Mechanistic insight into spontaneous transition from cellular alternans to arrhythmia—A simulation study

Cardiac electrical alternans (CEA), manifested as T-wave alternans in ECG, is a clinical biomarker for predicting cardiac arrhythmias and sudden death. However, the mechanism underlying the spontaneous transition from CEA to arrhythmias remains incompletely elucidated. In this study, multiscale rabbit ventricular models were used to study the transition and a potential role of INa in perpetuating such a transition. It was shown CEA evolved into either concordant or discordant action potential (AP) conduction alternans in a homogeneous one-dimensional tissue model, depending on tissue AP duration and conduction velocity (CV) restitution properties. Discordant alternans was able to cause conduction failure in the model, which was promoted by impaired sodium channel with either a reduced or increased channel current. In a two-dimensional homogeneous tissue model, a combined effect of rate- and curvature-dependent CV broke-up alternating wavefronts at localised points, facilitating a spontaneous transition from CEA to re-entry. Tissue inhomogeneity or anisotropy further promoted break-up of re-entry, leading to multiple wavelets. Similar observations have also been seen in human atrial cellular and tissue models. In conclusion, our results identify a mechanism by which CEA spontaneously evolves into re-entry without a requirement for premature ventricular complexes or pre-existing tissue heterogeneities, and demonstrated the important pro-arrhythmic role of impaired sodium channel activity. These findings are model-independent and have potential human relevance.Author summary: T-wave alternans (TWA), manifested as beat to beat alterations between large and small T-wave amplitudes on the electrocardiogram (ECG) is one of the prevalent clinical observations that are closely associated with cardiac arrhythmias and sudden death. TWA is believed to be underlined by cardiac alternans at the cellular level, but the extract mechanism for the transition from cellular alternans to that at the tissue level, and how this further spontaneously evolves into cardiac arrhythmias remains incompletely elucidated. In this study, multiscale rabbit ventricular computational models were used to address this issue by investigating the underlying mechanism(s) for the arrhythmogenesis of cardiac alternans, as well as a possible role of sodium channel on perpetuating cardiac arrhythmias. Our results demonstrated a spontaneous development of re-entry from cellular alternans, arising from a combined action of APD and CV restitution properties with the curvature-dependence of CV. Tissue inhomogeneity and anisotropy further promoted break-up of excitation waves, leading to multiple re-entrant excitation waves. It was also found impaired sodium channel with either increased or decreased channel current facilitated the arrhythmogenesis. This study provides new insights into underlying the mechanism, by which cellular cardiac alternans spontaneously evolves into cardiac arrhythmias. Similar results were observed in human atrial tissue models, suggesting our major findings are model-independent and of potential clinical relevance.