Feasibility of Linear Irreversible Electroporation Ablation in the Coronary Sinus.

INTRODUCTION: Previous studies demonstrated that the coronary sinus (CS) is an important target for ablation in persistent atrial fibrillation. However, radiofrequency ablation in the CS is associated with coronary vessel damage and tamponade. Animal data suggest irreversible electroporation (IRE) ablation can be a safe ablation modality in vicinity of coronary arteries. We investigated the feasibility of IRE in the CS in a porcine model. METHODS: Ablation and pacing was performed in the CS in six pigs (weight 60-75 kg) using a modified 9-French steerable linear hexapolar Tip-Versatile Ablation Catheter. Pacing maneuvers were performed from distal to proximal segments of the CS to assess atrial capture thresholds before and after IRE application. IRE ablations were performed with 100 J IRE pulses. After 3-week survival animals were euthanized and histological sections from the CS were analyzed. RESULTS: A total of 27 IRE applications in six animals were performed. Mean peak voltage was 1509 ± 36 V, with a mean peak current of 22.9 ± 1.0 A. No complications occurred during procedure and 3-week survival. At 30 min post ablation 100% isolation was achieved in all animals. At 3 weeks follow-up pacing thresholds were significant higher as compared to baseline. Histological analysis showed transmural ablation lesions in muscular sleeves surrounding the CS. CONCLUSION: IRE ablation of the musculature along the CS using a multi-electrode catheter is feasible in a porcine model.

Multielectrode Contact Measurement Can Improve Long-Term Outcome of Pulmonary Vein Isolation Using Circular Single-Pulse Electroporation Ablation.

BACKGROUND: Irreversible electroporation (IRE) ablation is generally performed with multielectrode catheters. Electrode-tissue contact is an important predictor for the success of pulmonary vein (PV) isolation; however, contact force is difficult to measure with multielectrode ablation catheters. In a preclinical study, we assessed the feasibility of a multielectrode impedance system (MEIS) as a predictor of long-term success of PV isolation. In addition, we present the first-in-human clinical experience with MEIS. METHODS: In 10 pigs, one PV was ablated based on impedance (MEIS group), and the other PV was solely based on local electrogram information (EP group). IRE ablations were performed at 200 J. After 3 months, recurrence of conduction was assessed. Subsequently, in 30 patients undergoing PV isolation with IRE, MEIS was evaluated and MEIS contact values were compared to local electrograms. RESULTS: In the porcine study, 43 IRE applications were delivered in 19 PVs. Acutely, no reconnections were observed in either group. After 3 months, 0 versus 3 (P=0.21) PVs showed conduction recurrence in the MEIS and EP groups, respectively. Results from the clinical study showed a significant linear relation was found between mean MEIS value and bipolar dV/dt (r2=0.49, P<0.001), with a slope of 20.6 mV/s per Ohm. CONCLUSIONS: Data from the animal study suggest that MEIS values predict effective IRE applications. For the long-term success of electrical PV isolation with circular IRE applications, no significant difference in efficacy was found between ablation based on the measurement of electrode interface impedance and ablation using the classical EP approach for determining electrode-tissue contact. Experiences of the first clinical use of MEIS were promising and serve as an important basis for future research.

Characteristics and time course of acute and chronic myocardial lesion formation after electroporation ablation in the porcine model.

INTRODUCTION: Electroporation ablation creates deep and wide myocardial lesions. No data are available on time course and characteristics of acute lesion formation. METHODS: For the acute phase of myocardial lesion development, seven pigs were investigated. Single 200 J applications were delivered at four different epicardial right ventricular sites using a linear suction device, yielding a total of 28 lesions. Timing of applications was designed to yield lesions at seven time points: 0, 10, 20, 30, 40, 50, and 60 min, with four lesions per time point. After killing, lesion characteristics were histologically investigated. For the chronic phase of myocardial lesion development, tissue samples were used from previously conducted studies where tissue was obtained at 3 weeks and 3 months after electroporation ablation. RESULTS: Acute myocardial lesions induce a necrosis pattern with contraction band necrosis and interstitial edema, immediately present after electroporation ablation. No further histological changes such as hemorrhage or influx of inflammatory cells occurred in the first hour. After 3 weeks, the lesions consisted of sharply demarcated loose connective tissue that further developed to more fibrotic scar tissue after 3 months without additional changes. Within the scar tissue, arteries and nerves were unaffected. CONCLUSION: Electroporation ablation immediately induces contraction band necrosis and edema without additional tissue changes in the first hour. After 3 weeks, a sharply demarked scar has been developed that remains stable during follow-up of 3 months. This is highly relevant for clinical application of electroporation ablation in terms of the electrophysiological endpoint and waiting period after ablation.

