Instability of cardiac excitation wave propagation and intracellular calcium dynamics (computer simulation study).

摘要

Ventricular fibrillation, the major cause of sudden cardiac death, is typically preceded by ventricular tachycardia, but the mechanisms underlying the transition from VT to VF are poorly understood. Intracellular calcium overload occurs during rapid heart rates typical of ventricular tachycardia and is also known to promote arrhythmias. Therefore, investigation of the role of intracellular calcium in promoting transition from tachycardia to fibrillation has great practical importance.; In this research, the effect of calcium dynamics on cardiac electrical activity is investigated for two mathematical models of ventricular action potential: Luo Rudy II model and its modification developed in this thesis. The modification incorporates the latest quantitative data about myocyte calcium handling and reproduces complex patterns of calcium transients observed in rapid pacing experiments. The study is done for: (1) Single cell; (2) Ring of cells; (3) Square sheet of cells.; On the single cell level, both models demonstrate that rapid pacing leads to increased intracellular calcium levels and complex patterns of action potential configuration and the intracellular calcium transients. The irregular membrane potential dynamics arise directly from the interaction with the intracellular calcium subsystem.; For the model of a ring, a new regime of pulse circulation caused by irregular calcium dynamics is obtained. During that regime, the distribution of action potential duration along the ring is completely irregular and cannot be predicted by the action potential duration restitution curve. Also, sustained circulation associated with instabilities at the tail of the pulse is found and explained. Under calcium concentration clamp conditions, this regime produces a quasiperiodic mode, predicted theoretically, but not obtained in previous computer simulation studies.; The simulation of two-dimensional propagation shows the breakup of initially stable spiral wave. This is caused by slowly developing irregular calcium dynamics during the spiral wave rotation. To the extent that spiral wave breakup is useful as a model for the transition from tachycardia to fibrillation, these findings suggest that intracellular calcium dynamics may play an important role in the destabilization of ventricular tachycardia and its degeneration into ventricular fibrillation.; The interaction between the calcium subsystem and membrane potential is mainly mediated by calcium current through the L-type channel, sodium-calcium exchanger and nonspecific calcium activated currents. In addition, the L-type channel plays an important role in regulation of conduction velocity by supporting slow conduction through highly unrecovered regions.; Finally, the contributions are outlined and directions for future studies are formulated.