Autonomic Denervation With Magnetic Nanoparticles

Lilei Yu, MD; Benjamin J. Scherlag, PhD; Kenneth Dormer, PhD; Kytai T. Nguyen, PhD; Carey Pope, PhD; Kar-Ming Fung, MD, PhD; Sunny S. Po, MD, PhD

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 Fe3O4 (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 (408% at baseline; 219% at 2 hours; P0.006). The lowest voltage of ARGP high-frequency stimulation inducing atrial fibrillation was increased from 5.90.8 V (baseline) to 10.20.9 V (2 hours; P0.009). Intracoronary infusion of MNPs suppressed the IRGP but not ARGP function (ventricular rate slowing: 578% at baseline, 208% at 2 hours; P0.002; sinus rate slowing: 317% at baseline, 338% at 2 hours; P0.604). 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. (Circulation. 2010;122:2653-2659.)

Key Words: arrhythmia  atrial fibrillation  nervous system, autonomic  magnetic nanoparticles

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