Local Delivery of a Hydrophobic Heparin Reduces Neointimal Hyperplasia After Balloon Injury in Rat Carotid but not Pig Coronary Arteries

Abstract

Background: Intimal hyperplasia following percutaneous interventional vascular procedures is a major cause of restenosis. Although heparin inhibits intimal hyperplasia, it has not proven clinically useful in part due to an inadequate duration of intramural drug residence. This study was designed to evaluate the efficacy of local delivery of hydrophobic heparin (PTIR-RS-1), exhibiting increased intramural binding, on neointimal hyperplasia after angioplasty injury. Methods and Results: PTIR-RS-1 was delivered locally into rat carotid arteries at three doses: 0.1 mM (440 IU), 0.3 mM (1320 IU), or 1.0 mM (4400 IU). Animals were killed at 14 days. In the pig, the doses tested were the low dose in the rat and a high dose 1 log higher. Animals were killed 28 days later. Morphometric analysis was performed to evaluate the intima:media ratio in rats and the normalized neointimal area in pigs. In rats a significant reduction in neointimal to medial area ratio from 0.73 ± 0.15 for control vs 0.80 ± 0.27 for sodium heparin (P = NS) and 0.15 ± 0.07 for the 0.1 mM PTIR-RS-l dose (P < 0.008). In pigs, PTIR-RS-1 the high dose reduced the normalized neointimal area by 16%, a difference that was not statistically significant. Conclusions: Increased hydrophobicity of heparin reduced neointimal area following balloon overstretch injury in the rat carotid but not the pig coronary artery model. This study attests to the importance of performing studies evaluating the pharmacologic effect of local delivery of a medication in at least two animal models of restenosis.