The use of coronary stents has increased significantly in recent years;¹⁾ however, in-stent restenosis (ISR) after stent implantation is major adverse effect.^2-4) The principal mechanism of ISR is thrombosis and neointimal hyperplasia, and it has been reported that there is a strong correlation between the degree of vascular inflammation and neointimal formation.^5-9) The pathological process of ISR is characterized by an inflammatory healing process after stretch and damage of the vessel wall.¹⁰⁾

Abciximab (Reopro®) is a potent anti-platelet agent. Systemic use of abciximab has significantly reduced thrombotic complications following complex angioplasty and stenting.^11-14) Alpha lipoic acid (ALA) is a potent antioxidant and acts as a cofactor of key mitochondrial enzymes such as pyruvate dehydrogenase and α-ketoglutarate dehydrogenase.¹⁵⁾ ALA is beneficial for improving endothelial function and preventing atherosclerosis-related disease.¹⁶⁾

Therefore, in this study, we compared the effect of a stent coated with abciximab and ALA with that of bare metal stent in a porcine coronary overstretch restenosis model.

Ten pigs were used in this study (10 pigs, 10 coronaries in each group). A bare metal stent (control) and a dual coated stent were implanted in proximal left anterior descending artery and proximal left circumflex artery by randomized in a pig.

Mortality for this study was zero. Quantitative coronary angiographies before and after stent implantation established the stent-to-artery diameter ratio as 1.33±0.06 for all 20 stented arteries. There was no significant difference in stent-to-artery ratio among the two stent groups.

On histopathologic analysis, various amounts of inflammatory cells and fibrin infiltrate surrounding on each strut section. In the neointima, most of the inflammatory cells in both groups were lymphohistiocytes. In contrast, eosinophils and plasma cells were not prominent. Carstair's fibrin stain for determining delayed arterial healing according to the discriminate fibrin score showed no difference between the two stent groups.

Significant correlations were found between the lymphohistiocyte count and the neointimal hyperplasia area (r=0.567, p<0.001) and between the lymphohitiocyte count and the percent area stenosis (r=0.476, p<0.001) (Fig. 4). There was no significant difference in the injury score between the two groups (1.44±0.59 in the dual-coated stent group vs. 1.33±0.66 in the control stent group, p=0.522), nor in the neointima area (1.55±0.82 mm² in the dual-coated stent group vs. 1.40±0.86 mm² in the control stent group, p=0.447) (Table 1). In the neointima, the lymphohistiocyte count was significantly lower in the dual-coated stent group compared with the control stent group (120±85 cells vs. 159±80 cells, p=0.048) (Fig. 5). There was no significant difference in the fibrin score between the two groups (0.16±0.34 in dual-coated stent group vs. 0.25±0.48 in the control stent group, p=0.446) (Fig. 3).

In our study, dual coating of a bare metal stent with abciximab and ALA by plasma polymerization of 1,2-DACH demonstrated no satisfactory inhibition of neointimal hyperplasia, but significantly lowered lymphohistiocyte counts compared with bare metal control stents.

Other studies have evaluated the effects of abciximab. In the EPIC trial, the incidence of further coronary events and the need for revascularization was reduced at 6 months post-stenting and beyond.¹³⁾ Data from the EPISTENT trial also suggested a beneficial effect for abciximab on restenosis, although this was limited to patients with diabetes.²¹⁾

Other studies have shown that abciximab-coated stents reduce neointimal hyperplasia by inhibition of neointimal cell proliferation and extracellular matrix synthesis when compared with bare-metal stents in a porcine coronary restenosis model.^22-24) Finally, two additional studies have reported that an abciximab-coated stent was feasible and produced significant inhibition of neointimal hyperplasia, showing a potential therapeutic benefit in the prevention of stent restenosis in human trials.^{25), 26)}

The results of the study presented here suggest that the possible mechanisms responsible for inhibition of neointimal hyperplasia by abciximab might be anti-platelet, anti-inflammatory, and anti-proliferative actions.

ALA exists endogenously and improves diabetic-induced endothelial dysfunction, probably due to antioxidant effects and direct free-radical scavenging properties.²⁷⁾ Moreover, ALA inhibits the inflammatory pathway and prevents neointimal hyperplasia after stenting in the carotid artery.²⁸⁾ Lim et al.²⁹⁾ have shown that an ALA-coated stent inhibits neointimal formation in a porcine coronary restenosis model. On histopathologic analysis, the neointimal area and the histopathologic area of stenosis were reduced in the ALA coated stent group compared with the control stent group. They hypothezied that by combining ALA and abciximab on a dual-coated stent, they could decrease the level of restenosis in the stented artery based on the anti-proliferative effects of ALA and anticoagulative effects of abciximab.²⁹⁾ Aditionally, delivery of these agents by loading them onto the stent might allow site-specific delivery of an appropriate dose over a prolonged period, thereby reducing potential unwanted systemic effects.

The most important mechanism of coronary stent restenosis is neointimal hyperplasia. However, the mechanism of the pathogenesis of neointimal hyperplasia is not well known. Previous studies have established that inflammation is a major contributor to restenosis after stenting and a significant correlation has been found between the inflammatory reaction and neointimal formation.³⁰⁾ By contrast in our study, a decrease in neointimal hyperplasia was not seen, in spite of the decreased inflammatory reaction seen in the group receiving the dual-coated stent when compared with the control group. We hypothesize that there are other, as yet unknown factors effecting neointimal hyperplasia as well as additional known factors on which the combination of abcixumab and ALA would have no effect. One of these known reasons is an increase in extracellular matrix, which is known to play an important role in neointimal hyperplasia after coronary artery stenting.³⁰⁾

Based on this data, we conclude that ALA and abciximab suppressed the inflammatory reaction, but did not suppress the other causes of neointimal hyperplasia such as the increase in theextracellular matrix. In contrast to preclinical studies on abciximab and ALA, our study demonstrated that a stent coated with abciximab and ALA by plasma polymerization showed no satisfactory inhibition of neointimal hyperplasia compared with control stents in a porcine coronary restenosis model. We suspect that while the rapid release of abciximab and ALA suppressed the inflammatory reaction, the dosage of abciximab and ALA on the stent was not sufficient to inhibit neointimal hyperplasia.

The authors have no financial conflicts of interest.

This work was supported by a Grant-in-Aid for Strategy Technology Development Programs (No. 10030039) from the Korea Ministry of Knowledge and Economy.