Edward James Jacobs

Pulsed field ablation (PFA) has rapidly emerged as a promising ablation modality for the treatment of cardiac arrhythmias because of its myocardial tissue preferential ablation and favourable safety profile. However, procedural control of lesion formation and reliable assessment of lesion durability remain important challenges. This review summarizes the main determinants of PFA efficacy and current approaches for intraprocedural lesion assessment. Experimental and clinical studies indicate that PFA lesion formation results from the interaction between delivered electrical energy, catheter design, tissue coupling, and application strategy. Lesion size and geometry are primarily determined by electric field distribution and cumulative electroporation exposure, while excessive energy delivery may induce unwanted thermal or electrochemical effects. Procedural efficacy also depends on stable catheter positioning, adequate tissue proximity, and sufficient lesion overlap. Unlike thermal ablation technologies, conventional procedural markers such as electrogram attenuation, impedance changes, and pacing threshold variation correlate poorly with durable irreversible electroporation. Multiparametric lesion estimation models integrating electrical, mechanical, and positional data have shown encouraging preclinical results, although clinical validation remains limited. Emerging strategies combining electroanatomical mapping, imaging, and automated electrogram analysis may improve real-time evaluation of lesion continuity and durability. Current PFA workflows rely mainly on standardized energy delivery protocols, optimized catheter positioning, and lesion overlap rather than real-time titration of energy. Although robust intraprocedural markers of irreversible electroporation are still lacking, ongoing advances in catheter technology, imaging, and lesion assessment tools are expected to improve procedural reproducibility and long-term lesion durability. Further studies are needed to establish validated endpoints for durable PFA lesion formation.

Objective: Pulsed field ablation (PFA) relies on irreversible electroporation to create nonthermal cardiac lesions, yet real-time indicators of electroporation progression and validated lethal electric field thresholds remain limited. This study aimed to develop a bioimpedance-based metric for real-time monitoring of cardiac electroporation, evaluate the impact of myocardial anisotropy under electroporation conditions, and derive waveform-specific lethal electric field thresholds. Introduction: Current PFA procedures lack direct intraoperative feedback on lesion formation, and uncertainty remains regarding the role of myocardial fiber orientation in shaping electric field distributions. Because electroporation dynamically alters tissue electrical properties, monitoring these changes during treatment may improve prediction of ablation outcomes. Methods: PFA was delivered to fresh ex vivo porcine ventricular tissue using clinically relevant and energy-matched waveforms with pulse widths from 1 to 100 µs. Inter-burst broadband electrical impedance spectroscopy was performed using a low-voltage diagnostic waveform to quantify burst-resolved impedance changes. Lesions were visualized using metabolic staining, then finite element models incorporating nonlinear electroporation-dependent conductivity were used to compare anisotropic and homogenized electric field distributions. Lethal electric field thresholds were estimated by fitting simulated contours to measured lesion areas and validated using uniform electric fields generated by a parallel electrode array. Results: Across all waveforms, impedance measurements showed a rapid initial decrease followed by stabilization, indicating early electroporation saturation. Burst-to-burst percent change in impedance slope provided a consistent, waveform-agnostic metric of electroporation progression. Lesion morphology was not systematically influenced by fiber orientation, and modeling demonstrated that electroporation-induced conductivity increases homogenized tissue anisotropy. Lethal electric field thresholds increased with decreasing pulse width, ranging from 517 ± 46 V/cm (100 µs) to 1405 ± 55 V/cm (1 µs), and were validated under uniform field conditions. Conclusion: Bioimpedance-assisted monitoring enables real-time assessment of cardiac electroporation, while electroporation-induced homogenization supports simplified modeling and standardized PFA treatment design.

