Objectives Human coronary bare metal stents (BMS) and drug-eluting stents (DES) from autopsy cases with implant durations >30 days were examined for the presence of neointimal atherosclerotic disease. Background Neointimal atherosclerotic change (neoatherosclerosis) following BMS implantation is rarely reported and usually occurs beyond 5 years. The incidence of neoatherosclerosis following DES implantation has not been reported. Methods All available cases from the CVPath stent registry (n=299 autopsies), which includes a total of 406 lesions (197 BMS, 209 DES [103 sirolimus-eluting stents (SES), and 106 paclitaxel-eluting stents (PES)]) with implant duration >30 days were examined. Neoatherosclerosis was recognized as clusters of lipid-laden foamy macrophages within the neointima with or without necrotic core formation. Results The incidence of neoatherosclerosis was significantly greater in DES (31%) than BMS (16%) lesions (p<0.001). The median stent duration with neoatherosclerosis was shorter in DES than BMS (DES; 420 [361–683], BMS; 2160 [1800–2880] days, p<0.001). Unstable lesions characterized as thin-cap fibroatheromas or plaque rupture were more frequent in BMS (n=7, 4%) than DES (n=3, 1%) (p=0.17), with relatively shorter implant durations for DES (1.5±0.4 years) compared to BMS (6.1±1.5 years). Independent determinants of neoatherosclerosis identified by multiple logistic regression included younger age (p<0.001), longer implant durations (p<0.001), SES usage (p<0.001), PES usage (p=0.001), and underlying unstable plaques (p=0.004). Conclusions Neoatherosclerosis is a frequent finding in DES and occurs earlier than in BMS. Unstable features of neoatherosclerosis are identified for both BMS and DES with shorter implant durations for the latter. The development of neoatherosclerosis may be yet another rare contributing factor to late thrombotic events.

Deployment of drug-eluting stents instead of bare-metal stents has dramatically reduced restenosis rates, but rates of very late stent thrombosis (>1 year postimplantation) have increased. Vascular endothelial cells normally provide an efficient barrier against thrombosis, lipid uptake, and inflammation. However, endothelium that has regenerated after percutaneous coronary intervention is incompetent in terms of its integrity and function, with poorly formed cell junctions, reduced expression of antithrombotic molecules, and decreased nitric oxide production. Delayed arterial healing, characterized by poor endothelialization, is the primary cause of late (1 month-1 year postimplantation) and very late stent thrombosis following implantation of drug-eluting stents. Impairment of vasorelaxation in nonstented proximal and distal segments of stented coronary arteries is more severe with drug-eluting stents than bare-metal stents, and stent-induced flow disturbances resulting in complex spatiotemporal shear stress can also contribute to increased thrombogenicity and inflammation. The incompetent endothelium leads to late stent thrombosis and the development of in-stent neoatherosclerosis. The process of neoatherosclerosis occurs more rapidly, and more frequently, following deployment of drug-eluting stents than bare-metal stents. Improved understanding of vascular biology is crucial for all cardiologists, and particularly interventional cardiologists, as maintenance of a competently functioning endothelium is critical for long-term vascular health.

Objectives To examine selective macrophage differentiation occurring in areas of intraplaque hemorrhage in human atherosclerosis. Background Macrophage subsets are recognized in atherosclerosis but the stimulus for and importance of differentiation programs remains unknown. Methods We used freshly isolated human monocytes, a rabbit model, and human atherosclerotic plaques to analyze macrophage differentiation in response to hemorrhage. Results Macrophages characterized by high expression of both mannose and CD163 receptors preferentially exist in atherosclerotic lesions at sites of intraplaque hemorrhage. These hemoglobin (Hb)-stimulated macrophages, M(Hb), are devoid of neutral lipids typical of foam cells. In vivo modeling of hemorrhage in the rabbit model demonstrated that sponges exposed to red cells showed an increase in mannose receptor positive macrophages only when these cells contained hemoglobin (Hb). Cultured human monocytes exposed to hemoglobin:haptoglobin complexes (Hb:Hp), but not IL-4, expressed the M(Hb) phenotype and were characterized by their resistance to cholesterol loading and upregulation of ABC transporters. M(Hb) demonstrated increased ferroportin (FPN) expression, reduced intracellular iron, and reactive oxygen species (ROS). Degradation of FPN using hepcidin increased ROS, inhibited ABCA1 expression, and cholesterol efflux to ApoAI, suggesting reduced ROS triggers these effects. Knockdown of liver x receptor alpha (LXRα) inhibited ABC transporter expression in M(Hb) and macrophages differentiated in the anti-oxidant superoxide dismutase. Lastly, liver X receptor α (LXR) luciferase reporter activity was increased in M(Hb) and significantly reduced by overnight treatment with hepcidin. Collectively, these data suggest reduced ROS triggers LXRα activation and macrophage reverse cholesterol transport (RCT). Conclusions Hb is a stimulus for macrophage differentiation in human atherosclerotic plaques. A reduction of macrophage intracellular iron plays an important role in this non- foam cell phenotype by reducing ROS, which drives transcription of ABC transporters through activation of LXRα. Reduction of macrophage intracellular iron may be a promising avenue to increase macrophage RCT.

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