3 Angiogenesis as a therapeutic option for untreatable CTO

Abstract

Introduction Up to 30% chronic total occlusions (CTO) cannot be revascularised by conventional angioplasty (BCIS data). Therapeutic angiogenesis to enhance existing antegrade collateral circulation and improve antegrade flow may offer a novel solution for such cases. Methods and results We describe in-vitro studies on two prolyl-hydroxylase inhibitors (PHI), FG-2216 and FG-4592 (already in clinical trials for renal anaemia), to assess their ability to stimulate angiogenesis as a potential therapeutic strategy for difficult CTO via stabilisation of hypoxia inducible factor–1α (HIF-1α). Western blotting analysis indeed demonstrated stabilisation of HIF-1α protein in human endothelial cells (EC) within 1–2 h of treatment with these PHI (Figure 1a). Both PHI demonstrated a dose response, pro-angiogenic effect on EC cultured on Matrigel, with enhanced tubule formation compared to control (1.2–5 fold increase, Figure 1b). qPCR showed a 1.2–2 fold increase in mRNA for the main angiogenic target of HIF-1α, vascular endothelial growth factor (VEGF), after treatment with these PHI. Conclusions As part of our strategy for the local, sustained delivery and release of PHI as an effective treatment for difficult CTOs, stent coating and elution studies have been conducted and we have developed proprietary programmable eluting polymers for optimal elution of each drug. FG-2216 and FG-4592-eluting stents are now being evaluated in in-vivo studies.