Biophys J, December 1999, p. 2930-2941, Vol. 77, No. 6

Intracellular Ca²⁺ Dynamics and the Stability of Ventricular Tachycardia

E. Chudin,^* J. Goldhaber,^# A. Garfinkel,^#¶ J. Weiss,^#§ and B. Kogan

Departments of  ^*Biomathematics,  ^#Medicine (Cardiology),  ^§Physiology,  ^¶Physiological Science, and  Computer Science, University of California, Los Angeles, California 90095-1679 USA

Ventricular 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 I_Ca, I_NaCa, and I_ns(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.

Biophys J, December 1999, p. 2930-2941, Vol. 77, No. 6
© 1999 by the Biophysical Society   0006-3495/99/12/2930/12  $2.00

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