Complexity analysis of electrical activity during endocardial and epicardial biventricular mapping of ventricular fibrillation.

BACKGROUND: Ventricular fibrillation (VF) is a lethal cardiac arrhythmia that is a significant cause of sudden cardiac death. Comprehensive studies of spatiotemporal characteristics of VF in situ are difficult to perform with current mapping systems and catheter technology. OBJECTIVE: The goal of this study was to develop a computational approach to characterize VF using a commercially available technology in a large animal model. Prior data suggests that characterization of spatiotemporal organization of electrical activity during VF can be used to provide better mechanistic understanding and potential ablation targets to modify VF and its substrate. We therefore evaluated intracardiac electrograms during biventricular mapping of the endocardium (ENDO) and epicardium (EPI) in acute canine studies. METHODS: To develop thresholds for organized and disorganized activity, a linear discriminant analysis (LDA)-based approach was performed to the known organized and disorganized activities recorded in ex vivo Langendorff-perfused rat and rabbit hearts using optical mapping experiments. Several frequency- and time-domain approaches were used as individual and paired features to identify the optimal thresholds for the LDA approach. Subsequently, VF was sequentially mapped in 4 canine hearts, using the CARTO mapping system with a multipolar mapping catheter in the ENDO left and right ventricles and EPI to capture the progression of VF at 3 discrete post-induction time intervals: VF period 1 (just after induction of VF to 15 min), VF period 2 (15 to 30 min), and VF period 3 (30 to 45 min). The developed LDA model, cycle lengths (CL), and regularity indices (RI) were applied to all recorded intracardiac electrograms to quantify the spatiotemporal organization of VF in canine hearts. RESULTS: We demonstrated the presence of organized activity in the EPI as VF progresses, in contrary to the ENDO, where the activity stays disorganized. The shortest CL always occurred in the ENDO, especially the RV, indicating a faster VF activity. The highest RI was found in the EPI in all hearts for all VF stages, indicating spatiotemporal consistency of RR intervals. CONCLUSION: We identified electrical organization and spatiotemporal differences throughout VF in canine hearts from induction to asystole. Notably, the RV ENDO is characterized by a high level of disorganization and faster VF frequency. In contrast, EPI has a high spatiotemporal organization of VF and consistently long RR intervals.

Bipolar Electroporation Across the Interventricular Septum: Electrophysiological, Imaging, and Histopathological Characteristics.

BACKGROUND: Pulsed electric field (PEF) ablation is an emerging modality for the treatment of cardiac arrhythmias. Data regarding effects on the interventricular septum are limited, and the optimal delivery protocol and electrode configuration remain undefined. OBJECTIVES: This study sought to evaluate the electrophysiological, imaging, and histological characteristics of bipolar direct-current PEF delivered across the interventricular septum. METHODS: PEF was applied between identical solid-tip ablation catheters positioned on either side of the septum in a chronic canine model. Intracardiac and surface electrophysiological data were recorded following delivery. In 4 animals, cardiac magnetic resonance (CMR) was performed early (6 ± 2 days) and late (30 ± 2 days) postablation. After 4 weeks of survival, cardiac specimens were sectioned for histopathological analysis. RESULTS: In 8 canines, PEF was delivered in 27 separate septal sites (45 ± 17 J/site) with either microsecond or nanosecond PEF. Acute complications included transient complete atrioventricular block in 5 animals (63%) after delivery at the anterobasal septum, with right bundle branch block persisting in 3 (38%). Ventricular fibrillation occurred in 1 animal during microsecond but not nanosecond PEF. Postprocedural CMR showed prominent edema and significant left ventricular systolic dysfunction, which recovered with late imaging. At 4 weeks, 36 individual well-demarcated lesions were demonstrated by CMR and histopathology. Lesion depth measured by histology was 2.6 ± 2.1 mm (maximum 10.9 mm and near transmural). CONCLUSIONS: Bipolar PEF ablation of the interventricular septum is feasible and can produce near transmural lesions. Myocardial stunning, edema, and conduction system injury may occur transiently. Further studies are required to optimize safe delivery and efficacious lesions.

