Koya, Taro

Abstract Background Many patients with atrial fibrillation (AF) suffer life-limiting symptoms and heart failure. Although enormous advances in rhythm control have been made, device-based therapies for treating recurrent episodes are limited. Using pulsed electric fields (PEF) to induce reversible electroporation of cardiac tissue may effectively terminate AF. Purpose To assess the feasibility of PEF delivery for converting atrial arrhythmias via reversible electroporation. Methods Four swine models were used in this acute study. Custom-made decapolar catheters for PEF delivery were deployed with the following configurations: 1. Endocardial right atrium (RA) and coronary sinus (CS), n=2; 2. Endocardial RA and epicardial left atrium (epiLA), n=2. AF and atrial flutter (AFL) were induced with programmed stimulation. PEF delivery was performed using the BTX 830 generator. For each attempt, a single monophasic pulse at 10 or 20µs pulse width was administered, with voltage varied across attempts (range 750-3000V). Successful (type 1 and 2 breaks) and unsuccessful conversion attempts were recorded. Post-PEF signal changes and arrhythmias were identified. Results A total of 58 AF/AFL (28 and 30 respectively) episodes were induced. Of the 37 successful conversion attempts, 33 (89.1%) were type 1 breaks. Conversion success probabilities generally increased with higher voltages for both configurations. >70% conversion success was seen with ≥1500V for the RA/CS configuration and ≥2000V for the RA/epiLA configuration. Arrhythmias including intra-atrial delay and high-grade atrioventricular block were seen, usually following successive PEF deliveries. Significant muscle stimulation was provoked with the current experimental setup. Conclusion Termination of atrial arrhythmias with PEF delivery is feasible, although further work is required to optimize its efficacy and safety.

Abstract Background Ventricular fibrillation (VF) is a leading cause of sudden cardiac death worldwide. Defibrillation via direct current shocks is effective but associated with significant pain and morbidity, prompting the need for alternative approaches. Reversible electroporation of cardiac tissue with pulsed electric fields (PEF) may be an effective means of terminating VF. Purpose To assess the feasibility of PEF delivery for terminating VF. Methods 5 acute swine models were used. Mechanical circulatory support with peripheral veno-arterial extracorporeal membrane oxygenation +/- percutaneous left ventricular assist device (Impella 5.5 L) was implemented and titrated to a mean arterial pressure ≥65 mmHg. Decapolar catheters were introduced into the endocardial right and/or left ventricle as well as epicardium. VF was induced with R on T shocks or rapid ventricular pacing. PEF was delivered with the endocardial catheter as the cathode and epicardial catheter as the anode; monophasic pulses (5-10) at 3000V, 100µs, and 200ms inter-pulse intervals were used. If VF persisted post-PEF, catheters were repositioned into regions of intact voltages for repeat delivery. Results 10 VF episodes were induced, 7 of which were successfully terminated with PEF delivery (70.0%). The median number of attempts to achieve VF termination was 2 (range 1-5). The post-VF rhythm was complete heart block with ventricular asystole in all successful defibrillation attempts, with no recovery after 30 minutes of observation. Significant muscle stimulation was seen with the utilized PEF parameters and catheter configurations. Conclusion Termination of VF using PEF – pulsed field defibrillation – is possible. However, further study is required to optimize delivery parameters/configurations to improve effectiveness and avoid muscle stimulation as well as conduction abnormalities.

BACKGROUND: Cardiac radioablation is emerging as a treatment modality for refractory ventricular tachycardia. This study aimed to evaluate the effects of radiation on the coronary arteries in a swine model of proton beam cardiac radioablation. METHODS: Eighteen swine underwent single-fraction 30 to 40 Gy pencil-beam scanning proton therapy targeting the left ventricle and were euthanized 12 to 40 weeks later. Treatment planning was performed without restricting the dose to the coronary arteries. The maximum point dose (D max ) to the epicardial coronary arteries was calculated. In secondary analyses, the mean (D mean ) and minimum dose received by the highest irradiated 0.01 cm 3 (D 0.01 ) of each coronary artery were also calculated. Coronary artery segments were harvested from the D max sites for histological analysis, and the D max was correlated with stenosis severity. RESULTS: Ninety-six coronary arteries were analyzed. No stenoses were observed by computed tomography imaging preirradiation. By histological analysis posteuthanasia, 25/96 (26%) coronaries sampled at their D max sites had ≥75% stenosis. The median D max was 4.7 Gy for the <75% stenosis group and 29.7 Gy for the ≥75% stenosis group ( P <0.001). The AUC-ROC for the association between D max and stenosis ≥75% was 92.2%. A D max value of 20.1 Gy best predicted stenosis ≥75%, with sensitivity 92.3% and specificity 87.1%. The AUC-ROCs for the associations of D mean and D 0.01 with stenosis ≥75% were 84.8% and 91.6%, respectively. In histopathologic analysis, intimal hyperplasia was the most common coronary artery abnormality at the D max sites, and it was present in 61.5% of all arteries and in 93.9% of arteries with D max ≥20 Gy. CONCLUSIONS: In this preclinical model of proton beam cardiac radioablation, coronary stenoses occurred in a dose-dependent manner, with D max showing the closest correlation with stenosis ≥75%. These data provide for the first time a framework for dose constraint considerations for the coronary arteries during treatment planning for cardiac radioablation and thoracic malignancy radiation.

