title: Role of constitutively active acetylcholine-mediated potassium current in atrial contractile dysfunction caused by atrial tachycardia remodelling.
abstract: OBJECTIVE
  Atrial fibrillation (AF)-induced contractile dysfunction contributes importantly to thrombo-embolic stroke, the most serious AF complication. Atrial cardiomyocytes have a constitutively active acetylcholine-regulated K(+)-current (I(KAChc)) that is enhanced by atrial tachycardia (AT). I(KAChc) contributes to action potential duration (APD) shortening in AT-remodelled atrial cardiomyocytes; APD regulates contractility by controlling Ca(2+)-loading and systolic Ca(2+)-release. This study investigated the potential role of I(KAChc) in AF-related contractile dysfunction.
  
  
  RESULTS
  Dogs were divided into two groups: (i) unpaced control (CTL); (ii) AT (400 bpm for at least 7 days). Tertiapin-Q (TQ), a selective I(KAChc) blocker, was used to define I(KAChc) contributions to contractility. Single-cell left atrial (LA) intracellular Ca(2+)-transients (CaTrs), cell-shortening (CS), and whole LA tissue tension-generation were measured. Atrial tachycardia increased I(KAChc). Whole LA contractility was decreased in AT (0.17 ± 0.05 g) compared with CTL (0.40 ± 0.09 g), with significant reversal (0.30 ± 0.06 g) after TQ administration. Ca(2+)-transient amplitude and CS in single-cell were decreased by AT compared with CTL (167 ± 14 vs. 88 ± 10 nM; 10.3 ± 1.3 vs. 1.7 ± 0.3 µm, respectively; P < 0.001). The AT-induced reductions in single-cell CaTr amplitude and CS were partly reversed by TQ administration (88 ± 10 vs. 112 ± 16 nM; P < 0.001; 1.7 ± 0.3 vs. 3.6 ± 0.7 µm; P < 0.01). We then measured CaTr and CS with carbachol and/or TQ to vary I(KACh) at various extracellular [Ca(2+)]. The CaTr-CS relationship was linear and AT results fell on the regression line, indicating that AT-remodelling effects on contractility are attributable to reduced CaTr.
  
  
  CONCLUSIONS
  Up-regulated I(KAChc) contributes to AF-related contractile dysfunction and could be a novel target to prevent hypocontractility-related thrombo-embolic complications.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kosin University School of Medicine, 34 Amnam-Dong, Seo-Ku, Busan 602-702, South Korea.
authors.forename: Sang-Ho
authors.initials: SH
authors.lastname: Koo
authors.forename: Reza
authors.initials: R
authors.lastname: Wakili
authors.forename: Jung-Ho
authors.initials: JH
authors.lastname: Heo
authors.forename: Denis
authors.initials: D
authors.lastname: Chartier
authors.forename: Hyun-Su
authors.initials: HS
authors.lastname: Kim
authors.forename: Sun-Jung
authors.initials: SJ
authors.lastname: Kim
authors.forename: Jae-Woo
authors.initials: JW
authors.lastname: Lee
authors.forename: Xiao Yan
authors.initials: XY
authors.lastname: Qi
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
authors.forename: Tae-Joon
authors.initials: TJ
authors.lastname: Cha
mesh_terms: D000109:Acetylcholine / Q000502:physiology*; D000818:Animals; D001281:Atrial Fibrillation / Q000150:complications / Q000503:physiopathology*; D001514:Bee Venoms / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects; D002217:Carbachol / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D006325:Heart Atria / Q000187:drug effects / Q000503:physiopathology; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D015221:Potassium Channels / Q000502:physiology*; D013610:Tachycardia / Q000150:complications / Q000503:physiopathology*; D013923:Thromboembolism / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control
chemical_list: D001514:Bee Venoms; D015220:Calcium Channels; D015221:Potassium Channels; C029738:tertiapin; D002217:Carbachol; D000109:Acetylcholine