Canard analysis reveals why a large Ca2+ window current promotes early afterdepolarizations in cardiac myocytes

Abstract

The pumping of blood through the heart is due to a wave of muscle contractions that are in turn due to a wave of electrical activity initiated at the sinoatrial node. At the cellular level, this wave of electrical activity corresponds to the sequential excitation of electrically coupled cardiac cells. Under some conditions, the normally-long action potentials of cardiac cells are extended even further by small oscillations called early afterdepolarizations (EADs) that can occur either during the plateau phase or repolarizing phase of the action potential. Hence, cellular EADs have been implicated as a driver of potentially lethal cardiac arrhythmias. One of the major determinants of cellular EAD production and repolarization failure is the size of the overlap region between Ca2+ channel activation and inactivation, called the window region. In this article, we interpret the role of the window region in terms of the fast-slow structure of a low-dimensional model for ventricular action potential generation. We demonstrate that the effects of manipulation of the size of the window region can be understood from the point of view of canard theory. We use canard theory to explain why enlarging the size of the window region elicits EADs and why shrinking the window region can eliminate them. We also use the canard mechanism to explain why some manipulations in the size of the window region have a stronger influence on cellular electrical behavior than others. This dynamical viewpoint gives predictive power that is beyond that of the biophysical explanation alone while also uncovering a common mechanism for phenomena observed in experiments on both atrial and ventricular cardiac cells.