Effects of Electrode-Tissue Proximity on Cardiac Lesion Formation Using Pulsed Field Ablation
Pulsed field ablation (PFA) is a novel energy modality for treatment of cardiac arrhythmias. The impact of electrode-tissue proximity on lesion formation by PFA has not been conclusively assessed. The objective of this investigation was to evaluate the effects of electrode-tissue proximity on cardiac lesion formation with a biphasic, bipolar PFA system.
PFA was delivered on the ventricular epicardial surface in an isolated porcine heart model (n=8) via a 4-electrode prototype catheter. An offset tool was designed to control the distance between electrodes and target tissue; deliveries were placed 0 mm (0 mm offset), 2 mm (2 mm offset), and 4 mm away from the tissue (4 mm offset). Lesions were assessed using tetrazolium chloride staining. Numerical models for the experimental setup with and without the offset tool validated and supported results.
Cardiac lesion dimensions decreased proportional to the distance between epicardial surface and electrodes. Lesion depth averaged 4.3±0.4 mm, 2.7±0.4 mm, and 1.3±0.4 mm for the 0, 2, and 4 mm and lesion width averaged 9.4±1.1 mm, 7.5±0.8 mm and 5.8±1.4 mm for the 0, 2, and 4 mm offset distances, respectively. Numerical modeling matched ex vivo results well and predicted lesion creation with and without the offset tool.
Using a biphasic, bipolar PFA system resulted in cardiac lesions even in the 0 mm offset distance case. The relationship between lesion depth and offset distance was linear, and the deepest lesions were created with 0 mm offset distance, that is, with electrodes in contact with tissue. Therefore, close electrode-tissue proximity increases the likelihood of achieving transmural lesions by maximizing the electric field penetration into the target tissue.
What Is Known?
Temperature-based ablation technologies such as radiofrequency ablation or cryoablation require direct tissue contact for energy transfer.
Pulsed field ablation is a field-based technology resulting in cell death via exposure of tissue to electric fields exceeding the threshold for irreversible electroporation.
What this Study Adds
Although ablation using pulsed fields does not require direct tissue contact for myocardial lesion creation, the deepest lesion were observed with direct tissue contact.
Thermal-based catheter ablation systems (eg, radiofrequency and cryoablation) are the cornerstone treatment modalities for patients with antiarrhythmic drug resistant, symptomatic paroxysmal, and persistent atrial fibrillation.1 Standard catheter ablation technologies depend upon electrode-tissue contact to optimize lesion delivery and clinical outcomes.2,3 Lack of contact with the tissue during ablation may lead to ineffective lesion formation using thermal technologies, although an important balance is often necessary to prioritize safety and avoid excessive energy delivery. Therefore, operators rely on multiple surrogate indicators of stable and safe catheter-tissue placement including the additional use of tactile feedback, contact force measurements, impedance and electrode temperature measurements, and identification of catheter location by imaging.4–7
Pulsed field ablation (PFA) is an emerging energy modality for catheter-based treatment of cardiac arrhythmias currently in clinical development.8–11 PFA employs a nonthermal ablative mechanism of action called irreversible electroporation, in which application of high voltage electric pulses induces transient permeabilization of cell membranes which (subsequently) leads to cell death.12–15 This mechanism is linked with potential clinical benefits, including avoiding/reducing the probability of forming atrioesophageal fistula and reduction in pulmonary vein stenosis.16 Additionally, existing preclinical work indicated that the heavily trabeculated appendages can be ablated in a durable, transmural manner with a circular PFA catheter.17 Nevertheless, the impact of electrode-tissue proximity on cardiac lesion formation with a biphasic, bipolar PFA system has not been conclusively assessed.
In our study, we hypothesize that direct electrode-tissue contact is not required to create effective cardiac lesions with PFA, due to irreversible electroporation dependence on the electric field distribution. We aimed to identify the impact of electrode-tissue proximity on lesion creation in an isolated porcine heart model using a prototype catheter and replicated these results with numerical modeling.
