CONICET | Buscador de Institutos y Recursos Humanos

Introduction: Cardiac calcium (Ca) transients can alternate in a large-small sequence from one beat to the next, a condition called Ca alternans (CaA), that usually occurs during rapid pacing or in some pathological conditions.The mechanisms of CaA remain controversial. The two main mechanisms under dispute are 1. Ca release refractoriness and 2. Inability of the sarcoplasmic reticulum (SR) Ca-ATPase (SERCA2a) to cope with the increased velocity of SR Ca uptake imposed by tachycardia. Aims and Methods: Using the Lascano-Negroni human cardiac myocyte mathematical model, known to accurately reproduce intracellular Ca handling, we explored these two possibilities. Results: In ?control? myocytes, increasing stimulation frequency (from 70 to 182 bpm), evoked an immediate alternation of the action potential (AP) and peak Ca current (ICaL) associated to CaA. After a few beats, AP and ICaL alternans stabilized whereas SR Ca content, SR Ca release and Ca transient increased until they reached a plateau (Ca release 9,1 µM/ms; Ca transient: 0,29 µM). Although SR Ca content remained high and constant (3448 µM), SR Ca release began to fluctuate (alternate). These results are reflecting an increased refractoriness at the level of the mechanisms that release Ca. However, the increase in SR Ca release after a few beats, evokes an incomplete SR Ca uptake that exacerbates CaA. CaA were completely abolished in myocytes mimicking RyR2 gain-of-function. However, they were exacerbated in myocytes with SERCA-gain of function. Conclusions: The model suggest that Ca release refractoriness governs the onset of intracellular CaA. However, deficits in Ca reuptake appear after a few beats and exacerbate CaA.