Functional coronary microvascular injury evident as increased permeability due to brief ischemia and reperfusion

Abstract

Although morphological studies suggest that coronary vascular injury is a result of prolonged ischemia and subsequent reperfusion, whether functional coronary microvascular injury develops during brief in vivo ischemia is unclear. In other organs, permeability is a sensitive indicator of functional vascular injury. Therefore, a new double-indicator method of assessing vascular protein permeability, a method that is both sensitive and specific for vascular injury, was used to investigate the effects of ischemia of graded duration followed by reperfusion on coronary microvascular function. To help confirm functional coronary vascular injury, endothelium-dependent vasodilation of isolated coronary vascular rings also was examined. Microvascular permeability was quantitatively assessed as a protein leak index by measuring the rate of extravascular accumulation of radiolabeled protein (indium 113m transferrin) normalized for vascular surface area (technetium 99m erythrocytes). Anesthetized dogs underwent 0 (control), 15, 30, or 60 minutes of left anterior descending coronary artery occlusion followed by 60 minutes of reperfusion. Even 15 minutes of ischemia increased the protein leak index by 50% (3.16 +/- 0.30 ischemic vs. 2.09 +/- 0.11 control). Longer periods of ischemia increased the protein leak index in proportion to the duration of ischemia. The protein leak index increased threefold (6.51 +/- 0.60) after 60 minutes of ischemia. At each duration of ischemia, there was significant regional variation in the protein leak index that correlated with the severity of ischemic blood flow to that region measured with microspheres. Endothelial injury also was evident after 15 and 30 minutes of ischemia as impaired vasodilation of isolated coronary rings in response to the endothelium-dependent vasodilators acetylcholine and the calcium ionophore A23187. Electron microscopy and in vitro direct immunofluorescence revealed evidence of vascular injury after 60 minutes but not after 15 minutes of ischemia. We conclude that even brief ischemia and reperfusion cause functional coronary vascular injury evident as increased microvascular permeability and impaired endothelium-dependent vasodilation and that regional differences in the degree of microvascular injury correlate with differences in the severity of ischemia.