Novel insights into the substrate involved in maintenance of ventricular fibrillation: results from continuous multipolar mapping in a canine model.

BACKGROUND: While the triggers for ventricular fibrillation (VF) are well-known, the substrate required for its maintenance remains elusive. We have previously demonstrated dynamic spatiotemporal changes across VF from electrical induction of VF to asystole. Those data suggested that VF drivers seemed to reside in the distal RV and LV. However, signals from these areas were not recorded continuously. The aim of this study was to map these regions of significance with stationary basket electrodes from induction to asystole to provide further insights into the critical substrate for VF rhythm sustenance in canines. METHODS: In six healthy canines, three multipolar basket catheters were positioned in the distal right ventricle (RV), RV outflow tract, and distal left ventricle (LV), and remained in place throughout the study. VF was induced via direct current application from an electrophysiologic catheter. Surface and intracardiac electrograms were recorded simultaneously and continuously from baseline, throughout VF, and until asystole, in order to get a complete electrophysiologic analysis of VF. Focused data analysis was also performed via two defined stages of VF: early VF (immediately after induction of VF to 10 min) and late VF (after 10 min up to VF termination and asystole). RESULTS: VF was continuously mapped for a mean duration of 54 ± 9 min (range 42-70 min). Immediately after initiation of VF in the early phase, the distal LV region appeared to drive the maintenance of VF. Towards the terminal stage of VF, the distal RV region appeared to be responsible for VF persistence. In all canines, we noted local termination of VF in the LV, while VF on surface ECG continued; conversely, subsequent spontaneous termination of VF in the RV was associated with termination of VF on surface ECG into a ventricular escape rhythm. Continuous mapping of VF showed trends towards an increase in peak-to-peak ventricular electrogram cycle length (p = 0.06) and a decrease in the ventricular electrogram amplitude (p = 0.06) after 40 min. Once we could no longer discern surface QRS activity, we demonstrated local ventricular myocardial capture in both the RV and LV but could not reinitiate sustained VF despite aggressive ventricular burst pacing. CONCLUSIONS: This study describes the evolution of VF from electrical initiation to spontaneous VF termination without hemodynamic support in healthy canines. These data are hypothesis-generating and suggest that critical substrate for VF maintenance may reside in both the distal RV and LV depending on stage of VF. Further studies are needed to replicate these findings with hemodynamic support and to translate such findings into clinical practice. Ventricular fibrillation maintenance may be dependent on critical structures in the distal RV. ECG: electrocardiogram; LV: left ventricle; RV: right ventricle; RVOT: right ventricular outflow tract; VF: ventricular fibrillation.

Open-chest Pulsed Electric Field Ablation of Cardiac Ganglionated Plexi in Acute Canine Models.

This study aimed to evaluate the safety and acute effect on markers of cardiac autonomic tone following pulsed electric fields (PEFs) delivered to epicardial ganglionated plexi (GP) during a cardiac surgical procedure. Ablation of GP as a treatment for atrial fibrillation (AF) has shown promise, but thermal ablation energy sources are limited by the risk of inadvertent collateral tissue injury. In acute canine experiments, median sternotomy was performed to facilitate the identification of 5 epicardial GP regions using an anatomy-guided approach. Each site was targeted with saline-irrigated PEF (1000 V, 100 µs, 10 electrocardiogram [ECG]-synchronized pulse sequences). Atrial effective refractory period (AERP) and local electrogram (EGM) amplitude were measured before and after each treatment. Histology was performed on samples from treatment-adjacent structures. In 5 animals, 30 (n = 2) and 60 (n = 3) pulses were successfully delivered to each of the 5 target sites. There was no difference in local atrial EGM amplitude before and after PEF application at each site (1.83 ± 0.41 vs. 1.92 ± 0.53 mV, P = .72). The mean AERP increased from 97 ± 15 ms at baseline to 115 ± 7 ms following treatment at all sites (18.6% increase; 95% confidence interval, 1.9-35.2; P = .037). There were no sustained ventricular arrhythmias or acute evidence of ischemia following delivery. Histology showed complete preservation of adjacent atrial myocardium, phrenic nerves, pericardium, and esophagus. Use of PEF to target regions rich in cardiac GP in open-chest canine experiments was feasible and effective at acutely altering markers of cardiac autonomic tone.

