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Cardiac surgery has been routinely performed using cardiopulmonary bypass (CPB) ever since its clinical introduction during the 1950s. CPB is, however, associated with an intense inflammatory response because of conversion to laminar flow, blood contact with the artificial bypass surface, cold cardiac ischaemia and hypothermia. The inflammatory reaction can intensify to a systemic inflammatory response syndrome (SIRS) associated with serious morbidity and mortality. Strategies to suppress inflammation had some success but fell short of controlling SIRS. The development of cardiac immobilization techniques allowing complete revascularization has caused a renaissance of coronary artery bypass grafting surgery on the beating heart (OPCAB). This strategy avoids all inflammation caused by CPB and reduces the pro-inflammatory stimulus to sternotomy and the revascularization procedure itself. This review summarises the pathophysiological features of the inflammatory response to CPB, revisits therapeutic anti-inflammatory strategies designed to suppress CPB-induced inflammation and balances the clinical evidence available comparing off-pump and on-pump revascularization.

Thrombomodulin (TM) is a vascular endothelial cell (EC) receptor that is a cofactor for thrombin-mediated activation of the anticoagulant protein C. The extracellular NH(2)-terminal domain of TM has homology to C-type lectins that are involved in immune regulation. Using transgenic mice that lack this structure (TM(LeD/LeD)), we show that the lectin-like domain of TM interferes with polymorphonuclear leukocyte (PMN) adhesion to ECs by intercellular adhesion molecule 1-dependent and -independent pathways through the suppression of extracellular signal-regulated kinase (ERK)(1/2) activation. TM(LeD/LeD) mice have reduced survival after endotoxin exposure, accumulate more PMNs in their lungs, and develop larger infarcts after myocardial ischemia/reperfusion. The recombinant lectin-like domain of TM suppresses PMN adhesion to ECs, diminishes cytokine-induced increase in nuclear factor kappaB and activation of ERK(1/2), and rescues ECs from serum starvation, findings that may explain why plasma levels of soluble TM are inversely correlated with cardiovascular disease. These data suggest that TM has antiinflammatory properties in addition to its role in coagulation and fibrinolysis.

Platelets are thought to play a causal role during atherogenesis. Platelet-endothelial interactions in vivo and their molecular mechanisms under shear are, however, incompletely characterized. Here, an in vivo platelet homing assay was used in hypercholesterolemic rabbits to track platelet adhesion to plaque predilection sites. The role of platelet versus aortic endothelial cell (EC) activation was studied in an ex vivo flow chamber. Pathways of human platelet immobilization were detailed during in vitro perfusion studies. In rabbits, a 0.125% cholesterol diet induced no lesions within 3 months, but fatty streaks were found after 12 months. ECs at segmental arteries of 3- month rabbits expressed more von Willebrand factor (VWF) and recruited 5-fold more platelets than controls (P <.05, n = 5 and 4, respectively). The 3-month ostia had an increased likelihood to recruit platelets compared to control ostia (56% versus 18%, P <.0001, n = 89 and 63, respectively). Ex vivo, the adhesion of 3-month platelets to 3-month aortas was 8.4-fold increased compared to control studies (P <.01, n = 7 and 5, respectively). In vitro, endothelial VWF-platelet glycoprotein (GP) Ib and platelet P-selectin- endothelial P-selectin glycoprotein ligand 1 interactions accounted in combination for 83% of translocation and 90% of adhesion (P <.01, n = 4) of activated human platelets to activated human ECs. Platelet tethering was mainly mediated by platelet GPIb alpha, whereas platelet GPIIb/IIIa contributed 20% to arrest (P <.05). In conclusion, hypercholesterolemia primes platelets for recruitment via VWF, GPIb alpha, and P-selectin to lesion-prone sites, before lesions are detectable.