Interpretation of arrhythmia generation induced by sarcoplasmic reticulum Ca2+ loss using a human myocyte mathematical model

FELICE, JUAN IGNACIO; VALVERDE, CARLOS ALFREDO; MATTIAZZI, RAMONA ALICIA; LASCANO, ELENA CATALINA; 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 bythe release 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 maytrigger arrhythmias2. Experimental data showed that transgenic micecarrying a mutation that represents a constitutive pseudophosphorylation ofRyR2 (S2814D) exhibit spontaneous action potentials (SAP) and that theintensity of these events decreased until reaching the level of delayedafterdepolarizations (DAD) when Ca2+ reuptake by the SR-Ca2+-ATPase(SERCA2a) was increased in mice with mutated RyR2 and phospholamban (PLN, aSERCA2a 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 and Conclusions. The model reproduced the arrhythmicevents. Simulations showed that in S2814D conditions, the enhancement indiastolic Ca2+ leak increased Ca2+ concentration in thedyadic cleft (DC) that surrounds RyR2 which is exchanged by Na+through the Na+-Ca2+ exchanger (NCX) working in forwardmode. Na+ entrance depolarizes the membrane to the threshold levelof Na+ channels giving rise to an action potential. In SDKOconditions, the increased Ca2+ reuptake produces lower NCX activityresulting in membrane depolarization below the threshold needed to generateSAP; 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] BersDM. Nature 415:198-205, 2002.[2] PrioriSG, et al. Circ Res 108:871-883, 2011.[3] Lascano EC, et al. J Mol Cell Cardiol 60:172-183,2013.