Tri, Jason

AbstractIntroductionPulsed field ablation (PFA) has emerged as an innovative therapy for cardiac arrhythmias. Drawing parallels with PFA's application in solid tumors, calcium chloride (CaCl2) as an adjuvant therapy, known as calcium electroporation, may amplify PFA's apoptotic effects. We propose that PFA in the atrium could enhance calcium uptake through PFA‐created pores, thereby increasing ablation efficacy even at reduced power levels by exploiting PFA's permeabilization effects.MethodsWe conducted in vivo ablations on the atria of seven pigs using low PFA power (250 V, 20 μs for 50 pulses at 200 ms intervals). Post‐PFA, we randomly administered an infusion of either 200 mg/2 ml CaCl2 (calcium group) or saline (control) directly to the ablation site via the catheter tip. We evaluated reduction in electrogram voltage amplitude, electrocardiography (ECG) parameters, ablation lesion parameters, and histology after PFA.ResultsNineteen lesions from control and calcium groups were examined. Control lesions showed no voltage decrease post‐PFA, whereas calcium‐treated lesions exhibited a significant voltage reduction. Gross pathology indicated marked differences in maximum lesion surface diameter, depth, and volume between the lesion groups. Histologically, calcium group lesions were characterized by a more severe acute PFA response with contraction band necrosis, myocytolysis and nuclear pyknosis in adjacent myocardium, in addition to microhemorrhages.ConclusionInfusing calcium chloride locally after PFA markedly improves the immediate efficacy of electroporation in porcine atria. This study suggests that calcium electroporation could bolster PFA outcomes without higher energy levels, potentially diminishing associated risks. These preliminary findings warrant further research into the long‐term efficacy and potential clinical application of calcium electroporation in PFA.

Epicardial pulsed field ablation (PFA) of ganglionated plexi (GPs) is being explored as a potential treatment for atrial fibrillation. Initial work using open-chest access with a monopolar ablation device has been completed. This study describes the early development work for a device that can be used with subxiphoid access and deliver bipolar ablation pulses. Electric field computational models have been used for the initial guidance on pulse parameters. An in vivo assessment of these ablation parameters has been performed in an open-chest canine study, while subxiphoid access and navigation of the device has been demonstrated in a porcine model. Results from this acute study have demonstrated the promising potential of this approach.

Abstract Background The use of irreversible electroporation (IRE) for cardiac ablation in the management of cardiac arrhythmias, known as Pulsed Field Ablation (PFA), has gained the attention of many researchers, physicians and companies. Despite the demonstrated efficacy and safety profiles of the technique, there are still many open questions. One of them deals with the effective electric field thresholds necessary for cardiac tissue ablation. Contrary to radiofrequency (RF) ablation, where the thermotemporal thresholds for tissue damage are well established, the electric field thresholds for effective IRE are uncertain and depend on the tissue type and the waveform characteristics of the delivered electric field. Purpose The use of numerical models to understand the electric field distribution and the corresponding lesion for a specific electrode geometry are widely used in IRE for cancer treatment. Models can predict ablation volumes when the field thresholds are known or can be used to estimate the field thresholds when the lesion geometry is established post-treatment. The goal of the present study was to build a subject-specific realistic 3D numerical model to assess the ability of modeling to predict PFA lesions. Methods PFA experiments were performed in male mongrel dogs following a protocol approved by the Mayo Clinic Institutional Animal Care and Use Committee. Briefly, animals were sedated and intubated, and two non-irrigated deflectable catheters with an 8-mm tip were positioned on both sides of the interventricular septum under fluoroscopy guidance. Submicrosecond pulses were delivered in a bipolar fashion across both catheters. Sequences of pulses of 300 ns duration (or other durations in that range) were repetitively applied with voltage levels in the kV range. 30 days after the procedure, MRI with late gadolinium enhancement (LGE) were acquired to assess the presence of ablation lesions in the treated tissue. Ventricular areas were segmented from MRI images and 3D volumes were created. The generated 3D geometries were imported into software COMSOL Multiphysics. Realistic 3D geometries of the catheters were placed in the same positions than during the experiments, fluoroscopy videos recorded during the procedures were used as a guidance. The computed electric field intensity distributions were compared to the LGE areas to extract the range of electric field thresholds where the predicted lesion size was compatible with the real size of the LGE areas for each application site and pulsing protocol. Results and conclusions Our results show how the numerical model is able to reproduce the shape of the LGE fibrotic lesion areas observed 30 days after the procedure. Additionally, the model clearly confirms the dose-dependent lesion sizes observed experimentally. This study supports that numerical modeling is a valuable tool for understanding PFA treatments and that it could be used as patient-specific treatment planning tool. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie

