Irreversible Electroporation Research Articles

Change in tissue resistance after irreversible electroporation in liver tumors as an indicator of treatment success - A multi-center analysis with long term follow-up

IntroductionA nationwide multicenter study was performed to examine whether there is a correlation between decrease in tissue resistance and time to local tumor recurrence after irreversible electroporation (IRE) in patients with hepatocellular carcinoma (HCC) and colorectal cancer liver metastases (CRCLM). MethodsAll patients treated with IRE for liver tumors in Sweden from 2011 until 2018 were included. Patient characteristics and recurrence patterns were obtained from medical records and radiological imaging. All procedural data from the IRE hardware at the three hospitals performing IRE were retrieved. The resistance during each pulse and the change during each treatment were calculated. The electrode pair with the smallest decrease in tissue resistance was used and compared with the time to LTP. Results149 patients with 206 tumors were treated. Exclusion due to missing and inaccurate data resulted in 124 patients with 170 tumors for the analyses. In a multivariable Cox regression model, a smaller decrease in tissue resistance and larger tumor size were associated with shorter time to local tumor recurrence for CRCLM, but not for HCC. ConclusionThere was an association between a decrease in tissue resistance and time to local tumor recurrence for CRCLM. The decrease in resistance, in combination with a rise in current, may be the parameters the interventionist should use during IRE to decide if the treatment is successful.

IRE made easy: introducing the robotic grid system for multiple parallel needle insertion in irreversible electroporation treatment

PurposeAccurate needle placement is crucial for successful tumor treatment using the irreversible electroporation (IRE) method. Multiple needles are inserted around the tumor, ideally in parallel, to achieve uniform electric field distribution. This paper presents a robot utilizing a grid system to enable multiple needles insertion while maintaining parallelism between them.MethodsThe robotic system has two degrees of freedom, which allow for the adjustment of the grid system to accommodate targeting lesions in various positions. The robot’s performance was evaluated by testing its accuracy across various configurations and target depth locations, as well as its ability to maintain the needle parallelism.ResultsThe robot has dimensions of ϕ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\\phi }$$\\end{document} 134 mm and a height of 46 mm, with a total weight of 295 g. The system accuracy test showed that the robot can precisely target points across different target depths and needle orientations, with an average error of 2.71±0.68\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$2.71\\pm 0.68$$\\end{document} mm. Moreover, multiple insertions at different grid locations reveal needle orientation deviations typically below 1∘\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$1^{\\circ }$$\\end{document}.ConclusionThis study presented the design and validation of a robotic grid system. The robot is capable of maintaining insertion accuracy and needle parallelism during multiple needle insertions at various robot configurations. The robot showed promising results with limited needle deviation, making it suitable for IRE procedures.

Probability and kinetics of rupture and electrofusion in giant unilamellar vesicles under various frequencies of direct current pulses.

Irreversible electroporation induces permanent permeabilization of lipid membranes of vesicles, resulting in vesicle rupture upon the application of a pulsed electric field. Electrofusion is a phenomenon wherein neighboring vesicles can be induced to fuse by exposing them to a pulsed electric field. We focus how the frequency of direct current (DC) pulses of electric field impacts rupture and electrofusion in cell-sized giant unilamellar vesicles (GUVs) prepared in a physiological buffer. The average time, probability, and kinetics of rupture and electrofusion in GUVs have been explored at frequency 500, 800, 1050, and 1250 Hz. The average time of rupture of many 'single GUVs' decreases with the increase in frequency, whereas electrofusion shows the opposite trend. At 500 Hz, the rupture probability stands at 0.45 ± 0.02, while the electrofusion probability is 0.71 ± 0.01. However, at 1250 Hz, the rupture probability increases to 0.69 ± 0.03, whereas the electrofusion probability decreases to 0.46 ± 0.03. Furthermore, when considering kinetics, at 500 Hz, the rate constant of rupture is (0.8 ± 0.1)×10-2 s-1, and the rate constant of fusion is (2.4 ± 0.1)×10-2 s-1. In contrast, at 1250 Hz, the rate constant of rupture is (2.3 ± 0.8)×10-2 s-1, and the rate constant of electrofusion is (1.0 ± 0.1)×10-2 s-1. These results are discussed by considering the electrical model of the lipid bilayer and the energy barrier of a prepore.

A Description and Safety Overview of Irreversible Electroporation for Prostate Tissue Ablation in Intermediate-Risk Prostate Cancer Patients: Preliminary Results from the PRESERVE Trial.

