Autonomic Denervation With Magnetic Nanoparticles

Abstract

Background— Prior studies indicated that ablation of the 4 major atrial ganglionated plexi (GP) suppressed atrial fibrillation. Methods and Results— Superparamagnetic nanoparticles (MNPs) made of Fe 3 O 4 (core), thermoresponsive polymeric hydrogel (shell), and neurotoxic agent (N-isopropylacrylamide 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°C, releasing NIPA-M. 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— 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. This novel targeted drug delivery system can be used intravascularly for targeted autonomic denervation.