Patient Selection for Cardioneuroablation
Although most patients with VVS can be treated with patient education and non-pharmacological measures, a minority of patients with severe forms, such as those with very frequent syncope affecting quality of life, recurrent syncope without prodromal symptoms which exposes the patient to a risk of trauma, and syncope occurring during a high-risk activity may require interventional therapies (8). The current guidelines suggest that cardiac pacing should be considered in patients aged >40 years with frequent recurrent reflex syncope when bradycardia-syncope correlation is confirmed by implantable loop recorder (ILR) (class IIa) or head-up tilt test (HUTT) (class IIb). However, while permanent pacing does appear to be beneficial for some patients, syncope may recur because of the coexistence of a vasodepressor reflex, which is present to some degree in virtually all patients. Also, no data is available to support the use of pacemakers in patients with VVS under the age of 40. Although, in all large cohorts related to CNA (9-11), VVS cases were included according to HUTT results, we recently demonstrated that ILR implantation may be used to select suitable candidates for CNA (12). Therefore, similarly, demonstration of bradycardia-syncope correlation by HUTT or ILR in patients that continue to experience frequent and burdensome VVS recurrences may be applied for CNA case selection. In our current approach, we prefer the Newcastle protocol which includes tilting to 70 degrees for a passive unmedicated phase of 20 minutes, and if positivity/discontinuation criteria are not reached, administration of 300-400 μg sublingual nitroglycerine at the 20th minute, followed by an additional 15-20 minutes of standing to select potential candidates for CNA (13). The patients should not be tilted down prior to developing syncope as this may reduce the proportion of patients that actually end up manifesting asystole > 3sec. It may be possible to make particularly strong recommendations for CNA in patients <40 years of age, and those with the cardioinhibitory or mixed type of VVS. Our practical decision pathway for the management of VVS is summarized in Figure 2.
Atropine sulfate as a vagolytic is a competitive antagonist of actions of acetylcholine and other muscarinic agonists that accelerates both sinus node and atrial myocyte automaticity and increases the speed of atrioventricular conduction. Theoretically, CNA should mimic sinoatrial and atrioventricular nodal effects of atropine. Therefore, to define procedural endpoint and to predict potential results of ablation, pre-procedure atropine response should be checked in all cases at least 24 hours prior. An atropine response test should be attempted in all VVS cases and only patients demonstrating a positive response should be selected as candidates for the procedure. The test is carried out after 4 hours of fasting. Intravenous atropine sulfate 0.04 mg/kg is administered for 30 min under continuous electrocardiogram recording, and a sinus rate increase of ≥25% or a sinus rate ≥90 bpm in the first 20 min after infusion is considered a positive response (9).
According to the 2018 American College of Cardiology/American Heart Association/Heart Rhythm Society guideline, permanent pacing should not be performed in patients with asymptomatic functional AVB (14). However, the guidelines recommend pacing in patients with symptomatic AVB attributable to a known reversable cause like vagal overactivity if AVB does not resolve despite treatment of the underlying cause. Because functional AVB usually occurs in younger population, these patients are particularly vulnerable to long-term complications and challenges from pacemakers and they may need several interventions over their lifetime. Additionally, there are legitimate concerns over lead malfunction, pacemaker dependency and right ventricular pacing induced cardiomyopathy. CNA can potentially overcome these limitations. In a patient with paroxysmal AVB, to determine the functional or vagal nature of the AVB, the relationship between sinus rate and AVB should be carefully evaluated. Functional AVB is usually characterized by a sinus node slowing before and during AVB episode or a progressive PR prolongation before AVB episode (15). In case of a negative Holter despite existence of typical symptoms, external or internal loop recorders should be preferred to rule out the presence of paroxysmal AVB and to establish a symptom–rhythm correlation. The patients demonstrating second- or advanced-degree AVB in 3 successive resting ECGs should be considered as persistent AVB. To differentiate intrinsic from functional AVB, atropine challenge (0.04 mg/kg, max 3 mg) and exercise stress test should be attempted. Complete resolution of AVB during atropine administration and exercise stress testing should be demonstrated in all cases (16). Regardless of the paroxysmal or persistent nature of AVB, an electrophysiological study with overdrive atrial pacing is indicated to exclude infra- or intra-Hisian AVB (17). In all AVB cases, pacemaker implantation as well as CNA should be discussed with the patient as treatment options. Despite the investigational nature of a CNA strategy in this cohort, the benefits of preserving physiological ventricular stimulation with a CNA procedure should always be considered.