PFA possesses a unique neurotropic selectivity that preserves vagal ganglionic cell viability while eliciting transient autonomic stimulation [21], evidenced by the absence of significant heart rate increase [22] and elevated post-procedural S100 protein levels [23], the former being a biomarker associated with denervation, as shown in Fig. 2. Experience based on current CBA application revealed that, preoperative intravenous administration of 1 mg atropine reduces severe vagal reactions from 92.3% (12/13) to 33.3% (4/12; p 0.01) [24]. Current PFA protocols do not require their prophylactic administration, while competitive muscarinic antagonists such as atropine and glycopyrrolate are frequently used to mitigate excessive vagal response. This situation requires critical re-evaluation due to the procedural demands of PFA, particularly the repeated pulsed field applications required to achieve sufficient lesion formation in the targeted anatomical regions [25, 26], substantially increasing the risk of vagal activation through electrical stimulation of the cardiac plexuses. Future procedural guidelines should explicitly address the management of intraoperative vagal response by incorporating standardized strategies such as preprocedural or intraprocedural application of competitive muscarinic antagonists and selective use of temporary ventricular pacing leads.

Fig. 2.

Electrocardiogram changes and local vagal response in patients after thermal ablation or after PFA during reablation.

The vagal ganglia localized in the subepicardial fat pads adjacent to the myocardial layer constitute critical mediators of neurocardiac regulation and represent strategic therapeutic targets for autonomic reflex modulation during cardiac ablation. These neural aggregates function as interconnected networks in the cardiac autonomic architecture (Fig. 3A). Hu F et al. [27]. confirmed that prioritizing intervention and regulation of the right anterior ganglionic plexus (RAGP) during PFA (Fig. 3B,C) significantly reduces the incidence of intraoperative vagus nerve involvement (2.5% vs. 62.5%). This RAGP-centric approach has equivalent efficacy across RFA modalities. Current prospective PFA data reveal a remarkable disparity in autonomic responses: an left superior pulmonary vein (LSPV)-first strategy elicit vagal reactions in 78% of cases versus 13% with right superior pulmonary vein (RSPV) prioritization. Furthermore, the RSPV-focused protocol significantly reduces temporary pacing requirements (35% vs. 8%; p 0.01) [28].

Fig. 3.

Modified ablation based on right superior vagal plexus modulation. (A) Gross distribution of the cardiac vagal plexus. (B) Conventional ablation sequence of PVI. (C) Modified ablation sequence of PVI. PVI, Pulmonary vein isolation; LIGP, Left Inferior Ganglionated Plex; LLGP, Left Lateral Ganglionated Plex; LSGP, Left Superior Ganglionated Plex; RAGP, Right Anterior Ganglionated Plex; RIGP, Right Inferior Ganglionated Plex.

The coronary spasm induced by PFA is primarily due to direct stimulation of the vascular smooth muscle by pulsed electric fields (PEF) and the cascade of local inflammatory responses [29, 30], as shown in Fig. 4. The reported incidence of such acute vascular reactions during PFA is from 0.08% to 0.14% [3, 15, 16, 31]. Intravenous nitroglycerin is frequently used as a prophylactic measure during the ablation of the anatomic site adjacent to the coronary artery [32]. However, the administration of this pharmacological treatment does not universally preclude the intracoronary administration to alleviate coronary spasm in all patients. Even with the prophylactic use of nitroglycerin, a subset of patient still experiences delayed and, clinically significant coronary spasm. A pertinent case report documented the occurrence of clinically apparent vasospasm induced by a pentaspline PFA catheter during cavotricuspid isthmus (CTI) ablation, despite the prophylactic administration of high-dose intravenous nitroglycerin prior to PFA. This episode was characterized by a significant vasospasm accompanied by a ST-segment elevation in leads II, III, and aVF on the electrocardiogram. The clinical scenario was further complicated by the onset of hemodynamically unstable nonsustained ventricular tachycardia, culminating in cardiac arrest in need of temporary pacing and an additional 4 mg nitroglycerin [33]. Our hypothesis was that the transient cellular electroshock effect induced by PEF further prolonged the metabolic clearance time of the aforementioned hyperphosphorylated myosin light chain, while reducing vascular smooth muscle sensitivity to nitric oxide, consequently exacerbating vasoconstrictor responses and increasing nitric oxide dosage requirements. As regards the increase of the efficacy of nitrate administration, Malyshev Y et al. [34] propose two innovative nitroglycerin delivery protocols: (1) multiple bolus injections (2–3 mg every 2 minutes) into the right atrium, and (2) a single bolus injection (3 mg) into the right atrium combined with continuous peripheral intravenous infusion (1 mg/min). These strategies show a significant effect in preventing severe spasm, although the optimal dosing regimen remains to be established due to the limited sample size in their study.

Fig. 4.

Intraoperative coronary spasm mediated by myosin hyperphosphorylation and local vasoconstrictor release.

PFA-induced coronary spasm shows distinct clinical characteristics, including acute onset patterns and specific anatomical predilections [32, 35, 36, 37, 38, 39, 40]. The mean distance between the endocardium and the right coronary artery at the CTI is 4.2 $\pm$ 2.1 mm, while the minimum distance at the mitral isthmus (MI) region is 3.8 $\pm$ 2.3 mm (Fig. 5) [41]. However, the ideal tissue proximity is identified as a significant factor influencing the formation of PFA-induced electrical isolation [42]. Clinical experience from pentaspline PFA catheter confirms that coronary spasm frequently occurs during the linear ablation of the CTI and superior MI [32, 43]. Most such cases involve subclinical vasospasm induced by localized electric field stimulation. However, optical coherence tomography observations by Tam MTK et al. [44] reveal significant vascular remodeling three months post-PFA, as the median vessel wall area increases by 17.1% and the lumen area decreases by 10.1%. Potential hemodynamic consequences need attention due to the established correlation between atherosclerosis severity and coronary spasm [45], particularly regarding PFA exacerbating flow impairment in patients with pre-existing coronary abnormalities such as atherosclerotic plaques or myocardial bridges.

