UCLA

Dynamical instabilities in the heart promote arrhythmias and sudden cardiac death (SCD), one of the most common causes of death in individuals with cardiovascular disease. Beat-to-beat changes in electrophysiological properties at the cellular level can promote arrhythmogenesis at the whole-heart level, yet the precise mechanisms are not well understood.

Cardiac cells possess memory, whereby certain physiological properties depend on the prior history. Here, we analyze the effects of short-term cardiac memory from two sources: the slow recovery of ion channels and the slow accumulation of ion concentrations over time. We demonstrate that under diseased conditions, namely early repolarization syndrome and long QT syndrome, action potentials become unstable during fixed pacing due to enhanced effects of memory on action potential duration. We develop new iterated map models that explicitly incorporates the effects of memory on action potential duration, and show that the dynamics of the iterated map models match very closely to the dynamics of detailed action potential models. Using the iterated map models, we propose new techniques of controlling action potential instability under the influence of memory and confirm their efficacy in the detailed action potential models.

Finally, we show that action potential instability at the cellular level can generate arrhythmias at tissue-scale levels. In a model of early repolarization syndrome driven by activation of small-conductance Ca2+-activated K+ (SK) channels, action potential instability promotes phase 2 reentry. Spiral wave dynamics become unstable due to early repolarization driven by the transient outward K+ current (Ito), suggesting that action potential instability induced by memory is a mechanism of arrhythmias like ventricular fibrillation.