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.