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Endothelial barrier dysfunction contributes to the systemic inflammatory response syndrome (SIRS) for which cardiac surgery necessitating cardiopulmonary bypass (snCPB) is a human model. A growing body of evidence suggests that the receptor for advanced glycation end products (RAGE) is also implicated in the pathogenesis of SIRS. While RAGE activation, in vitro, is known to decrease barrier function of cultured endothelial cells, the role of RAGE in regulating vascular permeability in patients undergoing snCPB is unknown. We hypothesised that plasma levels of markers of endothelial barrier dysfunction, syndecan-1, an endothelial glycocalyx component; and sFlt-1, a soluble form of the vascular endothelial cell growth factor (VEGF) receptor-1, will increase during snCPB and levels relate to patient outcome.ELISA measurements/western blotting was used to determine syndecan-1 and sFlt-1 levels in pre-, intra- and post-snCPB plasma samples; for comparison, glypican-1, another glycocalyx component and Robo4, an endothelial barrier stabilising protein, were also measured. Clinical indices: age, nature of operation, CPB time, ischaemic time, intensive care unit (ICU)/ hospital length of stay (LOS) were collected from electronic databases.Syndecan-1 was significantly higher during CPB (77.17±39.72 ng/ml) compared with pre-snCPB levels (35.26±25.81 ng/ml, n=14, p<0.01). Plasma levels of sFLt-1 were significantly (p<0.001) higher during (10 000 pg/ml±3601, n=10) and post-snCPB (4282±3271 pg/ml) compared with preoperative levels (69.68±35.22 pg/ml). Preoperative plasma syndecan-1 correlated positively with ICU LOS (r2=0.486, p=0.006); whereas, intraoperative sFlt-1 correlated negatively with ICU LOS (r2=0.406, p=0.048). Intraoperative syndecan-1 levels positively associated with ischaemic time (r2=0.383, p=0.018) and plasma sRAGE levels (r2=389, p=0.040); postoperative syndecan-1 levels correlated with sRAGE (r2=0.790, p=0.0003). Glypican-1 and Robo4 were also detected in snCPB plasma samples.Plasma levels of syndecan-1 and sFlt-1 were highest during snCPB. A positive association between preoperative syndecan-1 and ICU LOS is consistent with a relationship between endothelial barrier dysfunction and outcome. By contrast, higher intraoperative sFlt-1 correlating with shorter ICU LOS implied a protective role of sFlt-1. Associations between syndecan-1 and sRAGE suggest a link between RAGE and endothelial barrier dysfunction that merits further investigation; as do the novel findings that glypican-1 and Robo4 were detected in plasma of patients undergoing snCPB.