Cardiac-coronary interaction and the effects of its pathophysiological variations on spatial heterogeneity of coronary perfusion and myocardial work are still poorly understood. This hypothesis-generating study predicts spatial heterogeneities in both regional cardiac work and perfusion that offer a new paradigm on the vulnerability of the subendocardium to ischemia, particularly at the apex. We propose a mathematical and computational modeling framework to simulate the interaction of left ventricular mechanics, systemic circulation, and coronary microcirculation. The computational simulations revealed that the relaxation rate of the myocardium has a significant effect whereas the contractility has a marginal effect on both the magnitude and transmural distribution of coronary perfusion. The ratio of subendocardial to subepicardial perfusion density (Qendo/Qepi) changed by -12 to +6% from a baseline value of 1.16 when myocardial contractility was varied by +25 and -10%, respectively; Qendo/Qepi changed by 37% when sarcomere relaxation rate, b, was faster and increased by 10% from the baseline value. The model predicts axial differences in regional myocardial work and perfusion density across the wall thickness. Regional myofiber work done at the apex is 30-50% lower than at the center region, whereas perfusion density in the apex is lower by only 18% compared with the center. There are large axial differences in coronary flow and myocardial work at the subendocardial locations, with the highest differences located at the apex region. A mismatch exists between perfusion density and regional work done at the subendocardium. This mismatch is speculated to be compensated by coronary autoregulation.NEW & NOTEWORTHY We present a model of left ventricle perfusion based on an anatomically realistic coronary tree structure that includes its interaction with the systemic circulation. Left ventricular relaxation rate has a significant effect on the regional distribution of coronary flow and myocardial work.