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).