Background: Previous animal studies have shown no significant vascular injury from pulsed electrical field (PEF) ablation. We sought to assess the effect of PEF on swine coronary arteries. Methods: We performed intracoronary and epicardial (near the coronary artery) PEF ablations in swine pretreated with dual antiplatelet and antiarrhythmic therapy. Intracoronary PEF was delivered using MapiT catheters (Biotronik, Berlin), whereas epicardial PEF was delivered using EPT catheters (Boston Scientific, MA). PEF pulse duration was microseconds (Nanoknife 3.0, Angio Dynamics, NY) or nanoseconds (CellFX, Pulse Biosciences, CA). Results: We performed 39 intracoronary ablations in 10 swine and 20 epicardial-pericoronary ablations in 4 separate swine. Intracoronary PEF was delivered at higher energy compared with epicardial PEF (46 [interquartile range, IQR 20–85] J versus 10 [IQR 10–11] J, P < 0.01). Reversible coronary spasm occurred in 49% intracoronary ablations and 45% epicardial ablations ( P =0.80). At the end study, fixed coronary stenosis was demonstrated in 44% intracoronary ablations (80% for microsecond PEF and 18% for nanosecond PEF) and 0% epicardial ablations. Visible hemorrhagic and/or fibrotic myocardial lesions were observed at necropsy with similar frequency between intracoronary and epicardial PEF (45% versus 50%, P =0.70). Nanosecond PEF (49 ablations in 11 swine), when compared with microsecond PEF (10 intracoronary ablations in 3 swine), resulted in lower energy delivery (21 [IQR 10–46] J versus 129 [IQR 24–143] J, P =0.03) and less incidence of fixed coronary stenosis (18% versus 80%, P =0.04). Conclusions: In the swine model, intracoronary PEF resulted both in significant coronary spasm and fixed coronary stenosis. Epicardial PEF, delivered at lower energy, resulted in reversible spasm but no fixed coronary stenosis.

Background: Rigorous study of ventricular fibrillation (VF) is not feasible in humans. The spatiotemporal characteristics of prolonged VF remain undefined, limiting our understanding of this lethal rhythm. Methods: VF was mapped in 4 canines. The endocardial and epicardial left ventricle (LV) and right ventricle (RV) were sequentially mapped at 0 to 15, 15 to 30, 30 to 45, and 45 to 60 minutes post-induction. Ten consecutive beats were used to determine the average cycle length and regularity index of ventricular and His-Purkinje system signals in discrete regions during each time interval. Results: Average VF time was 58±12 minutes. The shortest ventricular cycle length was present in the RV apical region (70±10 msec) at 0 to 15 minutes and at 15 to 30 minutes (89±31 msec) and LV apical region at 45 to 60 minutes (242±163 msec). The His-Purkinje system cycle length was the shortest at the RV outflow tract (75±3 msec) at 0 to 15 minutes, RV inflow and free wall (89±12 msec) at 15 to 30 minutes, LV apical region (83±14 msec) at 30 to 45 minutes, and inferior and inferolateral LV (145±23 msec) at 45 to 60 minutes. Regularity index was the highest in the RV inflow and free wall (78%) at 0 to 15 minutes, RV apical region (86%) at 15 to 30 minutes, LV septum and epicardial anterior RV (80%) at 30 to 45 minutes, and anterior and anterolateral LV (75%) at 45 to 60 minutes. Conclusions: These data suggest significant regional changes in electrical activity throughout VF in canines. A transition of fastest electrical activity from RV to LV apical regions across VF was observed. These novel insights of the temporal and spatial changes of VF merit further evaluation in diseased hearts to assess for reproducibility of findings.

