Continuous Subcutaneous Angiopeptin Treatment Significantly Reduces Neointimal Hyperplasia in a Porcine Coronary In-Stent Restenosis Model

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Abstract
Background In-stent restenosis results primarily from neointimal hyperplasia. This study evaluated the efficacy and the optimal mode of administration of angiopeptin, a somatostatin analogue with antiproliferative activity, in a porcine coronary in-stent restenosis model. Methods and Results Forty pigs were randomly assigned to one of four groups (n=10 per group): (1) controls receiving saline infusion at the site of stent implantation via a local delivery catheter, (2) local treatment group receiving one-time treatment (200 μg angiopeptin) at the site of stent placement, (3) systemic treatment group receiving continuous angiopeptin over a 1-week period via a subcutaneous osmotic pump (200 μg/kg total dose), and (4) combined local and systemic treatment group. Then, one oversized Palmaz-Schatz stent (mean ratio of stent to artery diameters, 1.3:1) was implanted in the left anterior descending coronary artery. The degree of neointimal reaction was evaluated 4 weeks later by angiography (maximal percent diameter stenosis), intravascular ultrasound (total in-stent neointimal volume), and histology (maximal area stenosis). Systemic treatment produced the least neointimal hyperplasia and significantly reduced in-stent restenosis compared with the control group by all end points, despite similar degrees of injury. Angiography showed 25±17% versus 50±17% diameter stenosis in the systemic angiopeptin group versus the control group ( P <.0001), intravascular ultrasound revealed 23±10 versus 58±27 mm 3 neointimal volume in the systemic angiopeptin versus control group ( P =.0002), and histology showed 41±16% versus 69±18% area stenosis ( P =.0016) in the systemic angiopeptin versus control group. Plasma angiopeptin levels revealed rapid clearance (within 6 hours) after local therapy, whereas the levels persisted for up to 2 weeks in the systemic group. Conclusions This study shows that continuous subcutaneous treatment with angiopeptin after stent implantation significantly reduces in-stent restenosis by inhibiting neointimal hyperplasia.

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