Inflammation Coupling Between Unstable Carotid Plaque and Spleen-A 18F-Fluorodeoxyglucos Positron Emission Tomography Study.

BACKGROUND AND PURPOSE: This study was aimed to assess the hypothesis that unstable plaque formation in the carotid artery is one of phenotypes of chronic and systemic inflammation. METHODS: This study included 8 symptomatic patients with internal carotid stenosis (ICS) and 7 healthy controls. All subjects underwent 18F-fluorodeoxyglucos positron emission tomography (18F-FDG PET) of whole body. Plaque vulnerability was evaluated on magnetic resonance imaging (MRI). On 18F-FDG PET, the maximum standardized uptake (SUVmax) value was measured in the carotid plaque, aorta, spleen, liver, and bone marrow. The SUVmax ratio of the spleen or bone marrow to the liver was also calculated. These values were compared between 2 groups. All 8 patients in ICS group underwent carotid endarterectomy, and surgical specimens were subjected to immunohistochemistry. RESULTS: All 8 patients in ICS group had unstable plaque on MRI. The mean SUVmax of carotid plaque was 2.5 ± .2 in ICS group. The SUVmax of spleen was significantly higher in ICS group than in the controls (3.20 ±  .25 and 2.51 ±  .40, respectively; P = .003). The SUVmax ratio (spleen/liver) was also significantly higher in ICS group than in the controls (1.12 ±  .06 and .85 ±  .12, respectively; P = .001). The SUVmax of aorta was also significantly higher in ICS group than in the controls (2.16 ±  .27 and 1.48 ±  .15, respectively; P = .001). However, there were no significant differences in the SUVmax in the bone marrow and SUVmax ratio (bone marrow/liver) between the 2 groups (P = .811 and P = .731, respectively). Histological examination showed that the plaque strongly expressed endothelial progenitor cells, microvessels, and M1 macrophages. CONCLUSIONS: These data strongly suggest the inflammation coupling between the spleen and unstable carotid plaque, and may be useful to develop novel therapeutic strategies against systemic inflammation in patients with ICS.

Chronic intermittent hypoxia induces local inflammation of the rat carotid body via functional upregulation of proinflammatory cytokine pathways.

Maladaptive changes in the carotid body (CB) induced by chronic intermittent hypoxia (IH) account for the pathogenesis of cardiovascular morbidity in patients with sleep-disordered breathing. We postulated that the proinflammatory cytokines, namely interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α, and cytokine receptors (IL-1r1, gp130 and TNFr1) locally expressed in the rat CB play a pathophysiological role in IH-induced CB inflammation. Results showed increased levels of oxidative stress (serum 8-isoprostane and nitrotyrosine in the CB) in rats with 7-day IH treatment resembling recurrent apneic conditions when compared with the normoxic control. Local inflammation shown by the amount of ED1-containing cells (macrophage infiltration) and the gene transcripts of NADPH oxidase subunits (gp91(phox) and p22(phox)) and chemokines (MCP-1, CCR2, MIP-1α, MIP-1ß and ICAM-1) in the CB were significantly more in the hypoxic group than in the control. In addition, the cytokines and receptors were expressed in the lobules of chemosensitive glomus cells containing tyrosine hydroxylase and the levels of expressions were significantly increased in the hypoxic group. Exogenous cytokines elevated the intracellular calcium ([Ca(2+)](i)) response to acute hypoxia in the dissociated glomus cells. The effect of cytokines on the [Ca(2+)](i) response was significantly greater in the hypoxic than in the normoxic group. Moreover, daily treatment of IH rats with anti-inflammatory drugs (dexamethasone or ibuprofen) attenuated the levels of oxidative stress, gp91(phox) expression and macrophage infiltration in the CB. Collectively, these results suggest that the upregulated expression of proinflammatory cytokine pathways could mediate the local inflammation and functional alteration of the CB under chronic IH conditions.

Carotid aneurism with acute dissection: an unusual case of IgG4-related diseases.

AIM: IgG4-related disease is a systemic disease that involves organs and vascular structures, in particular, the aorta. This is the first case that showed the carotid artery involvement with dissection evolution. METHODS AND RESULTS: In a 67-year-old man with speech impairment and right-hand clumsiness, a brain computed tomography revealed signs of acute ischemia in the left frontal lobe while an echo-color Doppler sonography of the cervical vessels showed a tight stenosis of left internal carotid artery with a large pseudoaneurysm. Histological findings performed on the surgical specimen disclosed IgG4-related disease. CONCLUSIONS: To the best of our knowledge, this is the first manifestation of IgG4-related disease with carotid artery dissection complicated by pseudoaneurysm. Even though unsuccessful since the patients died within 48 h, this case highlights the diverse facets of the IgG4-related disease representing a new complication with important clinical implications of such a diagnosis targeting immunosuppressive therapy particularly B-cell depletion.

