Key result
SU11218 reduces in-stent intimal hyperplasia ~79% vs. placebo at 4 weeks.
Why the study?
Adventitial microvessels have been reported after arterial injury, but the underlying stimulus for this response, its relationship to intimal hyperplasia, and the effects of the tyrosine kinase inhibitor SU11218 were unknown.
Does the tyrosine kinase inhibitor SU11218 reduce adventitial microvessel formation and in-stent intimal hyperplasia in pigs undergoing coronary stenting?
RCT (n=40)
Placebo-controlled
Randomized
Does the tyrosine kinase inhibitor SU11218 reduce adventitial microvessel formation and in-stent intimal hyperplasia in pigs undergoing coronary stenting?
In a porcine coronary stenting model, arterial stenting induces vessel wall hypoxia and adventitial microvessel formation that correlates with intimal hyperplasia, both of which are significantly inhibited by the tyrosine kinase inhibitor SU11218.
Objectives The aim of this study was to delineate the temporal profile of adventitial microvessel (Ad-MV) formation after stenting, its relationship to arterial wall hypoxia, and the effects of a tyrosine kinase inhibitor (TKI), SU11218, on Ad-MV and in-stent intimal hyperplasia (IH). Background Adventitial microvessels have been reported after arterial injury; however, the underlying stimulus for this response and its relationship to IH is unknown. Methods Coronary stenting was performed in 40 pigs randomized to SU11218 (n = 20) or placebo (n = 20). Vessel wall hypoxia was assessed by pimonidazole adducts and hypoxia-inducible factor (HIF)-1 alpha expression. Adventitial microvessels were quantified by three-dimensional microscopic computed tomography (3D micro CT). Intimal hyperplasia was measured by intravascular ultrasound (IVUS), 3D micro CT, and morphometry. The effects of SU11218 were assessed in vitro on smooth muscle cell (SMC) and endothelial cell (EC) functions and in vivo on Ad-MV and IH. Results Hypoxia was evident in the vessel wall at 48 h and persisted for four weeks. Adventitial microvessels increased significantly at one week (24 +/- 7 microvessels/segment) and four weeks (23 +/- 7 microvessels/segment) compared with uninjured arteries (16 +/- 2 microvessels/segment; p < 0.001) and correlated with IH (r = 0.77, p < 0.001). The TKI SU11218 inhibited platelet-derived growth factor receptor-beta phosphorylation, EC and SMC DNA synthesis, and migration in a dose-dependent manner in vitro and significantly inhibited Ad-MV (16 +/- 5 vs. 23 +/- 7 microvessels/segment in placebo, p < 0.001) and produced approximately 80% reduction in IH (0.52 +/- 0.51 mm2 vs. 2.47 +/- 1.66 mm2 in placebo, p < 0.001) at four weeks in vivo. Conclusions Arterial stenting causes arterial wall hypoxia followed by Ad-MV formation. The TKI SU11218 inhibits both Ad-MV formation and IH and represents a promising therapeutic agent to prevent in-stent restenosis.
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Cheema et al. (2006) conducted an RCT in Coronary stenting / in-stent intimal hyperplasia (n=40). SU11218 (tyrosine kinase inhibitor) vs. Placebo was evaluated on In-stent intimal hyperplasia (mm2) and adventitial microvessel formation at 4 weeks (p=< 0.001). SU11218 significantly reduced in-stent intimal hyperplasia (0.52 vs. 2.47 mm2, p<0.001) and adventitial microvessels (16 vs. 23 microvessels/segment, p<0.001) vs. placebo at 4 weeks.
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