Comparison of In Vivo Tissue Temperature Profile and Lesion Geometry for Radiofrequency Ablation With High Power-Short Duration and Moderate Power-Moderate Duration: Effects of Thermal Latency and Contact Force on Lesion Formation.

[Figure: see text].

Efficacy of multi-electrode linear irreversible electroporation.

AIMS: We investigated the efficacy of linear multi-electrode irreversible electroporation (IRE) ablation in a porcine model. METHODS AND RESULTS: The study was performed in six pigs (weight 60-75 kg). After median sternotomy and opening of the pericardium, a pericardial cradle was formed and filled with blood. A linear seven polar 7-Fr electrode catheter with 2.5 mm electrodes and 2.5 mm inter-electrode spacing was placed in good contact with epicardial tissue. A single IRE application was delivered using 50 J at one site and 100 J at two other sites, in random sequence, using a standard monophasic defibrillator connected to all seven electrodes connected in parallel. The pericardium and thorax were closed and after 3 weeks survival animals were euthanized. A total of 82 histological sections from all 18 electroporation lesions were analysed. A total of seven 50 J and fourteen 100 J epicardial IRE applications were performed. Mean peak voltages at 50 and 100 J were 1079.2 V ± 81.1 and 1609.5 V ± 56.8, with a mean peak current of 15.4 A ± 2.3 and 20.2 A ± 1.7, respectively. Median depth of the 50 and 100 J lesions were 3.2 mm [interquartile range (IQR) 3.1-3.6] and 5.5 mm (IQR 4.6-6.6) (P < 0.001), respectively. Median lesion width of the 50 and 100 J lesions was 3.9 mm (IQR 3.7-4.8) and 5.4 mm (IQR 5.0-6.3), respectively (P < 0.001). Longitudinal sections showed continuous lesions for 100 J applications. CONCLUSION: Epicardial multi-electrode linear application of IRE pulses is effective in creating continuous deep lesions.

Pulmonary Vein Isolation With Single Pulse Irreversible Electroporation: A First in Human Study in 10 Patients With Atrial Fibrillation.

BACKGROUND: Irreversible electroporation (IRE) is a promising new nonthermal ablation technology for pulmonary vein (PV) isolation in patients with atrial fibrillation. Experimental data suggest that IRE ablation produces large enough lesions without the risk of PV stenosis, artery, nerve, or esophageal damage. This study aimed to investigate the feasibility and safety of single pulse IRE PV isolation in patients with atrial fibrillation. METHODS: Ten patients with symptomatic paroxysmal or persistent atrial fibrillation underwent single pulse IRE PV isolation under general anesthesia. Three-dimensional reconstruction and electroanatomical voltage mapping (EnSite Precision, Abbott) of left atrium and PVs were performed using a conventional circular mapping catheter. PV isolation was performed by delivering nonarcing, nonbarotraumatic 6 ms, 200 J direct current IRE applications via a custom nondeflectable 14-polar circular IRE ablation catheter with a variable hoop diameter (16-27 mm). A deflectable sheath (Agilis, Abbott) was used to maneuver the ablation catheter. A minimum of 2 IRE applications with slightly different catheter positions were delivered per vein to achieve circular tissue contact, even if PV potentials were abolished after the first application. Bidirectional PV isolation was confirmed with the circular mapping catheter and a post ablation voltage map. After a 30-minute waiting period, adenosine testing (30 mg) was used to reveal dormant PV conduction. RESULTS: All 40 PVs could be successfully isolated with a mean of 2.4±0.4 IRE applications per PV. Mean delivered peak voltage and peak current were 2154±59 V and 33.9±1.6 A, respectively. No PV reconnections occurred during the waiting period and adenosine testing. No periprocedural complications were observed. CONCLUSIONS: In the 10 patients of this first-in-human study, acute bidirectional electrical PV isolation could be achieved safely by single pulse IRE ablation.

