Remodeling of Ca2+-handling by atrial tachycardia: Evidence for a role in loss of rate-adaptation

James Kneller, Hui Sun, Normand Leblanc, Stanley Nattel

Research output: Contribution to journalArticlepeer-review

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 Ca2+-handling. The present studies were designed to quantify Ca2+-handling changes and then to apply a mathematical AP model to assess the contributions of Ca2+-handling abnormalities and ICR to loss of APD rate-adaptation. Methods: Indo-1 fluorescence was used to measure intracellular Ca2-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 Ca2+-transients of control and ATR myocytes. Results: In control, APD to 95% repolarization (APD95) decreased by 91 ms experimentally and by 88 ms in the model over the 1-6 Hz range. In ATR myocytes, APD95 failed to decrease over the 1-6 Hz range. Ca2+-handling abnormalities in ATR myocytes included slowed upstroke, decreased amplitude and strong single-beat post-rest potentiation. Unaltered Ca2+-handling properties included caffeine-releasable Ca2+-stores and Ca2+-transient relaxation before and after exposure to the sarcoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor cyclopiazonic acid (CPA). Including ICR alone in the model accounted for loss of APD50 rate-adaptation; however, KR alone reduced APD95 rate-adaptation by only 19% to 71 ms. When both ICR and Ca2+-handling changes were incorporated, APD95 rate-adaptation decreased to 6 ms, accounting for experimental observations. Conclusion: ICR alone does not fully account for loss of APD rate-adaptation with atrial remodeling: Ca2+-handling changes appear to contribute to this clinically significant phenomenon.

Original languageEnglish (US)
Pages (from-to)416-426
Number of pages11
JournalCardiovascular research
Volume54
Issue number2
DOIs
StatePublished - 2002
Externally publishedYes

Keywords

  • Arrhythmia (mechanisms)
  • Calcium (cellular)
  • Remodeling
  • SR (function)
  • Supraventr. arrhythmia

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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