Acute myocardial ischemia is a precursor of sudden arrhythmic death. Variability in its manifestation hampers understanding of arrhythmia mechanisms and challenges risk stratification. Our aim is to unravel the mechanisms underlying how size, transmural extent and location of ischemia determine arrhythmia vulnerability and ecG alterations. High performance computing simulations using a human torso/biventricular biophysically-detailed model were conducted to quantify the impact of varying ischemic region properties, including location (LAD/LcX occlusion), transmural/subendocardial ischemia, size, and normal/slow myocardial propagation. ecG biomarkers and vulnerability window for reentry were computed in over 400 simulations for 18 cases evaluated. Two distinct mechanisms explained larger vulnerability to reentry in transmural versus subendocardial ischemia. Macro-reentry around the ischemic region was the primary mechanism increasing arrhythmic risk in transmural versus subendocardial ischemia, for both LAD and LcX occlusion. transmural micro-reentry at the ischemic border zone explained arrhythmic vulnerability in subendocardial ischemia, especially in LAD occlusion, as reentries were favoured by the ischemic region intersecting the septo-apical region. St elevation reflected ischemic extent in transmural ischemia for LCX and LAD occlusion but not in subendocardial ischemia (associated with mild St depression). the technology and results presented can inform safety and efficacy evaluation of anti-arrhythmic therapy in acute myocardial ischemia
