The interplay between sarcoplasmic reticulum Ca2+ uptake and leak in Ca2+ triggered arrhythmias

VALVERDE, CARLOS A; MATTIAZZI, ALICIA; CELY-ORTIZ, ALEJANDRA; MAZZOCCHI, GABRIELA

Ciudad Autónoma de Buenos Aires

Congreso; 16th World Congress of Arrhythmias; 2019

Sociedad Argentina de Electrofisiología Cardíaca

Introduction: Calcium (Ca) triggered activity is one of the mechanisms responsible for cardiac arrhythmias. Moreover, non-ischemic as well as ischemic heart failure (HF) favors the conditions for triggered arrhythmias. Triggered activity in HF typically arises from delayed afterdepolarizations (DADs). DADs usually occur under conditions of elevatedsarcoplasmic reticulum (SR) Ca and/or increased RyR2 Ca sensitivity, which favor SR Ca leak. In HF, Ca leak has been associated to CaMKII-dependent phosphorylation of RyR2-Ser2814 site. Enhanced Ca leak activates sarcolemma Na/Ca exchanger, generating a depolarizing inward current (DAD), which might trigger a spontaneous action potential.Moreover, an increase in SR Ca uptake was proposed (and submitted to clinical trials) as a therapeutic maneuver to increase contractility in HF (Hulot et al, 2017). Unfortunately, this proposed increase in SR Ca uptake may exacerbate the risk for triggered arrhythmias by increasing SR Ca load and leak. Objectives: To study the role of increasing SR Ca uptake on Ca2+ triggered arrhythmias induced by SR Ca leak due to RyR phoshorylation by CaMKII.Methods: ECG in mice with constitutive pseudophosphorylation of RyR2-Ser2814 site (S2814D), with no phosphorylatable S2814 site (S2814A), SDKO mice (crossbred of S2814D/PLNKO, fosfolamban (PLN) ablation mice, to increase SR Ca uptake), and in SAKO (crossbred of S2814A/PLNKO mice). Wild type mice (WT) were used as controls.Ca leak and arrhythmogenic Ca waves were evaluated in isolated myocytes by confocal microscopy. Results: Under stress conditions, S2814D mice presented a higher number of arrhythmias vs the other strains. S2814D and S2814A myocytes significantly increased and decreased respectively, the frequency of SR Ca waves vs WT. The increase in SR Ca uptake in SDKO myocytes increased SR Ca leak but aborted Ca waves whereas in SAKO myocytes the increase in SR Ca load did not influence the lack of Ca waves observed in S2814A. Conclusion: The increase in SR Ca uptake, if high enough, is able to prevent Ca waves and triggered arrhythmias. When RyR2 phosphorylation and SR Ca leak are prevented, even a high increase in SR Ca uptake is unable to increase Ca waves and arrhythmias. The results suggest that prevention of SR Ca leak (i.e. CaMKII inhibition) is the safe maneuver to prevent Ca triggered arrhythmias when increasing SR Ca load is the therapeutic tool chosen to increase cardiac performance.