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Regulation of Ca²⁺ and electrical alternans in cardiac myocytes: role of CAMKII and repolarizing currents

Cardiac Bioelectricity and Arrhythmia Center, Washington University in St. Louis, St. Louis, Missouri

Submitted 10 December 2006 ; accepted in final form 26 January 2007

Alternans of cardiac repolarization is associated with arrhythmias and sudden death. At the cellular level, alternans involves beat-to-beat oscillation of the action potential (AP) and possibly Ca²⁺ transient (CaT). Because of experimental difficulty in independently controlling the Ca²⁺ and electrical subsystems, mathematical modeling provides additional insights into mechanisms and causality. Pacing protocols were conducted in a canine ventricular myocyte model with the following results: 1) CaT alternans results from refractoriness of the sarcoplasmic reticulum Ca²⁺ release system; alternation of the L-type calcium current has a negligible effect; 2) CaT-AP coupling during late AP occurs through the sodium-calcium exchanger and underlies AP duration (APD) alternans; 3) increased Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) activity extends the range of CaT and APD alternans to slower frequencies and increases alternans magnitude; its decrease suppresses CaT and APD alternans, exerting an antiarrhythmic effect; and 4) increase of the rapid delayed rectifier current (I_Kr) also suppresses APD alternans but without suppressing CaT alternans. Thus CaMKII inhibition eliminates APD alternans by eliminating its cause (CaT alternans) while I_Kr enhancement does so by weakening CaT-APD coupling. The simulations identify combined CaMKII inhibition and I_Kr enhancement as a possible antiarrhythmic intervention.

arrhythmia; calcium; sudden death; electrophysiology; calcium/calmodulin-dependent protein kinase II

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