Interpretation of arrhyithmia generation induced by sarcoplasmic reticulum Ca2+ lost using a human myocyte mathematical model

FELICE, JUAN IGNACIO; LASCANO, ELENA CATALINA; MATTIAZZI, ALICIA RAMONA; VALVERDE, CARLOS; NEGRONI, JORGE ANTONIO

Ciudad Autónoma de Buenos Aires

Congreso; XXII ISHR World Congress; 2016

International Society for Heart Research (ISHR)

Background. Contraction in cardiac myocytes is produced by therelease of Ca2+ from the sarcoplasmic reticulum (SR) throughryanodine receptor channels (RyR2) by Ca2+-induced Ca2+release (CICR)1. There are also spontaneous diastolic Ca2+discharges that are increased when RyR2 are altered and this situation may triggerarrhythmias2. Experimental data showed that transgenic mice carryinga mutation that represents a constitutive pseudophosphorylation of RyR2(S2814D) exhibit spontaneous action potentials (SAP) and that the intensity ofthese events decreased until reaching the level of delayed afterdepolarizations(DAD) when Ca2+ reuptake by the SR-Ca2+-ATPase (SERCA2a) was increased in mice with mutated RyR2 andphospholamban (PLN, a SERCA2a inhibitory protein) ablation (SDKO).Methods. To analyze the mechanisms involved in thesearrhythmic events, a human myocyte mathematical model3 was used torepresent both experimental conditions. Basal conditions and aproarrhythmogenic stress were simulated. The model was developed in MATLAB, andODE15s solver was used to solve the system of differential equations.Results andConclusions. Themodel reproduced the arrhythmic events. Simulations showed that in S2814D conditions,the enhancement in diastolic Ca2+ leak increased Ca2+concentration in the dyadic cleft (DC) that surrounds RyR2 which is exchangedby Na+ through the Na+-Ca2+ exchanger (NCX) workingin forward mode. Na+ entrance depolarizes the membrane to thethreshold level of Na+ channels giving rise to an action potential. InSDKO conditions, the increased Ca2+ reuptake produces lower NCX activityresulting in membrane depolarization below the threshold needed to generate SAP;in this situation only DAD appeared. Simultaneous representation of ionicfluxes in the myocyte using model-derived data allowed us to explain thedifferences in the arrhythmic events observed in both experimental conditions. [1] Bers DM. Nature415:198-205, 2002.[2] Priori SG, etal. Circ Res 108:871-883, 2011.[3]Lascano EC, et al. J Mol Cell Cardiol60:172-183, 2013.