This research protocol was approved by the Institutional Animal Care and Use Committee of the University of Minnesota and the animal experiments were performed at the University of Minnesota. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Isolated Heart Preparation
Isolated hearts were prepared from male Yorkshire pigs (n=8, mean weight 76.4±9.4 kg [SD]) as previously described.18 In brief, the hearts are explanted in toto, and, after a period of cardioplegic cardiac arrest, reperfused with modified Krebs-Henseleit buffer during which sinus cardiac rhythm, physiological temperatures (37 °C), and pressures were maintained throughout the experiment.
Overview of Experimental Procedure
The isolated porcine heart was reanimated on the apparatus,18 and once stable function was achieved, lesions were created on the epicardial surface of the beating ventricles using an offset tool filled with heparinized blood, PFA catheter, and PFA generator as described below. Three to 5 PFA lesions were created on the epicardial surface of the heart. For each lesion, 4 pulse trains were delivered. The left ventricle was chosen due to its wall thickness, to optimize a lesion dose-response curve. After a period of 2 hours of continued beating heart perfusion, tissue sections were excised for imaging. Freshly excised lesions, the triphenyl tetrazolium chloride (TTC) stained lesions, and cross-sections of TTC-stained lesions were imaged and analyzed using ImageJ software.19 Cross-sectioning was performed on the long axis of the lesion approximately orthogonal to the surface.
PFA Catheter and System
A prototype PFA catheter with a linear arrangement of 4 electrodes was built as shown in Figures 1A and 1B. A custom PFA research generator delivered 4 trains of high-voltage (1500 V) biphasic, bipolar pulses to the catheter.
An offset tool was developed to precisely control distance of the PFA electrodes from the epicardial surface (Figure 1A through 1C). Using different configurations, this tool allowed the PFA electrode array to be placed either directly on the epicardial surface (0 mm, Figure 1D, left), or at an offset of either 2 mm or 4 mm (Figure 1D, middle and right, respectively) as measured between the electrodes and the tissue surface. The electrodes were held against the pegs opposite of the tissue to ensure that there were no obstructions between the electrode array and the tissue to minimize any effect of the tool on the electric field distribution. During energy delivery, the catheter electrode chamber of the offset tool was filled with noncirculating heparinized blood. Three to 5 lesions were made on each porcine heart. Each heart had ablations performed at 0, 2, and 4 mm offset with additional ablations randomized (giving equal probability to additional 0, 2, and 4 mm offset) when surface area allowed.
Lesion Imaging and Analysis
The primary endpoint to demonstrate the effect of electrode-tissue proximity on PFA ablation was lesion depth. Tissue was stained using 1% TTC at ≈37 °C for 3 minutes. Lesion dimensions were then measured using ImageJ software (National Institute of Health).
COMSOL Multiphysics (Comsol AB, Stockholm, Sweden) was used for numerical simulation. The CAD model of the offset tool and catheter was placed adjacent to a 35×65×10 mm cuboid representing the ventricular tissue. A cuboid with the same dimensions was placed below the ventricular tissue to represent the perfusate-filled heart chamber (Figure 2). The tissue was modeled with anisotropic conductivity of myocardium, with a change in fiber direction of 180° between the epicardial and endocardial surface.20 The tissue conductivity also included an electric field–dependent conductivity increase. A similar model was created (marked as unlimited model) in which the offset tool was removed (Figure 2). A more detailed description of the model and equations used in the modeling as well as the material properties used in the simulations are listed in Supplementary Materials (Table S1).
The models were solved in a time domain study, where 1500 V was applied to the electrodes as a boundary condition. The calculated electric field at the end of the pulse trains was exported to MATLAB (Mathworks, Natick, MA) for extracting the lesion width and depth in the same locations as in the experiments. For model validation, simulated current was compared with measured values, and a good agreement was obtained (Table S2).
The numerical model was used to extract lesion depths at 7 sites below the catheter using a range of electric field thresholds (400–800 V/cm in 10 V/cm increments). These data were used to train an explicit numerical model of depth as a function of electrode-tissue distance and threshold that included all values not directly modeled. Subsequently, this model was used to calculate the threshold electric field value for the cardiac tissue that best fit each experimental result.