ABSTRACT Background Pulsed‐field ablation (PFA) offers myocardial selectivity with minimal thermal injury, but depth for ventricular lesions may be insufficient or heterogeneous at clinically tolerable field strengths. Calcium electroporation—local calcium chloride (CaCl₂) infusion after PFA—may amplify electroporation‐mediated cell death while maintaining low energy settings. Objective To determine whether immediate post‐PFA CaCl₂ infusion enhances acute and chronic ventricular lesion formation in vivo. Methods Nine swine underwent focal ventricular PFA (750–1000 V, biphasic, 20 μs × 50 pulses, 200 ms interpulse) via an irrigated focal catheter and benchtop electroporator. Immediately post‐PFA, lesions were randomized to saline, 0.2 g Ca, or 0.4 g Ca infused locally through the catheter tip. Acute hearts were explanted for TTC analysis; surviving animals were studied at 7 days for chronic lesion geometry. Results Among 41 acute lesions (17 control, 12 Ca 0.2 g, 12 Ca 0.4 g), Ca 0.4 g increased dark‐zone depth (3.5 ± 1.4 vs. 2.3 ± 0.8 mm; p = 0.038) and pale‐zone depth (2.6 ± 1.3 vs. 1.3 ± 0.8 mm; p = 0.011) versus control. At 7 days ( n = 33 lesions), Ca 0.4 g produced larger scars than control (width 11.6 ± 2.1 vs. 10.0 ± 1.9 mm; p = 0.027; depth 4.2 ± 1 vs. 3.0 ± 0.8 mm; p < 0.001; volume 193.6.4 ± 82.3 vs. 109.4 ± 48.2 mm³; p = 0.001). Conclusions Local CaCl₂ infusion after ventricular PFA significantly augments acute electroporation effect and chronic lesion size at low output, supporting facilitated PFA as a strategy for deeper, more durable ventricular ablation.

Background: Cardiac radioablation (CRA) is emerging as a treatment modality for refractory ventricular tachycardia (VT). This study aimed to evaluate the effects of radiation on the coronary arteries in a swine model of proton beam CRA. Methods: Eighteen domestic swine underwent 30–40 Gy pencil-beam scanning proton therapy in a single-fraction targeting the left ventricle with no attempt to spare coronary arteries and were euthanized 12-40 weeks later. Contrast-enhanced cardiac computed tomography (CT) was performed at baseline for treatment planning and at study end. Using dose-volume histograms, the maximum point (D max ), mean (D mean ) doses and the minimal doses received by the highest irradiated volumes of 0.01 cc (D 0.01cc ) for the left main, left anterior descending, circumflex, and right coronary artery, as well as the large diagonal and obtuse marginal branches were calculated. The D max location for each artery was mapped from the baseline planning CT onto the follow-up CT using deformable registration. Coronary artery segments were harvested from the D max sites for histological analysis. Receiver operating characteristic (ROC) analysis was performed to identify dose thresholds for predicting histologically severe coronary stenoses (≥75%). Results: Ninety-six coronary artery segments were analyzed. No stenoses were observed by CT imaging before irradiation. By histological analysis post-euthanasia, 25/96 (26%) coronary segments sampled at the Dmax site per artery had ≥75% stenosis. The median D max was 4.7 Gy for the <75% stenosis group and 29.7 Gy for the ≥75% stenosis group (p<0.001). The AUC-ROC for the association between D max and severe stenosis was 92.2%. A D max value of 20.1 Gy in a single fraction best predicted severe stenosis, with sensitivity of 92.3% and specificity of 87.1%. The AUC-ROC for the association between severe stenosis versus D mean and D 0.01cc was 84.8% and 91.6%, respectively. Based on histopathologic analysis, intimal hyperplasia was the most common coronary artery abnormality at the D max sites. Conclusion: In this pre-clinical model of proton beam CRA, coronary stenoses occurred in a dose-dependent manner, with D max being a better dosimetric predictor of stenosis than D mean and D 0.01cc . These data provide for the first time radiation dose constraint information for the epicardial coronary arteries that can be considered in treatment planning for CRA and radiation for thoracic malignancies.

