Prevention And Treatment Of Atrial Fibrillation By Low Level Vagosympathetic Nerve Stimulation

Jais in 1997 and Haissaguerre in 1998. found that some patients with paroxysmal atrial fibrillation (PAF) had focal firing from pulmonary vein (PV) myocardial sleeves which induced the arrhythmia. Others found that non-PV sites. specifically the myocardial sleeves of the superior vena cava (SVC) and the vestigial myocardium within the ligament of Marshall (LOM) were also triggering sites for PAF. However, the mechanism(s) underlying this abnormal activity remained unexplained. During the last decade investigators in our laboratory have systematically developed several different acute experimental animal models which closely simulated the clinical syndromes of PAF arising from pulmonary veins (PV) and the same non-PV sites described clinicallyThe common mechanistic basis of these experimental models relied on the findings that these tissues showed a singular sensitivity to the two major neurotransmitters acetylcholine and nor-epinephrine. Moreover, evidence was presented implicating clusters of neurons found within ganglionated plexi (GP) adjacent to the PV. within the LOM and adjacent to the SVC myocardial sleeves as the source of these neurotransmitters and the likely basis for triggered activity arising from these areas. We have proposed that hyperactivity of these GP is the pathologic event initially causing PAF in patients, particularly those whose AF was resistant to drugs.Evidence from clinical reports using a single procedure have provided confirmation of this hypothesis since ablation of GP at the PV atrial junctions with and without PV isolation have shown a higher follow-up success rate, compared to PV isolation alone.This study described a non-ablative method for prevention and termination the onset of AF in the some experimental models for PAF. In brief, low level vagal nerve stimulation (LL-VNS) over a period of 3 hours significantly reduced the inducibility of AF. LL-VNS was defined as a level of voltage that was 10% or 50% below that which was required to slow the heart rate or prolong AV conduction. We also tested the efficacy of LL-VNS to suppress AF inducibility in two different experimental models in which hyperactive GPs have been shown to be the basis of triggering for PAF.Part 1 Effects of Low-Level Vagosympathetic Stimulation to Suppress the Focal Atrial FibrillationIntroduction:We built an animol model of atrial fibrillation by using high frequency stimulation (HFS) delivered during the refractory period of the atrium (A) and pulmonary veins (PVs) to induce focal atrial fibrillation (AF).Objective:We want to testify that bilateral low-level vagosympathetic nerve stimulation (LL-VNS) could suppress HFS induced focal AF at atrial and PV sites.Methods:In 23 dogs, anesthetized with Na-pentobarbital, electrodes in the vagosympathetic trunks allowed LL-VNS at 1 volt below that which slowed the sinus rate or atrioventricular conduction. Multi-electrode catheters were attached to all PVs (RSPV, RIPV, LSPV. LIPV) and both atrial appendages (AA). LL-VNS was lasting for 3 hours. At the end of each hour, the HFS algorithm consisting of a 40 ms train of stimuli. (200 Hz. stimulus duration 0.1-1.0 msec) was delivered 2 ms after the atrial pacing stimulus at each PV and AA site. The Iowest voltage of HFS that induced AF was defined as the AF threshold (AF-TH). Five dogs without LL-VNS served as controls. Six dogs underwent LL-VNS but after transection of bilateral vagosympathetic trunks.Results:A progressive increase in AF-TH could be found at all PV and AA sites by LL-VNS. particularly significant (p<0.05) at RSPV. RIPV, LSPV and right AA but not at LIPV and left AA. There was no difference between bilateral vagosympathetic transection or not.The 5 controls showed no changes in AF-TH at all sites over 3 hours.Conclusions:LL-VNS may prevent episodic AF due to rapid PV and non-PV firing.Part 2 Prevention and Reversal of Atrial Fibrillation Inducibility and Autonomic Remodeling by Low LevelVagosympathetic Nerve StimulationObjective:We hypothesized that autonomic atrial remodeling can be reversed by low-level vagosympathetic nerve stimulation (LL-VNS).Background:Previously we showed that VNS can be anti-arrhythmogenic.Methods:Thirty-three dogs were subjected to electrical stimulation (20Hz) applied to both vagosympathetic trunks at voltages 10-50% below the threshold which slowed sinus rate or AV conduction. Group-1 (n=7):Programmed stimulation (PS) was performed at baseline and during 6-hour rapid atrial pacing (RAP). PS allowed determination of effective refractory period (ERP) and AF inducibility measured by window of vulnerability (WOV). LL-VNS was continuously applied from the 4th-6th hours. Group-2 (n=4):After baseline ERP and WOV determinations.6-hour concomitant RAP+LL-VNS was applied. Sustained AF was induced by injecting acetylcholine (ACh) 10 mM into the anterior right ganglionated plexus (Group-3. n=10) or applying ACh 10 mM to right atrial appendage (Group-4. n=9).Results:Group-1:The ERP progressively shortened and the?WOV (sum of WOV from all tested sites) progressively increased (p<0.05) during 3-hour RAP then returned toward baseline during 3-hour RAP+LL-VNS (p<0.05). Group-2:6-hour concomitant RAP+LL-VNS did not induce any significant change in ERP and?WOV. Group-3 and Group-4:AF duration (AF-D,seconds) and cycle length (AF-CL. msec) were markedly altered by 3-hour LL-VNS (Group-3:baseline:AF-D=389±90. AF-CL=45.1±7.8; LL-VNS:AF-D=50±15***, AF-CL=82.0±13.7***; Group-4:baseline:AF-D=505±162, AF-CL=48.8±6.6; LL-VNS:AF-D=71±21***,AF-CL=101.3±20.9***;***:p<0.001). Conclusion:LL-VNS can prevent and reverse atrial remodeling induced by RAP as well as suppress AF induced by strong cholinergic stimulation. Inhibition of the intrinsic cardiac autonomic nervous system by LL-VNS may be responsible for these salutary results.Condensed Abstract In this study, we demonstrated that low level vagosympathetic stimulation, which did not inhibit the sinus and AV nodal function, suppressed acute atrial remodeling and AF inducibility caused by 6-hour rapid atrial pacing as well as AF induced by strong cholinergic stimulation. Inhibition of the intrinsic cardiac autonomic nervous system may be responsible for these salutary effects. Low level vagosympathetic stimulation may serve as a novel therapeutic modality to treat AF, particularly to prevent AF from progressing to persistent forms of this arrhythmia.