One-way ANOVA using the Tukey method for multiple comparisons or linear regression analyses was used to evaluate the relationship between lesion size and offset of lesions (Minitab 20.1.3). A mixed effects model was used to evaluate inter-animal variability. Statistical significance was inferred if P values were <0.05.
Lesion Assessment (Isolated Heart Tissue)
A total of 32 ablations were performed across the 8 hearts; 11 at 0 mm offset, 11 at 2 mm offset, and 10 at 4 mm offset. Figure 3 shows superficial TTC-stained images from transversely cut TTC-stained images from tissue (left) and uncut tissue slices (right) for PFA applications at 0 mm, 2 mm and 4 mm offset. Lesion depth (Figure 4A and 4B) and width (Figure 4C and 4D) decreased significantly as the distance between epicardial surface and electrodes increased. Lesion depths averaged 4.3±0.4 mm, 2.7±0.4 mm, and 1.3±0.4 mm for the 0, 2, and 4 mm electrode-tissue distances, respectively. Lesion widths averaged 9.4±1.1 mm, 7.5±0.8 mm, and 5.8±1.4 mm for the 0, 2, and 4 mm electrode-tissue distances, respectively. Shown are individual lesion depths (in mm) with linear regression curves (Figure 4A: linear slope −0.7413, R2=0.91, P<0.0001; Figure 4C: linear slope=−0.8979, R2=0.65, P<0.0001), as well as Box-Whiskers plots with median, 25th to 75th percentile and minimum to maximum whiskers (Figure 4B and 4D). One-way ANOVA analysis using the Tukey multiple comparison test showed significant differences between the 0 mm, 2 mm, and 4 mm groups (P values for between-group comparisons are P<0.001 for depth, and P<0.01 for width). Accounting for multiple lesions performed on each porcine heart with a mixed model, the results were similar to the linear regression model due to no significant difference or major variability in lesion depth or width between each animal.
The average lethal dose threshold value of cardiac tissue (N=6) was determined to be 489±22 V/cm. That means the model on average best matched the ex vivo data when 489±22 V/cm was used as the threshold for defining the lesion boundary. This value was used to generate 2 optimized models: the Numerical model and the Numerical model without the offset tool (Figure 5).
Figure 6 presents the ex vivo data, the modeling of the ex vivo data (Numerical model), and an infinite blood pool model which removes the offset tool (Numerical model without the offset tool). The results of the numerical models correspond well with linear trends observed in the ex vivo data. Regression lines calculated for the ex vivo data and the Numerical model had slopes of –0.740 and –0.723 (mm depth/ mm offset) respectively (regression lines are not shown in Figure 6). The Numerical model without the offset tool had a slope of –0.947 (mm depth/ mm offset).
We have demonstrated that biphasic, bipolar PFA deliveries using a prototype catheter can form cardiac lesions even in the absence of direct electrode-tissue contact. Although direct electrode-tissue contact was not required to achieve a lesion, we demonstrated that a distance of 0 mm between the electrodes and target tissue resulted in the deepest lesions. The relationship between electrode-tissue proximity and lesion size showed a high linear correlation of R2=0.91. Furthermore, comparison of the experimental results to numerical modeling gave an estimate of the threshold value of cardiac susceptibility to PFA of 489±22 V/cm, which needs to be considered specific to this waveform delivery and system.
Existing preclinical work has indicated that heavily trabeculated appendages can be ablated in a durable, transmural manner with a circular PFA catheter, providing indirect evidence that PFA may result in lesions without direct electrode-tissue contact.16 Recently, Nakagawa et al21 reported no lesions when a focal catheter (3.5 mm irrigated TactiCath SE, Abbott) was ≈2 mm from the endocardium after PFA (Centauri, Galaxy Medical) when used in conjunction with electro-anatomical mapping and a unipolar PFA ablation system. Nevertheless, the well-controlled electrode-tissue proximity used in our study provides direct evidence of the ability of a biphasic, bipolar PFA system to create cardiac lesions in a beating heart ex vivo in the 0 mm offset distance case. Given challenges in achieving consistent and safe catheter stability using standard ablation catheters, particularly in trabeculated tissue or intracavitary cardiac structures, the ability to create lesions without need for perfect placement of electrodes on the target tissue is appealing.
