Abstract
Sudden cardiac death (SCD) is a leading cause of death worldwide, and the majority of SCDs are caused by acute ventricular arrhythmias (VAs). Early afterdepolarizations (EADs) are an important trigger of VA under pathological conditions, e.g., inherited or acquired long QT syndrome (LQTS). However, it remains unclear how EAD events at the cellular level are spatially organized at the tissue level to induce and maintain ventricular arrhythmias and whether the spatial-temporal patterns of EADs at the tissue level are associated with abnormal T-wave morphologies that are often observed in LQTS, such as broad-based, notched or bifid; late appearance; and pointed T-waves. Here, a tissue model of the Purkinje-ventricular system (PVS) was developed to quantitatively investigate the complex spatial-temporal dynamics of EADs during T-wave abnormalities. We found that (1) while major inhibition of ICaL can substantially reduce the excitability of the PVS leading to conduction failures, moderate ICaL inhibition can promote occurrences of AP alternans at short cycle lengths (CLs), and EAD events preferentially occur with a major reduction of IKr (>50%) at long CLs; (2) with a minor reduction of ICaL, spatially synchronized steady-state EAD events with inverted and biphasic T-waves can be "weakened" into beat-to-beat concurrences of spatially synchronized EADs and T-wave alternans, and as pacing CLs increase, beat-to-beat concurrences of localized EADs with late-appearing and pointed T-wave morphologies can be observed; (3) under certain conditions, localized EAD events in the midmyocardium may trigger slow uni-directional electric propagation with inverted (antegrade) or upright (retrograde) broad-based T-waves; (4) spatially discordant EADs were typically characterized by desynchronized spontaneous onsets of EAD events between two groups of PVS tissues with biphasic T-wave morphologies, and they can evolve into spatially discordant oscillating EAD patterns with sustained or self-terminated alternating EAD and electrocardiogram (ECG) patterns. Our results provide new insights into the spatiotemporal aspects of the onset and development of EADs and suggest possible mechanistic links between the complex spatial dynamics of EADs and T-wave morphologies.