Acute myocardial ischaemia caused by coronary artery disease is one of the main causes of sudden cardiac death. Even though sodium current blockers are used as anti-arrhythmic drugs, decreased sodium current availability, also caused by mutations, has been shown to increase arrhythmic risk in ischaemic patients. The mechanisms are still unclear. Our goal is to exploit perfect control and data transparency of over 300 high-performance computing simulations to investigate arrhythmia mechanisms in acute myocardial ischaemia with variable sodium current availability. The human anatomically based torso-biventricular electrophysiological model used includes representation of realistic ventricular anatomy and fibre architecture, as well as ionic to electrocardiographic properties. Simulations show that reduced sodium current availability increased arrhythmic risk in acute regional ischaemia due to both electrophysiological (increased dispersion of refractoriness across the ischaemic border zone) and anatomical factors (conduction block from the thin right ventricle to thick left ventricle). The asymmetric ventricular anatomy caused high arrhythmic risk specifically for ectopic stimuli originating from the right ventricle and ventricular base. Increased sodium current availability was ineffective in reducing arrhythmic risk for septo-basal ectopic excitation. Human-based multiscale modelling and simulations reveal key electrophysiological and anatomical factors determining arrhythmic risk in acute ischaemia with variable sodium current availability. © 2020 The Authors.