Mechanism of Calcium Cardiac alternans: Insights from a human myocyte mathematical model

CELY-ORTIZ, DIANA CATALINA ALEJANDRA; GONANO, LUIS; VALVERDE, CARLOS ALFREDO; FELICE, JUAN IGNACIO; LASCANO, ELENA CATALINA; MATTIAZZI, RAMONA ALICIA

A distancia

Congreso; Reunión Anual de la Sociedad Argentina de Fisiología (SAFIS) y de la Asociación Latino Americana de Ciencias Fisiológicas (ALACF); 2021

Sociedad Argentina de Fisiología (SAFIS)

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