Ventricular fibrillation (VF), the major cause of sudden cardiac death, is
typically preceded by ventricular tachycardia (VT) but the mechanisms under
lying 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 an
d mathematical modeling approach. Our results show that I) rapid pacing of
rabbit ventricular myocytes at 35 degrees 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+ tra
nsient 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+ dynamic
s, and showed good agreement with the experimental findings in isolated myo
cytes; and 4) when incorporated into simulated two-dimensional cardiac tiss
ue, 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 ro
le through its influence on Ca2+-sensitive membrane currents such as /(Ca),
/(NaCa),. and /(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 in
tracellular Ca2+ dynamics may play an important role in the destabilization
of VT and its degeneration into VF.