Amiodarone (AMI) is a potent anti-arrhythmic agent and is of therapeutic benefit in acute doses in the incidence of ventricular fibrilation or tachycardia. It is also used in chronic doses in patients with heart failure (HF) as arrhythmia is recognised as a leading cause of sudden death in this patient group (Doval 1994). The doses of amiodarone given in each instance differ and are shown to affect different ionic currents (Kamiya et al 2001). Several substrates for arrhythmia exist, both at the cellular level where initiation (triggered activity) occurs and at a tissue level where this activity can be propagated. We examined the effects of HF and AMI on these arrhythmia substrates using computational models of ventricular cells and tissue. A modified version of the Ten Tusscher Human Virtual Ventricle (Ten Tusscher & Panfilov 2006) was created for single cell models. Propagation of arrhythmia was examined in a 1D heterogeneous tissue strand model (Benson et al 2007). Results from the single cell models confirm HF to increase arrhythmia susceptibility; action potential duration (APD) is increased (from 308 ms to 323 ms) alongside a significant decrease in the calcium transient amplitude (factor 2.4) and an increase in its decay time (by 205 ms). Despite this, only endocardial cells in HF showed APD alternans in our model, with a smaller APD difference (68 ms control vs 14 ms HF). Simulation of acute AMI suppressed APD alternans in control and HF epicardial cell models, decreased delayed afterdepolarisation (DAD) amplitude and increased the threshold for triggered activity (TA) propagation (173% control, 128% HF). In contrast, simulation of chronic AMI increased DAD magnitude and decreased TA threshold (by 4 ms in control, 6 ms in HF). Doses of chronic AMI are therefore more arrhythmogenic at the cellular level. It was shown that chronic AMI can prevent propagation; it decreased the conduction velocity (CV) restitution curve slope in HF (0.0024 vs 0.002) and transmural dispersion of repolarisation (TDR) along the strand modelled (by 9.7ms control, 3.5ms HF). Both provide an explanation for clinical observations of the anti-arrythmic benefits of chronic AMI (Sign 2007). Acute AMI afforded a larger decrease in TDR (5 ms HF vs 3.5 ms control) and in the CV restitution curve slope. Again this shows acute AMI to be of superior benefit in reducing likelihood of arrhythmia propagation. Few studies have examined the contrasting effects of dosing regimens on substrates for arrhythmia. These results, showing that acute AMI suppresses cellular initiation and reduces propagation at the tissue level, suggest acute AMI may be more beneficial than chronic doses in HF patients; decreased exposure may improve tolerability.