Comparative vascular responses three months after paclitaxel and everolimus-eluting stent implantation in streptozotocin-induced diabetic porcine coronary arteries.
BACKGROUND
Diabetes remains a significant risk factor for restenosis/thrombosis following stenting. Although vascular healing responses following drug-eluting stent (DES) treatment have been characterized previously in healthy animals, comparative assessments of different DES in a large animal model with isolated features of diabetes remains limited. We aimed to comparatively assess the vascular response to paclitaxel-eluting (PES) and everolimus-eluting (EES) stents in a porcine coronary model of streptozotocin (STZ)-induced type I diabetes.


METHODS
Twelve Yucatan swine were induced hyperglycemic with a single STZ dose intravenously to ablate pancreatic β-cells. After two months, each animal received one XIENCE V® (EES) and one Taxus Liberte (PES) stent, respectively, in each coronary artery. After three months, vascular healing was assessed by angiography and histomorphometry. Comparative in vitro effects of everolimus and paclitaxel (10-5 M-10-12 M) after 24 hours on carotid endothelial (EC) and smooth muscle (SMC) cell viability under hyperglycemic (42 mM) conditions were assayed by ELISA. Caspase-3 fluorescent assay was used to quantify caspase-3 activity of EC treated with everolimus or paclitaxel (10-5 M, 10-7 M) for 24 hours.


RESULTS
After 3 months, EES reduced neointimal area (1.60 ± 0.41 mm, p < 0.001) with trends toward reduced % diameter stenosis (11.2 ± 9.8%, p = 0.12) and angiographic late-loss (0.28 ± 0.30 mm, p = 0.058) compared to PES (neointimal area: 2.74 ± 0.58 mm, % diameter stenosis: 19.3 ± 14.7%, late loss: 0.55 ± 0.53 mm). Histopathology revealed increased inflammation scores (0.54 ± 0.21 vs. 0.08 ± 0.05), greater medial necrosis grade (0.52 ± 0.26 vs. 0.0 ± 0.0), and persistently elevated fibrin scores (1.60 ± 0.60 vs. 0.63 ± 0.41) with PES compared to EES (p < 0.05). In vitro, paclitaxel significantly increased (p < 0.05) EC/SMC apoptosis/necrosis at high concentrations (≥ 10-7 M), while everolimus did not affect EC/SMC apoptosis/necrosis within the dose range tested. In ECs, paclitaxel (10-5 M) significantly increased caspase-3 activity (p < 0.05) while everolimus had no effect.


CONCLUSIONS
After 3 months, both DES exhibited signs of delayed healing in a STZ-induced diabetic swine model. PES exhibited greater neointimal area, increased inflammation, greater medial necrosis, and persistent fibrin compared to EES. Differential effects of everolimus and paclitaxel on vascular cell viability may potentially be a factor in regulating delayed healing observed with PES. Further investigation of molecular mechanisms may aid future development of stent-based therapies in treating coronary artery disease in diabetic patients.
Abbott Vascular, 3200 Lakeside Drive, Santa Clara, CA 95054, USA. alexander.sheehy@av.abbott.com
Alexander
A
Sheehy
Steven
S
Hsu
Amelie
A
Bouchard
Pablo
P
Lema
Claudine
C
Savard
Louis-Georges
LG
Guy
Julie
J
Tai
Igor
I
Polyakov
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002317:Cardiovascular Agents / Q000008:administration & dosage*; D002478:Cells, Cultured; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000209:etiology / Q000473:pathology / Q000628:therapy*; D023903:Coronary Restenosis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D003331:Coronary Vessels / Q000187:drug effects* / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003925:Diabetic Angiopathies / Q000209:etiology / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D054855:Drug-Eluting Stents; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D000068338:Everolimus; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology; D009336:Necrosis; D058426:Neointima; D017239:Paclitaxel / Q000008:administration & dosage*; D062645:Percutaneous Coronary Intervention / Q000009:adverse effects / Q000295:instrumentation*; D011474:Prosthesis Design; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*; D013552:Swine; D013997:Time Factors; D014945:Wound Healing / Q000187:drug effects
D002317:Cardiovascular Agents; D000068338:Everolimus; D017239:Paclitaxel; D020123:Sirolimus