The PRESERVE study (NCT04972097) aims to evaluate the safety and effectiveness of the NanoKnife System to ablate prostate tissue in patients with intermediate-risk prostate cancer (PCa). The NanoKnife uses irreversible electroporation (IRE) to deliver high-voltage electrical pulses to change the permeability of cell membranes, leading to cell death. A total of 121 subjects with organ-confined PCa ≤ T2c, prostate-specific antigens (PSAs) ≤ 15 ng/mL, and a Gleason score of 3 + 4 or 4 + 3 underwent focal ablation of the index lesion. The primary endpoints included negative in-field biopsy and adverse event incidence, type, and severity through 12 months. At the time of analysis, the trial had completed accrual with preliminary follow-up available. Demographics, disease characteristics, procedural details, PSA responses, and adverse events (AEs) are presented. The median (IQR) age at screening was 67.0 (61.0-72.0) years and Gleason distribution 3 + 4 (80.2%) and 4 + 3 (19.8%). At 6 months, all patients with available data (n = 74) experienced a median (IQR) percent reduction in PSA of 67.6% (52.3-82.2%). Only ten subjects (8.3%) experienced a Grade 3 adverse event; five were procedure-related. No Grade ≥ 4 AEs were reported. This study supports prior findings that IRE prostate ablation with the NanoKnife System can be performed safely. Final results are required to fully assess oncological, functional, and safety outcomes.

Pulsed electric field performance calculator tool based on an in vitro human cardiac model.

Pulsed Field Ablation (PFA) is a novel non-thermal method for cardiac ablation, relying on irreversible electroporation induced by high-energy pulsed electric fields (PEFs) to create localized lesions in the heart atria. A significant challenge in optimizing PFA treatments is determining the lethal electric field threshold (EFT), which governs ablation volume and varies with PEF waveform parameters. However, the proprietary nature of device developer's waveform characteristics and the lack of standardized nonclinical testing methods have left optimal EFTs for cardiac ablation uncertain. To address this gap, we introduced a laboratory protocol employing human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in monolayer format to evaluate the impact of a range of clinically relevant biphasic pulse parameters on lethal EFT and adiabatic heating (AH). Cell death areas were assessed using fluorescent dyes and confocal microscopy, while lethal EFTs were quantified through comparison with electric field numerical simulations. Our study confirmed a strong correlation between cell death in hiPSC-CMs and the number and duration of pulses in each train, with pulse repetition frequency exerting a comparatively weaker influence. Fitting of these results through machine learning algorithms were used to develop an open-source online calculator. By estimating lethal EFT and associated temperature increases for diverse pulse parameter combinations, this tool, once validated, has the potential to significantly reduce reliance on animal models during early-stage device de-risking and performance assessment. This tool also offers a promising avenue for advancing PFA technology for cardiac ablation medical devices to enhance patient outcomes.

Irreversible Electroporation as a Valid Treatment Option for Hepatic Epithelioid Hemangioendothelioma: An International Multicenter Experience

PurposeHepatic epithelioid hemangioendothelioma (HEHE) is a rare tumor with currently no established standard of care. This international multicenter retrospective study assesses the use of percutaneous irreversible electroporation (IRE) as an ablative tool to treat HEHE and provides a clinical overview of the current management and role of IRE in HEHE treatment.Material and MethodsBetween 2017 and 2023, 14 patients with 47 HEHE tumors were treated with percutaneous IRE using CT-scan guidance in 23 procedures. Baseline patient and tumor characteristics were evaluated. Primary outcome measures included safety and effectiveness, analyzed using Common Terminology Criteria for Adverse Events (CTCAE) and treatment response by mRECIST criteria. Secondary outcome measures included technical success, post-treatment tumor sizes and length of hospital stay. Technical success was defined as complete ablation with an adequate ablative margin (intentional tumor free ablation margin > 5 mm).ResultsIRE treatment resulted in technical success in all tumors. Following a median follow-up of 15 months, 30 tumors demonstrated a complete response according to mRECIST criteria. The average tumor size pre-treatment was 25.8 mm, accompanied by an average reduction in tumor size by 7.5 mm. In 38 out of 47 tumors, there was no evidence of local recurrence. In nine tumors, residual tumor was present. There were no cases of progressive disease. Median length of hospital stay was one day. Only one grade 3 CTCAE event occurred, a pneumothorax requiring chest tube placement.ConclusionThe current study provides evidence that IRE is a safe and efficacious minimally invasive treatment option for HEHE.Graphical

