title: Remodeling of Ca(2+)-handling by atrial tachycardia: evidence for a role in loss of rate-adaptation.
abstract: BACKGROUND
  Loss of rate-dependent action potential (AP) duration (APD) adaptation is a characteristic feature of atrial tachycardia-induced remodeling (ATR). ATR causes sarcolemmal ion-channel remodeling (ICR) and changes in Ca(2+)-handling. The present studies were designed to quantify Ca(2+)-handling changes and then to apply a mathematical AP model to assess the contributions of Ca(2+)-handling abnormalities and ICR to loss of APD rate-adaptation.
  
  
  METHODS
  Indo-1 fluorescence was used to measure intracellular Ca(2)-transients and whole-cell patch-clamp to record APs in atrial myocytes from control dogs and dogs subjected to atrial pacing at 400/min for 6 weeks. A previously developed ionic model of the canine atrial AP was modified to reproduce measured Ca(2+)-transients of control and ATR myocytes.
  
  
  RESULTS
  In control, APD to 95% repolarization (APD(95)) decreased by 91 ms experimentally and by 88 ms in the model over the 1-6 Hz range. In ATR myocytes, APD(95) failed to decrease over the 1-6 Hz range. Ca(2+)-handling abnormalities in ATR myocytes included slowed upstroke, decreased amplitude and strong single-beat post-rest potentiation. Unaltered Ca(2+)-handling properties included caffeine-releasable Ca(2+)-stores and Ca(2+)-transient relaxation before and after exposure to the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) inhibitor cyclopiazonic acid (CPA). Including ICR alone in the model accounted for loss of APD(50) rate-adaptation; however, KR alone reduced APD(95) rate-adaptation by only 19% to 71 ms. When both ICR and Ca(2+)-handling changes were incorporated, APD(95) rate-adaptation decreased to 6 ms, accounting for experimental observations.
  
  
  CONCLUSIONS
  ICR alone does not fully account for loss of APD rate-adaptation with atrial remodeling: Ca(2+)-handling changes appear to contribute to this clinically significant phenomenon.
authors.affiliation: Department of Medicine, Research Center, Montreal Heart Institute, University of Montreal, Quebec, Canada H1T 1C8.
authors.forename: James
authors.initials: J
authors.lastname: Kneller
authors.forename: Hui
authors.initials: H
authors.lastname: Sun
authors.forename: Normand
authors.initials: N
authors.lastname: Leblanc
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000200:Action Potentials; D000222:Adaptation, Physiological; D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism*; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002304:Cardiac Pacing, Artificial; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D002110:Caffeine; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium; C000543:cyclopiazonic acid