Guido R.Y. De Meyer

Histopathologic evaluation of a novel‐design nitinol stent: the Biflex stent

BACKGROUND: Optimalization and improvement in stent material, stent design and deployment may alleviate the problem of restenosis after stenting. The Biflex stent is a novel‐design stent made of nitinol; the vascular response after deployment in rabbit iliac arteries was evaluated. METHODS AND RESULTS: Normocholesterolemic New Zealand white rabbits (n = 8) were used. Iliac arteries were randomized to receive either a stainless steel control stent or a nitinol stent and rabbits were euthanized at 30 days after implantation. All animals survived and there were no adverse events. Vessels were harvested and prepared for histopathologic analysis and histomorphometry. Stents were well opposed to the vessel wall and thrombi were absent. The lumen area and the area within the internal elastic lamina were significantly larger in the nitinol stent group as opposed to the control group (3.8 ± 0.1 vs 3.3 ± 0.1 mm 2 , p = 0.009 and 4.6 ± 0.1 vs 4.1 ± 0.2 mm 2 , p = 0.03, respectively). There were no differences in injury score, neointimal area, medial area, area within the external elastic lamina and amount of inflammatory cells. Staining for alpha‐smooth muscle cell actin and endothelium did not show any differences between the two groups as assessed semiquantitatively. CONCLUSION: This nitinol stent with a novel design demonstrated acceptable biocompatibility in iliac arteries of normocholesterolemic rabbits with minimal foreign‐body reaction and minimal neointimal formation. (Int J Cardiovasc Intervent 2004; 1: 13–19)

The Role of Autophagy in Atherosclerosis

Atherosclerosis is a chronic inflammatory disease of large and middle-sized blood vessels, and the leading cause of death among adults in the Western world. Recent evidence suggests that several molecular and cellular mechanisms play an important role in atherosclerosis and plaque progression. One of these mechanisms includes autophagy, a subcellular process for elimination of damaged organelles and protein aggregates via lysosomes. According to in vitro observations, the autophagic machinery is stimulated by several stress-related stimuli inside plaques, such as oxidized lipids, endoplasmic reticulum stress, hypoxia, nutrient deprivation, and inflammation. Although its role in atherosclerosis has not yet been fully established, a growing body of evidence indicates that autophagy has a protective function in atherosclerosis. It stimulates cholesterol efflux and reduces foam cell formation. Moreover, it prevents apoptosis by removing oxidatively damaged hyperpolarized mitochondria before reactive oxygen species production and cytochrome c release. Another important recent finding is that macrophage autophagy plays an essential role in delaying lesion progression by suppressing inflammasome activation. Interestingly, excessive everolimus-induced autophagy leads to selective macrophage death, and is a promising plaque-stabilizing strategy. Overall, autophagy seems to be a major player in atherosclerosis, but further research has to be performed to fully clarify its role in this disease.

Dendritic Cells in Atherogenesis: From Immune Shapers to Therapeutic Targets

Atherosclerosis has been formerly considered as a lipid-mediated disease. It has long been assumed that atherogenesis could be simply explained by lipid accumulation in the vessel wall leading to endothelial dysfunction with adverse vascular wall remodelling. However, over the last decade, a number of studies have clearly demonstrated that lipids are not the whole story in the pathogenesis of atherosclerosis. Accumulating evidence has shown that inflammation and the immune system play a major role in the initiation, progression and destabilization of atheromata [1,2,3,4]. Mainly innate immunity pathways have long been believed to contribute to atherogenesis, and special attention has been given to macrophag‐ es, because these effector cells are important for intracellular lipid accumulation and foam cell formation [5]. Yet, although macrophages constitute the largest cell population, other immune cell subsets, namely dendritic cells (DCs) and T cells, can also be found within athe‐ rosclerotic plaques and seem to participate in immune responses during atherogenesis.

(Auto)Phagocytosis in Atherosclerosis: Implications for Plaque Stability and Therapeutic Challenges

This chapter is intended to describe the interactions between cell death, phagocytosis and autophagic survival in atherosclerosis, and how these processes could be attractive therapeutic targets for atherosclerotic plaque stabilization. Atherosclerosis is a long-term, progressive inflammatory disease characterized by the formation of atherosclerotic plaques in the intima of mediumand large-sized arteries. Progression of the disease is accelerated by well-known risk factors including gender, age, hypercholesterolemia, diabetes mellitus, hypertension, smoking, obesity and a sedentary life-style (Kannel et al., 2004). In the advanced stage, plaques can partially or totally occlude the blood vessel, known as arterial stenosis. However, not only the degree of stenosis, but also the composition and stability of the plaque determines the clinical outcome of the disease (Hansson, 2005). Indeed, plaques may become extremely unstable and prone to rupture through the presence of many inflammatory cells and mediators, a large necrotic core consisting of uncleared cell debris and lipids, a high degree of cell death leading to a scarce amount of smooth muscle cells, and the formation of leaky neovessels inside the plaque. Occlusive thrombi, as a result of plaque rupture, in turn cause acute (and often fatal) clinical manifestations, such as myocardial infarction and stroke. Current clinical therapy is focused on chirurgical interventions (stents, endarterectomy, bypass) and plasma cholesterol lowering drugs (e.g. statins). In addition, changes in diet and exercise have made significant inroads in preventing acute atherothrombotic events (Getz & Reardon, 2006). Although these aforementioned approaches have provided significant improvements, they are far from sufficient. Analysis of the cell death and phagocytosis machinery as well as survival strategies of cells in plaques could provide additional insights for development of new plaque stabilizing strategies.