In vitro analysis of the origin and characteristics of gaseous microemboli during catheter electroporation ablation.

INTRODUCTION: Recent studies demonstrated that irreversible electroporation (IRE) ablation may be an alternative method for thermal ablation for pulmonary vein isolation. Development of gaseous microemboli during catheter ablation might lead to asymptomatic ischemic events and is therefore an important research topic. Gas formation during arcing with direct current catheter ablation has been studied in the past, however not for nonarcing IRE-ablation. OBJECTIVE: The aim of the present study was to visualize, quantify, and characterize gas formation during nonarcing millisecond IRE-pulses using a multielectrode circular catheter. METHODS: In vitro, gas formation during IRE-pulses was studied using a high-speed imaging, direct volume measurements, and a bubble counter. Gas formation was compared between cathodal and anodal IRE-pulses and between a small and large catheter hoop diameter. RESULTS: High-speed images showed the location and dynamics of gas formation during cathodal and anodal millisecond IRE-pulses. The direct volume measurements demonstrated a significantly larger volume for cathodal than for anodal IRE-pulses (P < .001), and no significant difference between small and large hoop diameters. A strong linear relationship was found between delivered charge and total gas volume (r = 0.99). Bubble counter measurements showed that cathodal IRE-pulses produced more and larger gas bubbles than anodal IRE-pulses. The ratio of total gas volume between cathodal and anodal IRE-pulses is different as predicted from electrolysis theory. CONCLUSION: In vitro, millisecond anodal IRE-pulses produce significantly less and smaller gas bubbles than millisecond cathodal IRE-pulses. In vivo experiments are required to investigate the clinical implication of these observations.

High-frequency irreversible electroporation for cardiac ablation using an asymmetrical waveform.

BACKGROUND: Irreversible electroporation (IRE) using direct current (DC) is an effective method for the ablation of cardiac tissue. A major drawback of the use of DC-IRE, however, are two problems: requirement of general anesthesia due to severe muscle contractions and the formation of bubbles containing gaseous products from electrolysis. The use of high-frequency alternating current (HF-IRE) is expected to solve both problems, because HF-IRE produces little to no muscle spasms and does not cause electrolysis. METHODS: In the present study, we introduce a novel asymmetric, high-frequency (aHF) waveform for HF-IRE and present the results of a first, small, animal study to test its efficacy. RESULTS: The data of the experiments suggest that the aHF waveform creates significantly deeper lesions than a symmetric HF waveform of the same energy and frequency (p = 0.003). CONCLUSION: We therefore conclude that the use of the aHF enhances the feasibility of the HF-IRE method.

Electroporation and its Relevance for Cardiac Catheter Ablation.

Irreversible electroporation can be used as a nonthermal energy source to ablate tissue. Cardiac catheter ablation by irreversible electroporation may be a safe and effective alternative for thermal ablation techniques such as radiofrequency or cryoablation. Total applied current, not delivered power (watts), energy (joules), or voltage, is the parameter that most directly relates to the local voltage gradient that causes electroporation. Electroporation can be achieved with various modalities: direct current, alternating current, pulsed direct current, or any combination of these. Experimental cardiac and noncardiac studies have demonstrated tissue specificity with survival of arteries and nerves in large lesions. In addition, porcine data suggest that application inside a pulmonary vein does not lead to pulmonary vein stenosis and that the esophagus is remarkably insensitive to electroporation. Therefore, irreversible electroporation is a very promising technique for cardiac catheter ablation and especially for electrical pulmonary vein isolation.

Novel method for electrode-tissue contact measurement with multi-electrode catheters.

