PT  - JOURNAL ARTICLE
AU  - Stewart Heitmann
AU  - Jamie I Vandenberg
AU  - Adam P Hill
TI  - Arrhythmogenesis as the failure of repolarization
AID  - 10.1101/2020.07.02.185694
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.07.02.185694
4099  - http://biorxiv.org/content/early/2020/07/03/2020.07.02.185694.short
4100  - http://biorxiv.org/content/early/2020/07/03/2020.07.02.185694.full
AB  - Contemporary theories of cardiac fibrillation typically rely on the emergence of rotors to explain the transition from regular sinus rhythm to disordered electrophysiological activity. How those rotors spontaneously arise in the absence of re-entrant anatomical circuits is not fully understood. Here we propose a novel mechanism where arrhythmias are initiated by cardiac cells that fail to repolarize following a normal heartbeat. Those cells subsequently act as a focal ectopic source that drive the ensuing fibrillation. We used a simple computational model to investigate the impact of such cells in both homogeneous and heterogeneous excitable media. We found that heterogeneous media can tolerate a surprisingly large number of abnormal cells and still support normal rhythmic activity. At a critical limit the medium becomes chronically arrhythmogenic. Numerical analysis revealed that the critical threshold for arrhythmogenesis depends on both the strength of the coupling between cells and the extent to which the abnormal cells resist repolarization. Arrhythmogenesis was also found to emerge first at tissue boundaries where cells naturally have fewer neighbors to influence their behavior. These findings may explain why atrial fibrillation typically originates from the cuff of the pulmonary vein.Author summary Cardiac fibrillation is a medical condition where normal heart function is compromised as electrical activity becomes disordered. How fibrillation arises spontaneously is not fully understood. It is generally thought to be triggered by premature depolarization of the cardiac action potential in one or more cells. Those premature beats, known as early-afterdepolarizations, subsequently initiate a self-sustaining rotor in the otherwise normal heart tissue. In this study, we propose an alternative mechanism whereby arrhythmias are initiated by cardiac cells that fail to repolarize of their own accord but still operate normally when embedded in functional heart tissue. We find that such cells can act as focal ectopic sources under appropriate conditions of inter-cellular coupling. Moreover, cells on natural tissue boundaries are more susceptible to arrhythmia because they are coupled to fewer cells. This may explain why the pulmonary vein is often implicated as a source of atrial fibrillation.Competing Interest StatementThe authors have declared no competing interest.