Attempt to establish an experimental animal model of moyamoya disease using immuno-embolic material--histological changes of the arterial wall resulting from immunological reaction in cats.

In this study, we investigated the relationship between intimal thickening of the internal carotid artery (ICA) and immunological reaction, and between occlusion of the ICA and development of basal collateral vessels in moyamoya disease. Rod-shaped lactic acid-glycolic acid copolymer (LGA-50) and N-acetylmuramyl-L-alanyl-D-isoglutamine (muramyl dipeptide: MDP), and immuno-embolic material, were injected into cats unilaterally via the common carotid artery. Histological changes of duplication of the internal elastic lamina could be seen mainly in the terminal portion of the ICA in the animals injected with rod-shaped LGA-50 containing MDP. No angiographic changes were seen in any of the animals. These findings suggest that the immunological reaction induced by MDP caused histological changes in the intima of the ICA similar to those observed in moyamoya disease. This experimental study, however, could not clarify the development of the basal collateral vessels.

IgG-anticardiolipin-antibodies are markers for cerebral and peripheral artery disease.

Anticardiolipin-antibodies are antibodies to phospholipids which were first detected in patients with arterial thrombosis and lupus erythematosus. In this prospective study, IgG- and IgM-anticardiolipin-antibodies were determined in patients with cerebral and/or peripheral artery disease but without autoimmune disorders. 123 randomly selected patients (88 males, 35 females; mean: 65 +/- 10, range: 41-85 years) were included and divided into four groups: 18 patients with isolated cerebrovascular disease (group A), 35 patients with peripheral artery disease only (group B), 35 patients suffering from cerebral and peripheral artery disease (group C) and 35 patients as controls (group D). In family history, cholesterol, blood sugar and prothrombin time the four patient groups did not differ significantly, whereas patients of group B and C were more often smokers than those in groups A and D. However, IgG-anticardiolipin-antibody-levels were significantly elevated in patients with cerebral and peripheral artery disease compared to controls (p less than 0.01). The highest values were seen in group C where patients suffered from cerebral and peripheral artery disease (n.s.). On the other hand, IgM-anticardiolipin-antibody-levels did not show any differences in the four groups. Furthermore, there was no correlation between vascular risk factors and/or laboratory findings with IgG- and IgM-antibody-levels. Thus, elevated IgG-anticardiolipin-antibodies appear to be independent markers for severe cerebral and peripheral artery disease and should be determined in patients at increased risk.

Identification of inflamed atherosclerotic lesions in vivo using PET-CT.

Inflammation plays a major pathogenetic role in the development of atherosclerotic plaques and related thromboembolic events. The identification of vulnerable plaques is of the utmost importance, as this may allow the implementation of more effective preventive and therapeutic interventions. Fluorodeoxyglucose positron emission tomography (FDG-PET) has been shown to be useful for tracing inflammation within plaques. However, its relationship to immunohistochemical findings in different territories of the peripheral circulation was not completely elucidated. We aimed to determine whether plaque inflammation could be measured by PET in combination with computer tomography (CT) using FDG and what is the relationship between FDG uptake and immunohistochemical findings in the removed atherosclerotic lesions of the femoral and carotid arteries. The study included 31 patients, 21 patients with high-grade stenosis of the internal carotid artery (ICA) and 10 patients with occlusion of the common femoral artery (CFA), all of whom underwent endarterectomy. Before endarterectomy in all patients, FDG-PET/CT imaging was performed. FDG uptake was measured as the maximum blood--normalized standardized uptake value, known as the target to background ratio (TBR max). TBR max amounted to 1.72 ± 0.8, and in patients with ICA, stenosis was not significantly different from patients with CFA occlusion. Immunohistochemical and morphometric analyses of the plaques obtained at endarterectomy showed that the density of T lymphocytes and macrophages (number of cells per square millimeter) was significantly higher in subjects with stenosis of the ICA than in subjects with occlusion of the femoral arteries: lymphocytes, 1.26 ± 0.21 vs. 0.77 ± 0.29; p = 0.02 and macrophages, 1.01 ± 0.18 vs. 0.69 ± 0.23; p = 0.003. In the whole group of patients, the density of inflammatory cells significantly correlated with FDG uptake represented by PET-TBR max: T lymphocytes, r = 0.60; p < 0.01 and macrophages, r = 0.65; p < 0.01. The results of our study show that FDG uptake is related to the accumulation of inflammatory cells in atherosclerotic lesions. This finding suggests that FDG uptake reflects the severity of atherosclerotic vessel wall inflammation, and in stenotic lesions, it could be an indicator of their vulnerability. However, data from large outcome studies is needed to estimate the usefulness of this technique in identifying the most dangerous atherosclerotic lesions and vulnerable patients.

