Stent-based release of a selective PDGF-receptor blocker from the bis-indolylmethanon class inhibits restenosis in the rabbit animal model.

Long-term success of modern therapies for myocardial ischemia is limited by restenosis, with proliferation and migration of vascular smooth muscle cells (VSMC) as key events. Since findings in recent years indicate, that the Platelet Derived Growth Factor (PDGF) is an important selective factor in mitogenic and motogenic pathways of VSMC, different concepts for reducing restenosis by inhibiting PDGF signaling have been investigated, with local delivery of small receptor kinase inhibitors looking most promising. We tested the stent-based delivery of the PDGF-receptor inhibitor D-65495, a bis(1H-2-indolyl)methanone, in the rabbit iliac artery model of restenosis. New Zealand white rabbits underwent balloon dilation of iliac arteries for implantation of D-65495-coated or non-coated (solvent, either DMSO or 90%THF / 10% DMSO) coronary stents. After 4 weeks stents were removed and neointima formation in medial and proximal/ distal stent sections was histomorphometrically and immunohistochemically analyzed. Arteries with D-65495 eluting stents showed an up to 50% reduced restenosis compared to control stents. Also, the neointimal area was reduced, but there were no significant differences in injury score. Importantly, endothelialization was similar for control stents as well as for D-65495-coated stents, suggesting absence of a general cytostatic effect of the inhibitor. The impact of D-65495 on PDGF-receptor signaling in the vessel wall was indirectly assessed by immunohistochemical staining for activated protein kinase Akt, and PCNA as a proliferation marker and revealed some reduction for the inhibitor-treated vessels. In conclusion, the application of D-65495 caused a significant decrease in neointima formation, further supporting the concept of using locally released PDGF-receptor kinase inhibitors as anti-restenotic agents.

Growth factors in the collateral circulation of chronic total coronary occlusions: relation to duration of occlusion and collateral function.

BACKGROUND: Despite extensive animal experimental evidence, there are few data on the relation of growth factors and collateral function in humans. METHODS AND RESULTS: In 104 patients with a chronic total coronary occlusion (CTO; >2 weeks' duration), collateral function was assessed invasively during recanalization by intracoronary Doppler and pressure recordings. A collateral resistance index, R(Coll), was calculated. Blood samples were drawn from the distal coronary bed supplied by the collaterals and from the aortic root to measure basic fibroblast growth factor (bFGF), monocytic chemotactic protein-1 (MCP-1), transforming growth factor-beta (TGF-beta), placenta growth factor (PlGF), and tumor necrosis factor-alpha (TNF-alpha). The bFGF concentration in the collateralized artery was higher than in the aortic root (34+/-20 versus 18+/-14 pg/mL; P<0.001). bFGF was highest in recent occlusions (2 to 12 weeks) with the highest R(Coll). Higher collateral concentrations were also observed for MCP-1, TGF-beta, and PlGF, but without a close relation to the duration of occlusion. TNF-alpha was not increased in collaterals compared with the systemic circulation. MCP-1, PlGF, and TGF-beta were significantly increased in small collaterals with the highest shear stress. Diabetic patients had lower bFGF and higher MCP-1 levels than nondiabetics. CONCLUSIONS: In CTOs, the continuous release of bFGF into collaterals showed a close relation to the duration of occlusion and collateral function, which underscores its therapeutic potential. Other factors influencing growth factor release appeared to be shear stress for MCP-1, TGF-beta, and PlGF and the presence of diabetes.

Regression of collateral function after recanalization of chronic total coronary occlusions: a serial assessment by intracoronary pressure and Doppler recordings.

BACKGROUND: Collaterals can maintain myocardial function or preserve viability in chronic total coronary occlusions (CTOs). It is unknown whether and to what extent collaterals regress after successful recanalization of a CTO. METHODS AND RESULTS: In 103 patients with successful recanalization of a CTO collateral function was assessed by intracoronary Doppler and pressure recordings before and after recanalization, and again after 5.0+/-1.3 months. Doppler (CFI) and pressure-derived collateral function indexes (CPI) and collateral (RColl) and peripheral resistance indexes (RP) were calculated. In 10 patients with reocclusion, all without myocardial infarction during follow-up, collateral function had reached a similar level as before the first recanalization. In the other 93 patients with or without restenosis, collateral function was attenuated during follow-up. CPI had decreased by 23% immediately after recanalization (P<0.001) and decreased further by another 23% at follow-up (P<0.001). The RColl increased immediately after recanalization by 82% (P<0.001) and by a further 273% at follow-up (P<0.001). In contrast, RP increased only by 22% after recanalization (P<0.001) and by an additional 12% at follow-up (P<0.05). The initial size of the collaterals but not the incidence of a restenosis influenced the collateral regression. Only 18% of patients at follow-up had collaterals with a CPI >0.30, presumably sufficient to prevent ischemia during acute occlusion. CONCLUSIONS: Collateral function regresses during long-term follow-up, especially in collaterals with a small diameter. In the majority of patients, collaterals are not readily recruitable in the case of acute occlusion. However, collaterals have the potential to recover in the case of chronic reocclusion.

Determinants of target vessel failure in chronic total coronary occlusions after stent implantation. The influence of collateral function and coronary hemodynamics.

OBJECTIVES: The goal of this study was to assess the influence of collateral function, coronary hemodynamics, and the angiographic result on the risk of target vessel failure (TVF) after recanalization of a chronic total coronary occlusion (CTO). BACKGROUND: Collaterals may have an adverse effect on TVF. METHODS: In 111 consecutive patients, a CTO (duration >2 weeks) was successfully recanalized with stent implantation. Collateral function was assessed by intracoronary Doppler flow velocity and pressure recordings distal to the occlusion. Baseline collateral function was determined before the first balloon inflation, and recruitable collateral function after stenting during a balloon reocclusion. Finally, the coronary flow velocity reserve (CFVR) and the fractional flow reserve (FFR) were measured. RESULTS: Angiographic follow-up after 5 +/- 4 months in 106 patients showed a reocclusion in 17% and a restenosis in 36%. The major determinants of TVF were the stent length (p < 0.01) and number of implanted stents (p < 0.01). No difference was observed in baseline or recruitable collateral function between patients with and without TVF; 52% of patients had a CFVR >or= 2.0, and only 18% a CFVR >or=2.5 after percutaneous transluminal coronary angioplasty, but neither cutoff-value predicted TVF. A low FFR discriminated patients with reocclusion (0.81 +/- 07 vs. 0.86 +/- 08, p < 0.05) but not with restenosis (0.87 +/- 0.06). CONCLUSIONS: This study showed that there is no relation between a well-developed collateral supply and the risk of TVF in recanalized CTOs. This was rather determined by the stented segment length. There was also no adverse effect of the frequently observed impaired CFVR on TVF, whereas a low FFR was associated with a higher risk of reocclusion.