Decreasing ryanodine receptors (RyR2) activity diminishes the propensity to Ca-induced arrhythmias but increase the propensity to Ca alternans (CaA), according to a mathematical model of human myocyte

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

La Plata

Congreso; Congreso anual de la Sección Latinoamericana de la International Society for Heart Research: ISHR-Lat 2022; 2022

Sección Latinoamericana de la International Society for Heart Research

By using theLascano-Negroni mathematical model of human myocyte, we previously showed thatCa-induced arrhythmias were dependent on the relationship between RyR2 activityand the velocity of SR Ca uptake. The model demonstrated that the increase inthe activity of RyR2 (simulated by the increase in RyR2 conductance) was a mainfactor in outlining the Ca-induced arrhythmogenic zone. These in silico results were validated byexperimental studies (Valverde et al., Cardiovasc Res, 2019). These resultssupported the idea that RyR2 inhibition may be used as a therapeutic tool todiminish the probability of Ca-induced arrhythmias (Maruyama et al., 2013, Zanget al., 2015, Gonano et al., 2018).In the presentstudy, we used the same model to study the dependence of CaA on therelationship between RyR2 activity and the velocity of SR Ca uptake. To thatpurpose, the myocyte model was submitted to a protocol of increasingstimulation frequency (from 70 beats/min to 185 beats/min). The results showed that decreasing RyR2 activityin the region of “normal” SR Ca uptake, increased CaA.  Therefore, as shown in the figure, whereasdecreasing RyR2 activity may preclude from Ca-induced arrhythmias, thisdecrease may enhance the propensity to CaA