Aims: With multi-electrode catheters, measuring contact force (CF) on each electrode is technically challenging. Present electrical methods, like the electrical coupling index (ECI) may yield false positive values in pulmonary veins. We developed a novel method that measures electrode-interface resistance (IR) by applying a very local electrical field between neighbouring catheter electrodes while measuring voltage between each catheter electrode and a skin patch. The aim of this study was to evaluate the new IR method to measure electrode-tissue contact. Methods and results: In vitro, effects of remote high-impedance structures were studied. In addition, both ECI and IR were directly compared with true electrode-tissue CF. In five pigs, the influence of high-impedance pulmonary tissue on ECI and IR was investigated while navigating the free floating catheter into the caval veins. Inside the left atrium (LA), IR was directly compared with CF. Finally, multi-electrode IR measurements in the LA and inferior pulmonary vein (IPV) were compared. In vitro, IR is much less affected by remote high-impedance structures than ECI (3% vs. 32%). Both IR and ECI strongly relate to electrode-tissue CF (r2 = 0.84). In vivo, and in contrast to ECI, IR was not affected by nearby pulmonary tissue. Inside the LA, a strong relation between IR and CF was found. This finding was confirmed by simultaneous multi-electrode measurements in LA and IPV. Conclusion: Data of the present study suggest that electrode-tissue contact affects the IR while being highly insensitive to remote structures. This method facilitates electrode-tissue contact measurements with circular multi-electrode ablation catheters.

Low vulnerability of the right phrenic nerve to electroporation ablation.

BACKGROUND: Circular electroporation ablation is a novel ablation modality for electrical pulmonary vein isolation. With a single 200-J application, deep circular myocardial lesions can be created. However, the acute and chronic effects of this energy source on phrenic nerve (PN) function are unknown. OBJECTIVE: The purpose of this study was to analyze nerve vulnerability to electroporation ablation in a porcine model. METHODS: In 20 animals (60-75 kg), the course of the right PN was pace-mapped inside the superior caval vein (SCV). Thereafter, a single 200-J circular electroporation ablation was performed via a multipolar circular catheter in firm contact with the inner SCV wall. RESULTS: In 19 of 20 animals, the PN could be captured along an estimated 6-8 cm trajectory above the right atrial contour. Directly after the application, the PN could be captured above the ablation level in 17 of 19 animals and after maximally 30 minutes in all animals. Fifteen animals were restudied after 3-13 weeks, and PN functionality was unaffected in all. Histological analysis in 5 animals in which the application had been delivered in the muscular sleeve just above the right atrium showed a transmural circular lesion. However, no lesion was found in the other animals in which the application had been delivered in the fibrous section more cranial in the SCV. CONCLUSIONS: Electroporation ablation at an energy level that may create deep myocardial lesions may spare the targeted right PN. These animal data suggest that electroporation may be a safe ablation modality near the right PN.

Pulmonary vein stenosis after catheter ablation: electroporation versus radiofrequency.

BACKGROUND: Radiofrequency ablation inside pulmonary vein (PV) ostia can cause PV stenosis. A novel alternative method of ablation is irreversible electroporation, but the long-term response of PVs to electroporation ablation is unknown. METHODS AND RESULTS: In ten 6-month-old pigs (60-75 kg), the response of PVs to circular electroporation and radiofrequency ablation was compared. Ten consecutive, nonarcing, electroporation applications of 200 J were delivered 5 to 10 mm inside 1 of the 2 main PVs, using a custom-deflectable, 18-mm circular decapolar catheter. Inside the other PV, circular radiofrequency ablation was performed using 30 W radiofrequency applications via an irrigated 4-mm ablation catheter. PV angiograms were made before ablation, immediately after ablation, and after 3-month survival. PV diameters and heart size were measured. With electroporation ablation, PV ostial diameter decreased 11±10% directly after ablation, but had increased 19±11% after 3 months. With radiofrequency ablation, PV ostial diameter decreased 23±15% directly after ablation and remained 7±17% smaller after 3 months compared with preablation diameter despite a 21±7% increase in heart size during aging from 6 to 9 months. CONCLUSIONS: In this porcine model, multiple circumferential 200-J electroporation applications inside the PV ostia do not affect PV diameter at 3-month follow-up. Radiofrequency ablation inside PV ostia causes considerable PV stenosis directly after ablation, which persists after 3 months.

Practical ways to reduce radiation dose for patients and staff during device implantations and electrophysiological procedures.

