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Microsecond pulsed electric fields induce myocardial ablation by secondary mitochondrial damage and cell death
Qiqi Gao1, Mengjia Zhang1, Ruoshi Chen2
1Department of Pathology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310012, Zhejiang, China.
Abstract:
Microsecond pulsed electric field (µsPEF) is a newer treatment modality to replace catheter ablation treatment of Atrial fibrillation (AF) due to its fewer side effects. This study aims to find out experimental parameters that effectively induce cardiomyocyte death and the precise mechanisms for microsecond pulsed electric fields (µsPEFs) ablation of cardiomyocytes. CCK8 and flow apoptosis analysis were employed to examine the effects of different µsPEFs on cardiomyocytes in vitro. The mechanisms by which the µsPEFs ablation works were explored through a combination of transcriptome study, transmission electron microscope (TEM) observation of mitochondria, pathway enrichment analysis, and interaction network analysis. In vivo experiments on mice involving HE, Masson, TUNEL and Immunofluorescence staining examinations were conducted to confirm the in vitro experimental results. When more than 30 pulses were applied, a continuous decline in post-ablation relative cell activity was observed, decreasing from 0.36 at 3 h to 0.13 (p < 0.01) at 48 h. Notably, at a voltage of 1500 V/cm and a pulse count of 50, the apoptosis rate exceeded 95%, coupled with a more stable and consistent cell ablation. Following ablation, a notable upregulation in mitochondria-related transcription levels was observed, accompanied by mitochondrial membrane disruption and an increase in Cytochrome C levels. Within a certain range, an increase in voltage and number of electric pulses corresponded to a greater quantity of cell mortality in the ablation zone. The µsPEFs induced cell injury by impairing mitochondrial function and potentially triggering the mitochondrial apoptosis pathway.
Insights
Microsecond pulsed electric fields (µsPEFs) offer a safer alternative for Atrial fibrillation ablation. This study identified optimal parameters for µsPEFs to induce cardiomyocyte death by impairing mitochondrial function and apoptosis.
Area of Science:
- Cardiovascular Science
- Biophysics
- Cell Biology
Background:
- Atrial fibrillation (AF) ablation traditionally uses catheter-based methods with potential side effects.
- Microsecond pulsed electric fields (µsPEFs) present a novel, potentially safer alternative for AF treatment.
- Understanding µsPEFs' cellular mechanisms is crucial for optimizing this therapeutic approach.
Purpose of the Study:
- To determine effective experimental parameters for µsPEF-induced cardiomyocyte death.
- To elucidate the precise molecular and cellular mechanisms underlying µsPEF ablation of cardiomyocytes.
- To validate in vitro findings with in vivo experiments.
Main Methods:
- In vitro studies utilized CCK8 and flow cytometry to assess cardiomyocyte viability and apoptosis under varying µsPEF conditions.
- Transcriptome analysis, transmission electron microscopy (TEM) of mitochondria, pathway enrichment, and network analysis explored ablation mechanisms.
- In vivo validation involved HE, Masson, TUNEL, and immunofluorescence staining in mouse models.
Main Results:
- Optimal ablation was achieved with 50 pulses at 1500 V/cm, resulting in >95% apoptosis and consistent cell death.
- Increased voltage and pulse number correlated with higher cell mortality within the ablation zone.
- µsPEFs induced significant mitochondrial dysfunction, including membrane disruption and increased Cytochrome C release, alongside upregulated mitochondrial gene expression.
Conclusions:
- Microsecond pulsed electric fields effectively induce cardiomyocyte apoptosis through mitochondrial pathway disruption.
- µsPEFs demonstrate a dose-dependent effect on cell mortality, with specific parameters yielding high ablation efficiency.
- This modality shows promise as a safer and effective alternative to catheter ablation for Atrial fibrillation.
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