Purpose: Atherosclerotic vascular disease remains a leading cause of morbidity and mortality worldwide. Current treatments such as angioplasty, stenting, and atherectomy are invasive and limited by restenosis, thrombosis, and incomplete long-term efficacy. Pulsed field ablation (PFA), a nonthermal electroporation-based modality, has demonstrated safety in other cardiovascular applications, but it has not been applied for the treatment of endoluminal vascular diseases. We investigated whether pulsed electric fields could be delivered within the coronary artery and if PFA could selectively ablate the cellular components of atherosclerotic plaques. Methods: An endoluminal bipolar PFA probe was fabricated using a balloon catheter with flexible electrodes and evaluated in potato and ex vivo porcine hearts. The electrical conductivities of human atherosclerotic plaques were derived from previous impedance measurements for patient-specific multi-tissue and single-cell electroporation modeling. PFA was then evaluated for selective decellularization within an electrical conductivity-matched 3D fibrotic atherosclerosis tissue mimic using high concentrations of human macrophages and aggregated oxidized low-density lipoproteins, encapsulated within a collagen matrix. Results: Endoluminal probe positioning and high-voltage pulsed electric field delivery feasibility was established within the porcine left coronary arteries, with susequent potato lesions experiments demonstrating maximum ablations (6.99 cm ² ) and current (13 A) with equal treatment parameters. The multi-tissue model then indicated that endoluminal PFA can effectively cover > 95% of severe and thick plaques with irreversible electroporation, with single-cell modeling supporting the electroporation of foam cells within the plaque. The 3D atherosclerosis mimic validated the ability of PFA to completely ablate the foam cells with fibrotic tissue at > 1000 V/cm. Conclusions: This study provides practical demonstration of PFA for the treatment of atherosclerotic vascular disease. By combining experimental validation with computational modeling, we establish proof-of-concept that endoluminal PFA can selectively ablate diseased cells while preserving extracellular architecture, laying the groundwork for future translational development of this therapy.

Irreversible electroporation (IRE) is a nonthermal ablation modality used clinically for treating unresectable tumors while preserving vital structures through controlled application of pulsed electric fields. Previous data suggest that patient outcomes are enhanced with the induction of an anti-tumor immune response, but current research focuses on using immune checkpoint inhibitors, which function through conventional immune pathways that may be down-regulated by cancer or dysregulated by chemo-induced lymphodepletion. Chimeric antigen receptor (CAR) T cells overcome this limitation, as they are engineered with synthetic receptors that redirect lymphocytes to recognize and target cells expressing tumor-specific structures. CARs are engineered to have an increased binding affinity compared to in situ T-cell binding, amplify internal stimulation cascades, and release pro-inflammatory cytokines that can modulate the endogenous immune system. However, there are still major limitations for adoptive cell therapies in solid tumors, including life-threatening on-target off-tumor cytotoxicity, antigen escape, and failure to infiltrate and persist in solid tumors. Given the substantial evidence that IRE overcomes many of the challenges associated with immune infiltration and persistence in solid tumors, there is a strong premise for using targeted cell therapies following IRE, which would then target residual cancer that could repopulate the lesion. Here, we present the first proof-of-concept combination of IRE with CAR T cells. We validated that the cell membrane CAR target is not affected in electroporated cells that survive IRE, allowing for subsequent binding and elimination of residual tumor. The research demonstrates the feasibility and synergy of a novel combination of 2 clinically used techniques.

