Mechanisms of calcium alternans in cardiac cells

Life-threatening cardiac arrhythmia is the most common cause of sudden cardiac death, killing more than 400,000 people each year. Abnormal calcium (Ca2+) handling has recently been suggested as a potential initiator of arrhythmia. One example of abnormal Ca2+ handling in cardiac cells is Ca2+ alternans; characterized by a beat-to-beat alternation in the amplitude of the intracellular Ca2+ transient at a constant rate of electrical stimulus. In this dissertation we, use mathematical model to explore possible underlying mechanisms of Ca2+ alternans.; Mathematical models and experimental data suggest that a steep and nonlinear dependence of sarcoplasmic reticulum (SR) Ca2+ release on SR Ca2+ content is a mechanism of Ca2+ alternans. Here, we build a time discrete model of Ca2+ movement that uses a nonlinear function of SR release with steep slope. The model shows that reduced effectiveness of SR Ca2+ release leads to a build up of the SR content above a threshold value, causing alternation of the SR content and the Ca2+ transient. The discrete time model prompts further investigation to find what determines the steeply nonlinear function.; To explore the basis for this steep nonlinear SR Ca2+ dependence, we use a temporal model of Ca2+ cycling to show that reopening of ryanodine receptor (RyR) channel under Ca2+ overload produces spontaneous SR Ca2+ release and yields a nonlinear relationship between SR Ca2+ release and SR content.; A new RyR kinetic model is built based on the hypothesis that calsequestrin (CSQ), a SR lumenal Ca2+ buffer, inhibits and activates RyR channel activity by sensing the SR lumenal Ca2+ concentration. The RvR, kinetic model is derived systematically by assuming two Ca 2+ binding sites on the cytosolic side and one CSQ binding site within the SR membrane of the RyR channel. A local control model using the RyR kinetic model produces a nonlinear relationship between fractional SR Ca2+ release and SR content similar to experimental data.; Finally, we use a spatial-temporal model to show that an alternating pattern of Ca2+ wave propagation occurs under Ca2+ overload condition with high rate of Ca2+ stimulation. This model suggests that delayed recovery of refractoriness of the RyR channel is a mechanism of alternans without an alternation of SR content. This mechanism of alternans is different from the steeply nonlinear Ca2+ release function.