Characterization of Phrenic Nerve Response to Pulsed Field Ablation

Abstract

Background: Phrenic nerve palsy is a well-known complication of cardiac ablation, resulting from the application of direct thermal energy. Emerging pulsed field ablation (PFA) may reduce the risk of phrenic nerve injury but has not been well characterized.

Methods: Accelerometers and continuous pacing were used during PFA deliveries in a porcine model. Acute dose response was established in a first experimental phase with ascending PFA intensity delivered to the phrenic nerve (n=12). In a second phase, nerves were targeted with a single ablation level to observe the effect of repetitive ablations on nerve function (n=4). A third chronic phase characterized assessed histopathology of nerves adjacent to ablated cardiac tissue (n=6).

Results: Acutely, we observed a dose-dependent response in phrenic nerve function including reversible stunning (R²=0.965, P<0.001). Furthermore, acute results demonstrated that phrenic nerve function responded to varying levels of PFA and catheter proximity placements, resulting in either: no effect, effect, or stunning. In the chronic study phase, successful isolation of superior vena cava at a dose not predicted to cause phrenic nerve dysfunction was associated with normal phrenic nerve function and normal phrenic nerve histopathology at 4 weeks.

Conclusions: Proximity of the catheter to the phrenic nerve and the PFA dose level were critical for phrenic nerve response. Gross and histopathologic evaluation of phrenic nerves and diaphragms at a chronic time point yielded no injury. These results provide a basis for understanding the susceptibility and recovery of phrenic nerves in response to PFA and a need for appropriate caution in moving beyond animal models.

Keywords: animals; catheter; diaphragm; electroporation; phrenic nerve.

Figure 1.

Experimental setup. Two catheter sites and 4 accelerometer sites were used to capture and measure phrenic nerve function and subsequent diaphragmatic activity (A). Two catheters were placed in the superior vena cava (SVC; B). One catheter was placed in a more superior position to pace the phrenic nerve. The second catheter was placed in an inferior position for ablation. Two more catheters were placed in the inferior vena cava (IVC), with the superiorly positioned catheter used to pace the phrenic nerve and inferiorly positioned catheter used to ablate (C). This experimental model was leveraged for all 3 stages of this investigation. LA indicates left atrium; LV, left ventricle; RA, right atrium; RAA, right atrial appendage; and RV, right ventricle.

Figure 2.

Sample accelerometer data demonstrated increasing pulsed field ablation (PFA) voltage eventually leads to a temporary decrease in function (*) as measured by reduced accelerometer response to diaphragmatic movement (measured in g). In this experiment, first stunning is seen at 1200 V (†). Stunning time is measured as shown (‡). No effect was observed at low levels of therapy delivery (time <15 min).

Figure 3.

Ablation threshold levels from acute phase 1 data. Shown are nonlinear regression curves (modeled as a log function) based on the data set. Pacing threshold is representative of the current delivered to the electrode array. The dashed regression line represents the maximum voltage applied without any observation of phrenic nerve (PN) dysfunction, while the solid line represents the first-dose level that elicited a stunning response from the nerve (R² for stunning =0.869, R² for no effect =0.866).

Figure 4.

Dose-dependent increase in stunning time. Linear regression used to assess relationship (R²=0.965, slope significantly nonzero [P<0.001]). Data were normalized to accommodate different experimental thresholds to first stunning occurrence (see Figure 2). Shown are means and SEM. N indicates the number of experiments at which a threshold determination was made.

Figure 5.

Predicted responses of phrenic nerve function based on experimental data collected previously and a measure of the minimum phrenic pacing threshold as a metric for proximity to the nerve. Repeated ablations at 700 V cause no effect on phrenic function ([A] predicted response: no effect, phrenic nerve threshold 1.8 V), modulation of phrenic function ([B] predicted response: effect, phrenic nerve threshold 0.7 V), and temporary stunning of the phrenic ([C] predicted response: stunning, phrenic nerve threshold 0.6 V). At the end of each series, 2 ablations at 1500 V were performed.

Figure 6.

Normal phrenic nerve thresholds (A) and maintained peak-to-peak acceleration (measured via abdominal accelerometer, as a surrogate for diaphragmatic function, B) demonstrate intact phrenic nerve function at all time points in chronic study. No significant differences were detected between groups (repeated measures ANOVA, P=not significant).

Figure 7.

Gross images of the right phrenic nerve (RPN, top row, arrows) over the treated superior vena cava (SVC) or beneath the treated right superior pulmonary vein (RSPV). All nerves were grossly normal after pulsed field ablation to these vascular structures about 4 wk earlier. Photomicrographs of randomly chosen phrenic nerves from this study (bottom row) illustrate that there were no histopathologic changes. The Masson trichrome stain indicates no increase in epineural, perineural, and endoneural connective tissue around the entirety of the nerve fascicles at low magnification in this cross-section (CS) view. The 2 hematoxylin and eosin stains showcase a CS and longitudinal section (LS) through a single nerve fascicle. Note the absence of inflammation, Wallerian degeneration, or atrophy of the nerve fascicle. Scale bars inserted.