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

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 11 (CaMKII) activity extends the range of CaT and APD altemans to slower frequencies and increases afternans 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 afternans by eliminating its cause (CaT alternans) while I-Kr. enhancement does so by weakening CaT-APD coupling. The simulations identify combined CaMKII inhibition and 1(Kr) enhancement as a possible antiarrhythmic intervention.