Plasma interleukin-5 levels are related to antibodies binding to oxidized low-density lipoprotein and to decreased subclinical atherosclerosis.

OBJECTIVES: This study's aim was to assess the role of interleukin (IL)-5 in modulating the levels of antibodies binding to oxidized low-density lipoprotein (OxLDL) in human atherosclerosis. BACKGROUND: Various pro- and anti-inflammatory cytokines have been implicated in atherogenesis, and recent findings in mice indicate that the cytokine IL-5 plays a protective role in atherosclerosis in part via the induction of antibodies binding to OxLDL. METHODS: Plasma IL-5 levels and antibody titers to 2 most commonly used models of OxLDL (copper OxLDL and malondialdehyde-modified LDL) were measured in 1,011 Finnish middle-aged subjects with chemiluminescent enzyme-linked immunosorbent assay. Intima-media thickness (IMT) was assessed ultrasonographically from the internal carotid artery, the bifurcation, and the common carotid artery. RESULTS: There was a significant positive association between plasma IL-5 levels and antibody titers to copper OxLDL (p = 0.010 and p = 0.044, immunoglobin [Ig] M and G, respectively) and IgM to malondialdehyde-modified LDL (p < 0.001) in the association analysis performed between different IL-5 quartiles. Furthermore, plasma IL-5 levels were found to be inversely associated with bifurcational IMT, and even after adjustments for traditional risk factors of atherosclerosis (age, gender, smoking, systolic blood pressure, LDL, and body mass index), IL-5 remained an independent determinant of the mean bifurcational IMT (p = 0.010). CONCLUSIONS: Our data demonstrate that plasma IL-5 levels are related to the plasma levels of antibodies binding to OxLDL and to decreased subclinical atherosclerosis in humans. These results are in line with earlier findings in murine atherosclerosis and indicate for the first time that IL-5 may play a role in human atherosclerosis.

[Statins and their influence on inflammatory processes in internal carotid artery stenosis]. / Statine und ihr Einfluss auf entzündliche Prozesse in arteriosklerotischen Plaques bei Patienten mit Stenose der Arteria carotis interna.

Arterio-arterial emboli originating from a high-grade stenosis of the internal carotid artery are a common cause for cerebral ischemias. Inflammatory processes are not only pivotal in the development of atherosclerotic vessel wall changes, but also for their clinical destabilization. Inflammatory cells, like macrophages, can turn a chronic high-grade carotid stenosis into a high-risk area for the development of arterial thromboses by way of a complex pathogenesis involving the elevation of proinflammatory factors, biosynthesis of collagen-degrading matrix metalloproteinases and expression of prothrombotic tissue factor. This process could affect the occurrence of perioperative complications during carotid endarterectomies. Statins are potent cholesterol-lowering agents. Among other lipid-independent effects, statins appear to play a significant role in preventing cardiovascular events. A number of studies have shown that statins possess plaque-stabilizing effects and that they improve cerebral autoregulation. A growing evidence supports the preoperative administration of statins in patients with high-grade stenoses of the internal carotid artery.

Endothelial apoptosis does not determine symptom status in carotid artery disease.

BACKGROUND: We examined the hypothesis that endothelial denudation in advanced carotid plaques (CPs) occurs by increased apoptosis of endothelial cells (ECs) using scanning electron microscopy (SEM) as well as markers of cellular proliferation and apoptosis in advanced symptomatic CPs (SCPs) and asymptomatic CPs (ACPs). METHODS: 93 consecutive patients underwent carotid endarterectomy. Five additional specimens were studied by SEM. We performed TUNEL assays, and immunostaining against Fas receptor (FasR), Fas ligand (FasL), activated caspase 3 (ACA3) and Ki-67. RESULTS: SEM revealed morphological changes consistent with EC detachment. Surprisingly, ACA3 positivity was more pronounced on the endothelium of ACPs (4.6 +/- 0.7% of total EC count) than on SCPs (3.3 +/- 0.7%, p = 0.049), and was found to correlate positively with nuclear Ki-67 expression (r(s) = 0.275, p = 0.040). FasL expression was significantly increased on the endothelium of SCPs compared with ACPs (66.4 +/- 4.4 vs. 53.9 +/- 4.5%, p = 0.047). CONCLUSIONS: Absence of increased positivity of apoptotic markers dismisses apoptosis as a dominant mechanism underlying endothelial detachment of SCPs. Rather, increased ACA3 with co-expression of Ki-67 in ACPs might suggest that renewal of endothelium by active cell turnover may contribute to clinically silent evolution of plaques with preserved EC integrity. These observations may assist in designing novel therapies to prevent endothelial decay and symptom generation in advanced carotid artery disease.

