Patients with substantial carotid artery narrowing are at increased risk for major stroke,^1-6 but the pathogenic mechanisms linking carotid atherosclerosis and ischemic brain injury still need to be fully clarified.Clinical trials designed to evaluate the beneficial effects of endarterectomy in symptomatic and asymptomatic patients have focused on carotid stenosis severity and plaque ulceration as risk factors for cerebrovascular events. The results of the European Carotid Surgery Trial^2,3 and the North American Symptomatic Carotid Endarterectomy Trial(NASCET)^4,5 suggest that surgery is indicated for stroke prevention when stenosis is more than 70%. TheNASCET study showed that among symptomatic patients with high-grade carotid stenosis (>70%) not treated by surgery, the 2-year rate of any ipsilateral stroke was 26.0% for major stroke and 13.1% for fatal stroke.⁵ The Asymptomatic Carotid Atherosclerosis Study⁷ suggested that indications for carotid endarterectomy could be broadened to include asymptomatic patients with carotid stenosis of more than 60% and that the aggregate risk over 5 years for ipsilateral stroke and any perioperative stroke was estimated at 11.0% for asymptomatic patients treated medically.

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of fatty deposits in the inner walls of vessels. These plaques restrict blood flow and lead to complications such as heart attack or stroke. The development of atherosclerosis is influenced by a variety of factors, including age, genetics, lifestyle, and underlying health conditions such as high blood pressure or diabetes. Atherosclerotic plaques in stable form are characterized by slow growth, which leads to luminal stenosis, with low embolic potential or in unstable form, which contributes to high risk for thrombotic and embolic complications with rapid clinical onset. In this complex scenario of atherosclerosis, macrophages participate in the whole process, including the initiation, growth and eventually rupture and wound healing stages of artery plaque formation. Macrophages in plaques exhibit high heterogeneity and plasticity, which affect the evolving plaque microenvironment, e.g., leading to excessive lipid accumulation, cytokine hyperactivation, hypoxia, apoptosis and necroptosis. The metabolic and functional transitions of plaque macrophages in response to plaque microenvironmental factors not only influence ongoing and imminent inflammatory responses within the lesions but also directly dictate atherosclerotic progression or regression. In this review, we discuss the origin of macrophages within plaques, their phenotypic diversity, metabolic shifts, and fate and the roles they play in the dynamic progression of atherosclerosis. It also describes how macrophages interact with other plaque cells, particularly T cells. Ultimately, targeting pathways involved in macrophage polarization may lead to innovative and promising approaches for precision medicine. Further insights into the landscape and biological features of macrophages within atherosclerotic plaques may offer valuable information for optimizing future clinical treatment for atherosclerosis by targeting macrophages.

Background — Hyperglycemia impairs functional properties of cytosolic and nuclear proteins via O-linked glycosylation modification (O-GlcNAcylation). We studied the effects of O-GlcNAcylation on insulin signaling in human coronary artery endothelial cells. Methods and Results — O-GlcNAcylation impaired the metabolic branch of insulin signaling, ie, insulin receptor (IR) activation of the IR substrate (IRS)/phosphatidylinositol 3-kinase (PI3-K)/Akt, whereas it enhanced the mitogenic branch, ie, ERK-1/2 and p38 (mitogen-activated protein kinase). Both in vivo and in vitro phosphorylation of endothelial nitric oxide synthase (eNOS) by Akt were reduced by hyperglycemia and hexosamine activation. Insulin-induced eNOS activity in vivo was reduced by hyperglycemia and hexosamine activation, which was coupled to increased activation and expression of matrix metalloproteinase-2 and -9; these phenomena were reversed by inhibition of the hexosamine pathway. Finally, carotid plaques from type 2 diabetic patients showed increased endothelial O-GlcNAcylation with respect to nondiabetics. Conclusions — Our data show that hyperglycemia, through the hexosamine pathway, impairs activation of the IR/IRS/PI3-K/Akt pathway, resulting in deregulation of eNOS activity.

F2-Isoprostanes are prostaglandin (PG) isomers formed in situ in cell membranes by peroxidation of arachidonic acid. 8-epi PGF2alpha and IPF2alpha-I are F2-isoprostanes produced in humans which circulate in plasma and are excreted in urine. Measurement of F2-isoprostanes may offer a sensitive, specific, and noninvasive method for measuring oxidant stress in clinical settings where reactive oxygen species are putatively involved. We determined whether isoprostanes were present in human atherosclerotic lesions, where lipid peroxidation is thought to occur in vivo. 8-epi PGF2alpha ranged from 1.310-3.450 pmol/micromol phospholipid in atherectomy specimens compared with 0.045-0.115 pmol/micromol phospholipid (P < 0.001) in vascular tissue devoid of atherosclerosis. Corresponding values of IPF2alpha-I were 5.6-13.8 vs. 0.16-0.44 pmol/micromol phospholipid (P < 0.001). Levels of the two isoprostanes in vascular tissue were highly correlated (r = 0.80, P < 0.0001). Immunohistochemical studies confirmed that foam cells adjacent to the lipid necrotic core of the plaque were markedly positive for 8-epi PGF2alpha. These cells were also reactive with anti-CD68, an epitope specific for human monocyte/macrophages. 8-epi PGF2alpha immunoreactivity was also detected in cells positive for anti-alpha-smooth muscle actin antibody, which specifically recognizes vascular smooth muscle cells. Our results indicate that 8-epi PGF2alpha and IPF2alpha-I, two distinct F2-isoprostanes and markers of oxidative stress in vivo, are present in human atherosclerotic plaque. Quantitation of these chemically stable products of lipid peroxidation in target tissues, as well as in biological fluids, may aid in the rational development of antioxidant drugs in humans.

Inflammation plays a major role in all phases of atherosclerosis. Stable plaques are characterized by a chronic inflammatory infiltrate, whereas vulnerable and ruptured plaques are characterized by an “active” inflammation involved in the thinning of the fibrous cap, predisposing the plaque to rupture. Although a single vulnerable atherosclerotic plaque rupture may cause the event, there are many other types of plaques, several of which are vulnerable. The existence of multiple types of vulnerable plaques suggests that atherosclerosis is a diffuse inflammatory process. A current challenge is to identify morphologic and molecular markers able to discriminate stable plaques from vulnerable ones, allowing the stratification of patients at high risk for acute cardiovascular and cerebrovascular events before clinical syndromes develop. With that aim in mind, this article summarizes the natural history of atherosclerotic plaques, focusing on molecular mechanisms affecting plaque progression and serum markers correlated with plaque inflammation.