title: Focal pharmacological modulation of atrioventricular nodal conduction via implantable catheter: a novel therapy for atrial fibrillation?
abstract: BACKGROUND
  Pharmacological ventricular rate control is an acceptable atrial fibrillation (AF) therapy limited by systemic toxicity. We postulate that focal catheter-based drug delivery into the atrioventricular nodal (AVN) region may effectively control ventricular rate during AF without systemic toxicity. This study evaluated the effects of focally administered acetylcholine on AVN conduction and refractoriness during sinus rhythm and AF.
  
  
  RESULTS
  Canines (n=7) were anesthetized and instrumented to assess cardiac electrophysiology and blood pressure. A custom drug delivery catheter was implanted in the AVN region. Incremental doses of acetylcholine starting at 10 microg/min were infused until complete AV block was achieved. Acetylcholine induced dose-dependent AV block. AF induction and electrophysiology measurements were performed during baseline and acetylcholine-induced first-degree and third-degree AV block. During AF, infusion of acetylcholine decreased ventricular rates from 182+/-32 to 77+/-28 and 28+/-8 bpm (first-degree and third-degree AV block, respectively; P<0.05). At the first-degree AV block dose, AVN effective refractory period increased from 186+/-37 to 282+/-33 ms, and Wenckebach cycle length increased from 271+/-29 to 378+/-58 ms (P<0.05). The first-degree AV block dose prolonged AV and AH intervals by 26% and 23% (P<0.05), whereas AA intervals and blood pressure remained unchanged, demonstrating a local effect. All effects were reversed 20 minutes after infusion was stopped.
  
  
  CONCLUSIONS
  Focal acetylcholine delivery into the AVN increased AVN refractoriness and significantly decreased ventricular rate response during induced AF in a dose-related, reversible manner without systemic side effects. This may represent a novel therapy for AF whereby ventricular rate is controlled with the use of an implantable drug delivery system.
authors.affiliation: Medtronic, Inc, Minneapolis, MN 55432, USA. daniel.c.sigg@medtronic.com
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Sigg
authors.forename: Prasanga
authors.initials: P
authors.lastname: Hiniduma-Lokuge
authors.forename: James A
authors.initials: JA
authors.lastname: Coles
authors.forename: Phillip
authors.initials: P
authors.lastname: Falkner
authors.forename: Rebecca
authors.initials: R
authors.lastname: Rose
authors.forename: Jon F
authors.initials: JF
authors.lastname: Urban
authors.forename: Michael R
authors.initials: MR
authors.lastname: Ujhelyi
mesh_terms: D000109:Acetylcholine / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy*; D001283:Atrioventricular Node / Q000503:physiopathology*; D002408:Catheters, Indwelling; D004195:Disease Models, Animal; D004285:Dogs; D016503:Drug Delivery Systems; D005260:Female; D006339:Heart Rate / Q000502:physiology*; D008297:Male; D009431:Neural Conduction / Q000502:physiology*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D014665:Vasodilator Agents; D000109:Acetylcholine