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Highlighted articles August

Volume 263 Issue August 2017

By Simona Negrini and Arnold von Eckardstein (Editor–in-Chief).

Although atherosclerosis is a disease of the arterial wall, the nowadays strategies of management of cardiovascular risk are built on management of risk factors measured outside of the arterial wall, that is blood lipids and glucose or blood pressure. The successful anti-inflammatory theory in the CANTOS trial highlights the importance of a better understanding and diagnostics of the pathogenic processes within the arterial wall. This issue of Atherosclerosis contains several article addressing the pathogenic events in the arterial wall as well as their local approach by diagnostic tracers and therapies.

Issue highlights


    Highlighted articles

    Type 1 diabetes increases retention of low-density lipoprotein in the atherosclerosis-prone area of the murine aorta

    Individuals with type 1 diabetes mellitus are at high risk of developing atherosclerotic cardiovascular disease, but the underlying mechanisms by which type 1 diabetes accelerates atherosclerosis remain unknown. It has been suggested that an increase in retained LDL could contribute to the increased atherosclerotic burden seen in type 1 diabetic patients. To test this hypothesis, Hagensen et al. assessed whether retention of low-density lipoprotein (LDL) is increased in atherosclerotic-prone areas using a murine model of type 1 diabetes.

    Fluorescently-labelled human LDL from healthy non-diabetic individuals was injected into diabetic Ins2Akita mice and non-diabetic, wild-type littermates. Fluorescence microscopy of cryosections and scans of en face preparations were used to quantify the amount of retained LDL after 24 h. Vascular gene expression in the inner curvature of the aortic arch was analyzed by microarray and quantitative PCR.

    The results showed that type 1 diabetic mice had 8.1-fold more retained LDL in atherosclerosis-prone areas of the aortic arch in the intimal and medial layers compared to wild-type mice. These findings were confirmed in independent experiments using near-infrared scanning of en face preparations of the aorta. The expression of genes known to be involved in LDL retention was not affected.

    Type 1 diabetes increases the ability of the vascular wall to retain LDL in mice. These changes could contribute to the increased atherosclerotic burden in type 1 diabetic patients.

    Bacterial profile in human atherosclerotic plaques

    Several studies have confirmed the presence of bacterial DNA in atherosclerotic plaques, but its contribution to plaque stability and vulnerability is unclear. In this study, Lindskog Jonsson et al. investigated whether the bacterial plaque-profile differed between asymptomatic or symptomatic patients and whether there were local differences in the microbial composition within the plaque.

    Plaques were removed by endarterectomy from both asymptomatic and symptomatic patients and divided into three different regions with different histological vulnerability: upstream of the maximum stenosis, site for maximum stenosis, and downstream of the maximum stenosis. Bacterial DNA composition in the plaques was assessed by pyrosequencing of the 16S rRNA genes, and total bacterial load was determined by qPCR.

    The presence of bacterial DNA in the atherosclerotic plaque was confirmed, but no difference was observed in the amount of DNA in either asymptomatic and symptomatic patients or the three different plaque regions. Unweighted UniFrac distance metric analysis revealed no distinct clustering of samples by patient group or plaque region. Operational taxonomic units (OTUs) from 5 different phyla were identified, with the majority of the OTUs belonging to Proteobacteria and Actinobacteria. There was no difference between asymptomatic and symptomatic patients, or plaque regions, when analyzing the origin of DNA at phylum, family or OTU level.

    In conclusion, plaque vulnerability cannot be explained by differences in bacterial composition.

    Evaluation of ultrasmall superparamagnetic iron-oxide (USPIO) enhanced MRI with ferumoxytol to quantify arterial wall inflammation

    Inflammation in atherosclerotic plaques is an important determinant of plaque vulnerability, and can be detected non-invasively using ultra-small superparamagnetic iron-oxide (USPIO) enhanced MRI. In this study, Smits et al. aimed to determine whether ferumoxytol can be used as a contrast agent for USPIO-MRI of atherosclerotic plaques, to further establish a protocol for quantitative USPIO-MRI of carotid artery plaques using ferumoxytol and to study the relation between USPIO uptake and plaque burden and 18F-fluorodeoxyglucose (FDG) uptake in atherosclerotic plaques.

    In 9 patients with carotid artery stenosis >30% and 4 healthy controls, quantitative R2* MRI scans of the carotid arteries were performed before and 72 h after USPIO administration. USPIO uptake was assessed by quantifying the difference in R2* between baseline and post-USPIO scans. In addition, 18F-FDG PET/CT was performed on both carotid arteries. MR and PET/CT images were co-registered, and 18F-FDG uptake was quantified in all slices containing atherosclerotic plaque.

