An intact and healthy endothelium is coated by a glycocalyx (EG) of 0.4-0.5mm thickness, important for regulating inflammation and permeability. Especially in the coronary system, plasma protein extravasation and shear-stress mediated dilatation rely strongly on a patent EG. Firm adhesion of leukocytes (PMN) is virtually impossible in the presence of an intact endothelial surface layer. We present evidence for destruction of the EG in ischemia and reperfusion. Major components of the EG, syndecan-1 and heparan sulfate, were washed from guinea pig hearts reperfused after 20min ischemia. Electron microscopy verified the loss. Edema, coronary low-reflow, colloid leak and specific adhesion of PMN (basal 10%, postischemic 30% of applied bolus) increased. EG protection prevented the changes. Patients referred for elective coronary artery bypass surgery showed a 3- to 6-fold increase in syndecan-1 and a 2-fold increase in heparan sulfate concentrations in plasma (n=17). Anesthesia and initiation of surgery caused no changes. At the end of surgery, plasma syndecan-1 and heparan sulfate had returned to basal. Immunohistochemistry substantiated both as components of the human EG. Measurement of syndecan-1 and heparan sulfate concentrations in blood plasma may represent new diagnostic tools for detecting discrete endothelial damage. Protection of the EG seems a must for alleviating reperfusion injury.