As a relatively new treatment option, cardioneuroablation (CNA) aims to modify the behavior of the cardiac autonomic nervous system to prevent some/all of the autonomic processes occurring in vasovagal syncope (VVS) and functional bradyarrhythmias by using endocardial ablation techniques [1,2,3,4,5]. The fundamental approach of CNA involves pinpointing clusters of autonomic ganglia called ganglionated plexi (GPs), situated within epicardial atrial fat pads. There are three main approaches for identification of GPs: high-frequency stimulation (HFS)-guided, anatomy-guided, and spectral mapping/fractionation-guided approaches [1,2,3,4,5]. Focal pulsed field ablation (PFA) has emerged as a cutting-edge technology in the field of cardiac electrophysiology, offering a promising alternative to the thermal ablative modalities for the treatment of cardiac arrhythmias [6]. Here, we propose another application of this exciting tool, a novel approach aimed at guiding and evaluating the immediate effect of CNA.

Two patients in their early 40 s were referred to our center after experiencing multiple episodes of cardio inhibitory VVS (CI-VVS) over the past 3 months, confirmed through head-up tilt-test for one patient and implantable loop recorder (ILR) for the other. The third patient, a 35-year-old female, had been admitted for the third time in the last 6 months due to symptomatic sinus bradycardia, accompanied by significant premature ventricular contractions (PVCs) that exacerbated her symptoms. Following thorough discussions about various management options, CNA with PFA guidance was proposed as a therapeutic intervention. Here, we present our proposed workflow.

Under conscious sedation and local anesthesia, access was obtained via a right femoral venous approach. High-resolution electroanatomic mapping (PentaRay Nav, Biosense Webster, Irvine, CA, USA) of the left atrium was performed using a three-dimensional mapping system (Carto 3, Biosense Webster, Irvine, CA, USA). Subsequently, an irrigated ablation catheter (Thermocool ST nonSF, D-type, Biosense Webster, Irvine, CA, USA) was introduced into the left atrium and connected to the CENTAURI PFA generator (Galvanize Therapeutics, San Carlos, CA, USA). Initially, focal PFA (25 A/30 pulses) was applied to the anterosuperior aspect of the right superior pulmonary vein ostium, assumed to be an anatomical marking of the superior right atrial GP (RSGP), to provoke transient vagal response (VR) and bradycardia (Fig. 1A). Following this, radiofrequency ablation (RFA) with a targeted ablation index of up to 550 was applied in the described segment with the same catheter, progressing ostial and antral towards the interatrial septum. During RFA, the sinus rate increased, and PVCs were suppressed/not detectable after the first lesion. In a single patient, a similar amplitude of sinus bradycardia was induced after initial RFA lesion set at the same anatomical site using focal PFA. Subsequently, we proceed with RFA targeting the right side, aligning with our original plan for biatrial ablation. The ablation catheter was then introduced into the right atrium, in an area that is anatomically nearly inseparable from the left set of lesions, resulting in a significant increase in sinus rate. The right set of lesions was consolidated to a total of 6 lesions. Afterward, no sinus bradycardia was provoked with focal PFA on the right side and finally on the left side at the same position as at the beginning (Fig. 1C and D). This represented an acute endpoint and suggested ablation of the RSGP. During the observation period, sinus rhythm was maintained, and no ventricular ectopic activity was detected. For the post-procedural follow-up assessment, the patient exhibiting bradycardia and PVCs underwent a 24-h Holter ECG monitoring 2 months after the initial intervention. The analysis revealed a normal heart rate, without ventricular ectopy. For the remaining two patients, one underwent a repeat HUTT one week after the procedure, while the other continued his clinical follow-up with regular IRL examinations. Notably, the result of the HUTT was negative, indicating the absence of cardio-inhibitory response (Table 1).

Fig. 1
figure 1

A First PFA application from left atrium inducing vagal response. B Full lesion set on 3D EAM from superior view. C PFA from right atrium after last RFA. D PFA from left atrium after last RFA

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Table 1 Patient characteristics and follow-up details
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The PFA could achieve pulmonary vein isolation (PVI) without any of collateral damage in patients with paroxysmal AF, including vein stenosis, phrenic nerve injury, or esophageal damage [6]. However, authors demonstrated vagal responses (VR) during PFA energy delivery. Whether the VRs are nerve damage or a neurological stress response due to electrical stimulation like HFS response was unclear. Recently, Reddy et al. [7] assessed the impact of PFA on the GPs in patients undergoing PVI. In the prospective phase, pre-PFA HFS identified 65 GP sites. During PFA, vagal effects were noted in 45% of first PF applications, persisting through all applications in 83%. HFS post-PFA reproduced vagal effects in 29 of 38 sites (76%) in low-voltage tissue. Unlike with thermal ablation, between baseline and 3 months, heart rate did not increase in PFA arm.

Our initial experience demonstrates the potential of focal PFA guided CNA as an effective therapeutic strategy for patients suffering from functional bradyarrhythmia and CI-VVS. Through meticulous patient selection and the integration of cutting-edge technologies such as PFA into the CNA procedure, we have successfully guided and assessed the acute effects of this intervention. The outcomes in our patients, particularly the resolution of symptomatic sinus bradycardia and suppression of PVCs, highlight the efficacy of this combined approach. Also, there might be another positive aspect of this approach, as focal PFA could enhance RFA penetration to epicardial tissues. This remains an intriguing area for further investigation.

While our experience provides valuable insights into the immediate effects of PFA-guided CNA, small sample size, involving only three patients, necessitates cautious interpretation of the results. Long-term follow-up studies and larger patient cohorts are essential to establish the durability and safety of this approach.