While serum-circulating complement destroys invading pathogens, intracellularly active complement, termed the “complosome,” functions as a vital orchestrator of cell-metabolic events underlying T cell effector responses. Whether intracellular complement is also nonredundant for the activity of myeloid immune cells is currently unknown. Here, we show that monocytes and macrophages constitutively express complement component (C) 5 and generate autocrine C5a via formation of an intracellular C5 convertase. Cholesterol crystal sensing by macrophages induced C5aR1 signaling on mitochondrial membranes, which shifted ATP production via reverse electron chain flux toward reactive oxygen species generation and anaerobic glycolysis to favor IL-1β production, both at the transcriptional level and processing of pro–IL-1β. Consequently, atherosclerosis-prone mice lacking macrophage-specific C5ar1 had ameliorated cardiovascular disease on a high-cholesterol diet. Conversely, inflammatory gene signatures and IL-1β produced by cells in unstable atherosclerotic plaques of patients were normalized by a specific cell-permeable C5aR1 antagonist. Deficiency of the macrophage cell-autonomous C5 system also protected mice from crystal nephropathy mediated by folic acid. These data demonstrate the unexpected intracellular formation of a C5 convertase and identify C5aR1 as a direct modulator of mitochondrial function and inflammatory output from myeloid cells. Together, these findings suggest that the complosome is a contributor to the biologic processes underlying sterile inflammation and indicate that targeting this system could be beneficial in macrophage-dependent diseases, such as atherosclerosis.

Objective.Juvenile idiopathic arthritis (JIA) is the most common inflammatory rheumatic disease in childhood. It is regarded as a systemic inflammatory disease with possible increased risk of cardiovascular disease (CVD). The aim of this study was to assess carotid intima-media thickness (IMT) and carotid stenosis as surrogate measures for CVD in adults with longterm active JIA and healthy age- and sex-matched controls.Methods.Seventy-five patients with JIA (age 28–45 yrs) with persistently active disease at least 15 years after disease onset were reexamined after a median of 29 years and compared with 75 matched controls. Patients and controls were examined by color duplex ultrasound of the carotid arteries to compare carotid IMT and carotid stenosis in the 2 groups.Results.Patients with JIA did not have increased carotid IMT values compared with the controls (mean ± SD: 0.56 mm ± 0.09 vs 0.58 mm ± 0.07, p = 0.289). Patients with a higher disease activity indicated by the Juvenile Arthritis Disease Activity Score value above the median value had increased carotid IMT compared with the patients with a lower value, but not statistically different compared with controls. No carotid stenoses were detected in patients or controls.Conclusion.We found similar carotid IMT values in adult patients with JIA and controls.

Background: The composition of a carotid plaque is important for plaque vulnerability and stroke risk. The main aim of this study was to assess the potential of semiautomated segmentation of carotid plaque magnetic resonance imaging (MRI) in the assessment of the size of the lipid-rich necrotic core (LRNC). Methods: Thirty-four consecutive patients with carotid stenosis of 70% or higher, who were scheduled for carotid endarterectomy, underwent a clinical neurological examination, Color duplex ultrasound, 3-T MRI with an 8-channel carotid coil, and blood tests. All examinations were performed less than 24 hours prior to surgery and plaques were assessed histologically immediately following endarterectomy. Plaques were defined as symptomatic when associated with ipsilateral cerebral ischemic symptoms within 30 days prior to inclusion. The level of agreement between the size of the LRNC and calcification on MRI to the histological estimation of the same tissue components, plaque echolucency on ultrasound, and symptoms was assessed. Results: The size of the LRNC on MRI was significantly correlated to the percentage amount of lipid per plaque on histological assessment (P = .010, r = .5), and to echogenicity on ultrasound with echolucent plaques having larger LRNC than echogenic plaques (P = .001, r = -.7). Conclusions: In this study, we found that semiautomated MRI assessments of the percentage LRNC in carotid plaques were significantly correlated to the percentage LRNC per plaque on histological assessment, and to echogenicity on ultrasound with echolucent plaques having larger LRNC than echogenic plaques.

Background Carotid artery plaque inflammation is thought to be an important marker of plaque vulnerability and increased stroke risk. Aim The main aim of this study was to assess the level of agreement between 2-deoxy-2-[ 18 F] fluoro-D-glucose (18F-FDG) uptake on PET (positron emission tomography) scan in carotid plaques, with cerebrovascular symptoms, carotid plaque ultrasound echogenicity and histological assessments of plaque inflammation. Methods Thirty-six patients with ≥70% carotid stenosis scheduled for carotid endarterectomy underwent a Colour Duplex ultrasound, 18 F-FDG PET/CT and blood tests less than 24 h prior to surgery. Plaques were defined as symptomatic when associated with ipsilateral cerebral ischemic symptoms within 30 days prior to inclusion. Plaques were assessed histologically following endarterectomy. The level of agreement between 18 F-FDG uptake (mean SUV max and SUV max ), and target-to-background ratio, symptoms, plaque echolucency, and histological evidence of inflammation was assessed. Results The amount of 18 F-FDG uptake in plaques and the amount of inflammation on histological assessment were significantly correlated (r = 0·521, P = 0·003). 18 F-FDG uptake was significantly higher in symptomatic plaques with median SUV max 1·75 (1·26–2·04) in symptomatic, and 1·43 (1·15–2·28) in asymptomatic patients ( P = 0·03). 18 F-FDG uptake was also positively correlated with echolucency on Doppler ultrasound ( P = 0·03). Conclusion 18 F-FDG uptake on PET/CT correlated with histological assessments of inflammation and was higher in patients with symptomatic compared with asymptomatic carotid artery plaques. These results support the use of 18 F-FDG PET/CT in the detection inflammation in carotid atherosclerosis, which may be of help in the detection of vulnerable plaques.

