Despite many years of study, certain aspects of myocardial ischemia remain incompletely understood. One observation that motivated this study is that acute, complete occlusion produces elevations but never depression of the ST-segment potentials in electrocardiographic leads over the ischemic zone. Limited flow, on the other hand, leads to ST-segment depression, both in in situ experiments and during clinical stress tests. The prevailing biophysical theory of ischemia suggests that complete occlusion should produce at least transient ST-segment depression, a finding we have neither observed in our own studies nor uncovered in the literature. Our goal with these experiments was to understand the difference between complete occlusion and reduced coronary flow, specifically the behavior at the transition between the two. We have performed experiments by using isolated dog hearts with a cannulated left anterior descending artery suspended in a human shaped electrolytic tank. To create a range of ischemic conditions, we changed coronary flow rates both suddenly and in controlled sequences and varied the heart rate of the isolated heart. The main finding was that in the isolated heart preparation, epicardial ST-segment depression over the ischemic zone arose only under conditions of combined restricted flow and elevated heart rate. Reduced coronary flow alone never produced ST-segment depression. These findings suggest that hear( rate and probably metabolic work create (lie conditions necessary for subendocardial ischemia that reduced flow alone cannot provoke. They furthermore suggest that the degree of ST-segment depression for a given restriction in coronary flow may depend on heart rate, which supports the notion of rate correction for clinical stress electrocardiogram testing.