Autonomic denervation with magnetic nanoparticles.
BACKGROUND
prior studies indicated that ablation of the 4 major atrial ganglionated plexi (GP) suppressed atrial fibrillation.


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.
Department of Cardiology, Renmin Hospital of Wuhan University, China.
Lilei
L
Yu
Benjamin J
BJ
Scherlag
Kenneth
K
Dormer
Kytai T
KT
Nguyen
Carey
C
Pope
Kar-Ming
KM
Fung
Sunny S
SS
Po
D000178:Acrylamides / Q000627:therapeutic use; D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000601:surgery; D017763:Autonomic Denervation / Q000379:methods*; D017115:Catheter Ablation / Q000379:methods*; D004285:Dogs; D005290:Ferric Compounds / Q000627:therapeutic use; D005725:Ganglia, Autonomic / Q000187:drug effects / Q000601:surgery; D006325:Heart Atria / Q000294:innervation; D008280:Magnetics; D053768:Metal Nanoparticles / Q000627:therapeutic use*; D023421:Models, Animal; D009498:Neurotoxins / Q000627:therapeutic use*
D000178:Acrylamides; D005290:Ferric Compounds; D009498:Neurotoxins; C000499:ferric oxide; C067295:N-isopropylacrylamide