Christian W. Zemlin

Aims: Pulsed field ablation (PFA) has emerged as a novel ablation modality for the treatment of cardiac arrhythmias and has rapidly reshaped contemporary electrophysiology practice. This article provides a comprehensive analysis on the mechanisms underlying the specific effects of PFA on myocardial, neural tissue structures, and the cardiac conduction system, integrating biophysical principles with preclinical and clinical evidence relevant to contemporary electrophysiology practice. Methods and results: This document provides an exhaustive mechanistic explanation for the preferential effects of PFA on myocardium and the limits of the ‘tissue-selectivity’ concept. The complex interplay between cellular and tissue-level biophysics, biological responses, and tissue regenerative capacity that determines differential susceptibility to electroporation across tissues is analysed. Distinct patterns of lesion formation and maturation following PFA are also reviewed, highlighting the temporal and histopathological differences compared with radiofrequency ablation. Additionally, lesion formation in heterogeneous substrates is analysed, including fibrotic and adipose-rich myocardium, where local electric field distribution critically influences lesion durability. Conclusion: The article further examines the interaction between pulsed electric fields and neural tissue, with emphasis on the phrenic nerve and intrinsic cardiac autonomic nervous system. While nerve stimulation and transient reversible conduction disturbances produced by reversible electroporation can occur during ablation, permanent neural injury appears extremely rare in current clinical experience. Finally, this manuscript examines current understanding regarding the specific effects of PFA on the cardiac conduction system, which according to the limited available evidence appear strongly dependent on electric field dose and anatomical proximity.

Objective: We evaluated a novel radiofrequency (RF) clamp that enables isolation of the entire left atrial posterior wall (LAPW) with a single application and was designed to reduce ablation time without sacrificing efficacy. Methods: Six Yorkshire pigs (47 ± 4 kg) underwent median sternotomy. A dual-generator RF clamp was used to create a lesion that isolated the LAPW with a single application. An additional lesion was created to isolate the left atrial appendage (LAA). Exit block testing was performed for all lesions. Hearts were perfused with triphenyl tetrazolium chloride (TTC), arrested, and explanted, and lesions were transversely sectioned at 5 mm intervals. Lesion transmurality was assessed with TTC staining and confirmed on histology when necessary. Ablation time and delivered energy were determined and compared with those from the previously tested single-generator version of this device. Results: Surgical ablation was successfully performed on all 6 animals. A total of 12 lesions, 6 LAPW and 6 LAA, were created, corresponding to 297 histological sections. Exit block was uniformly demonstrated (12 of 12). Transmurality was achieved in 100% of cross sections (297 of 297). LAPW ablation time was 37.9 ± 9.1 s, a 48% reduction compared with the single-generator clamp (72.5 ± 7.5 s, P < 0.001). The total energy delivered was 1,109 ± 343 J, similar to that of the single-generator clamp (1,231 ± 138 J, P = 0.45). Conclusions: The dual-generator, split-electrode RF clamp created transmural lesions with a single application while nearly halving ablation time compared with the previous single-generator clamp.

Background: Mitral regurgitation (MR) is a major risk factor for the development of atrial fibrillation (AF), yet the molecular mechanisms linking volume overload to arrhythmogenic remodeling remain poorly understood. Although fibrosis has long been considered the primary substrate for AF, increasing evidence suggests that fibroblast heterogeneity and cell-cell interactions may play important roles in disease progression. Methods: MR was created endovascularly by chordal avulsion in 12 dogs with 6 controls. AF inducibility was assessed by transvenous burst pacing, left atrial volume by echocardiography, and collagen content by Masson trichrome and picrosirius red staining. Single-nucleus RNA sequencing (snRNA-seq) was performed on left atrial posterior wall tissue from control, 4-week, and 6-month MR animals. Fibroblast subpopulations and fibroblast-cardiomyocyte communication were analyzed and markers validated by RNA in situ hybridization in all 18 animals. Results: MR resulted in progressive left atrial dilation, but neither the change in left atrial volume from baseline nor total collagen burden correlated with the inducibility of AF (n=6 each). SnRNA-seq resolved seven major cardiac cell populations and identified four transcriptionally distinct fibroblast populations (NOX4/GRIA4, PCOLCE2, ADRB2/HCN1, PTX3/ICAM1). Fibroblast composition shifted markedly: matrix-associated PCOLCE2 fibroblasts starkly declined by 6 months, whereas inflammatory-associated PTX3/ICAM1 fibroblasts expanded stepwise over time. Cardiomyocyte-to-fibroblast signaling, dominated by PTPRM and LAMA2, was progressively redirected toward PTX3/ICAM1 fibroblasts. RNAscope confirmed a stepwise rise in ICAM1 transcripts and higher ICAM1 in AF-inducible than non-inducible animals. Conclusions: In a canine model of MR, the inducibility of AF was associated with fibroblast state remodeling rather than with atrial dilation or collagen burden. Progressive expansion of inflammatory-associated PTX3/ICAM1 fibroblasts, together with reorganized fibroblast-cardiomyocyte signaling, defines a candidate arrhythmogenic mechanism and therapeutic target in MR.

