Simulation of postacidotic arrhythmias in a human myocyte model. Role of CAMKII

LASCANO E; SAID M; VITTONE L; MATTIAZZI A; MUNDIÑA WEILENMANN C; NEGRONI J.

Santiago

Congreso; . XX Reunión Anual de la Sección Latinoamericana de la ISHR.; 2012

International Society for Heart Research. Sección Latinoamericana

Postacidotic arrhythmias are associated to increased sarcoplasmic reticulum (SR) Ca2+ load and Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation, but the underlying mechanisms are still unclear. To understand this process, acidosis effects were incorporated into a myocyte model of contractility, including acidotic inhibition of L-type Ca2+ channel (ICaL), Na+-Ca2+ exchanger, Ca2+ release through SR ryanodine receptor (RyR2) (Irel), Ca2+ reuptake by the SR Ca2+ ATPase2a (Iup), Na+–K+ pump and K+ efflux and increased activity of the Na+–H+ exchanger (INHE). CaMKII effects on Irel, Iup, ICaL, INHE and late INa were introduced to partially compensate acidosis as experimentally reported. Assuming that diastolic Ca2+ leak through RyR2 was modulated by the resting state of this channel, postacidotic delayed afterdepolarizations (DADs) were triggered upon returning to normal pH after 6 min acidosis at 30% CO2-induced pH=6.7. The model confirmed that DADs depend on Ca2+ leak from Ca2+ overloaded SR and CaMKII activation, as their inhibition abrogated DADs. The model further revealed that in the transition to normal pH, DADs are determined by SR Ca2+ load and thereafter maintained by SR reloading with Ca2+ influx through the reverse NCX mode during the time period in which [Na+]i is elevated.