sirolimus and Hyperlipoproteinemia-Type-II

The utility of animal models for the prediction of drug-eluting stent (DES) efficacy in human clinical trials is still unclear. The familial hypercholesterolemic swine (FHS) model has been shown to induce a human-like neointimal response to bare metal stent (BMS) implantation. However, its utility to discriminate efficacy signals following DES implantation is unknown. In this study, we aimed to test the efficacy and healing response of several everolimus-eluting stent (EES) platforms in the coronary territory of the FHS.. A total of 19 EES platforms (SYNERGY=6, SYNERGY½-dose=7, and PROMUS Element=6) and an identical BMS control (Element=6) were implanted into the coronary arteries of nine FHS. All implants were performed under intravascular ultrasound guidance using a 1.2 : 1 overstretch ratio. At 30 days, the vascular response to the implant was evaluated by quantitative coronary angiography, optical coherence tomography, and histology.. At 28 days, all EES platforms showed a significant decrease in angiographic late lumen loss (between 27 and 37%) compared with the BMS control group. This finding was confirmed both by optical coherence tomography (mean neointimal thickness=28-42% reduction) and by histology (mean neointimal thickness=44-55% reduction). All EES platforms showed similar degrees of neointimal inhibition. The presence of moderate to severe para-strut inflammation was observed in 83% of the stent sections in the BMS group compared with 28.6% in the SYNERGY½-dose group and 0% in the SYNERGY and PROMUS groups (P=0.0002). There was a 68-95% reduction in MMP9 expression in the media in all EES platforms compared with the BMS controls. The presence of mild to moderate para-strut fibrin deposits ranged from 66.7 to 83.4% in all EES platforms compared with 16.7% in the EBMS group.. The FHS coronary injury model showed the efficacy of several EES platforms compared with an identical BMS control. Everolimus eluted from different polymeric platforms showed lower levels of inflammation and slightly higher fibrin deposits compared with BMS controls.

Topics: Animals; Blood Vessel Prosthesis Implantation; Coronary Angiography; Coronary Vessels; Disease Models, Animal; Drug-Eluting Stents; Everolimus; Humans; Hyperlipoproteinemia Type II; Immunosuppressive Agents; Male; Models, Cardiovascular; Neointima; Polymers; Sirolimus; Swine; Tomography, Optical Coherence; Treatment Outcome; Ultrasonography, Interventional

Topics: Animals; Coronary Vessels; Disease Models, Animal; Drug-Eluting Stents; Everolimus; Humans; Hyperlipoproteinemia Type II; Male; Neointima; Sirolimus

Drug-coated balloons are rapidly emerging as a therapeutic alternative for the interventional treatment of peripheral vascular disease. The purpose of this study was to test the hypothesis that an angioplasty balloon coated with the mTOR inhibitor zotarolimus (ZCB) would inhibit neointimal hyperplasia in a novel injury-based superficial femoral artery model in the familial hypercholesterolemic swine.. A total of 44 familial hypercholesterolemic swine were included (12 designated to study tissue pharmacokinetics and 32 to study safety and efficacy). Fogarty balloon denudation was performed in all superficial femoral artery segments, followed by balloon angioplasty. In the pharmacokinetic study, a total of 24 ZCBs (300 μg/cm(2)) were used. Zotarolimus was detected in arterial tissue at 5 minutes (162 ng/mg of tissue), 24 hours (5.9 ng/mg of tissue), and 28 days (0.007 ng/mg of tissue) after ZCB inflation. In the safety and efficacy study, superficial femoral artery segments were randomized to either high-dose (600 μg/cm(2), n=16), low-dose (300 μg/cm(2), n=16), or paired uncoated balloons (high-dose ZCB control, n=16; low-dose ZCB control, n=16). At 28 days, the percentage of angiographic stenosis was similar among all tested groups. Histological analysis demonstrated a reduction in neointimal formation in both ZCB groups compared with controls (high-dose ZCB 44% reduction, P=0.007; low-dose ZCB 22% reduction, P=0.08). There was no evidence of delayed arterial healing or vascular toxicity in any of the ZCB groups.. The single delivery of zotarolimus via coated balloon is feasible, and therapeutic levels are maintained up to 28 days. The ZCB technology appears to be effective in the reduction of neointimal proliferation in the superficial femoral artery of the familial hypercholesterolemic swine.

Topics: Angioplasty, Balloon; Animals; Catheterization; Clinical Protocols; Femoral Artery; Humans; Hyperlipoproteinemia Type II; Infusion Pumps, Implantable; Models, Animal; Neointima; Postoperative Complications; Radiography; Sirolimus; Swine; TOR Serine-Threonine Kinases

A 68-year-old man with familial hypercholesterolemia developed effort angina and received a sirolimus-eluting stent (SES) to treat 99% stenosis in segment 6 of the left anterior descending coronary artery in January 2005. A further stent was implanted 14 months later to treat 99% restenosis at the proximal stent edge. A 66-year-old man with diabetes developed acute anterior myocardial infarction and underwent SES implantation to treat 90% stenosis in segment 4 atrioventricular node artery branch of the right coronary artery in April 2006. Heart failure developed 14 months later. Another stent was implanted to treat 100% obstructive stenosis of the proximal stent site. Late stent restenosis may occur over 1 year after SES implantation, so longer follow-up is required compared to bare metal stent.

Topics: Aged; Angina Pectoris; Coronary Artery Disease; Coronary Restenosis; Humans; Hyperlipoproteinemia Type II; Male; Myocardial Infarction; Sirolimus; Stents