Abstract
The cellular basis of cardiac pacemaking activity, and specifically the quantitative contributions of particular mechanisms, is still debated. Reliable computational models of sinoatrial node (SAN) cells may provide mechanistic insights, but competing models are built from different data sets and with different underlying assumptions. To understand quantitative differences between alternative models, we performed thorough parameter sensitivity analyses of the SAN models of Maltsev & Lakatta (2009) and Severi et al (2012). Model parameters were randomized to generate a population of cell models with different properties, simulations performed with each set of random parameters generated 14 quantitative outputs that characterized cellular activity, and regression methods were used to analyze the population behavior.Our analysis pointed out that the two models, exhibit clearly different (sometime even opposite) sensitivity to several parameters. As relevant examples: (1) Na+-K+ pump activity, rapid delayed rectifier current (IKr) activation and SR Ca2+ pump activity had a greater effect on cycle length (CL) in the Maltsev model; (2) conversely, parameters describing the funny current (If) had a greater effect on CL in the Severi model; (3) changes in IKr conductance (GKr) had opposite effects on action potential (AP) amplitude in the two models.Within the population, a greater percentage of model cells failed to exhibit APs in the Maltsev model (27%) compared with the Severi model (7%), implying greater robustness in the latter. Confirming this initial impression, bifurcation analyses indicated that smaller changes in GKr or Na+-K+ pump activity led to failed APs in the Maltsev model.Overall, the results suggest experimental tests that can distinguish between models and alternative hypotheses, and the analysis offers strategies for developing anti-arrhythmic pharmaceuticals by predicting their effect on the pacemaking activity.
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