Recent evidence indicates that leukocytes (LEU) are large, stiff, viscous cells that naturally adhere to vascular endothelium. Their broad role in the early myocardial microvascular response to acute ischemia was suggested by 1) the role of leukocyte capillary plugging in the no-reflow phenomenon, 2) resistance increases in skeletal muscle with LEU infusions, and 3) salvage of ischemic myocardium by anti-LEU agents. We perfused the coronary circulation under matched, controlled conditions with whole blood or granulocyte-depleted whole blood. During 1 h of ischemia (left anterior descending occlusion) circumflex perfusion pressure was servocontrolled to a constant value. In whole blood-perfused hearts, flow measured by the radiolabeled microsphere method decreased in endocardium from 0.12 +/- 0.05 at 5 min of ischemia to 0.09 +/- 0.04 ml X min-1 X g-1 at 60 min of ischemia and in epicardium from 0.27 +/- 0.17 to 0.21 +/- 0.16 ml X min-1 X g-1, both P less than 0.05. In granulocyte-depleted blood-perfused hearts, flow increased over the same period from 0.18 +/- 0.15 to 0.29 +/- 0.18 ml X min-1 X g-1 in endocardium (P less than 0.05) and did not change significantly in epicardium (0.36 +/- 0.22 to 0.41 +/- 0.24 ml X min-1 X g-1). The LEU-depleted blood perfusate contained less than 33 granulocytes/microliter, whereas control perfusate contained 4,265/microliter. Reperfusion at normal pressures with carbon suspension allowed for histologic evaluation of the no-reflow phenomenon. With whole blood perfusion the no-reflow phenomenon in the endocardium was present with 27% of capillaries occluded, compared with nearly complete reperfusion in LEU-depleted animals (1% of capillaries occluded, P less than 0.05). Furthermore, LEU depletion prevented the increases in tissue water content seen in control hearts and decreased the incidence of ventricular arrhythmias. These studies demonstrate the significant participation of granulocytes in the unfavorable responses of flow, edema formation, and arrhythmias to the 1st h of myocardial ischemia and further document their role in the no-reflow phenomenon.

Although exercise radionuclide ventriculography was initially reported to be a highly specific test for coronary-artery disease, later studies reported a high false-positive rate. To verify this turnabout, we analyzed the responses in 77 angiographically normal patients; 32 were studied from 1978 to 1979 (the early period), and 45 from 1980 to 1982 (the recent period). Most patients studied in the early period had normal responses (94 per cent for ejection fraction and 84 per cent for wall motion). In contrast, normal responses were less frequent in patients studied in the recent period (49 per cent for ejection fraction and 36 per cent for wall motion, P less than 0.001). The probability of coronary disease before testing was higher in these patients (38 vs. 7 per cent, P less than 0.001). More patients studied in the recent period underwent radionuclide ventriculography before angiography (78 vs. 22 per cent, P less than 0.001), and more of these prior studies had abnormal results than those performed after angiography (55 vs. 6 per cent, P less than 0.0001). Thus, two factors are responsible for the temporal decline in specificity: a change in the population being tested (pretest referral bias) and a preferential selection of patients with a positive test response for coronary angiography (post-test referral bias).

The radionuclide ventriculographic exercise response was evaluated in three patient populations representing alternative referent standards for cardiac normality: patients with normal coronary arteriograms, healthy volunteers, and uncatheterized patients with a low probability of coronary artery disease. Disease probability was determined by Bayesian analysis of age, sex, symptoms, and the results of cardiac fluoroscopy, exercise electrocardiography, or thallium scintigraphy. A wide range of ventriculographic responses was noted in the 62 catheterized normal patients; 21 (34%) had an abnormal ejection fraction response and 22 (35%) had an abnormal wall motion response. In contrast, the ejection fraction and wall motion responses were normal in the 9 volunteers. In 90 patients (18 catheterized and 72 uncatheterized) who had low disease probability (less than 1%), abnormal responses were rare; the ejection fraction response was abnormal in only 7% and the wall motion response was abnormal in 8%. Thus, these three populations are not equivalent referent standards of normality. Volunteers and patients with low disease probability provide too strict a standard, and their use can overestimate test specificity; catheterized normal patients, on the other hand, provide too lenient a standard, and their use can underestimate test specificity.

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