Background
Growing interest in His bundle pacing (HBP) is being seen worldwide. HBP is an attractive option for permanent cardiac pacing as it maintains a physiological pattern of ventricular activation and thus may prevent the development of right ventricular pacing-induced cardiomyopathy. The permanent HBP procedure has a two-decade track record and has been refined and improved along the way [1]. However, despite general optimism on ’physiological pacing’, concerns about the performance, safety, and clinical benefits of HBP still exist. In the 2021 European Society of Cardiology (ESC) guidelines on cardiac pacing an abstaining prevails and there is no first-class recommendation with HBP as first-line therapy [2].
Hypothesized herein, that in a situation of vagal surge some patients with HBP may be endangered by loss of capture due to parasympathetic influence on His-Purkinje system (HPS). For this group of patients a change to left bundle branch pacing, which is usually not selective, thereby assuring direct ventricular myocardium stimulation, or implantation of the back-up right ventricular electrode may be necessary. Another reasonable approach, based on a relatively novel therapeutic technique — cardioneuroablation (CNA), i.e., percutaneous radiofrequency ablation of the parasympathetic ganglionated plexi of the heart [3]. The implementation of extracardiac vagal nerve stimulation (ECANS) and recently introduced ultrasound-guided ECANS (US-ECANS) enables validation of impact of right and left vagal nerve stimulation on parameters of automaticity and conduction [4]. Although, ECANS is associated with sinus asystole or atrioventricular (AV) block during atrial pacing, the incidence of vagally mediated HBP exit block and changes in pacing threshold have not been investigated.
To test the present hypothesis it was decided to conduct a study on the effects of ECANS on pacing parameters in patients with permanent HBP [5]. The aim of this clinical investigation is to assess efficacy of HBP during strong activation of parasympathetic system. As ECANS is a novel, non-standardized diagnostic method, another aim of the study is an assessment of effects of left- versus right-sided ECANS on underlying rhythm and/or HBP parameters.
Methods
HIS-STORY is an investigator-initiated, prospective, multicenter, randomized, interventional clinical study. All the measured parameters, as well as demographic and clinical data will be recorded in the study database. All patients will provide an informed consent form. Patients with indications for permanent pacing, according to the latest ESC guidelines, will be enrolled. All participants will undergo permanent pacemaker implantation for HBP. Subsequently, an invasive electrophysiological study (EPS) and ECANS will be performed under general anesthesia. The study will recruit patients with existing HBP systems and also those in whom a HBP device will be implanted just before the EPS/ECANS procedure. ECANS can be performed from right or left interior jugular vein (IJV) at two levels: at the level of jugular foramen (superior ECANS) or at the level of the angle of mandible (inferior ECANS). Superior ECANS can be fluoroscopy-guided only, however inferior ECANS can be guided by fluoroscopy, ultrasound (US) or both. This study has a factorial design and 2×2 randomization and will be performed thus: patients will be randomized to begin superior ECANS from the right or left IJV; a second randomization will assess the feasibility of the US-guided inferior ECANS. Patients will be randomized into two groups, blinded to the main operator; to undergo US-guided inferior ECANS or to undergo sham US-guidance. During ECANS, pacing parameters will be tested using a dedicated programmer and will be compared with baseline values. Possible effects of ECANS are depicted in the Figure 1. Patients with an exit block or an increase in a pacing threshold of an HBP electrode will be further managed by electrophysiologists from the research group. The management will be based on clinical relevance and share-decision making with the patient and may involve observation, pacemaker reprogramming, pacemaker upgrade with a back-up pacing electrode implantation, or cardioneuroablation. Moreover, additional substrates for supraventricular and ventricular arrhythmias will be managed according to shareddecision-making with the patient. Ablations for any arrhythmias will, however, be performed only if they will be clinically justified and indicated by the current ESC guidelines. Study protocol was approved by the Local Bioethical Committee and is registered on clinicaltrials.gov (NCT04816864; https:/clinicaltrials. gov/ct2/show/NCT04816864). Enrollment began on January 02, 2021, and the study was registered on March 25, 2021.
Study population
The target study population is 60. Inclusion and exclusion criteria are shown in Table 1.
