Preclinical evaluation of coronary stents: focus on safety issues.

In recent years, we have witnessed a revolution in the treatment of coronary artery disease. The development and improvement of drug eluting stents (DES) have lowered the incidence of restenosis to one-digit figures. In the search for a superior efficacy, animal models have played a key role. The classical swine model of coronary stenting remains the preferred model to measure restenosis, although the rabbit iliac artery stenting has become an accepted alternative. After widespread clinical use of DES, an unforeseen complication arose: late stent thrombosis. In a back-to-bench step, some data from animal models helped to explain the phenomenon. A delayed and incomplete vascular healing was detected. Toxic and hypersensitivity reactions to polymers and/or drugs seem to be the underlying causes. So, translational research focused on the safety aspect of these devices: development of better drug carriers as absorbable polymers or fully bioresorbable scaffolds, selection of different drugs and assessment of the re-endothelialization process. We review and evaluate the efficacy and safety of coronary stents in different animal models. Further improvements in this field such as, the selection of better animal models (e.g. hyperlipidemic, diabetic, atherosclerotic) that closely mimic the clinical setting and longer follow-up periods to detect late complications are also discussed.

Vasomotor response to different endothelium-dependent vasodilators in an animal model.

BACKGROUND AND OBJECTIVES: Incomplete re-endothelialization of stents can be revealed as paradoxical vasoconstriction with endothelium-dependent vasodilators. As no consensus exists about the best method or agent, our objective is to analyze the response to different drugs in a coronary swine model. METHODS: Twenty-seven stents were implanted in 9 domestic swine. The vessel diameter of proximal and distal segments (≥5 mm) was assessed immediately post implantation. Different endothelium-dependent vasodilators were used: intracoronary (IC) acetylcholine, 20 µg (A2) and 40 µg (A4), IC serotonin (S), 100 µg, and isoproterenol (I), intravenous infusion. The results are presented as constriction (%) compared with maximal vasodilation with IC nitroglycerin (N, 200 µg). RESULTS: In 10 vessels (37%), A4 provoked an occlusive spasm. Acetylcholine induced a higher degree of vasoconstriction (A4, 42 ± 39%; A2, 16 ± 14%) than the rest of the agonists (S, 6 ± 12%; I, 6 ± 11%; P<.01). The constriction rate was not related to the induced hemodynamic changes. CONCLUSIONS: After focal endothelial denudation in a coronary swine model, the constriction rate induced by different endothelium-dependent vasodilators is highly variable. The highest value is observed after IC acetylcholine bolus. The constriction rate does not correlate with the observed hemodynamic changes.

La reestenosis en el stent depende del daño vascular inducido. ¿Son válidos los modelos experimentales actuales de análisis de los stents farmacoactivos? / Instent restenosis related to vessel injury score degree. Are current experimental models valid for drug-eluting stents analysis?

Introducción y objetivos. Los stents farmacoactivos son una herramienta útil para prevenir la reestenosis, pero los mecanismos involucrados en la respuesta proliferativa tras su implante aún no son conocidos en su totalidad. El objetivo de este estudio es comparar la histomorfometría vascular coronaria tras el implante de stents sin recubrir o stents farmacoactivos en un modelo porcino. Métodos. En 20 hembras de cerdos de la raza Large White de 2 meses de edad se implantó de forma aleatoria un total de 60 stents distribuidos en dos grupos: convencionales (n=20) y farmacoactivos (paclitaxel) (n=40). A los 28 días se procedió a eutanasia y análisis histomorfométrico. Se clasificó el grado de daño vascular en función de integridad o rotura de la túnica limitante elástica interna. Resultados. En el grupo de integridad de lámina elástica interna no se encontraron diferencias significativas entre stents farmacoactivos y stents convencionales para las variables área de neoíntima y porcentaje de reestenosis (1,3 [1,1-2,2] frente a 2 [1,3-2,5] mm2; p=0,6; y 14 [12,1-20,8] frente a 22,2 [14,1-23,3] %; p=0,5). En cambio, en el grupo de rotura de la lámina elástica interna sí se encontraron diferencias significativas (área de neoíntima, 1,2 [0,8-2] frente a 2,9 [2,3-3,7] mm2; p=0,001 y porcentaje de reestenosis, 16,63 [11,2-23,5] frente a 30,4 [26,4-45,7] %; p=0,001). Conclusiones. En el modelo porcino de coronarias sanas, la integridad de la lámina elástica interna no permite apreciar diferencias en la respuesta proliferativa entre stent farmacoactivo y convencional; la diferencia se establece sólo cuando el daño vascular es más profundo (AU)

Introduction and objectives. Drug-eluting stents are useful for preventing restenosis, but the patho-physiological processes involved in the proliferative response after implantation are still not known in detail. The aim of this study is to compare the coronary vascular histomorphometry after implanting drug-eluting stents and bare metal stents in a swine model. Methods. Sixty stents were randomly implanted in 20 Large White female pigs with a ratio of baremetal/drug-eluting stents of 1:2. After 28 days, euthanasia and histomorphometry were performed. We defined the vessel injury score in accordance to whether the internal elastic lamina was intact or ruptured. Results. There were no differences between drug-eluting stents and bare metal stents in the intact internal elastic lamina group regarding neointimal area or % restenosis (1.3 [1.1-2.2]) vs 2.0 [1.3-2.5] mm2; P=.6; and 14.0 [12.1-20.8] vs 22.2 [14.1-23.3] %; P=.5). We assessed statistically significant differences for the ruptured internal elastic lamina group, (neointimal area 1.2 [0.8-2.0] vs 2.9 [2.3-3.7] mm2; P=.001 and % restenosis 16.63 [11.2-23.5] vs 30.4 [26.4-45.7] %; P=.001). Conclusions. In our swine model, we did not find any differences between proliferative response of drug-eluting stents and bare metal stents when the internal elastic lamina is intact; differences are only found when vascular injury is deeper (AU)

[Instent restenosis related to vessel injury score degree. Are current experimental models valid for drug-eluting stents analysis?]. / La reestenosis en el stent depende del daño vascular inducido. ¿Son válidos los modelos experimentales actuales de análisis de los stents farmacoactivos?

INTRODUCTION AND OBJECTIVES: Drug-eluting stents are useful for preventing restenosis, but the patho-physiological processes involved in the proliferative response after implantation are still not known in detail. The aim of this study is to compare the coronary vascular histomorphometry after implanting drug-eluting stents and bare metal stents in a swine model. METHODS: Sixty stents were randomly implanted in 20 Large White female pigs with a ratio of baremetal/drug-eluting stents of 1:2. After 28 days, euthanasia and histomorphometry were performed. We defined the vessel injury score in accordance to whether the internal elastic lamina was intact or ruptured. RESULTS: There were no differences between drug-eluting stents and bare metal stents in the intact internal elastic lamina group regarding neointimal area or % restenosis (1.3 [1.1-2.2]) vs 2.0 [1.3-2.5] mm²; P=.6; and 14.0 [12.1-20.8] vs 22.2 [14.1-23.3] %; P=.5). We assessed statistically significant differences for the ruptured internal elastic lamina group, (neointimal area 1.2 [0.8-2.0] vs 2.9 [2.3-3.7] mm²; P=.001 and % restenosis 16.63 [11.2-23.5] vs 30.4 [26.4-45.7] %; P=.001). CONCLUSIONS: In our swine model, we did not find any differences between proliferative response of drug-eluting stents and bare metal stents when the internal elastic lamina is intact; differences are only found when vascular injury is deeper.