Numerical simulation of neural excitation during brain tumor ablation by microsecond pulses

Replacing monopolar pulse with bipolar pulses of the same energized time can minimize unnecessary neurological side effects during irreversible electroporation (IRE). An improved neural excitation model that considers dynamic conductivity and thermal effects during brain tumor IRE ablation was proposed for the first time in this study. Nerve fiber excitation during IRE ablation by applying a monopolar pulse (100 μs) and a burst of bipolar pulses (energized time of 100 μs with both the sub-pulse length and interphase delay of 1 μs) was investigated. Our results suggest that both thermal effects and dynamic conductivity change the onset time of action potential (AP), and dynamic conductivity also changes the hyperpolarization amplitude. Considering both thermal effects and dynamic conductivity, the hyperpolarization amplitude in nerve fibers located 2 cm from the tumor center was reduced by approximately 23.8 mV and the onset time of AP was delayed by approximately 17.5 μs when a 500 V monopolar pulse was applied. Moreover, bipolar pulses decreased the excitable volume of brain tissue by approximately 68.8 % compared to monopolar pulse. Finally, bipolar pulses cause local excitation with lesser damage to surrounding healthy tissue in complete tumor ablation, demonstrating the potential benefits of bipolar pulses in brain tissue ablation.

EW-7197, transforming growth factor β inhibitor, combined with irreversible electroporation for improving skin wound in a rat excisional model

To evaluate the safety and efficacy of combining EW-7197 with irreversible electroporation (IRE) for improving wound healing, 16 male Sprague–Dawley rats were randomly divided into four groups of four rats each after dorsal excisional wound induction: sham control group; oral administration of EW-7197 for 7 days group; one-time application of IRE group; and one-time application of IRE followed by oral administration of EW-7197 for 7 days group. Measurement of wound closure rate, laser Doppler scanning, histological staining (hematoxylin and eosin and Masson’s trichrome), and immunohistochemical analyses (Ki-67 and α-SMA) were performed to evaluate the efficacy. Fifteen of 16 rats survived throughout the study. Statistically significant differences in wound closure rates were observed between the combination therapy group and the other three groups (all P < 0.05). The degrees of inflammation, α-SMA, and Ki-67 were reduced in the EW-7197 and IRE monotherapy groups; however, not statistically significant. The fibrosis score exhibited significant reduction in all three treatment groups, with the most prominent being in the combination therapy group. This study concludes that oral administration of EW-7197 combined with IRE demonstrated effectiveness in improving skin wound in a rat excisional model and may serve as a potential alternative for promoting healing outcomes.

State-of-the-art pulsed field ablation for cardiac arrhythmias: ongoing evolution and future perspective.

Pulsed field ablation (PFA) is an innovative approach in the field of cardiac electrophysiology aimed at treating cardiac arrhythmias. Unlike traditional catheter ablation energies, which use radiofrequency or cryothermal energy to create lesions in the heart, PFA utilizes pulsed electric fields to induce irreversible electroporation, leading to targeted tissue destruction. This state-of-the-art review summarizes biophysical principles and clinical applications of PFA, highlighting its potential advantages over conventional ablation methods. Clinical data of contemporary PFA devices are discussed, which combine predictable procedural outcomes and a reduced risk of thermal collateral damage. Overall, these technological developments have propelled the rapid evolution of contemporary PFA catheters, with future advancements potentially impacting patient care.

Effectiveness and safety of irreversible electroporation when used for the ablation of stage 3 pancreatic adenocarcinoma: A registry study (DIRECT).