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Inclusion criteria |
Exclusion criteria |
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Signed informed consent form |
Age below 18 years |
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Age of 18 years or older |
Contraindications to invasive electrophysiology study |
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Effective and stable His bundle pacing |
Contraindications to general anesthesia |
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Sinus rhythm during the intervention procedure |
Contraindications to atropine administration (e.g., glaucoma) |
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Persistent atrial fibrillation or atrial flutter |
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Pregnancy |
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Diseases that may cause autonomic system neuropathy |
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Use of medications that may affect the parasympathetic system |
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A history of cardiac surgery |
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A history of ablation due to arrhythmia |
Intervention
The study intervention will consist of three steps, all of which will be performed under general anesthesia:
ECANS
A steerable quadripolar catheter will be inserted through the right femoral vein and advanced under fluoroscopic guidance to the right and left jugular vein at the level of the jugular foramen. The tip of the catheter will be directed medially and 5 s of stimulation with square wave pulsed of 50 µs at a frequency of 50 Hz and amplitude of 0.5 to 1.0 V/kg (max: 70 V) will be delivered. Subsequently the catheter will be pulled back under fluoroscopic guidance so that the tip will be at level of the angle of mandible (inferior ECANS). In accordance with prior randomization the US operator will guide the main operator to place the tip near the vagus nerve or only pretend to do so. Timing of the ECANS will be at the discretion of the US operator, so that the main operator will stay blinded for sham or US-guided ECANS. In patients with subclavian, vena cava superior or IJV thrombosis associated with the lead detailed imaging and clinical management will be performed and ability to cannulate IJV will be recorded.
Endpoints
Primary outcome measures:
Secondary outcome measures:
Statistical analysis
For statistical analysis Statistica (Statsoft Polska, Krakow, Poland) software will be used.
The continuous variables will be presented as means and standard deviations or medians and interquartile ranges due to their distribution and compared with the Student t-test or the Mann--Whitney U test. Discrete variables will be presented as numbers and percentages and compared with the c2 test.
The presented outcomes will be assessed as to their presence or absence. The logistic regression analysis and classification and regression trees analysis will be performed to find factors associated with the outcomes. The models will be constructed using variables which differ in univariate analysis with p < 0.15 or clinically significant.
The multivariable analysis will be performed for the continuous dependent variables. P less than 0.05 will be considered as significant.
Discussion
It has been shown that hyperactivity of the parasympathetic system might induce AV conduction disturbances. Zyśko et al. [6] analyzed electrocardiographic characteristics of AV conduction abnormalities induced by neurocardiogenic reflex during tilt-testing and found AV blocks in 3.9% of patients. Taking into account that even 40% of the general population experiences at least one episode of syncope during their life and that about 20% of all syncopes are reflex syncope, vagally mediated functional AV block does not seem to be an uncommon clinical condition [7]. Moreover, excessive vagal tone has been shown to be responsible not only for transient but also for some permanent AV block cases [4]. Therefore, some patients with indications for permanent cardiac pacing who have received the HBP may actually have vagally mediated functional AV conduction abnormalities. Although the impact of ECANS on sinus and AV node electrophysiological properties is well-known, the incidence of functional, vagally mediated reflexes on HPS remain unexplained [8]. In the literature, however, plenty of evidence on vagal innervation and influence on ventricular tissue exists [9, 10]. Similar prospective studies have been performed, however they were assessing the impact of ECANS on the conduction system and electrophysiological properties inferior or superior to HPS [11, 12]. Therefore, the present study might provide new insight into our knowledge of parasympathetic innervation of the conduction tissue. Moreover, some clinically important hypothesis will be tested, as aforementioned remarks raise suspicion that in some patients, vagal surge might be strong enough to hyperpolarize conduction tissue below the AV node level, thereby causing an acute increase in the capture threshold and even exit block. Such patients are in danger of transient loss of ventricular pacing.
Limitations of the study
Iatrogenic high parasympathetic tone induced by vagal nerve stimulation might never be experienced by the patient in natural, real-life circumstances, thereby increases in pacing thresholds or loss of capture may not necessarily be clinically important.
