© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Remodeling of Ca2+-handling by atrial tachycardia: evidence for a role in loss of rate-adaptation
Departments of Medicine and Physiology, Research Center, Montreal Heart Institute, University of Montreal, and Department of Pharmacology, McGill University, 5000 Belanger Street East, Montreal, Quebec, Canada H1T 1C8
* Corresponding author. Tel.: +1-514-376-3330x3990; fax: +1-514-376-1355 nattel{at}icm.umontreal.ca
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.
KEYWORDS Arrhythmia (mechanisms); Calcium (cellular); Remodeling; SR (function); Supraventr. arrhythmia
1 Both authors contributed equally.
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