e16301 Background: Outcomes for patients with Stage 3 pancreatic ductal adenocarcinoma (PDAC) remain poor with a mean overall survival (OS) of 11 months. Irreversible electroporation (IRE) is a method of local tumor ablation that causes cell death by disrupting homeostasis in the cell membrane. Previous research suggests IRE can be useful in the multi-disciplinary treatment of Stage 3 PDAC. The present study was designed to assess the effectiveness and safety of IRE for Stage 3 PDAC in a real-world setting after induction chemotherapy. Methods: Patients with Stage 3 PDAC treated with IRE were prospectively enrolled in a multicenter registry study. Enrollment required 3 months of active multi-agent chemotherapy, with no progression before IRE treatment. Endpoints were 30- and 90-day mortality from enrollment and the new onset of an adverse event (AE). Results: 87 patients were enrolled in the registry between May 2019 and May 2023. Mean age was 64.0 ± 8.4 years, 57.5% were female and mean tumor diameter was 2.2 ± 0.7 cm. Mean time from diagnosis to IRE treatment was 8.9 ± 4.9 months. All subjects underwent induction chemotherapy with the most common being FOLFIRINOX alone, gemcitabine with albumin-bound paclitaxel, or a combination of both in 47 (54.0%) patients. Thirty-seven (42.5%) patients had prior radiation therapy. All procedures were performed using an open approach with 50 (57.5%) for in-situ tumor ablation and 37 (42.5%) with the intent of margin accentuation in combination with resection. Major adjunctive procedures were performed for 70 (80.5%) patients. Common adjunctive surgeries were cholecystectomy (33.3%), Whipple procedure (28.7%) and either distal or subtotal pancreatectomy (11.4%). Mean IRE delivery time was 55.7 ± 54.5 minutes with an average of 3.1 probes (range 2 to 6) used per procedure. There was a mean of 1031.1 ± 882.1 pulses delivered per procedure. The 30- and 90-day mortality was 3/87 (3.4%) and 4/82 (4.9%) respectively. There were 21 (24.1%) patients who developed AEs related to IRE treatment during the 90-day post-procedure period (9 patients had AEs that were definitely related to IRE, 5 probably and 7 possibly). Of these related events, only three were Grade 4 or higher (arterial hemorrhage, cardiac arrest, and septic shock). Overall, gastrointestinal related AEs were the most common representing 16 of the 28 (57.1%) of all AEs associated with the IRE procedure. One patient died within 30 days of the procedure due to an intraperitoneal arterial hemorrhage that was deemed to be definitely related to the IRE treatment. Conclusions: The use of IRE for curative intent tumor ablation alone or in combination with resection following induction chemotherapy in patients with locally advanced Stage 3 PDAC has acceptable safety and is associated with acceptable morbidity and mortality rates in appropriately selected patients. Clinical trial information: NCT03899649 .

A novel MRI-based tumor-targeting theragnostic agent: Magnetoelectric nanoparticles in an in vivo murine KRAS/P53 pancreatic flank tumor model.

3075 Background: Magnetoelectric nanoparticles (MENPs) are a novel material with a magnetoelectric (ME) property that allows for conversion of an external magnetic field to a local electric field (EF) that can be exploited to generate a Coulomb force to target and electroporate the relatively non-polarized tumor cell walls. We hypothesized that their local EF and superparamagnetic cores can be exploited as an MRI-based anti-cancer theragnostic agent for solid tumors. Methods: 35 immunocompetent C57BL/6 mice were inoculated with KPC961 pancreatic adenocarcinoma cells in their flank. The 27 mice with the largest tumors at 4 weeks were randomized into 5 cohorts based on treatment: 300 µg of MENP (300; n=6), 600 µg of MENP (600; n=6), 300 µg of low-ME coefficient MENP (LM; n=5), 300 µg of MENP without M1 MRI (NM; MRI field control, n=5), and normal saline (NS; MENP causal effect control; n=5). The 300, 600, LM, and NS cohorts had T2 MRI maps (M0) on a 7T MRI. NM had T2 weighted MRIs at M0. All mice had a neodymium magnet placed over their tumors for 12 hours after tail vein injections (300 µl for all mice) for targeting. The 300, 600, LM, and NS cohorts then underwent MRI mapping (M1) after magnet removal (No M1 MRI for NM). MRI mapping was repeated 5 days after (M2). NM had a T2 weighted MRIs at M2. M1 and M2 data were used to assess relaxation time (contrast effect) and tumor volume from M0, respectively. Student t and ANOVA tests were used to compare differences for tumor volume and relaxation time data and one-sided Fisher’s exact test was used for complete response (CR) data. Results: The median M0 tumor volume was 109.6 mm3 for all mice, and there were no differences between any cohort ( p = 0.978; Table). The 300 and 600 MENP cohorts demonstrated a 102.7% reduction in volume (M2/M0; 56.7% vs. 159.4% for NS and NM controls, p = &lt;0.001) and a 7.2% T2 negative contrast effect (M1/M0; 94.2% vs. 101.3% for NS, p = 0.046) compared to controls. Six mice in 300, 600, and LM (2 each) achieved a clinical CR (between 1 to 2 weeks after M1) vs. none in the NS and NM control cohorts ( p = 0.0418), without any recurrences until end of study (6 weeks after M2). Conclusions: This is the first report demonstrating the theragnostic effects of MENPs having both T2 contrast and locally ablative therapy properties as an in vivo tumor targeting agent. These results confirm prior pilot study and point towards irreversible electroporation as the likely mechanism of action (MOA) since the antitumor effect is not seen within the NM cohort. Additional studies characterizing the MOA, dose-response relationships, and immunomodulatory effects are needed to better understand their full clinical potential.[Table: see text]

Changes in Mitochondrial Membrane Potential in In Vitro Electroporation with Nano- and Microsecond Pulses.

