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CLINICAL RESEARCH: INTERVENTIONAL CARDIOLOGY

A Novel Drug-Eluting Stent Coated With an Integrin-Binding Cyclic Arg-Gly-Asp Peptide Inhibits Neointimal Hyperplasia by Recruiting Endothelial Progenitor Cells

Rüdiger Blindt, MD^_*,_*, Felix Vogt, MD^_*,, Irina Astafieva, PhD, Christian Fach, MD^_*,, Mihail Hristov, MD^,, Nicole Krott, MSc^_*,, Berthold Seitz, MS^_*, Aphrodite Kapurniotu, PhD^||, Connie Kwok, PhD, Manfred Dewor, MSc^||, Anja-Katrin Bosserhoff, PhD^¶, Jürgen Bernhagen, PhD^¶, Peter Hanrath, MD^_*, Rainer Hoffmann, MD^_* and Christian Weber, MD^_*,,

^_* Department of Cardiology, University Hospital Aachen, Aachen, Germany
Interdisciplinary Center for Clinical Research in Biomaterials and Tissue-Material Interaction in Implants BIOMAT, University Hospital Aachen, Aachen, Germany
Guidant Corporation, Santa Clara, California
Department of Molecular Cardiovascular Research, University Hospital Aachen, Aachen, Germany
^|| Institute of Biochemistry, University Hospital Aachen, Aachen, Germany
^¶ Institute of Pathology, University of Regensburg, Regensburg, Germany

Manuscript received July 28, 2005; revised manuscript received November 22, 2005, accepted November 30, 2005.

^_* Reprint requests and correspondence: Dr. Rüdiger Blindt, Department of Cardiology, University Hospital Aachen, Pauwelsstr 30, 52074 Aachen, Germany (Email: ruediger.blindt{at}post.rwth-aachen.de).

OBJECTIVES: Novel stents loaded with an integrin-binding cyclic Arg-Gly-Asp peptide (cRGD) were analyzed for their potential to limit coronary neointima formation and to accelerate endothelialization by attracting endothelial progenitor cells (EPCs).

BACKGROUND: Re-endothelialization is important for healing after arterial injury.

METHODS: Effects of cRGD on EPC number, recruitment in flow, and invasion were analyzed in vitro. A durable polymer coating containing 67 µg cRGD per stent was developed for Guidant Tetra stents. Twelve cRGD-loaded polymer, 12 unloaded polymer, and 12 bare metal stents were deployed in porcine coronary arteries. Quantification of cRGD in peri-stent tissue was established by high-performance liquid chromatography (HPLC) and mass spectrometry (MS). Histomorphometry and immunostaining were performed after 4 and 12 weeks. Recruitment of labeled porcine EPCs was assessed 7 days after intracoronary infusion.

RESULTS: The cRGD clearly supported the outgrowth, recruitment, and migration of EPCs in vitro. At 4 weeks, there was no difference for mean neointimal area and percent area stenosis in the cRGD-loaded, polymer, or bare metal stent group. At 12 weeks, neointimal area (2.2 ± 0.3 mm²) and percent area stenosis (33 ± 5%) were significantly reduced compared with polymer stents (3.8 ± 0.4 mm², 54 ± 6%; p = 0.010) or bare metal stents (3.8 ± 0.3 mm², 53 ± 3%; p < 0.001). The HPLC/MS confirmed cRGD tissue levels of 1 to 3 µg/stent at 4 weeks, whereas cRGD was not detectable at 12 weeks. Staining for CD34 and scanning electron microscopy indicated enhanced endothelial coverage on cRGD-loaded stents at 4 weeks associated with a significant increase in the early recruitment of infused EPCs.

CONCLUSIONS: Stent coating with cRGD may be useful for reducing in-stent restenosis by accelerating endothelialization.

Abbreviations and Acronyms   BSA = bovine serum albumine   CIC = chronic inflammatory cells   cRGD = integrin-binding cyclic Arg-Gly-Asp peptide   DiI-Ac-LDL = 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine-labeled Ac-low-density lipoprotein   EPC = endothelial progenitor cell   HPLC = high-performance liquid chromatography   ISR = in-stent restenosis   MS = mass spectrometry   RP = reverse-phase   SMC = smooth muscle cell   VEGF = vascular endothelial growth factor

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