Inhibition of neointimal hyperplasia by a specific thrombin inhibitor

OBJECTIVE: Restenosis secondary to neointimal hyperplasia remains the major limiting factor after vascular interventions. Thrombin generated in high concentrations at the site of vascular injury plays a central role in thrombosis and hemostasis. Thrombin has also been implicated as a mitogen for smooth muscle cell proliferation that contributes to restenosis. This study was designed to determine the effects of a specific thrombin inhibitor on neointimal hyperplasia after balloon injury in a rat carotid artery model. DESIGN: A total of 47 male Sprague-Dawley rats were divided into five groups. All groups underwent balloon injury of the left carotid artery. A specific thrombin inhibitor, inogatran, was given in four different regimens: low and high dose injections, short-term infusion for 3 h, and long-term infusion for 1 week. After 2 weeks the animals were killed and the carotid neointima/media area ratio and the luminal narrowing were calculated. RESULTS: All treatments significantly reduced the neointimal hyperplasia. Inogatran given as a long-term infusion for 1 week had the lowest neointima/media ratio compared with the other groups. The percentage of lumen narrowing was also significantly lower in all treatment groups compared with the control group. CONCLUSION: A specific direct thrombin inhibitor, inogatran, reduces neointimal hyperplasia after arterial injury in rats. A more prolonged administration of the thrombin inhibitor gave a further reduction of the neointimal hyperplasia. It seems that inhibition of thrombin activity is not only important early after injury, but also later. This could have clinical implications in the treatment of restenosis and needs to be further evaluated.