Abstract 4921: Differential Healing in Paclitaxel and Sirolimus-Eluting Stents in Combination with Oral PPAR Gamma Agents: The Role of Drug Interaction in Delayed Healing

Abstract

Drug eluting stents (DES) contain different pharmacologic agents, yet the clinical relevance of this is unknown. Overlap exists between the molecular targets of sirolimus (SRL) (i.e. PI3K/mTOR) and many agents used to treat diabetes (DM). Because paclitaxel (PAC) works through other mechanisms, it might avoid this issue. The impact of interactions between eluted drug and commonly used DM meds on healing remains unknown. In rabbits receiving bare (BMS), PAC, and SRL DES, we investigated the effect of oral PPAR gamma agents, rosiglitazone (RSG) and pioglitazone (Pio), on stent endothelialization (ENDO). Rabbits were randomized to SRL, PAC or BMS and to placebo (PLC) versus RSG(3mg/kg/day) or Pio(10mg/kg/day). Animals were sacrificed at 28 days and arteries evaluated by scanning electron microscopy (SEM). 14day organ culture (OC) was also conducted. Cell culture experiments used human aortic endothelial cells (HAEC). RSG significantly reduced ENDO of the stent by SEM in animals receiving SRL vs. PLC, but no differences were seen in animals receiving PAC or BMS (table ). OC studies revealed significantly reduced VEGF levels in animals received SRL +RSG versus SRL +PLC, whereas animals receiving BMS and PAC demonstrated increased VEGF versus PLC. Similar results were seen in animals randomized to Pio vs. PLC. RSG +SRL additively inhibited p70s6k and SRL significantly blocked phosphorylation of Akt by RSG in HAEC. QRT-PCR revealed that SRL inhibited transcriptional upregulation of VEGF and heme oxygenase, a PPAR target gene, by RSG and suggests that in addition translational regulation, sirolimus may inhibit PPAR activity. RSG +SRL inhibits endothelialization because of significant drug interaction. No effect of PPAR gamma agonists is seen in animals receiving BMS or PAC. Our data suggest that SRL DES should be avoided in DM receiving PPAR gamma agonists and that investigation of other DM agents in combination with SRL is needed. 28 Day Endothelialization by SEM