Myocardial ischemia is transmurally heterogeneous where the subendocardium is at higher risk. Stenosis induces reduced perfusion pressure, blood flow redistribution away from the subendocardium, and consequent subendocardial vulnerability. We propose that the flow redistribution stems from the higher compliance of the subendocardial vasculature. This new paradigm was tested using network flow simulation based on measured coronary anatomy, vessel flow and mechanics, and myocardium-vessel interactions. Flow redistribution was quantified by the relative change in the subendocardial-to-subepicardial perfusion ratio under a 60-mmHg perfusion pressure reduction. Myocardial contraction was found to induce the following: 1) more compressive loading and subsequent lower transvascular pressure in deeper vessels, 2) consequent higher compliance of the subendocardial vasculature, and 3) substantial flow redistribution, i.e., a 20% drop in the subendocardial-to-subepicardial flow ratio under the prescribed reduction in perfusion pressure. This flow redistribution was found to occur primarily because the vessel compliance is nonlinear (pressure dependent). The observed thinner subendocardial vessel walls were predicted to induce a higher compliance of the subendocardial vasculature and greater flow redistribution. Subendocardial perfusion was predicted to improve with a reduction of either heart rate or left ventricular pressure under low perfusion pressure. In conclusion, subendocardial vulnerability to a acute reduction in perfusion pressure stems primarily from differences in vascular compliance induced by transmural differences in both extravascular loading and vessel wall thickness. Subendocardial ischemia can be improved by a reduction of heart rate and left ventricular pressure. coronary flow; stress and flow analysis; coronary network anatomy; myocardial contraction effects; myocardial ischemia MYOCARDIAL ISCHEMIA, a major cause of morbidity and mortality, is transmurally heterogeneous where the subendocardium is at higher risk than the midwall or epicardium (22). Despite the significant clinical relevance, the physical determinants of subendocardial vulnerability remain controversial. Although subendocardial metabolic demands are somewhat higher than subepicardial ones (22), data have suggested that it is the lower blood supply to the subendocardium, rather than the higher demand, that induces subendocardial vulnerability (23). For example, under partial occlusions (2) or otherwise decreased (9) perfusion pressure in the nonautoregulated coronary circulation, subendocardial blood supply has been observed to be compromised to a higher extent than subepicardial flow, whereas increased perfusion pressure was found to improve primarily the subendocardial supply (3). Hence, changes in perfusion pressure induce transmural flow redistribution, i.e., changes in the subendocardial-to-subepicardial perfusion ratio (Endo/Epi).Subendocardial vulnerability to ischemia has been previously attributed to several mechanisms, namely, ...