Carotid rupture and intraplaque hemorrhage: immunophenotype and role of cells involved.

BACKGROUND: A complete immunohistochemical characterization in complicated carotid plaques is still lacking. The cellular components of 165 carotid endarterectomy specimens were analyzed to assess their role in the pathogenesis of plaque rupture and intraplaque hemorrhage without rupture. METHODS AND RESULTS: The fibrous caps at the sites of plaque rupture showed CD68+ macrophages, T-lymphocytes, and scarce B-lymphocytes. Ruptured plaques showed mononuclear infiltrates in the caps, shoulders, and bases of the plaques in 85% of the cases. Only 46% of nonruptured plaques showed such infiltrates (P <.0001). Two types of lipid cores were recognized: avascular or mildly vascularized and highly vascularized. The vessels of the latter type reacted with CD31 and CD34. In 57.5% of the cases, the base and the shoulders of the plaques showed neoformed, CD34+ vessels, often surrounded by mononuclear infiltrates. Intraplaque hemorrhage without rupture had highly vascularized lipid cores in all cases. T-lymphocytes and macrophages were in close contact with neoformed vessels. CONCLUSIONS: Plaque rupture is characterized by mononuclear cell infiltration of the caps, whereas intraplaque hemorrhage without rupture is characterized by extensive vascularization of the plaque.

[Unstable carotid stenosis--an inflammatory disease?]. / Die instabile Karotisstenose--eine entzündliche Erkrankung?

Arterioarterial thromboembolism from extracranial internal carotid artery (ICA) stenosis is an important pathogenic mechanism of ischemic stroke. However, even a high-grade ICA stenosis carries a greatly variable annual risk of stroke, as high as 13% following a recent occurrence of transient or minor cerebral ischemia or as low as 1-2% in clinically asymptomatic patients. There is increasing evidence that inflammatory processes play a central role in atherosclerosis and particularly in plaque destabilization converting chronic atherosclerosis into an acute neurological disorder. In thromboendarterectomy specimens from patients with high-grade ICA stenoses, the extent of inflammatory infiltration and the expression of matrixmetalloproteinase-9 correlated to clinical and ultrasonic features of plaque destabilization such as cerebral microembolism. Inflammation might become a new therapeutic target in symptomatic carotid artery disease.

Human leukocyte antigen in patients with moyamoya disease.

BACKGROUND AND PURPOSE: Progressive stenosis or occlusion of bilateral internal carotid arteries by fibrocellular intimal thickening results in cerebral ischemia in moyamoya disease. In an attempt to elucidate the still-unknown etiologic factors in moyamoya disease, we assessed human leukocyte antigens in patients with this disease. METHODS: We investigated 32 unrelated Japanese patients with moyamoya disease for typing of human leukocyte antigen A, B, C, and DR/DQ and compared the results with those from 178 unrelated control subjects. RESULTS: We found a significant association of human leukocyte antigen B51 with moyamoya disease (corrected P < .05, chi 2 test). Although no significant associations were observed in DR/DQ typing, the frequency of the B51-DR4 combination was significantly higher in moyamoya patients than in control subjects (P < .002, Fisher's exact test). CONCLUSIONS: These findings suggest that there may be a genetic predisposition for moyamoya disease and that host factors may play a role in the development of intimal thickening in early childhood.

Moyamoya-like disease with inflammation.

A 29-year-old Caucasian male died from massive cerebral infarction due to unilateral occlusion of the terminal internal carotid artery. The carotid occlusion was secondary to subendothelial fibrous tissue proliferation which was associated with a considerable mononuclear cell infiltration of the carotid wall, characterised as T cells by immunoperoxidase methods. Angiography showed vascular network at the base of the brain compatible with Moyamoya disease. We suggest that the pathogenesis of Moyamoya-like disease in our patient involved a T-cell-mediated attack to a vascular antigen.