Despite the advent of non-fluoroscopic technology, fluoroscopy remains the cornerstone of imaging in most interventional electrophysiological procedures, from diagnostic studies over ablation interventions to device implantation. Moreover, many patients receive additional X-ray imaging, such as cardiac computed tomography and others. More and more complex procedures have the risk to increase the radiation exposure, both for the patients and the operators. The professional lifetime attributable excess cancer risk may be around 1 in 100 for the operators, the same as for a patient undergoing repetitive complex procedures. Moreover, recent reports have also hinted at an excess risk of brain tumours among interventional cardiologists. Apart from evaluating the need for and justifying the use of radiation to assist their procedures, physicians have to continuously explore ways to reduce the radiation exposure. After an introduction on how to quantify the radiation exposure and defining its current magnitude in electrophysiology compared with the other sources of radiation, this position paper wants to offer some very practical advice on how to reduce exposure to patients and staff. The text describes how customization of the X-ray system, workflow adaptations, and shielding measures can be implemented in the cath lab. The potential and the pitfalls of different non-fluoroscopic guiding technologies are discussed. Finally, we suggest further improvements that can be implemented by both the physicians and the industry in the future. We are confident that these suggestions are able to reduce patient and operator exposure by more than an order of magnitude, and therefore think that these recommendations are worth reading and implementing by any electrophysiological operator in the field.

Myocardial lesion depth with circular electroporation ablation.

BACKGROUND: Recently, we demonstrated the feasibility and safety of circular electroporation ablation in porcine pulmonary vein ostia, but the relationship between the magnitude of the application and lesion dimensions is still unknown. METHODS AND RESULTS: An in vivo porcine study was performed on left ventricular epicardium submerged under 10 mm of blood, using devices that mimic a 20-mm-diameter 7F circular ablation catheter. Model D contained 10 separate electrodes, whereas model M consisted of 1 circular electrode. Ablations were performed at 50, 100, and 200 J with model D and at 100 J with model M. Lesion dimensions were measured after 3-week survival. All applications resulted in smooth voltage waveforms demonstrating the absence of vapor globe formation, arcing, and a pressure wave. Applications up to 100 J with model D resulted in separate lesions under the electrodes. At 200 J, continuous deep circular lesions were created despite the use of separate electrodes. There was a significant relationship between applied current and median lesion depth, with a slope of 0.17 mm/A. At 100 J, there was no difference in lesion depth or width between models D and M. The electrodes and ablation site directly after ablation showed no signs of thermal damage. CONCLUSIONS: In an epicardial porcine model with blood around the application site, continuous circular lesions, deep enough for electric pulmonary vein isolation, were created with a single circular 200-J application. Lesions were continuous despite the use of separate electrodes. Lesion depth increased with the magnitude of the application.

RF catheter ablation: Lessons on lesions.

The present treatment of atrial fibrillation by radiofrequency catheter ablation requires long continuous lesions in the thin walled left atrium where side effects may lead to serious complications. Better understanding of the physical processes that take place during ablation may help to improve the quality, safety, and outcome of these procedures. These processes include the distribution of power between blood, tissue, and patient; the mechanisms of tissue heating and coagulum formation; the relation between tissue and electrode temperatures; and the effects of increased electrode size and internal and external electrode cooling. With normal electrode-tissue contact, only a fraction of all power is effectively delivered to the tissue. Due to the variability of blood flow cooling, applied power and electrode temperature rise are poor indicators of lesion formation. With a longer electrode, the efficiency of tissue heating is decreased and the greater variation in tissue contact caused by electrode orientation makes lesion formation even more unpredictable. The absence of impedance rise during ablation does not guarantee the absence of blood clot formation on the tissue contact site. Blood clots may unnoticeably be created on the lesion surface and are caused by thermal denaturization of blood proteins, independent of heparinization. Irrigated ablation with external flush may prevent blood clot formation. Irrigation minimally affects lesion size by cooling the tissue surface. Larger lesions may only be created by the application of higher power levels. Electrode cooling, however, impedes electrode temperature feed back and blinds the operator for excessive tissue heating. External cooling alone with preservation of temperature feed back is a promising concept that may lead to improved procedural safety and success.