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

Background

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.

Objective

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.

Methods

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.

Results

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.

Conclusion

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.

Keywords:  Early afterdepolarizations , Reentry , Bi-excitability , Bi-stability , Torsades de pointes

Abbreviations:  2D, two-dimensional, ECG, electrocardiogram, APD, action potential duration, EAD, early afterdepolarization, I_Ca,L, L-type calcium current, I_Na, sodium current, LQTS, long QT syndrome, NRVM, neonatal rat ventricular myocyte, PVC, premature ventricular complex, PVT, polymorphic ventricular tachycardia, TdP, torsades de pointes, VF, ventricular fibrillation