With the introduction of nanosecond (ns) pulses, it was suggested that such pulses could be used to permeabilize intracellular membranes, including the mitochondrial membrane. The results presented thus far, however, are not conclusive. Interestingly, the effect of longer microsecond (μs) pulses on changes in mitochondria has never been investigated. We, therefore, investigated the changes in mitochondrial membrane permeability through changes in mitochondrial membrane potential (MMP) in CHO and H9c2 cells after electroporation with 4 ns, 200 ns, and 100 μs pulses. In the range of reversible electroporation, the decrease in MMP generally depended on the cell line. In CHO, ns pulses decreased MMP at lower electroporation intensities than μs. In H9c2, ns and μs were equally effective. In the range of irreversible electroporation, MMP decreased even further, regardless of pulse duration and cell type. The analysis at different time points showed that the changes in MMP within the first hour after pulse treatment are dynamic. Our results on the efficacy of ns pulses are consistent with published data, but with this study we show that μs pulses cause similar changes in MMP as ns pulses, demonstrating that electroporation affects MMP regardless of pulse duration. At the same time, however, differences in MMP changes were observed between different cell lines, indicating some dependence of MMP changes on cell type.

Burst sine wave electroporation (B-SWE) for expansive blood-brain barrier disruption and controlled non-thermal tissue ablation for neurological disease.

The blood-brain barrier (BBB) limits the efficacy of treatments for malignant brain tumors, necessitating innovative approaches to breach the barrier. This study introduces burst sine wave electroporation (B-SWE) as a strategic modality for controlled BBB disruption without extensive tissue ablation and compares it against conventional pulsed square wave electroporation-based technologies such as high-frequency irreversible electroporation (H-FIRE). Using an in vivo rodent model, B-SWE and H-FIRE effects on BBB disruption, tissue ablation, and neuromuscular contractions are compared. Equivalent waveforms were designed for direct comparison between the two pulsing schemes, revealing that B-SWE induces larger BBB disruption volumes while minimizing tissue ablation. While B-SWE exhibited heightened neuromuscular contractions when compared to equivalent H-FIRE waveforms, an additional low-dose B-SWE group demonstrated that a reduced potential can achieve similar levels of BBB disruption while minimizing neuromuscular contractions. Repair kinetics indicated faster closure post B-SWE-induced BBB disruption when compared to equivalent H-FIRE protocols, emphasizing B-SWE's transient and controllable nature. Additionally, finite element modeling illustrated the potential for extensive BBB disruption while reducing ablation using B-SWE. B-SWE presents a promising avenue for tailored BBB disruption with minimal tissue ablation, offering a nuanced approach for glioblastoma treatment and beyond.

Acute intracardiac electrogram changes and their relation to pulsed field ablation dose in porcine left ventricle

Abstract Background Pulsed field ablation (PFA) is an emerging cardiac ablation modality based on irreversible electroporation with promising preclinical and clinical results. Acute reduction of intracardiac electrograms (bipolar iEGMs) is consistently observed, similar to other ablation modalities, e.g. radiofrequency ablation. We and others have previously reported lesion size dependence on PFA dosing. However, the relevance of iEGM changes and their dependence on the PFA dose is not established. Furthermore, our study shows that unipolar iEGM signals may contain additional information about the effects of PFA in cardiac tissue. Purpose To quantify the effect of different PFA dosing on changes observed in bipolar and unipolar iEGMs within 5 minutes after the ablation. Methods In total, PFA was applied endocardially at 40 sites in the left ventricles of 8 pigs via a 5 mm tip catheter using a modified decapolar catheter in the inferior vena cava for current return (all electrodes). The following PFA doses (voltage and number of pulse trains) were used: 1000 V, 4 trains; 1300 V, 4 trains; 1500 V, 1 train; 1500 V, 4 trains; 1500 V, 8 trains; and 1500 V, 16 trains. For standard bipolar iEGMs (30 Hz – 500 Hz) the reduction in peak-to-peak amplitude after PFA was considered as a measure of the effect. In addition, unipolar iEGMs (0.5 Hz – 500 Hz) were decomposed into non-overlapping frequency sub-bands with Daubechies order 6 discrete wavelet transform (Figure 1A) allowing separate analysis in high-frequency (HF) and low-frequency (LF) ranges (63 Hz – 500 Hz and 0.5 Hz – 8 Hz, respectively). Results In total, 30 standard bipolar and 35 unipolar iEGMs (with at least 3.5 minutes of artefact-free post-ablation duration) were analysed. No dose dependency was observed for standard bipolar iEGMs within 5 minutes post-ablation (data not shown). However, the HF and LF content of unipolar iEGMs revealed opposing effects: a decrease in the HF and an increase in the LF content. Correlation with the dose was clearer in the LF content 3.5 minutes post-ablation, the difference being significant (p&amp;lt;0.05) between the lowest and the highest doses (Figure 1B and C). Discussion The decrease in HF content could reflect electrical silencing, ie. stunning of locally affected cardiomyocytes, most likely caused by irreversibly electroporated (ablated) cells located close to the catheter tip and by reversibly electroporated or otherwise temporarily silenced cells in adjacent tissue. The increase in LF content could reflect the current-of-injury effect, which is a broader area phenomenon derived from electrical potential differences between affected (reversibly and irreversibly electroporated) and non-affected regions. Conclusion Unipolar iEGMs acquired with a broadened frequency range and decomposed into HF and LF content provide new insight into the effects of PFA and correlate with PFA dosing in this pre-clinical porcine model.

