The Modulation Of Intrinsic Cardiac Autonomic Nervous Activity In Atrial Fibrillation

Objectives:1 To investigate the the effect of LL-VNS on ICANS activity and the atrial fibrillation2 To investigate the effect of LL-SVCS on the ICANS activity and atrial fibrillation.3 To investigate the effects of MNPs on ICANS activity and atrial fibrillation.Methods:1 Wire electrodes inserted into both vagosympathetic trunks allowed LL-VNS at 10% or 50% below the voltage required to slow the sinus rate or atrioventricular conduction. Multielectrodecatheters were attached to atria, atrial appendages and all pulmonary veinsElectrical stimulation at theanterior right and superior left ganglionated plexi (ARGP, SLGP) was used to simulate a hyperactive state ofthe ICANS. Effective refractory period (ERP) and window of vulnerability (WOV) for AF were determined at baseline and during ARGP+SLGP stimulation in the presence or absence of LL-VNS. Neural activity was recorded from the ARGP or SLGP.2 In 29 anesthetized dogs, we attached multi-electrode catheters on atria, all pulmonary veins and right stellate ganglion (RSG). A basket catheter was expanded in the superior vena cava (SVC) for high frequency stimulation (HFS,20 Hz) of the adjacent vagal preganglionics. Microelectrodes inserted into the anterior right ganglionated plexi (ARGP) recorded neural activity. At baseline, programmed stimulation determined the effective refractory period (ERP) and window of vulnerability (WOV), a measure of AF inducibility. For the next 3 hours, AF was induced by rapid atrial pacing (RAP), and the same parameters were measured hourly, during sinus rhythm. During hours 4-6 of RAP, we delivered low-level vagal stimulation at the SVC (LL-SVCS),50% below that which induced slowing of the sinus rate (SR). In six other dogs, the voltage/SR response curve during RSG and ARGP stimulation was compared after 2-hour LL-SVCS.3 Superparamagnetic nanoparticles (MNPs) made of Fe3O4 (core), thermor-esponsive polymeric hydrogel (shell), and neurotoxic agent (N-isopropylacry-lamide monomer [NIPA-M]) were synthesized. In 23 dogs, a right thoracotomy exposed the anterior right GP (ARGP) and inferior right GP (IRGP). The sinus rate and ventricular rate slowing responses to high-frequency stimulation (20 Hz,0.1 ms) were used as the surrogate for the ARGP and IRGP functions, respectively. In 6 dogs, MNPs carrying 0.4 mg NIPA-M were injected into the ARGP. In 4 other dogs, a cylindrical magnet (2600 G) was placed epicardially on the IRGP. MNPs carrying 0.8 mg NIPA-M were then infused into the circumflex artery supplying the IRGP. The hydrogel shell reliably contracted in vitro at temperatures 37℃, releasing NIPA-M.Results:1 ARGP+SLGP stimulation induced shortening of ERP, increase of ERP dispersion and increase of AF inducibility (WOV), all of which were suppressed by LL-VNS (10% or 50% below threshold) at all tested sites. Sham LL-VNS failed to induce these changes. The effects of LL-VNS were mediated by inhibition of the 1CANS, as evidenced by (1) LL-VNS suppression of the ability of the ARGP stimulation to slow the sinus rate, (2) the frequency and amplitude of the neural activity recorded from the ARGP or SLGP was markedly suppressed by LL-VNS, and (3) the spatial gradient of the ERP and WOV from the PV-atrial junction toward the atrial appendage was eliminated by LL-VNS.2 During hours 1-3 of RAP, there was a progressive decrease in the ERP, increase in WOV and increase in neural activity vs. baseline (all p<0.05). With LL-SVCS during hours 4-6, ERP, WOV and neural activity returned towards baseline levels (all p<0.05, compared to the 3rd hour values). (2) The ability of RSG and ARGP stimulation to increase and decrease SR. respectively, was blunted by LL-SVCS.3 MNPs injected into the ARGP suppressed high-frequency stimulation-induced sinus rate slowing response (40±8% at baseline; 21±9% at 2 hours; P<0.006). The lowest voltage of ARGP high-frequency stimulation inducing atrial fibrillation was increased from 5.9±0.8 V (baseline) to 10.2±0.9 V (2 hours; P<0.009). Intracoronary infusion of MNPs suppressed the IRGP but not ARGP function (ventricular rate slowing:57±8% at baseline,20±8% at 2 hours; P<0.002; sinus rate slowing:31±7% at baseline,33±8% at 2 hours; P<0.604). Prussian Blue staining revealed MNP aggregates only in the IRGP, not the ARGP.Conclusions:1 LL-VNS suppressed AF inducibility by inhibiting the neural activity of major GP within the ICANS.2 LL-SVCS can significantly suppress AF inducibility and mitigate sympathetic and parasympathetic effects on SR. This transvenous approach suggests a feasible clinical method for treating AF or inappropriate sinus tachycardia.3 Intravascularly administered MNPs carrying NIPA-M can be magnetically targeted to the IRGP and reduce GP activity presumably by the subsequent release of NIPA-M and/or microvascular embolization. This novel targeted drug delivery system can be used intravascularly for targeted autonomic denervation.