BACKGROUND:Psoriasis is an immune-mediated inflammatory skin condition of unknown aetiology which usually requires life-long treatment. It is regarded a systemic inflammatory disease with a possible increased risk of cardiovascular disease. The aim of this study was to assess carotid intima-media thickness (IMT), plaque prevalence and carotid stenosis as surrogate measures for cardiovascular disease in psoriasis patients and healthy controls.METHODS:Sixty-two patients with psoriasis and thirty-one healthy controls were included in the study. All were examined by Colour duplex ultrasound of the carotid arteries to compare carotid IMT values, carotid plaques and carotid stenosis in the two groups. Adjustments were made for traditional cardiovascular risk factors.RESULTS:Patients with psoriasis had increased carotid IMT values compared to the controls: mean ± SD 0.71 ± 0.17 mm vs. 0.59 ± 0.08 mm; p = 0.001. When adjusted for known atherosclerotic risk factors this difference remained significant (p = 0.04). Carotid plaques were also more common (p = 0.03) in patients with psoriasis 13 (21%) compared to controls 1 (3%). There was no difference with regard to the number of carotid stenoses in patients and controls.CONCLUSION:The results of this study support previous evidence which suggests that psoriasis is associated with an increased risk for atherosclerosis and subsequent cardiovascular disease.

BACKGROUND:Atherosclerosis is the underlying cause of the majority of myocardial infarctions and ischemic strokes. Carotid intima-media thickness (IMT) is a surrogate measure of atherosclerotic cardiovascular disease. Left ventricular (LV) function can be accurately assessed by 2D speckle-tracking strain echocardiography (2D-STE). The aim of this study was to assess the relationship between carotid IMT and LV dysfunction assessed by strain echocardiography in patients with coronary artery disease (CAD).METHODS:Thirty-one patients with symptoms of CAD were examined with coronary angiography, cardiac echocardiography and carotid ultrasound. Layer-specific longitudinal strains were assessed from endo-, mid- and epicardium by 2D-STE. LV global longitudinal strain (LVGLS) was averaged from 16 longitudinal LV segments in all 3 layers. LVGLS results were compared with coronary angiography findings in a receiver operating curve (ROC) to determine the cut-off for normal and pathological strain values. The calculated optimal strain value was compared to maximal carotid IMT measurements.RESULTS:The ROC analysis for strain versus coronary angiography was: area under curve (AUC)=0.91 (95% CI 0.80 - 1.0), cut-off value for endocardial LVGLS: -16.7%. Further analyses showed that increased carotid IMT correlated with low absolute strain values (p=0.006) also when adjusted for hypertension, smoking, hyperlipidemia, diabetes and BMI (p=0.02).CONCLUSIONS:In this study increased carotid IMT values were associated with decreased LV function assessed by strain measurements. These findings support the use of carotid IMT measurements to predict the risk of coronary heart disease.

BACKGROUND AND PURPOSE:Multipurpose ultrasound probes combined with ultra-mobile ultrasound instrumentation have the potential to increase the availability and use of ultrasound examinations in the assessment of atherosclerotic burden and cardiac disease. The aim of this study was to compare the agreement of a newly developed multipurpose probe to a standard linear carotid probe in detection of atherosclerosis of the precerebral arteries.METHODS:We examined 103 patients with a multipurpose probe (General Electric, G9L MPP-9 MHz) and a standard linear probe (General Electric, Vivid 7-M12L-14 MHz). Measurements included intima-media thickness (IMT) in the common carotid arteries (CCA), carotid bifurcations (BIF), internal carotid arteries (ICA), and detection of carotid plaques and stenoses.RESULTS:We found a significant level of agreement between the two probes for all IMT measurements with intraclass correlation coefficients (ICC) of: left CCA .91, left BIF .68, left ICA .75, right CCA .84, right BIF .74, and right ICA .59. Agreement with regard to carotid plaque and stenosis detection had kappa values of .94 and .93.CONCLUSION:The multipurpose probe showed agreement with a standard linear probe in detecting atherosclerosis of the carotid arteries and has therefore the potential for use in both cardiac and precerebral ultrasound examinations.