Figure 7. Mechanisms of afterdepolarization formation in cardiomyocytes.

In ventricular myocytes from large mammals, phase-2 EADs are associated with I_Ca recovery from inactivation and reactivation during prolonged APs (A). Spontaneous SR Ca²⁺ release, which increases Ca²⁺ extrusion via NCX (inward current), can lead to phase-3 EADs (B) or DADs (C) when occurring during or after E_m repolarization respectively. In murine ventricle, phase-3 EADs are favored by potentiated (triggered) Ca²⁺ transient and AP shortening (D). The former causes I_NCX augmentation and AP plateau prolongation (at negative E_m), during which non-equilibrium I_Na reactivation (permitted by rapid I_Na recovery during fast repolarization) can occur. This, which is shown here to be relevant in the human atrium, could be a universal mechanism underlying EAD formation in both atria (especially PVs) and ventricles ([26]) of large mammals. Indeed, phase-3 EADs mediate re-initiation of atrial (and ventricular) fibrillation. ECG, E_m and tension recorded in canine atrium (E, reproduced with permission from [5]) show phase-3 EADs occurring after termination of fast atrial pacing, which are accompanied by increased contractile force.