Background: Atherosclerotic vascular disease remains a leading cause of morbidity and mortality worldwide. Current treatments such as angioplasty, stenting, and atherectomy are invasive and limited by restenosis, thrombosis, and incomplete long-term efficacy. Pulsed field ablation (PFA), a nonthermal electroporation-based modality, has demonstrated safety in other cardiovascular applications, but it has not been applied for the treatment of endoluminal vascular diseases. We investigated whether pulsed electric fields could be delivered within the coronary artery and if PFA could selectively ablate the cellular components of atherosclerotic plaques. Methods: A bipolar catheter-based PFA probe was fabricated using a balloon catheter with flexible electrodes and evaluated through a combination of ex vivo evaluations. The electrical conductivities of human atherosclerotic plaques were derived from previous impedance measurements for patient-specific multi-tissue and single-cell electroporation modeling. PFA was then evaluated for selective decellularization within an electrical conductivity-matched 3D fibrotic atherosclerosis tissue mimic using high concentrations of human macrophages and aggregated oxidized low-density lipoproteins, encapsulated within a collagen matrix. Results: Endoluminal bipolar probe evaluation demonstrated probe positioning and high voltage pulsed electric field delivery within the left coronary artery of ex vivo porcine hearts, with maximum ablations (6.99 cm ² ) and current (13 A) evaluated within live potato tissue. The multi-tissue model then indicated that endoluminal PFA can effectively cover >95% of severe and thick plaques with irreversible electroporation, with single-cell modeling supporting the electroporation of foam cells within the plaque. The 3D atherosclerosis mimic validated the ability of PFA to completely ablate the foam cells with fibrotic tissue at >1000 V/cm. Conclusions: This study provides the first demonstration of PFA for the treatment of atherosclerotic vascular disease. By combining experimental validation with computational modeling, we establish proof-of-concept that PFA can selectively ablate diseased cells while preserving extracellular architecture, laying the groundwork for future translational development of this therapy.

Objective: This study characterizes the effects of external conductivity on electroporation to develop methods to overcome potential patient-to-patient variability. Impact Statement: We demonstrate that constant power pulsed electric fields (PEFs) achieve consistent treatment outcomes despite variations in conductivity, thereby improving the predictability and efficacy of electroporation-based therapies. Introduction: Electropermeabilization-based therapies typically deliver static voltages between electrodes to induce cell permeabilization. However, tissue conductivity variations introduce uncertainty in treatment outcomes, as the tissue-specific electric field thresholds that induce electroporation also depend on the extracellular conductivity. Methods: Cell-laden hydrogels were fabricated with varying extracellular conductivities and treated with constant voltage PEFs. The voltages and currents were recorded to calculate the applied powers, and the reversible and irreversible electroporation thresholds were quantified using cell-impermeant and viability assays. Homogeneous and heterogeneous multi-tissue finite element models were employed to simulate the impact of tumor conductivity variability on the outcomes of reversible and irreversible electroporation for constant applied voltage, current, and power PEFs. Additionally, an in vivo murine pancreatic tumor model assessed the correlation between PEF delivery and treatment efficacy. Results: The In vitro experiments revealed that the electric field and current density thresholds were conductivity dependent, whereas the power density thresholds remained stable under variable conductivities. Computational modeling indicated that constant power PEFs best predicted tumor coverage in both homogeneous and heterogeneous multi-tissue models. Similarly, the in vivo tumor responses were also better predicted by applied power rather than voltage or current alone. Conclusions: Applying constant power PEFs enables consistent electroporation outcomes despite variations in conductivity.

Purpose: High-frequency irreversible electroporation (H-FIRE) is a pulsed field ablation (PFA) technique that employs a series of high-voltage, microseconds-long positive and negative pulses, separated by interphase (d1) and interpulse (d2) delays to non-thermally ablate tissue. Previous experimental and computational data suggest an impact of delays on nerve excitation and electrochemical effects. However, the impact of delays on PFA outcomes, such as change in resistance and ablation generation, has only recently started to be elucidated. Methods: While recording the applied voltage and currents, we delivered a series of increasing voltages, termed voltage ramps, into tuber and cardiac tissues using both needle electrode pairs and flat plate electrodes. Tissues were stained for metabolic activity to measure irreversible electroporation areas following treatment. Results: Our findings support previous in vitro data that delays do not significantly affect ablation areas. While there were significant differences in applied current, resistance, and conductivity between different pulse widths at sub-electroporation electric fields, we found no significant differences after inducing electroporation between different delays and pulse widths. Consequently, since delays do not affect ablation areas or local conductivity, the data suggests that delays should not affect the electric field threshold or Joule heating within the tissue. Conclusion: The findings presented here provide critical insights into electroporation-dependent tissue conductivity changes from H-FIRE with implications for improving H-FIRE parameterization and computational models for treatment planning in cancer and cardiac pulsed field ablation.