Bi-stable wave propagation and early afterdepolarization-mediated cardiac arrhythmias

In normal atrial and ventricular tissue, the electrical wavefronts are mediated by the fast sodium current (I _Na), whereas in sinoatrial and atrioventricular nodal tissue, conduction is mediated by the slow L-type calcium current (I _Ca,L). However, it has not been shown whether the same tissue can exhibit both the I _Na-mediated and the I _Ca,L-mediated conduction. This study sought to test the hypothesis that bi-stable cardiac wave conduction, mediated by I _Na and I _Ca,L, respectively, can occur in the same tissue under conditions promoting early afterdepolarizations (EADs), and to study how this novel wave dynamics is related to the mechanisms of EAD-mediated arrhythmias. Computer models of two-dimensional (2D) tissue with a physiologically detailed action potential model were used to study the bi-stable wave dynamics. Theoretical predictions were tested experimentally by optical mapping in neonatal rat ventricular myocyte monolayers. In the same 2D homogeneous tissue, we could induce spiral waves that are mediated by either I _Na or I _Ca,L under conditions in which the action potential model exhibited EADs. This bi-stable wave propagation behavior was similar to bi-stability shown in many other nonlinear systems. Because the bi-stable states are also excitable, we call this novel behavior bi-excitability. In a 2D heterogeneous tissue, the I _Ca,L-mediated spiral wave meanders, giving rise to a twisting electrocardiographic QRS axis, resembling torsades de pointes, whereas the coexistence and interplay between the I _Na-mediated wavefronts and I _Ca,L-mediated wavefronts give rise to polymorphic ventricular tachycardia. We also present experimental evidence for bi-excitability under EAD-promoting conditions in neonatal rat ventricular myocyte monolayers exposed to BayK8644 and isoproterenol. Under EAD-prone conditions, both I _Na-mediated conduction and I _Ca,L-mediated conduction can occur in the same tissue. These novel wave dynamics may be responsible for certain EAD-mediated arrhythmias, such as torsades de pointes and polymorphic ventricular tachycardia.