Karolina Skagen

Interleukin 23 Levels Are Increased in Carotid Atherosclerosis Possible Role for the Interleukin 23/Interleukin 17 Axis

Background and Purpose— Interleukin (IL)-23 is a cytokine in the IL-12 family, mainly produced by antigen-presenting cells with a central role in inflammation. We hypothesize that IL-23 is also important in atherogenesis and investigate this in a population with carotid atherosclerosis. Methods— Plasma levels of IL-23 were measured in patients with carotid artery stenosis and in healthy controls. The mRNA levels of IL-23 and its receptor, IL-23R, were measured in atherosclerotic plaques, nonatherosclerotic vessels, peripheral blood mononuclear cells, and plasmacytoid dendritic cells. Results— Our findings were as follows: (1) patients with carotid atherosclerosis (n=177) had significantly raised plasma levels of IL-23 when compared with healthy controls (n=24) with particularly high levels in those with the most recent symptoms. (2) mRNA levels of IL-23 and IL-23R were markedly increased in carotid plaques (n=68) when compared with nonatherosclerotic vessels (n=8–10). Immunostaining showed colocalization to plaque macrophages. (3) Patients with carotid atherosclerosis had increased mRNA levels of both IL-23 and IL-23R in plasmacytoid dendritic cells, but not in peripheral blood mononuclear cells. (4) IL-23 increased IL-17 release in monocytes and particularly in peripheral blood mononuclear cells from patients with carotid atherosclerosis, but not in cells from healthy controls. (5) IL-23 gave a prominent tumor necrosis factor release in monocytes from patients with carotid atherosclerosis but not in cells from healthy controls. (6) High plasma levels of IL-23 were associated with increased mortality during follow-up. Conclusions— We have shown an association between IL-23 and disease progression in patients with carotid atherosclerosis, potentially involving IL-17-related mechanisms.

The Carnitine-butyrobetaine-trimethylamine-N-oxide pathway and its association with cardiovascular mortality in patients with carotid atherosclerosis

BACKGROUND AND PURPOSE γ-butyrobetaine (γBB) is a metabolite from dietary Carnitine, involved in the gut microbiota-dependent conversion from Carnitine to the pro-atherogenic metabolite trimethylamine-N-oxide (TMAO). Orally ingested γBB has a pro-atherogenic effect in experimental studies, but γBB has not been studied in relation to atherosclerosis in humans. The aim of this study was to evaluate associations between serum levels of γBB, TMAO and their common precursors Carnitine and trimethyllysine (TML) and carotid atherosclerosis and adverse outcome. METHODS Serum γBB, Carnitine, TML and TMAO were quantified by high performance liquid chromatography in patients with carotid artery atherosclerosis (n = 264) and healthy controls (n = 62). RESULTS Serum γBB (p = 0.024) and Carnitine (p = 0.001), but not TMAO or TML, were increased in patients with carotid atherosclerosis. Higher levels of γBB and TML, but not TMAO or Carnitine were independently associated with cardiovascular death also after adjustment for age and eGFR (adjusted HR [95%] 3.3 [1.9-9.1], p = 0.047 and 6.0 [1.8-20.34], p = 0.026, respectively). CONCLUSIONS Patients with carotid atherosclerosis had increased serum levels of γBB, and elevated levels of γBB and its precursor TML were associated with cardiovascular mortality. Long-term clinical studies of γBB, as a cardiovascular risk marker, and safety studies regarding dietary supplementation of γBB, are warranted.

Increased expression of NAMPT in PBMC from patients with acute coronary syndrome and in inflammatory M1 macrophages.

AIM The aim of the present study were to elucidate the role of NAMPT in atherosclerosis, by examine NAMPT expression in peripheral blood mononuclear cells (PBMC) in patients with coronary artery disease (CAD) and healthy controls and by examining the regulation and effect of NAMPT on macrophage polarization, hypothesizing that it could influence the polarization to inflammatory and resolving macrophages. METHOD AND RESULTS We analyzed RNA levels of NAMPT in PBMC from CAD and healthy controls and found NAMPT to be increased in PBMC from patients with acute coronary syndrome (n = 39) compared to healthy controls (n = 20) and patients with stable CAD (n = 22). Within the PBMC NAMPT was correlated to several inflammatory cytokines and the antioxidant enzyme superoxide dismutase 2. In vitro cell experiments revealed that NAMPT is increased both intracellular and extracellular in inflammatory M1 macrophages compared to in anti-inflammatory M2 macrophages. In addition, inhibiting NAMPT enzymatic activity inhibited M1 polarization in macrophages. CONCLUSION Based on our in vivo and in vitro findings we suggest that NAMPT could contribute to systemic and plaque inflammation in atherosclerotic disorders at least partly through effect on macrophages.

Carotid Plaque Inflammation Assessed with 18F-FDG PET/CT is Higher in Symptomatic Compared with Asymptomatic Patients

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-[18F] 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, 18F-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 18F-FDG uptake (mean SUVmax and SUVmax), and target-to-background ratio, symptoms, plaque echolucency, and histological evidence of inflammation was assessed. Results The amount of 18F-FDG uptake in plaques and the amount of inflammation on histological assessment were significantly correlated (r = 0·521, P = 0·003). 18F-FDG uptake was significantly higher in symptomatic plaques with median SUVmax 1·75 (1·26–2·04) in symptomatic, and 1·43 (1·15–2·28) in asymptomatic patients (P = 0·03). 18F-FDG uptake was also positively correlated with echolucency on Doppler ultrasound (P = 0·03). Conclusion 18F-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 18F-FDG PET/CT in the detection inflammation in carotid atherosclerosis, which may be of help in the detection of vulnerable plaques.

