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(Circulation Research. 2005;96:459.)
© 2005 American Heart Association, Inc.

Cellular Biology

Action Potential Duration Restitution and Alternans in Rabbit Ventricular Myocytes

The Key Role of Intracellular Calcium Cycling

Joshua I. Goldhaber, Lai-Hua Xie, Tan Duong, Christi Motter, Kien Khuu, James N. Weiss

From the UCLA Cardiovascular Research Laboratory, Departments of Medicine (Cardiology) and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, Calif.

Correspondence to Joshua I. Goldhaber, MD, David Geffen School of Medicine at UCLA, Division of Cardiology, 47-123 CHS, 10833 LeConte Ave, Los Angeles, CA 90095-1679. E-mail jgoldhaber{at}mednet.ucla.edu

Action potential duration (APD) restitution properties and repolarization alternans are thought to be important arrhythmogenic factors. We investigated the role of intracellular calcium (Ca²⁺_i) cycling in regulating APD restitution slope and repolarization (APD) alternans in patch-clamped rabbit ventricular myocytes at 34 to 36°C, using the perforated or ruptured patch clamp techniques with Fura-2-AM to record Ca²⁺_i. When APD restitution was measured by either the standard extrastimulus (S1S2) method or the dynamic rapid pacing method, the maximum APD restitution slope exceeded 1 by both methods, but was more shallow with the dynamic method. These differences were associated with greater Ca²⁺_i accumulation during dynamic pacing. The onset of APD alternans occurred at diastolic intervals at which the APD restitution slope was significantly <1 and was abolished by suppressing sarcoplasmic reticulum (SR) Ca²⁺_i cycling with thapsigargin and ryanodine, or buffering the global Ca²⁺_i transient with BAPTA-AM or BAPTA. Thapsigargin and ryanodine flattened APD restitution slope to <1 when measured by the dynamic method, but not by the S1S2 method. BAPTA-AM or BAPTA failed to flatten APD restitution slope to <1 by either method. In conclusion, APD alternans requires intact Ca²⁺_i cycling and is not reliably predicted by APD restitution slope when Ca²⁺_i cycling is suppressed. Ca²⁺_i cycling may contribute to differences between APD restitution curves measured by S1S2 versus dynamic pacing protocols by inducing short-term memory effects related to pacing-dependent Ca²⁺_i accumulation.

Key Words: alternans • arrhythmia • Ca²⁺ transients • action potential restitution

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