Fig. 5.

The anatomical basis of coronary artery spasm and the response of different ablation sites to pulsed electric fields.

The reported incidence of AKI following hemolysis in PFA procedures ranges from 0% to 5.26% among clinical series [49, 50, 51, 52]. A prospective analysis by De Smet MAJ et al. [49] identifies AKI-prone patients as older individuals with comorbidities including chronic kidney disease, heart failure, diabetes, and hypertension, typically requiring extended duration of the ablation. Among them, a patient with stage 3 AKI with a baseline glomerular filtration rate of 14 mL/min developed progressive kidney injury (serum creatinine from 3.58 to 3.79 mg/dL) with hyperkalemia after only 32 pentaspline PFA ablations and started to receive renal replacement therapy. Previous studies demonstrated that patients with a baseline glomerular filtration rate 50 mL/min exhibit a statistically significant increase in serum creatinine levels after PFA ($\mathrm{\Delta }$crea: 27.0 $\pm$ 103.1 vs. –0.2 $\pm$ 12.1 µmol/L; p = 0.010) [50]. This finding suggests that individuals with pre-existing significant renal impairment may represent a high-risk population for PFA-related complications rather than obtaining clinical benefit from the procedure. More importantly, patients with significant preoperative renal dysfunction may experience substantial renal deterioration even with standard PFA protocols.

The cumulative number of PFA applications is considered as the most significant intraprocedural determinant of postprocedural hemolysis and renal dysfunction. Venier S et al. [51] pioneered the investigation of AKI after PFA, demonstrating a significant inverse correlation between plasma haptoglobin levels and total application count (median [Interquartile Range]: 75 [62–127] vs. 62 [54–71] in hemolytic-positive vs. negative cohorts, p = 0.011). Subsequent validation studies further corroborated these findings, establishing a predictive application threshold range from 54 to 74 discharges for hemolysis risk [50, 51, 53]. Receiver operating characteristic (ROC) curve analysis identifies 70 applications as an optional predictive threshold (area under the curve (AUC): 0.709) with balanced sensitivity and specificity. Procedural safety of Farapulse system can be stratified by discharge frequency (Fig. 7). Hemolysis risk is minimized with less than 54 PFA applications, whereas applications between 54 and 74 markedly increase hemoglobinuria incidence. This dose-dependent effect is particularly significant in patients with persistent AF requiring extensive ablation [49, 52, 54, 60]. Tamirisa KP et al. [61] show that application thresholds must be individualized according to the specific PFA system used. Since catheter-induced hemolysis correlates with non-contact electrode exposure in the atrial blood pool, discharge thresholds derived from pentaspline experience cannot be broadly extrapolated to standardize PFA procedures. Although clinical guidelines currently lack specific discharge thresholds for PFA, our recommendations are the following: (1) prioritize focal ablation or single catheters with minimal footprint when anticipating extra ablation; (2) use sensitive biomarkers as red blood cell microparticles to evaluate hemolysis severity. Since red blood cell microparticles are not routinely used in clinical practice, lactate dehydrogenase, haptoglobin, indirect bilirubin and plasma-free hemoglobin may serve as the preferred alternative parameters [61].

Fig. 7.

Effect of intraoperative discharge dose on hemolysis.

Nies M et al. [56] performed in vitro experiments to investigate the relationship between tissue contact and hemolysis using a pentaspline catheter. Analysis of 76 blood samples from four swine indicates that non-contact applications induce significantly greater hemolysis, with free plasma hemoglobin (fHB) levels becoming statistically significant after four applications (0.12 $\pm$ 0.03 vs. 0.05 $\pm$ 0.03 g/dL; p = 0.008). This phenomenon was also observed with loop catheters, where both contact and non-contact groups show a linear dose-response relationship between fHB levels and PFA applications. The fHB increase per application is 0.0003 g/dL in contact and 0.00056 g/dL in non-contact conditions [57]. Although previous experience suggested that the damage by PFA is not entirely dependent on contact force, poor adherence to tissue can further predict the degree of intraoperative hemolysis [58].

The perioperative treatment is considered the basis for avoiding severe renal insufficiency caused by hemolysis. The gadolinium-diethylenetriamine-penta-acetic acid, a clinically approved magnetic resonance imaging (MRI) contrast medium, was introduced for reducing PFA-induced hemolysis through erythrocyte membrane stabilization. Preclinical studies reveal that the above acid modulates erythrocyte membrane stability, improving the resistance to electroporation-mediated membrane disruption during PFA [59]. However, this approach is still in the stage of animal model-based validation due to the lack of reliable evidence. Postoperative hydration is the only treatment established in clinical practice to reduce hemolysis-associated kidney injury. Mohanty S et al. [55] demonstrated that, the planned intravenous infusion of 0.9% sodium chloride $\ge$2 L effectively prevents serum creatinine increase in 75 patients after ablation. Despite this approach probably complicated the postoperative management due to the risk of volume overload and subsequent clinical deterioration, this measure is necessary especially for patients with preoperative renal insufficiency.