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.

Stellate ganglia stimulation counteracts vagal stimulation by significantly increasing heart rate and blood pressure.

BACKGROUND: Vasovagal syncope (VVS) is the leading cause of syncope. The most frequent mechanism is that of a cardioinhibitory response, vasodepressor response, or mixture of both. Neural stimulation that negates or overcomes the effects of vagal tone may be used as a treatment strategy for VVS. METHODS: Six male canines were studied. Stimulation (10-Hz, 2 ms pulse duration, 2 min duration) of the cervical vagus (CV), thoracic vagus (TV), and stellate ganglia (SG) was performed using needle electrodes at 3 V, 5 V, and 10 V output. SG stimulation at an output of 10 V overlaying TV stimulation at the same output was performed. Heart rate (HR), blood pressure (BP), and cardiac output (CO) were measured before, during, and after stimulation. RESULTS: Right cervical vagal stimulation was associated with significant hemodynamic changes. HR, SBP, and DBP were reduced (107 ± 16 vs. 78 ± 15 bpm [P < 0.0001], 116 ± 24 vs. 107 ± 28 mmHg [P = 0.002] and 71 ± 18 vs. 58 ± 20 mmHg [P < 0.0001]), respectively, while left cervical vagal stimulation had minimal changes. CV stimulation was associated with greater hemodynamic changes than TV stimulation. Left and right SG stimulation significantly increased systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR at 5 V and 10 V, which could be observed within 30 s after stimulation. An output-dependent increase in hemodynamic parameters was seen with both left and right SG stimulation. No difference between left and right SG stimulation was seen. SG stimulation overlay significantly increased HR, BP, and CO from baseline vagal stimulation bilaterally. CONCLUSIONS: Stellate ganglia stimulation leads to increased HR and BP despite significant vagal stimulation. This may be exploited therapeutically in the management of vasovagal syncope.

Epicardial Pulsed Field Ablation of Ganglionated Plexi: Computational and Pre-Clinical Evaluation of a Bipolar Sub-Xiphoid Catheter for the Treatment of Atrial Fibrillation.

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.

Effects of Pulsed Electric Fields on the Coronary Arteries in Swine.

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.

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].

Intramural conduction system gradients and electrogram regularity during ventricular fibrillation.

INTRODUCTION: The His-Purkinje system has been shown to harbor triggers for ventricular fibrillation (VF) initiation. However, the substrate responsible for VF maintenance remains elusive. We hypothesized that standard, electrode-based, point-to-point mapping would yield meaningful insight into site-specific patterns and organization which may shed light on the critical substrate for maintenance of VF. METHODS: VF was induced under general anesthesia by direct current (DC) application to the right ventricle in 7 acute canines. A standard EPT Blazer mapping catheter (Boston Scientific, Natuck, MA) was used for mapping in conjunction with a Prucka recording system. We collected 30 consecutive electrograms at 24 distinct sites, confirmed by fluoroscopy and intracardiac echo. These sites included both endocardial and epicardial locations throughout the ventricles and conduction system. RESULTS: A total of 5040 individual data points were collected in 7 separate canine studies. During VF mapping, a transmural disparity was found between the epicardium (average cycle length [CL] of 1136 m s) and the endocardium (average CL of 123 m s) with a p value of <0.01. An additional, intramural gradient was found when comparing the proximal, insulated conduction system to the distal, non-insulated conduction system (average CL 218 versus 111 m s [p = 0.03]). CONCLUSION: Our data are supportive of a novel observation of intramural difference between insulated and non-insulated regions of the His-Purkinje network in canines. In addition, certain areas exhibited periods of regular electrogram characteristics; this was despite the heart remaining in terminal VF. These early canine data merit further study to investigate if specific ablation of the distal conduction system can perturb or extinguish VF.

Ventricular dyssynchrony assessment using ultra-high frequency ECG technique.

PURPOSE: The aim of this proof-of-concept study is to introduce new high-dynamic ECG technique with potential to detect temporal-spatial distribution of ventricular electrical depolarization and to assess the level of ventricular dyssynchrony. METHODS: 5-kHz 12-lead ECG data was collected. The amplitude envelopes of the QRS were computed in an ultra-high frequency band of 500-1000 Hz and were averaged (UHFQRS). UHFQRS V lead maps were compiled, and numerical descriptor identifying ventricular dyssynchrony (UHFDYS) was detected. RESULTS: An electrical UHFQRS maps describe the ventricular dyssynchrony distribution in resolution of milliseconds and correlate with strain rate results obtained by speckle tracking echocardiography. The effect of biventricular stimulation is demonstrated by the UHFQRS morphology and by the UHFDYS descriptor in selected examples. CONCLUSIONS: UHFQRS offers a new and simple technique for assessing electrical activation patterns in ventricular dyssynchrony with a temporal-spatial resolution that cannot be obtained by processing standard surface ECG. The main clinical potential of UHFQRS lies in the identification of differences in electrical activation among CRT candidates and detection of improvements in electrical synchrony in patients with biventricular pacing.

Evaluation of a Unique Defibrillation Unit with Dual-Vector Biphasic Waveform Capabilities: Towards a Miniaturized Defibrillator.

BACKGROUND: Automated 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. METHODS: We 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. RESULTS: A 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). CONCLUSIONS: Our 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.

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.

A Review Of The Relevant Embryology, Pathohistology, And Anatomy Of The Left Atrial Appendage For The Invasive Cardiac Electrophysiologist.

The three-dimensional morphology of the left atrial appendage provides the substrate for thrombus generation, and is a harbinger for embolic material due to its direct connection to the left-sided circulation. Appreciating the development of the appendage from mesodermal layer to its adult form provides the basis to improve exclusion from the atrial circulation, and thereby can lead to a significant reduction in stroke risk. This process also provides insight into the role of the left atrial appendage as an endocrine organ, its involvement in fluid homeostasis, and its connection to the autonomic nervous system. Knowledge of the surrounding structural arrangement is critical to identify landmarks from both an endocardial and epicardial perspective to improve targeted device placement. Furthermore, correlation of the left atrial appendage body, neck, and ostium to the surrounding anatomy can also improve both procedural efficacy and safety. In addition, a working knowledge of the regional anatomy adds a prudent degree of awareness for procedural complications, and allows for early identification and timely intervention as these situations arise. A detailed understanding of the left atrial appendage embryology, histology, and gross anatomy is imperative to identify the correct device and approach for each individual patient. In addition, this increased awareness can identify areas that are in need of further innovation, and thus provide the ability to adapt and refine existing technologies to overcome pitfalls currently facing catheter-based approaches.