Increased subclinical atherosclerosis in patients with chronic plaque psoriasis

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.

Large-Vessel Occlusion Stroke: Effect of Recanalization on Outcome Depends on the National Institutes of Health Stroke Scale Score

BACKGROUND Arterial recanalization is currently considered the main standard of successful early management of acute ischemic stroke. Intravenous (IV) thrombolysis with tissue plasminogen activator (tPa) is the only Food and Drug Administration-approved medical treatment. Large-vessel occlusion, estimated to account for up to 40% of all acute ischemic strokes, is often refractory to IV thrombolysis and is associated with a poor patient outcome. Mechanical recanalization procedures are therefore increasingly used in the treatment of large-vessel occlusion refractory to, or presenting outside the accepted time window for, IV thrombolysis. The aim of this study was to investigate the effect of early vessel recanalization on clinical outcome in patients with large-vessel occlusion stroke. METHODS This is a single-center cohort study, analyzing prospectively collected data on 152 patients with large-vessel occlusion and acute ischemic stroke. Seventy-one patients received endovascular treatment (of whom 57.7% also received IV tPA), and 81 (55.6% of whom also received IV tPa) were not treated with endovascular therapy. Clinical outcome was compared for 2 cohorts: patients who recanalized (n = 46) and patients with persisting large-vessel occlusion (n = 106). RESULTS Early recanalization was an independent predictor of a good clinical outcome in only those patients who presented with a severe ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score >15; P = .017). This was not the case for less severe strokes (NIHSS score ≤ 15) where recanalization did not lead to more patients with functional independence at 90-day follow-up (P = .21). CONCLUSIONS In this study of acute large-vessel occlusion stroke, we found that clinical outcome following early recanalization was dependent on the patients pretreatment NIHSS score. A non-negligible proportion of patients with milder strokes did well despite persistent large-vessel occlusion. These results may suggest that in patients who are able to maintain adequate collateral flow despite proximal arterial occlusion, effective adaptive mechanisms are present, which for some patients are long-lasting. This may influence the process of appropriate patient selection for endovascular therapy.

Unstable carotid artery plaque: new insights and controversies in diagnostics and treatment

Cardiovascular disease is estimated to be the leading cause of death, globally causing 14 million deaths each year. Stroke remains a massive public health problem and there is an increasing need for better strategies for the prevention and treatment of this disease. At least 20% of ischemic strokes are thromboembolic in nature, caused by a thromboembolism from an atherosclerotic plaque at the carotid bifurcation or the internal carotid artery. Current clinical guidelines for both primary and secondary prevention of stroke in patients with carotid stenosis caused by atherosclerotic plaques remain reliant on general patient characteristics (traditional risk factors for stroke) and static measures of the degree of artery stenosis. Patients with similar traditional risk factors, however, have been found to have different risk of stroke, and it has in recent years become increasingly clear that the degree of artery stenosis alone is not the best estimation of stroke risk. There is a need for new methods for the assessment of stroke risk to improve risk prediction for the individual patient. This review aims to give an overview of new methods available for the identification of carotid plaque instability and the assessment of stroke risk.

Blood Pressure Lowering Treatment in Patients with Carotid Artery Stenosis

Stroke is the second most common cause of death and the most common cause of disability worldwide. Up to 30% of ischaemic strokes are caused by carotid atherosclerosis, usually due to thromboemboli from an atherosclerotic plaque at the carotid bifurcation. High blood pressure is an important risk factor for atherosclerosis, the development of unstable carotid plaques, and ischaemic strokes. Differentiation between asymptomatic and symptomatic carotid atherosclerosis is critical to treatment management because of the difference in natural history. Intensive medical treatment including blood pressure lowering medication reduces the risk of both primary and secondary vascular events in patients at risk. This review summarises recent data on blood pressure management in patients with carotid artery stenosis.

Semiautomated Magnetic Resonance Imaging Assessment of Carotid Plaque Lipid Content

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.

Enhanced base excision repair capacity in carotid atherosclerosis may protect nuclear DNA but not mitochondrial DNA

BACKGROUND Lesional and systemic oxidative stress has been implicated in the pathogenesis of atherosclerosis, potentially leading to accumulation of DNA base lesions within atherosclerotic plaques. Although base excision repair (BER) is a major pathway counteracting oxidative DNA damage, our knowledge on BER and accumulation of DNA base lesions in clinical atherosclerosis is scarce. Here, we evaluated the transcriptional profile of a wide spectrum of BER components as well as DNA damage accumulation in atherosclerotic and non-atherosclerotic arteries. METHODS BER gene expression levels were analyzed in 162 carotid plaques, 8 disease-free carotid specimens from patients with carotid plaques and 10 non-atherosclerotic control arteries. Genomic integrity, mitochondrial (mt) DNA copy number, oxidative DNA damage and BER proteins were evaluated in a subgroup of plaques and controls. RESULTS Our major findings were: (i) The BER pathway showed a global increased transcriptional response in plaques as compared to control arteries, accompanied by increased expression of several BER proteins. (ii) Whereas nuclear DNA stability was maintained within carotid plaques, mtDNA integrity and copy number were decreased. (iii) Within carotid plaques, mRNA levels of several BER genes correlated with macrophage markers. (iv) In vitro, some of the BER genes were highly expressed in the anti-inflammatory and pro-resolving M2 macrophages, showing increased expression upon exposure to modified lipids. CONCLUSIONS The increased transcriptional response of BER genes in atherosclerosis may contribute to lesional nuclear DNA stability but appears insufficient to maintain mtDNA integrity, potentially influencing mitochondrial function in cells within the atherosclerotic lesion.