Mechanisms of calcium alternans: Insights from a human cardiac myocyte model

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

Encuentro; XXXV Anual Meeting; 2020

Asociación Latinoamericana de Ciencias Fisiológicas (ALACF)

Introduction: During rapid pacing or in somepathologic conditions, cardiac calcium (Ca) transients can alternate in alarge-small-large-small sequence. This disturbance in Ca handling, known as Caalternans (CaA), is linked to the genesis of lethal arrhythmias. The molecularmechanisms underlying CaA remain poorly defined. Slow Ca release restitution(CRR), defined as the necessary time for Ca release recovery after a beat, wassuggested as a main mechanism responsible for CaA.Aims: To test the hypothesis that accelerating CRRprevents CaA.Methods: We used previous results frommouse cardiomyocytes (Institutional Animal Care and Use Committee,CICUAL-T05-01-17) and from a mathematical human cardiomyocyte model (Cely-Ortizet al., 2020). Cardiomyocytes from three mouse strains were used in theexperiments: WT (wild type), S2814D (constitutive pseudophosphorylation ofryanodine receptors; leaky sarcoplasmic reticulum -SR-) and PLNKO(phospholamban ablation; high SR Ca uptake and content). Since one of the mainfactors determining CRR is SR Ca load, CRR curves were generated by a two-pulseprotocol in cardiomyocytes at increasing SR Ca loads generated by higherextracellular Ca (Cao).Results: The exponential time constants ofthe CRR curves (Tau, ms) were 233±9* (WT), 216±15* (S2814D) and 103±3 (PLNKO)at 2 mM Cao (Mean ± SEM; ANOVA, Tukey?s Post Test, *p<0.0001 vs PLNKO). Themathematical model (WTSIM, S2814DSIM, PLNKOSIM) reproduced the experimentalfindings. We then interrogated the model about its susceptibility to generateCaA by increasing the stimulation frequency from 70 to 182 beats/min. Thisevoked a sustained CaA pattern in WTSIM, transient CaA in S2814DSIM and failedto produce CaA in PLNKOSIM at 2 mM Cao. When Tau was decreased by increasingCao in WTSIM and S2814DSIM, CaA were largely prevented. Conversely, when Tauwas increased by decreasing Cao in PLNKOSIM, CaA were generated.Conclusion: A faster CRR is stronglyassociated with the prevention of CaA.