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01.12.2012 | Original investigation | Ausgabe 1/2012 Open Access

Cardiovascular Diabetology 1/2012

Comparative vascular responses three months after paclitaxel and everolimus-eluting stent implantation in streptozotocin-induced diabetic porcine coronary arteries

Zeitschrift:
Cardiovascular Diabetology > Ausgabe 1/2012
Autoren:
Alexander Sheehy, Steven Hsu, Amelie Bouchard, Pablo Lema, Claudine Savard, Louis-Georges Guy, Julie Tai, Igor Polyakov
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1475-2840-11-75) contains supplementary material, which is available to authorized users.

Competing interests

A. Sheehy, S. Hsu, J. Tai, and I. Polyakov are employees of Abbott Vascular. A. Bouchard, P. Lema, C. Savard, and L.G. Guy are employees of AccelLab, Inc. AccelLab, Inc. receives sponsored study research support from Abbott Vascular, Biotronik, Boston Scientific, Medtronic, Baxter, Atrium Medical, Arsenal Medical, Cardio3 Biosciences, Elixir Medical, Cordis, and Avantec.

Authors’ contributions

AS participated in the overall design, data interpretation, writing and presentation of this work. SH participated in design of in vitro cell viability experiments, data interpretation, performed statistical analysis, drafted portions of the manuscript, and critically revised the manuscript before final approval. AB contributed to the in vivo data collection and interpretation. PL was the attending veterinarian, contributed to the model design, and overall conduct of the study. CS contributed to the pathological evaluation and interpretation. LG contributed to the overall in vivo study design and data interpretation. JT participated in design of in vitro cell viability experiments, data interpretation, and critically revised the manuscript before final approval. IP contributed to the in vivo study design, data interpretation, and pathology peer review. All authors read and approved the final manuscript.

Abstract

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.

Method

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.

Conclusion

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.
Zusatzmaterial
Authors’ original file for figure 1
12933_2012_481_MOESM1_ESM.pdf
Authors’ original file for figure 2
12933_2012_481_MOESM2_ESM.pdf
Authors’ original file for figure 3
12933_2012_481_MOESM3_ESM.pdf
Authors’ original file for figure 4
12933_2012_481_MOESM4_ESM.pdf
Literatur
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