Abstract 16647: PKC Inhibition Using a Nonpolymeric Drug-Eluting Stent Platform Does Not Affect Neointimal Hyperplasia in a Porcine Coronary Model
PKC412 (Midostaurin) is a lipophyllic, cell permeable inhibitor of multiple isoforms of the serine/threonine protein kinases, including PKC. Targets include VEGFR-2, PDGF-R, c-KIT, and Pgp-mediated multidrug resistance gene MDR. PKC412 potently inhibits cell growth, and in mice microcirculation it upregulates eNOS gene expression and preserves eNOS function, all these making it a candidate drug for eluting stents (DES). We therefore studied the efficacy of a polymer-free DES (hydroxyapatite, HAp) eluting three different doses of PKC 412 in a porcine coronary model. The lowest dose was calculated to reach a maximum cumulative concentration of 100 μM, 100 times higher than the IC50 in sarcoma cell lines. The drug was released with and without a release regulating layer (L).
Methods & Results: Stents were placed with a B/A ratio of 1.1:1 in Yorkshire swine (∼30 kg). At follow-up, arteries were processed for histology and morphometry of neointimal thickening (NI). Histology indicated that controls and all PKC formulations showed complete healing and endothelialization at 28 days, regardless of dose and release layer. Morphometry (table) seems to indicate that PKC without a regulating lipid layer shows a temporary increase in NI at 28 days. However, regression analysis with drug, release layer, dose, vessel size, B/A ratio and fu-time as model parameters, showed that only vessel size (≤ 3.0 mm) and FU-time, but not drug, dose or release layer were independently associated with NI.
Conclusion: Midostaurin does not affect vascular healing, or intimal thickening at 28 and 90 days. The presence of a release regulating layer did not affect the vascular response. In this model, small vessel size is an independent predictor of intimal thickening.
- © 2010 by American Heart Association, Inc.