ST-segment depression is commonly seen in patients with acute coronary syndromes. Most authors have attributed it to transient reductions in coronary blood flow due to nonocclusive thrombus formation on a disrupted atherosclerotic plaque and dynamic focal vasospasm at the site of coronary artery stenosis. However, ST-segment depression was never reproduced in classic animal models of coronary stenosis without the presence of tachycardia. We hypothesized that ST-segment depression occurring during acute coronary syndromes is not entirely explained by changes in epicardial coronary artery resistance and thus, evaluated the effect of a slow, progressive epicardial coronary artery occlusion on the ECG and regional myocardial blood flow in anesthetized pigs. Slow, progressive occlusion over 72±27 min of the left anterior descending coronary artery in 20 anesthetized pigs led to a 90% decrease in coronary blood flow and the development of ST-segment elevation associated with homogeneous and transmural myocardial blood flow reductions, confirmed by microspheres and myocardial contrast echocardiography. ST-segment depression was not observed in any ECG lead prior to the development of ST-segment elevation. At normal heart rates, progressive epicardial stenosis of a coronary artery results in myocardial ischemia associated with homogeneous, transmural reduction in regional myocardial blood flow and ST-segment elevation, without preceding ST-segment depression. Thus, in coronary syndromes with ST-segment depression and predominant subendocardial ischemia, factors other than mere increase in epicardial coronary resistance must be invoked to explain the heterogeneous parietal distribution of flow and associated ECG changes.