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

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.