolate arrhythmic activity in the hiPSC-derived cardiac circular cell sheets. CONCLUSIONS: Cardiac electroporation may be studied using hiPSC-derived cardiac tissue, providing novel insights into PFA temporal and electrophysiological characteristics, facilitating electroporation protocol optimization, screening for potential PFA-sensitizers, and investigating the mechanistic nature of PFA antiarrhythmic properties.
AB - BACKGROUND: Electroporation is a promising nonthermal ablation method for cardiac arrhythmia treatment. Although initial clinical studies found electroporation pulsed-field ablation (PFA) both safe and efficacious, there are significant knowledge gaps concerning the mechanistic nature and electrophysiological consequences of cardiomyocyte electroporation, contributed by the paucity of suitable human in vitro models. Here, we aimed to establish and characterize a functional in vitro model based on human-induced pluripotent stem cells (hiPSCs)-derived cardiac tissue, and to study the fundamentals of cardiac PFA. METHODS: hiPSC-derived cardiomyocytes were seeded as circular cell sheets and subjected to different PFA protocols. Detailed optical mapping, cellular, and molecular characterizations were performed to study PFA mechanisms and electrophysiological outcomes. RESULTS: PFA generated electrically silenced lesions within the hiPSC-derived cardiac circular cell sheets, resulting in areas of conduction block. Both reversible and irreversible electroporation components were identified. Significant electroporation reversibility was documented within 5 to 15-minutes post-PFA. Irreversibly electroporated regions persisted at 24-hours post-PFA. Per single pulse, high-frequency PFA was less efficacious than standard (monophasic) PFA, whereas increasing pulse-number augmented lesion size and diminished reversible electroporation. PFA augmentation could also be achieved by increasing extracellular Ca2+levels. Flow-cytometry experiments revealed that regulated cell death played an important role following PFA. Assessing for PFA antiarrhythmic properties, sustainable lines of conduction block could be generated using PFA, which could either terminate or isolate arrhythmic activity in the hiPSC-derived cardiac circular cell sheets. CONCLUSIONS: Cardiac electroporation may be studied using hiPSC-derived cardiac tissue, providing novel insights into PFA temporal and electrophysiological characteristics, facilitating electroporation protocol optimization, screening for potential PFA-sensitizers, and investigating the mechanistic nature of PFA antiarrhythmic properties.
KW - arrhythmia, cardiac
KW - electroporation
KW - human induced pluripotent stem cell
KW - voltage-sensitive dye imaging
UR - http://www.scopus.com/inward/record.url?scp=85188258310&partnerID=8YFLogxK
U2 - 10.1161/CIRCEP.123.012278
DO - 10.1161/CIRCEP.123.012278
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C2 - 38344845
AN - SCOPUS:85188258310
SN - 1941-3149
VL - 17
SP - E012278
JO - Circulation: Arrhythmia and Electrophysiology
JF - Circulation: Arrhythmia and Electrophysiology
IS - 3
ER -