Atrial fibrillation (AF) is the most common sustained arrhythmia worldwide and is associated with substantial morbidity, increased stroke risk, and a significant healthcare burden. While antiarrhythmic medications and catheter ablation remain central to rhythm control strategies, the efficacy of these therapies declines in persistent and long-standing persistent AF. Surgical ablation has consistently demonstrated superior long-term rhythm control, but this approach remains underutilized due to the associated perceived invasiveness and procedural complexity. Meanwhile, advances in energy sources have transformed the field, with bipolar radiofrequency (RF) and cryoablation established as the gold standard for lesion creation, supported by decades of durable outcomes. Nonetheless, both modalities possess limitations related to thermal injury and technical demands. Pulsed-field ablation (PFA), a non-thermal modality that induces irreversible electroporation (IRE), represents a promising new direction. Indeed, PFA preferentially ablates cardiomyocytes while sparing adjacent structures, enabling rapid, reproducible lesion formation with an improved safety profile. Preclinical studies have demonstrated the ability of this technology to create transmural lesions. Meanwhile, catheter-based studies have shown the associated efficacy and safety with this technology, and early feasibility trials suggest that surgical PFA clamps can replicate most of the Cox-Maze lesion set. Current surgical ablation lesion sets rely primarily on RF or cryoablation. However, emerging modalities such as PFA are poised to enable effective epicardial ablation on the beating heart, a challenge for thermal-based ablation technologies. With the advent of hybrid strategies that combine epicardial surgical ablation with catheter-based endocardial ablation, PFA may broaden the role of surgical ablation in advanced AF.

Mouse models are valuable for studying the systemic effects of arrhythmia, but traditional methods of heart pacing are invasive and technically complex. Cardiac optogenetics enables precise control of cardiac activity using light-sensitive ion channels and has been used for tachypacing, resynchronization, and defibrillation in animal models. Recent advances in opsins with red-shifted activation spectra and optimized light delivery strategies have enhanced noninvasive pacing approaches, particularly in mammalian models. Here, we use an area illumination approach for light stimulation through the intact chest to perform in vivo, noninvasive optogenetic tachypacing in transgenic mice expressing ReaChR with low irradiance (2 ). We assess both cardiac and cortical hemodynamic responses via echocardiography and optical intrinsic signal imaging (OISI). Our findings reveal that whole-heart arrhythmic stimulation alters cortical hemodynamic activity, highlighting the direct impact of arrhythmias on brain perfusion and oxygenation. This work provides insight into the heart-brain connection and the broader systemic consequences of cardiac dysfunction.

BACKGROUND: Stereotactic arrhythmia radiotherapy (STAR) has emerged as a potential therapy for treatment-refractory ventricular tachycardia (VT). However, the mechanisms underlying STAR efficacy, such as scar or other electromechanical changes, are still unclear. The goal of this study was to develop a translational porcine model of ischemic monomorphic VT treated with STAR to examine the physiological changes after a typical clinical STAR treatment. METHODS: We treated a previously validated porcine model of monomorphic VT after myocardial infarction with a clinically derived STAR protocol. A dose of 25 Gy was prescribed to the planning target volume and 35 Gy to the clinical target volume (regions of scar), while controls underwent a sham STAR treatment. All investigators in the study were blinded except the treating investigator. The primary study outcome was VT inducibility at 6 weeks post-STAR. Animals underwent pre- and post-STAR cardiac magnetic resonance imaging to quantify myocardial scar and function, as well as body surface mapping. Six weeks post-STAR, animals underwent a VT induction study, and tissue was harvested for optical mapping and histological analysis. RESULTS: Six animals completed the study, which ended before finishing enrollment because all animals had inducible VT. We found a significantly longer local effective refractory period in the left ventricular apex and longer VT cycle lengths in STAR-treated animals compared with controls ( P <0.05). We found no difference in myocardial scar burden, mechanical function, or body surface recordings when comparing pre- and post-STAR. CONCLUSIONS: Our data suggest a novel therapeutic mechanism of STAR driven by increasing the effective refractory period in locally treated areas, corresponding to increased tissue wavelength. Our results corroborate clinical case reports and anecdotal evidence that STAR increases VT cycle length. Importantly, these effects were not mediated by an increase in myocardial scar burden. However, our studies do not examine the long-term effects of STAR.