BACKGROUND: Power-controlled radiofrequency ablation with irrigated-tip catheters has been the norm for ventricular ablation for almost 2 decades. New catheter technology has recently integrated more accurate tissue temperature sensing enabling temperature-controlled irrigated ablation. We aimed to investigate the in vivo ablation parameters and lesion formation characteristics in ventricular myocardium using a novel temperature-controlled radiofrequency catheter. METHODS: Twenty canines were divided into 3 groups: 4 noninfarcted, acute (phase I); 8 noninfarcted, chronic (phase II); and 8 infarcted, chronic (phase III). Lesions were delivered with a temperature-controlled radiofrequency system utilizing a chemical vapor deposit diamond for efficient thermal diffusivity. In phase I, 17 ablation settings were tested (temperature set points, 50/60/70 °C; ablation duration, 15/30/60/90/120 s; and power limit, 30/50 W). Four and one of these sets of parameters were further tested in phases II and III, respectively. Lesions were assessed by ex vivo contrast-enhanced magnetic resonance imaging and gross pathology 5 weeks after ablation in phases II/III. RESULTS: Across all phases, 111 ablation lesions were delivered. Ablation with the power limit of 50 W, the temperature set point of 60 °C, and the duration of 60 s produced significantly larger and deeper lesions (mean, 569.2 mm 3 ; mean maximal depth, 9.8 mm) compared with 50 W/60 °C/30 s (mean, 340.4 mm 3 ; mean maximal depth, 8.3 mm) and 50 W/50 °C/60 s (mean, 227 mm 3 ; mean maximal depth, 6.9 mm), with P <0.05 for all pairwise comparisons. Ablation of infarcted myocardium in phase III (50 W/60 °C/30 s) resulted in smaller impedance and bipolar electrogram amplitude changes and lesion size compared with ablation in normal myocardium with the same settings. No steam pop, myocardial perforation, or char formation was observed in any of the 111 ablations across all phases. CONCLUSIONS: In vivo radiofrequency ablation in a canine model with a diamond-tip temperature-controlled catheter using a temperature set point of 60 °C and a power limit of 50 W created large lesions without steam pop risk in both normal and infarcted ventricular myocardia.

ABSTRACT Background Pulsed‐field ablation (PFA) is an innovative non‐thermal method for arrhythmia treatment. The efficacy of various PFA configurations in relation to contact force (CF) has not been well‐studied in vivo. Objectives This study evaluated the effect of CF on acute bipolar PFA lesions in both a vegetal and an in vivo porcine heart model. Methods Bipolar PFA (500 V, 20 μs for 50 pulses) was applied to eight porcine ventricles, with CF categorized as standard (5–15 g), high (16–30 g), or very high (> 30 g) using the CARTO 3 system. PFA lesions were assessed by gross pathology, histology, and post‐ablation voltage amplitude. Additionally, a vegetal model using oscillating russet potatoes replicated the motion of a beating heart to compare lesion parameters under dynamic conditions and various PFA configurations (monopolar vs. bipolar). Results A total of 61 in vivo bipolar PFA lesions across all groups were analyzed. No significant differences in lesion surface diameter, depth, or volume were found among CF groups. In the vegetal model, monopolar setting had a better correlation between CF and lesion depth compared to bipolar setting. In addition, oscillations and catheter position (perpendicular or parallel) significantly affected lesion dimensions. Conclusion Increasing CF has a minimal effect on the size of acute bipolar PFA lesions in the porcine ventricle, suggesting that, for bipolar PFA, adequate CF is more critical than its intensity in a beating heart. For monopolar PFA, greater CF can impact lesion depth.

