The β-_D-Endoglucuronidase Heparanase Is a Danger Molecule That Drives Systemic Inflammation and Correlates with Clinical Course after Open and Endovascular Thoracoabdominal Aortic Aneurysm Repair: Lessons Learnt from Mice and Men

Thoracoabdominal aortic aneurysm (TAAA) is a highly lethal disorder requiring open or endovascular TAAA repair, both of which are rare, but extensive and complex surgical procedures associated with a significant systemic inflammatory response and high post-operative morbidity and mortality. Heparanase is a beta-D-endoglucuronidase that remodels the endothelial glycocalyx by degrading heparan sulfate in many diseases/conditions associated with systemic inflammation including sepsis, trauma, and major surgery. We hypothesized that (a) perioperative serum levels of heparanase and heparan sulfate are associated with the clinical course after open or endovascular TAAA repair and (b) induce a systemic inflammatory response and renal injury/dysfunction in mice. Using a reverse-translational approach, we assessed (a) the serum levels of heparanase, heparan sulfate, and the heparan sulfate proteoglycan syndecan-1 preoperatively as well as 6 and 72 h after intensive care unit (ICU) admission in patients undergoing open or endovascular TAAA repair and (b) laboratory and clinical parameters and 90-day survival, and (c) the systemic inflammatory response and renal injury/dysfunction induced by heparanase and heparan sulfate in mice. When compared to preoperative values, the serum levels of heparanase, heparan sulfate, and syndecan-1 significantly transiently increased within 6 h of ICU admission and returned to normal within 72 h after ICU admission. The kinetics of any observed changes in heparanase, heparan sulfate, or syndecan-1 levels, however, did not differ between open and endovascular TAAA-repair. Postoperative heparanase levels positively correlated with noradrenalin dose at 12 h after ICU admission and showed a high predictive value of vasopressor requirements within the first 24 h. Postoperative heparan sulfate showed a strong positive correlation with interleukin-6 levels day 0, 1, and 2 post-ICU admission and a strong negative correlation with lactate clearance during the first 6 h post-ICU admission. Moreover, systemic administration of heparanase and heparan sulfate induced an inflammatory response and a small degree of renal dysfunction in mice. In conclusion, these results suggest that heparanase and heparan sulfate exhibit a substantial role as clinically relevant danger molecules and may serve as both, promising biomarkers and therapeutic targets in patients undergoing open or endovascular TAAA repair and, indeed, other conditions associated with significant systemic inflammation.