A Validated Computational Model of Cardiac Pacemaking: Mechanisms of Physiological and Pharmacological Rate Modulation

The cellular basis of heart's pacemaking activity, and specifically the degree of contribution of the different mechanisms involved, is still debated. Reliable computational models of the sinoatrial (SAN) action potential (AP) may help gain a deeper understanding of the phenomenon. Recently, novel models incorporating a detailed calcium-handling dynamics have been proposed, but they fail in reproducing experimental effects of “funny” current (If) reduction. We therefore developed a SAN AP model, based on available experimental data, to reproduce and investigate autonomic and drug-induced rate modulation. Cell compartmentalization and all the intracellular Ca2+ handling mechanisms were formulated as in the Maltsev-Lakatta model. Membrane current equations were revised on the basis of published experimental data. Modifications to the current formulations to simulate autonomic modulation and drug effects (Acetylcholine, Isoprenaline, Ivabradine, Cesium, BAPTA, Ryanodine) were derived from experimental data. The model generates AP waveforms typical of rabbit SAN cells, whose parameters fall within the experimental ranges: 176ms AP duration, 329ms cycle length, 73mV AP amplitude, −56mV maximum diastolic potential and 6.23V/s maximum upstroke velocity. Rate modulation by If-blocking drugs agrees with experimental findings: 18% and 20% Cesium-induced (5mM) and Ivabradine-induced (3μM) rate reductions, respectively. The model reproduces the autonomic modulation effects, with Acetylcholine- and Isoprenaline-induced rate variations, in a way that is quantitatively consistent with experimental data. Model testing of Ryanodine and BAPTA effects showed slowing of rate without cessation of beating. Our up-to-date model describes satisfactorily experimental data concerning autonomic stimulation, funny-channel blockade and inhibition of the Ca-related system by specific drugs, making it a useful tool for further investigations. Simulation results suggest that a detailed description of the intracellular calcium fluxes is fully compatible with the observation that If is a major component of pacemaking and rate modulation.