Background: Proton beam irradiation to the ventricular myocardium may enable non-invasive targeting of ventricular tachycardia. Previous work has demonstrated the feasibility of imaging ablation lesion with late gadolinium enhanced (LGE) cardiac magnetic resonance imaging (MRI). Hypothesis: We hypothesize that proton beam irradiation will lead to progressively increasing density of LGE corresponding to lesion formation during follow-up after treatment delivery. Aim: The aim of the current study was to determine the time course of LGE intensity in ventricular myocardium following proton beam therapy. Methods: Eleven swine were irradiated with 40 Gy proton beam in the anterior or lateral left ventricular (LV) followed by LGE cardiac MRI every 4 weeks for up to 24 weeks. After manual contouring of the endocardial and epicardial myocardium, a region of interest (ROI) in the area irradiated with 0-5 Gy was contoured (remote ROI). The mean and standard deviation (SD) of the signal intensity (SI) of the remote ROI were calculated. Light LGE was defined as voxels with SI > mean+2SD but < mean+3SD of the remote ROI, while voxels with SI > mean+3SD of the remote ROI were classified as having dense LGE. Voxels identified as bright due to image artifacts or noise were manually removed. The analysis was conducted in a fashion blinded to swine ID and time point after irradiation. Results: A total of 33 time points were analyzed (3.1 ± 1.4 MRI studies per swine). Figure 1A shows a representative time course of LGE in the same swine, progressing from diffuse light LGE at 8 weeks to dense LGE at 16-24 weeks. Figure 1B demonstrates the proportion of light versus dense LGE across timepoints in irradiated myocardial regions. At 8 weeks, light and dense LGE areas were evenly distributed. At 12 to 24 weeks, dense LGE increased to approximately 75%. The proportion of dense versus light LGE was significantly higher at 12, 16, and 24 weeks, as compared to 8 weeks. Conclusion: In ventricular myocardium, diffuse light LGE evident at 8 weeks progresses to denser LGE at 12-24 weeks following proton beam irradiation corresponding with lesion formation.

Background: Pulsed field ablation (PFA) is an innovative modality for treating arrhythmias that is mostly non-thermal and renders myocardial tissue non-viable by creating pores in cardiac cell membranes. The impact of contact force (CF) on PFA efficacy is not well characterized. Hypothesis: We hypothesize that, while contact is necessary for PFA, increasing CF will not have a significant effect on in vivo ablation lesion size. Aim: We seek to investigate the effects of CF on acute PFA lesions in a beating porcine heart model. Methods: The ventricles of 7 porcine animals were ablated in vivo with PFA (500V, at 20μs for 50 pulses separated by 200ms) using a focal bipolar irrigated ablation catheter and BTX 830 electroporation generator (Harvard Apparatus). CF was measured before and after each PFA application using CARTO 3. Lesions were divided into standard CF (5-15g), high CF (16-30g), and very high CF (>31g). Results: A total of 46 lesions were analyzed. Gross pathology showed no significant difference in maximum width, lesion depth, and lesion volume between the three groups ( Figure 1A-B ). Linear regression showed a decrease of 0.003 mm in depth (depth = -0.003 × CF + 1.8, R = 0.05), an increase of 0.01 mm in width (width = 0.01 × CF + 5.7, R = 0.09), and a decrease of 0.05 mm 3 in volume (volume = -0.05 × CF + 26.8, R = 0.03) for each additional gram of CF ( Figure 1C ). Conclusion: While contact is necessary, increasing CF did not have a significant effect on in-vivo PFA lesion dimensions in a beating porcine heart model.

Background: Pulsed field ablation (PFA) has emerged as an innovative technology for treating cardiac arrhythmias. PFA increases cell permeability, which can lead to apoptosis. Greater PFA energy may be necessary to ablate ventricular myocardium for ventricular tachycardia circuits, but this carries risks of side effects such as gaseous formation (microbubbles) and hemolysis. Ethanol (EtOH) infusion has been used to ablate pathologic myocardial tissues in hypertrophic cardiomyopathy and for refractory arrhythmias. Hypothesis: We hypothesize that PFA in the ventricle can increase EtOH uptake through PFA-generated pores, thereby enhancing ablation efficacy, even at low powers, by utilizing the cell permeability effects of PFA. Aim: The aim of this study is to investigate the effect of local EtOH infusion after PFA on lesion size in porcine ventricles. Methods: The ventricles of five porcine subjects were ablated in vivo with a PFA low power setting (750 V, at 20 μs for 50 pulses separated by 200 ms) using a focal bipolar irrigated ablation catheter and BTX 830 electroporation generator (Harvard Apparatus). After PFA was performed, 2 ml of 90 % EtOH vs. saline (control) was infused through the catheter tip to the site of ablation. We compared the electrograms voltage amplitude reduction before and after PFA, and the ablation lesion characteristics. Results: A total of 10 lesions in the control group and 9 lesions in the EtOH group were analyzed. For the controls, the voltage after PFA was not reduced. In contrast, for the EtOH group, the voltage after PFA was significantly reduced ( Figure 1A ). On gross pathology, there were significant differences in ablation lesion depths and volumes between the 2 lesion sets ( Figure 1A-B ). Conclusion: Local EtOH infusion after ventricular PFA enhanced acute efficacy of electroporation. Concurrent PFA with local EtOH infusion has the potential to improve efficacy without requiring higher energy parameters, thereby reducing PFA risks. Future studies on chronic efficacy are warranted.