Abstract Background Slowing electrical conduction by cooling the myocardium can be used for defibrillation. We previously demonstrated the efficacy of a small cold device placed in oblique sinus (OS) in terminating atrial fibrillation (AF). However, the parameters needed to achieve effective atrial defibrillation are unknown. Purpose Assess effect of the size of cooled myocardium on frequency of AF termination in acute canine animal models. Methods Sternotomy was performed under general anesthesia in 10 acute canine experiments. AF was induced using rapid atrial pacing and intra-myocardial epinephrine and acetylcholine injections. Once AF sustained for at least 30s, either a cool (7–9°C) or placebo (body temperature) device was placed in the OS. Four device sizes were tested; ½X½, ¾X¾, and 1X1 inch devices and two ¾X¾ inch devices placed side by side simultaneously. Time to AF termination was recorded. Chi-squared or Fisher's exact test were used to compare the frequency of arrhythmia termination with cooling versus placebo. Results A total of 166 applications were performed (89 cool vs 77 placebo) in 10 animal experiments. Overall, AF terminated in 82% of the cooling applications vs. 67.5% of placebo (P=0.03, Figure 1). For the ½X½ inch device 88% of cold applications restored sinus rhythm vs. 63.6% for placebo (P=0.05). The frequency of sinus restoration for cold ¾X¾, 1X1 and two ¾X¾ side by side devices was 86.7%, 83.3% and 70% respectively. Time to sinus restoration when achieved was within three minutes was also not significantly changed. Conclusion Placing a cool device in the oblique sinus can terminate AF and efficacy is not affected by the size of device. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): MediCool Technologies

Abstract Background His bundle pacing aims to mimic the activation pattern of normal conduction to maintain ventricular synchrony. However, selective His capture can be challenging, and the activation sequence during His pacing may not replicate normal conduction. Purpose Compare the right ventricular (RV) and left ventricular (LV) activation pattern in sinus rhythm and His bundle pacing. Methods Baseline LV and RV map was created in sinus rhythm using Rhythmia mapping system (Boston Scientific Corporation) in canine animal model. Medtronic 3830 lead was placed near the bundle of His under fluoroscopic, intracardiac echocardiogram, and electroanatomic guidance. Conduction system capture was confirmed by observing a QRS duration &lt;120ms and an isoelectric segment between pacing artifact and QRS on surface ECG. Repeat LV and RV activation map was obtained during His pacing. Average QRS, HV and pacing to V intervals were calculated with standard deviation. Results Mapping was performed successfully in four animals. At baseline, the average QRS duration was 44±2.6ms and HV interval was 32±4.2ms. Earliest site of myocardial activation was in the mid-septal LV region. The earliest RV myocardial activation was also at the septum closer to the apex, but later than the LV (Figure1A). With His pacing, the average QRS duration was 70±17.0ms and the average stim to V interval was 31±8.7ms. During His pacing, the earliest site of activation was in the RV septum, with an activation pattern from base to apex in both the RV and LV. Conclusion Unlike normal physiology, the activation pattern during conduction system pacing is from base to apex with earliest site in the RV. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Mayo Clinic

BackgroundAutomated external defibrillators can provide life‐saving therapies to treat ventricular fibrillation. We developed a prototype unit that can deliver a unique shock waveform produced by four independent capacitors that is delivered through two shock vectors, with the rationale of providing more robust shock pathways during emergent defibrillation. We describe the initial testing and feasibility of this unique defibrillation unit, features of which may enable downsizing of current defibrillator devices.MethodsWe tested our defibrillation unit in four large animal models (two canine and two swine) under general anesthesia. Experimental defibrillation thresholds (DFT) were obtained by delivery of a unique waveform shock pulse via a dual‐vector pathway with four defibrillation pads (placed across the chest). DFTs were measured and compared with those of a commercially available biphasic defibrillator (Zoll M series, Zoll Medical, Chelmsford, MA, USA) tested in two different vectors. Shocks were delivered after 10 seconds of stable ventricular fibrillation and the output characteristics and shock outcome recorded. Each defibrillation series used a step‐down to failure protocol to define the defibrillation threshold.ResultsA total of 96 shocks were delivered during ventricular fibrillation in four large animals. In comparison to the Zoll M series, which delivered a single‐vector, biphasic shock, the energy required for successful defibrillation using the unique dual‐vector biphasic waveform did not differ significantly (P = 0.65).ConclusionsOur early findings support the feasibility of a unique external defibrillation unit using a dual‐vector biphasic waveform approach. This warrants further study to leverage this unique concept and work toward a miniaturized, portable shock delivery system.