Ventricular nanosecond pulsed electric field delivery using active fixation leads: a proof-of-concept preclinical study.

BACKGROUND: Mid-myocardial ventricular arrhythmias are challenging to treat. Cardiac electroporation via pulsed electric fields (PEFs) offers significant promise. We therefore tested PEF delivery using screw-in pacemaker leads as proof-of-concept. METHODS: In 5 canine models, we applied nanosecond PEF (pulse width 300 ns) across the right ventricular (RV) septum using a single lead bipolar configuration (n = 2) and between two leads (n = 3). We recorded electrograms (EGMs) prior to, immediately post, and 5 min after PEF. Cardiac magnetic resonance imaging (cMRI) and histopathology were performed at 2 weeks and 1 month. RESULTS: Nanosecond PEF induced minimal extracardiac stimulation and frequent ventricular ectopy that terminated post-treatment; no canines died with PEF delivery. With 1 lead, energy delivery ranged from 0.64 to 7.28 J. Transient ST elevations were seen post-PEF. No myocardial delayed enhancement (MDE) was seen on cMRI. No lesions were noted on the RV septum at autopsy. With 2 leads, energy delivery ranged from 56.3 to 144.9 J. Persistent ST elevations and marked EGM amplitude decreases developed post-PEF. MDE was seen along the septum 2 weeks and 1 month post-PEF. There were discrete fibrotic lesions along the septum; pathology revealed dense connective tissue with < 5% residual cardiomyocytes. CONCLUSIONS: Ventricular electroporation is feasible and safe with an active fixation device. Reversible changes were seen with lower energy PEF delivery, whereas durable lesions were created at higher energies. Central illustration: pulsed electric field delivery into ventricular myocardium with active fixation leads.

Regional and Temporal Variation of Ventricular and Conduction Tissue Activity During Ventricular Fibrillation in Canines.

[Figure: see text].

Electroporation ablation of bronchial smooth muscle cells: A novel non-thermal asthma therapy.

OBJECTIVE: Asthma is a common disease which places significant burden on the US healthcare system and which can be associated with significant patient morbidity and mortality. Current medical therapies are costly and not curative. A new approach for a more permanent asthma treatment is the use of radiofrequency ablation. However, this radiofrequency approach is thermal-based and can result in deleterious effects to the airways, such as stenosis or ulceration. We describe a novel, improved therapeutic approach for smooth muscle ablation using non-thermal DC electroporation ablation. METHODS: We developed and tested prototype electroporation ablation devices that access the airways both endoscopically and via a bronchoscope. We tested the feasibility of this approach and demonstrated proof-of-concept in 2 mongrel dogs. In order to assess for smooth muscle function, we performed functional studies pre and post ablation with methacholine challenge to assess for airway reversibility. We also evaluated bronchial lesions via direct vision with bronchoscopy. RESULTS: We developed novel electroporation catheters to delivery energy to the bronchial smooth muscle through an endoscopic approach. We tested these catheters in 2 acute canine studies and successfully demonstrated the ability to destroy smooth muscle tissue via novel prototypes and saline irrigation for widespread non-thermal electroporation ablation. Our functional studies demonstrate the efficacy of this approach. CONCLUSION: We report a novel method for non-thermal bronchial smooth muscle ablation using novel prototypes and electroporation with normal saline. These early findings require further evaluation in larger, chronic canine studies to assess for use as a potential curative therapy.