Aman BioPhysical_2014a v2

Cardiovascular disease is the leading cause of death world-wide due in large part to arrhythmias. Here we examine the cellular and subcellular basis of Ca2+ dependent arrhythmias. In order to understand how calcium dynamics, plays a role in arrhythmogenesis, we have investigated normal and dysfunctional Ca2+ signaling in heart cells at high temporal and spatial resolution. Spontaneous calcium release occurs normally as Ca2+ sparks. Under pathological conditions, Ca2+ sparks can combine to form Ca2+ waves. These propagating elevations of [Ca]i can activate inward Na+-Ca2+ exchanger current (INCX ) that contribute to early after-depolarization (EADs) and delayed after-depolarizations (DADs). However, how cellular currents lead to full depolarization of the myocardium and how they initiate extra systoles is still not fully understood. Some earlier studies that have investigated this question suggest that as many as about ~700,000 cells must undergo such behavior to initiate a propagating action potential or an arrhythmia [3]. Here we present the results of our study which explores how many cells must be entrained to initiate arrhythmogenic depolarizations in "realistic" computational models. The model presented here suggests that only a small number cells must activate in order to trigger an arrhythmogenic propagating action potential. These conditions were examined in 1D, 2D, and 3D taking into account heart geometry. The finding that only a small number of cells is required to trigger an arrhythmia provides a plausible mechanism by which cardiac arrhythmias might occur.