Theoretical background of intrinsic cardiac autonomic nervous
system modulation for vasovagal syncope and atrial fibrillation
As the most common type of syncope, VVS is characterized by an abrupt
dysregulation of the ANS to maintain adequate blood pressure and/or
heart rate for cerebral perfusion (42). Central or peripheral triggers
initiate three well-defined efferent responses: a cardioinhibitory
response due to parasympathetic overactivity manifested by persistent
bradycardia or prolonged pauses; a vasodepressor response due to
sympathetic withdrawal manifested by significant hypotension; and a
mixed response manifested by co-existing bradycardia and hypotension
(Online Supplemental Figure 2) (42). Theoretically, neuromodulation of
the intrinsic cardiac ANS works by preventing the parasympathetic
efferent arm of the reflex arc in cardioinhibitory VVS and in mixed VVS
types with a predominant cardioinhibitory response. The clinical
efficiency of catheter based neuromodulation in patients with VVS has
been reported by several groups (43-49), with freedom from syncope of
between 80% and 100%.
After demonstration of the PV myocardial sleeves as the main foci for
initiation of paroxysmal AF, studies have focused on the difference in
electrophysiological properties of PVs and the adjacent LA myocardium.
Experimental studies have shown that stimulation of epicardial ganglia
causes both sympathetic and parasympathetic activation and PV myocytes
are more prone to effects of local autonomic nerve stimulation compared
to LA myocytes (13-16, 50-54). While parasympathetic effect shortens the
action potential duration, norepinephrine enhances the calcium transient
in the PVs. The disparity between the short action potential duration
and the enhanced calcium transient results in early afterdepolarization
and triggered firing in the PVs (Online Supplemental Figure 2). Scherlag
et al (50) showed that stimuli applied to PVs could not induce AF unless
there was also simultaneous stimulation of the adjacent
epicardiac ganglia. Furthermore,
blockade of muscarinic cholinergic receptors by atropine suppressed
triggered firing from the PVs. Although experimental data have shown
potential importance of intrinsic cardiac ANS, clinical studies
investigating the role of adding ANS modulation to PV isolation in
patients with AF have shown conflicting results (52-54). After
demonstration of that high-frequency stimulation (HFS) at the LOM may
cause parasympathetic responses characterized by significant slowing of
atrioventricular nodal conduction and AF induction in animal and human
experiments, the role of the vein of Marshall ethanol infusion has been
investigated in patients with AF (55, 56). In the VENUS Randomized
Clinical Trial, addition of vein of Marshall ethanol infusion to
catheter ablation, compared with catheter ablation alone, increased the
likelihood of remaining free of AF or atrial tachycardia at 6 and 12
months. (57). A similar experience was confirmed in recently published
Marshall-Plan study (58).
Detection ofintrinsic cardiac
autonomic nervous system during electrophysiological study
Three different approaches have been used for clinical identification of
intrinsic cardiac ANS in atria in the catheter laboratory: 1) HFS; 2)
electrogram analysis; and 3) empirical anatomic ablation (9, 10).