Changes in local endocardial electrograms immediately after PFA show dose-dependent variations

Abstract Background/Introduction Pulsed field ablation (PFA) is a novel nonthermal cardiac ablation technology based on irreversible electroporation. The behaviour of local electrograms after PFA has been poorly characterized and it remains unknown if it is possible to differentiate between different electroporation levels based on local electrogram analysis. Purpose The objective of this study was to characterize the alterations in bipolar and unipolar endocardial electrograms after performing PFA at different doses. Methods Five anesthetized pigs were submitted to PFA treatments. Endovascular access to the right atrium was gained through the femoral vein to create a line of ablation between the superior and inferior vena cava using a focal monopolar catheter. The catheter was switched between a conventional cardiac navigation system (CARTO system) and a custom PFA generator. Two different PFA doses were used: a high dose (HD-1600V) at top and bottom of the line and a low dose (LD-1000V) in the central part of the ablation line. Bipolar and unipolar electrograms were recorded with the ablation catheter before and immediately after each ablation. Additionally, high-density electroanatomical maps were acquired with a multielectrode catheter before and immediately after the procedures. Four weeks later, the animals were remapped again and subsequently euthanized. Atrial tissue was removed and processed to identify the presence of fibrosis in the previously ablated lesions. Results We performed 106 ablations (84 high dose vs. 22 low dose). Four weeks later, histological staining of chronic lesions revealed that the HD lesions were larger and more fibrotic than the LD (Figure 1). Immediately after each ablation R/S-wave amplitudes and their corresponding |dV/dt|max decreased for the bipolar and unipolar electrograms. The percentages of bipolar electrogram reduction HD vs. LD were: R wave 73% vs. 39%, S wave 68% vs. 37% and |dV/dt|max 81% vs. 38%; 1 way-ANOVA p&amp;lt;0.05 for all, Figure 2). The R-wave amplitude in M1-M2 was significantly lower in HD compared to LD (HD vs. LD: 0.3 ± 0.2 mV vs. 0.7 ± 0.6 mV; 1 way-ANOVA p&amp;lt;0.01). S-wave and |dV/dt|max of unipolar electrograms presented a similar behaviour (M2 |dV/dt|max HD vs. LD: -116 ± 118 mV/s vs. -260 ± 267 mV; 1 way-ANOVA p&amp;lt;0.01). Conclusion Local electrograms display PFA dose-dependent variations. This information could result useful to create new metrics to assess in real time the performance of PFA systems.Figure 1.EAM maps and histology studyFigure 2.EGM signals and statistics

Pulsed-field ablation of atrial fibrillation in elderly and frail patients: procedural efficacy and safety from a single-center experience