Lesion dimension assessments were consistent with numerical modeling; both lesion depth and width decrease with increasing electrode-tissue distance. The slopes observed in the ex vivo study and the numerical model showed values of −0.74 (ex vivo), and −0.72 (Numerical model), respectively. This means that for every millimeter of offset distance added, the lesion depth decreased by an average of 0.74 mm (ex vivo) and 0.72 mm (Numerical model). However, when modeling the system without the offset tool (Numerical model without the offset tool), the calculated slope was −0.945, suggesting that the field distribution in blood and tissue was similar and approximating a 1:1 relationship.
Although these findings are specific to this device and waveform, clinically these results may be relevant to the growing field of PFA, in which multiple systems are employing multipolar PFA catheters. This is advantageous since larger regions can be targeted (like entire pulmonary veins), allowing for a shorter, more time-efficient procedure. However, given the natural variations in human cardiac anatomy, it is often not possible to orient a large, multipolar device to have complete and perfect electrode-tissue proximity along its entire circumference. As we are still able to create lesions without direct electrode-tissue contact, PFA can be considered more forgiving than thermal sources of ablation where a lack of direct electrode-tissue proximity results in no lesion formation. However, inadequate lesion formation may result without direct electrode-tissue contact.22 Current clinical workflow of most PFA systems involving multiple applications and overlapping catheter positioning is therefore likely justified to ensure optimal, contiguous lesion formation.
This experimental study was conducted under controlled laboratory conditions using an isolated porcine working heart model perfused with Krebs-Henseleit buffer. Only the ventricular myocardium was targeted in order to facilitate clear lesion visualization and measurements. Applicability of this work to clinical practice will require further study, including in diseased cardiac tissues (eg, remodeled atrial tissue, infarcted fibrotic ventricular tissue) and long-term durability of lesions. With regards to the limitation of lesion durability, it should be noted that tetrazolium chloride has been shown to correlate very well with histological cell damage in cardiac ischemic cell death and is widely used in preclinical histopathological studies.23 Also, reported lesion dimensions of these epicardial lesions may not be representative of endocardial lesion dimensions.
In order to address the potential limitation of directing the electrical field with the offset tool, we modeled the catheter offset and its effects on cardiac lesions without the offset tool. The Unlimited model was comprehensive, including electrical and thermal conductivity and heat capacity (Supplementary Appendix). Although a small effect of the offset tool was observed, the numerical model with the offset tool matched the experimental setup very well, providing good confidence that the Unlimited model represents reality accurately.
This investigation employed a prototype catheter that was custom-built for research purposes and does not represent PFA systems in clinical use. Each PFA system design is different, and this data cannot be extrapolated to other PFA systems, waveforms, or catheters. Furthermore, we have only investigated one set of pulse wave parameters based on what has been investigated in the PULSED AF clinical study (https://clinicaltrials.gov/ct2/show/NCT04198701), which has not yet been Food and Drug Administration approved or received regulatory approval for commercialization.11 For example, we do not know if a similar phenomenon could be observed using unipolar PFA delivery.
This study provides strong evidence that pulsed electric fields create cardiac lesions even in the absence of direct electrode-tissue contact case. We demonstrate lesion creation even when the PFA electrodes were as far as 4 mm from the epicardial surface. However, the optimal, deepest lesions were created with 0 mm offset distance.
Sources of Funding
This study was funded by Medtronic.
Detailed Model Description
pulsed field ablation
Disclosures Dr Howard, Dr Mattison, Dr Onal, M.T. Stewart, and Dr Sigg are employees of Medtronic. Drs Verma, Tzou, Kos, and Miklavčič are Medtronic consultants.
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