Received for publication June 17, 2008.
Revised August 12, 2008.
Accepted for publication August 12, 2008.

Bivalirudin decreases NO bioavailability by vascular immobilization of myeloperoxidase

Abstract

Bivalirudin - a direct thrombin inhibitor - has emerged as an important alternative to heparin in patients undergoing percutaneous coronary intervention. However, it remains elusive if potentially adverse extra-coagulant properties are responsible for the fact that its favorable effects in clinical studies are mainly driven by a reduction in bleeding events. The aim of the current study was to determine the effects and mechanisms of acute treatment with bivalirudin in comparison to heparin on NO bioavailability, an important factor for the pathogenesis of ischemic events. In particular, we studied the interaction between bivalirudin and myeloperoxidase (MPO) a leukocyte-derived enzyme which consumes endothelial derived nitric oxide (NO) and modifies a variety of biological targets and thus affects the integrity of the vessel wall. In patients undergoing elective percutaneous coronary intervention bivalirudin in contrast to heparin exhibited a significant decrease in plasma MPO levels (p=0.03) accompanied by a deterioration of flow-mediated dilation (p=0.02), a surrogate for endothelial NO bioavailability. In vitro experiments revealed avid binding of bivalirudin to both bovine aortic endothelial cells (BAEC) and MPO. Methylation of bivalirudin carboxyl groups at the carboxyterminal end revealed the specific binding site of bivalirudin to MPO. Bivalirudin-facilitated binding of MPO to BAEC resulted also in functional changes in terms of increased NO consumption as well as enhanced MPO-mediated redox modifications. These results illustrate dichotomous extra-coagulant properties of heparins and thrombin inhibitors and suggest that bivalirudin acutely impairs endothelial NO bioavailability thereby underscoring the potentially critical role of MPO as a mediator of vascular function.

Key words: NO bioavailability, bivalirudin, endothelial cells, endothelial function, heparin, myeloperoxidase