Intracellular Ca2+ Dynamics and the Stability of Ventricular Tachycardia

AbstractVentricular fibrillation (VF), the major cause of sudden cardiac death, is typically preceded by ventricular tachycardia (VT), but the mechanisms underlying the transition from VT to VF are poorly understood. Intracellular Ca2+ overload occurs during rapid heart rates typical of VT and is also known to promote arrhythmias. We therefore studied the role of intracellular Ca2+ dynamics in the transition from VT to VF, using a combined experimental and mathematical modeling approach. Our results show that 1) rapid pacing of rabbit ventricular myocytes at 35°C led to increased intracellular Ca2+ levels and complex patterns of action potential (AP) configuration and the intracellular Ca2+ transients; 2) the complex patterns of the Ca2+ transient arose directly from the dynamics of intracellular Ca2+ cycling, and were not merely passive responses to beat-to-beat alterations in AP; 3) the complex Ca2+ dynamics were simulated in a modified version of the Luo-Rudy (LR) ventricular action potential with improved intracellular Ca2+ dynamics, and showed good agreement with the experimental findings in isolated myocytes; and 4) when incorporated into simulated two-dimensional cardiac tissue, this action potential model produced a form of spiral wave breakup from VT to a VF-like state in which intracellular Ca2+ dynamics played a key role through its influence on Ca2+-sensitive membrane currents such as ICa, INaCa, and Ins(Ca). To the extent that spiral wave breakup is useful as a model for the transition from VT to VF, these findings suggest that intracellular Ca2+ dynamics may play an important role in the destabilization of VT and its degeneration into VF