Abstract Introduction The demographic data shows a growing population, mostly elderly and with multiple comorbidities, therefore becoming increasingly frail. In this context Atrial fibrillation (AF) is the predominant sustained arrhythmia, and over the years trans-catheter isolation of pulmonary veins (PVI) has become a crucial approach in AF treatment. Among the technologies and energy resources employed through the years to perform atrial fibrillation transcatheter ablation, a novel technique has recently begun to gain ground, specifically pulsed-field ablation (PFA). PFA employs sequential brief and high amplitude electrical pulses to induce selective and irreversible electroporation of the myocardium, leading to cell death. The high selectivity of the lesion, ensured by the lower electroporation threshold of myocardial tissue compared to adjacent anatomic structures, allows for a decrease in potential complications associated with conventional thermal ablation. Purpose To assess the efficacy and safety in the use of pulsed field ablation in a selected population of elderly and frail patients undergoing atrial fibrillation ablation. Method We conducted a retrospective study focusing on elderly and frail patients admitted to our centre for paroxysmal or persistent AF ablation. The inclusion criteria were: age greater than 75 years and a Clinical Frailty Scale ≥ 5. The study population consisted of 26 patients [male gender 18, mean age 78 ± 3 years] including 8 who were affected by an oncological or haematological disease at the time of admission. The majority of patients were affected by paroxysmal AF while two of them presented persistent AF (9%). The primary ablation endpoint was the pulmonary vein isolation (PVI) that was achieved by delivering an energy of 2 kV over 8 applications, employing an alternating approach between the two configurations of the basket and flower catheter for each individual vein. Results The short-term success, represented by the complete and verified electrical isolation of the veins was achieved in all 26 patients without any periprocedural complications. First-pass pulmonary vein isolation (FPI) was universally achieved among the patient in study, with a mean skin-to-skin procedural time of 70 ± 30 minutes. From the procedural data perspective, ablation was achieved using an average fluoroscopy time of 22 ± 8.4 minutes and an average dose area product (DAP) of 1320 cGy×cm2. Conclusions In elderly and frail patients, we assessed the efficacy and safety of ablative procedures using the PFA technique. Successful electrical PVI was achieved without additional touch-ups, thanks to a high FPI rate. This results in lower procedural times and shorter intra-operative radiation exposure. These data confer an augmented value within the elderly-frail population, wherein shorter procedural times contribute to a better postoperative course, characterized by reduced bed rest and shorter intra-hospitalization periods.

Safety and myocardio-necrosis laboratory data trend in patients undergoing atrial fibrillation catheter ablation: pulsed field ablation vs. radiofrequency ablation

Abstract Background Pulsed Field Ablation (PFA) is an innovative technology to perform atrial fibrillation (AF) catheter ablation. No form of thermal energy is used, but an irreversible electroporation mechanism that causes selective cardiomyocytes death, sparing the cells of adjacent tissues. There are few data in the literature about peri-procedural trend of myocardium-necrosis laboratory data in patients undergoing PFA versus those with radiofrequency (RF). Purpose Compare the short-term safety and the peri-procedural trend of myocardium-necrosis laboratory data in patients undergoing PFA with those undergoing standard-power (40W) RF catheter ablation. Methods 50 patients undergoing paroxysmal AF catheter ablation with pulmonary veins isolation were retrospectively enrolled, 25 treated with PFA and 25 with RF (matched for age, sex, BMI, left atrium size). The PFA protocol involved four two-second deliveries with the penta-spline catheter in the "basket" and in the "flower" configuration; about RF ablation, circular lesions were carried out at the antrum of each pulmonary vein. All patients underwent serial blood samples including troponin I (TnI, n.v. 0-50 ng/L) and CKMB (n.v 0-5 ng/mL) at time 0 and at 3, 24 and 48 post-procedure hours. Complication were evaluated at pre-discharge visit and at 3-month follow-up. Results The clinical and echocardiographic patient’s characteristics are summarized in Table 1. The TnI and CKMB baseline values were within normal range for all patients, both those treated with PFA and those treated with RF, and there were no statistically significant differences between the two group. Regarding the TnI and CKMB values temporal increase, a statistically significant increase was observed in patients treated with PFA (Table 2). The TnI percentage decrease over the 48 hours in RF-treated patients, although not statistically significant, is slower compared to patients treated with PFA. This data could be explained by considering that PFA causes acute damage (myocardiocytes necrosis by electroporation) with less inflammation and a less progressive nature, while RF causes damage with greater irritation and progression (coagulative necrosis) that may result in myocardial necrosis even in the subsequent hours. Despite evidence of greater myocardial necrosis, there were not procedural complications in those treated with PFA. Therefore, the TnI increase is indicative of selective myocardial damage, likely more antral. Conclusion The increase of myocardio-necrosis laboratory data appears to be higher using PFA compared to RF, and it is not associated with greater adverse events. The trend of the myocardio-necrosis laboratory data shows different reduction curves between PFA and RF, probably related to different ablation power source; these data will need to be re-analysed with a greater number of cases.Table 1Table 2

Efficacy and safety of irreversible electroporation in unresectable perihilar cholangiocarcinoma: a systematic review and meta-analysis.

