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

VALVERDE, CARLOS A; NEGRONI, JORGE ANTONIO; CELY ORTIZ, D.C. ALEJANDRA; GONANO, LUIS; MATTIAZZI, RAMONA ALICIA; FELICE, JUAN IGNACIO; LASCANO, ELENA CATALINA

Virtual - Meet

Congreso; Reunión conjunta SCHCF + ALACF 2020; 2020

SCHCF - ALACF

Introduction: During rapid pacing or in some pathologic conditions, cardiac calcium (Ca) transients can alternate in a large-small-large-small sequence. This disturbance in Ca handling, known as Ca alternans (CaA), is linked to the genesis of lethal arrhythmias. The molecular mechanisms underlying CaA remain poorly defined. Slow Ca release restitution (CRR), defined as the necessary time for Ca release recovery after a beat, was suggested as a main mechanism responsible for CaA.Aims: To test the hypothesis that accelerating CRR prevents CaA.Methods: We used previous results from mouse cardiomyocytes (Institutional Animal Care and Use Committee, CICUAL-T05-01-17) and from a mathematical human cardiomyocyte model (Cely-Ortiz et al., 2020). Cardiomyocytes from three mouse strains were used in the experiments: WT (wild type), S2814D (constitutive pseudophosphorylation of ryanodine receptors; leaky sarcoplasmic reticulum -SR-) and PLNKO (phospholamban ablation; high SR Ca uptake and content). Since one of the main factors determining CRR is SR Ca load, CRR curves were generated by a two-pulse protocol in cardiomyocytes at increasing SR Ca loads generated by higher extracellular Ca (Cao).Results: The exponential time constants of the 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). The mathematical model (WTSIM, S2814DSIM, PLNKOSIM) reproduced the experimental findings. We then interrogated the model about its susceptibility to generate CaA by increasing the stimulation frequency from 70 to 182 beats/min. This evoked a sustained CaA pattern in WTSIM, transient CaA in S2814DSIM and failed to produce CaA in PLNKOSIM at 2 mM Cao. When Tau was decreased by increasing Cao in WTSIM and S2814DSIM, CaA were largely prevented. Conversely, when Tau was increased by decreasing Cao in PLNKOSIM, CaA were generated.Conclusion: A faster CRR is strongly associated with the prevention of CaA.