The prognosis of patients with perihilar-cholangiocarcinoma (PHC) is poor, with the majority presenting with unresectable disease at diagnosis. Palliative chemotherapy (CHT) is the standard treatment for unresectable PHC. Irreversible electroporation (IRE) has been introduced as a novel ablation technique, working predominantly nonthermal. This review aims to analyse the efficacy and safety of IRE in treating unresectable PHC. This systematic review and meta-analysis was performed according to a specific protocol designed a priori, and reported according to the PRISMA. PubMed/MEDLINE, Scopus, and Cochrane CENTRAL were searched up to December 2023. Primary Outcome of interest of our meta-analysis was the mean Overall Survival (OS). Secondary outcomes were progression-free survival (PFS) and adverse event rate (AE). The mean OS was estimated at 25.49 months (CI, 21.47-38.72, I2 81.37%), PFS 17.86 (CI, 13.00-22.72, I2 11.42%), with an AE incidence of 12% (CI, 7%-31%, I2 83.57%). High heterogeneity was found among studies, with no single study fully responsible for it, suggesting high variability among facilities/populations. IRE is effective and relatively safe for unresectable PHC. However, the lack of prospective studies and randomized trials comparing chemotherapy or locoregional treatment with IRE prevents drawing sufficiently robust conclusions. IRE appears a safe and effective technique for treating unresectable perihilar cholangiocarcinoma.

Pulsed Field Energy in Atrial Fibrillation Ablation: From Physical Principles to Clinical Applications.

Atrial fibrillation, representing the most prevalent sustained cardiac arrhythmia, significantly impacts stroke risk and cardiovascular mortality. Historically managed with antiarrhythmic drugs with limited efficacy, and more recently, catheter ablation, the interventional approach field is still evolving with technological advances. This review highlights pulsed field ablation (PFA), a revolutionary technique gaining prominence in interventional electrophysiology because of its efficacy and safety. PFA employs non-thermal electric fields to create irreversible electroporation, disrupting cell membranes selectively within myocardial tissue, thus preventing the non-selective damage associated with traditional thermal ablation methods like radiofrequency or cryoablation. Clinical studies have consistently shown PFA's ability to achieve pulmonary vein isolation-a cornerstone of AF treatment-rapidly and with minimal complications. Notably, PFA reduces procedure times and has shown a lower incidence of esophageal and phrenic nerve damage, two common concerns with thermal techniques. Emerging from oncological applications, the principles of electroporation provide a unique tissue-selective ablation method that minimizes collateral damage. This review synthesizes findings from foundational animal studies through to recent clinical trials, such as the MANIFEST-PF and ADVENT trials, demonstrating PFA's effectiveness and safety. Future perspectives point towards expanding indications and refinement of techniques that promise to improve AF management outcomes further. PFA represents a paradigm shift in AF ablation, offering a safer, faster, and equally effective alternative to conventional methods. This synthesis of its development and clinical application outlines its potential to become the new standard in AF treatment protocols.

Recurrences after Pulsed Field Ablation of Atrial Fibrillation: Incidence, Mechanisms, Predictors, and Comparison with Thermal Energy

Pulsed Field Ablation (PFA) is the latest and most intriguing technology for catheter ablation of atrial fibrillation, due to its capability to generate irreversible and cardiomyocytes-selective electroporation of cell membranes by delivering microsecond-lasting high-voltage electrical fields, leading to high expectations. The first trials to assess the clinical success of PFA, reported an arrhythmia-free survival at 1-year of 78.5%, while other trials showed less enthusiastic results: 66.2% in paroxysmal and 55.1% in persistent AF. Nevertheless, real world data are encouraging. The isolation of pulmonary veins with PFA is easily achieved with 100% acute success. Systematic invasive remapping showed a high prevalence of durable pulmonary vein isolation at 75 and 90 days (range 84–96%), which were significatively lower in redo procedures (64.3%). The advent of PFA is prompting a reconsideration of the role of the autonomic nervous system in AF ablation, as PFA-related sparing of the ganglionated plexi could lead to the still undetermined effect on late arrhythmias’ recurrences. Moreover, a new concept of a blanking period could be formulated with PFA, according to its different mechanism of myocardial injury, with less inflammation and less chronic fibrosis. Finally, in this review, we also compare PFA with thermal energy.