    Infusion of ferumoxytol resulted in higher R2* values after 72 h in atherosclerotic plaques, but not in the healthy control vessel wall. USPIO uptake in patients was higher in atherosclerotic plaques compared to the patient non-plaque vessel wall. No correlation was found between USPIO uptake and 18F-FDG uptake in atherosclerotic plaques.

    Ferumoxytol is selectively taken up by atherosclerotic plaques and can thus be used for carotid USPIO-MRI. As USPIO and 18F-FDG uptake in atherosclerotic plaque do not correlate in this cohort, these agents may visualize different pathophysiological aspects of plaque inflammation.

    18F-sodium fluoride positron emission tomography for molecular imaging of coronary atherosclerosis based on computed tomography analysis

    Kitagawa et al. aimed at evaluating the relation between 18F-sodium fluoride (18F-NaF) uptake on positron emission tomography (PET) and coronary atherosclerosis detected by computed tomography (CT).

    Thirty-two patients with one or more coronary atherosclerotic lesions underwent 18F-NaF PET/CT. Each coronary atherosclerotic lesion was evaluated on CT angiography for plaque types (calcified plaque, non-calcified plaque, partially calcified plaque), and the presence of CT-based high-risk features. Focal 18F-NaF uptake of each lesion was quantified using maximum tissue-to-background ratio (TBRmax).

    In a patient-based analysis, logarithmically transformed coronary calcium score correlated positively with 18F-NaF uptake, and 15 patients with myocardial infarction or unstable angina history showed a higher 18F-NaF uptake than those without. In a lesion-based analysis, partially calcified plaques showed greater uptake than calcified or non-calcified plaques, and the lesions with high-risk features (plaques with positive remodeling, large lipid cores and micro-calcifications) showed the highest 18F-NaF uptake.

    Coronary arterial 18F-NaF uptake was related to total plaque burden, coronary event history, and specific features of coronary atherosclerosis based on CT analysis. 18F-NaF PET/CT, in combination with cardiac CT, may provide a new molecular imaging approach to identify high-risk patients and coronary atherosclerotic lesions.

    In his editorial, Raggi emphasizes the importance of these results confirming that NaF co-localizes with atherosclerosis in lesions at greatest risk of rupture, therefore potentially giving some valuable prognostic information.

    Dynamic contrast-enhanced MR imaging of carotid vasa vasorum in relation to coronary and cerebrovascular events

    Dynamic contrast-enhanced MR imaging (DCE-MRI) provides a noninvasive approach to the functional status of carotid adventitial vasa vasorum. Contrast extravasation rate, (Ktrans) derived from kinetic modeling of adventitial enhancement, has been correlated with plaque neovascularization and inflammation. In a retrospective analysis, Wang et al. aimed to investigate the clinical implications of Ktrans by evaluating its relationship with documented cardiovascular events (CVE).

    Seventy patients with carotid plaque at clinical ultrasound examination were recruited and imaged with a previously-described bright-blood DCE-MRI protocol. Patients were classified by the presence of documented coronary and/or cerebrovascular events. Adventitial Ktrans was estimated via kinetic modeling of outer wall enhancement as captured by DCE-MRI.

    After excluding six patients with insufficient image quality, 64 patients were submitted to DCE-MRI measurements. Patients with documented CVE showed significantly higher adventitial Ktrans than those without, whereas comparable measurements were observed among patients with coronary events alone, cerebrovascular events alone, and both. Carotid adventitial Ktrans was negatively correlated with time since clinical event in statin-treated patients.

    Patients with documented CVE demonstrated increased rate of contrast extravasation from carotid adventitial vasa vasorum on DCE-MRI irrespective of the territory affected. Systemic factors implicated in the pathophysiology of acute atherothrombotic events may influence the functional status of adventitial vasa vasorum.

    In their editorial, Calcagno et al. highlight how vascular DCE-MRI may be integrated with other non-invasive imaging techniques, targeting other specific aspects of the atherosclerotic cascade, for a more effective stratification of individuals. The authors also describe the potential challenges in developing such integrated “imaging equivalents” of plaque vulnerability.

    Effects of atorvastatin and diet interventions on atherosclerotic plaque inflammation and [18F]FDG uptake in Ldlr−/−Apob100/100 mice

    Positron emission tomography (PET) tracer 2-deoxy-2-[18F]-fluoro-d-glucose ([18F]FDG) is a sensitive marker of inflammation in atherosclerosis since it is taken up by cells utilizing glucose, including active macrophages. To assess the anti-inflammatory effects of statin treatment, Hellberg et al. studied whether atorvastatin reduced aortic [18F]FDG uptake in hypercholesterolemic mice deficient in low-density lipoprotein receptor (Ldlr), and expressing only apolipoprotein B-100 (Ldlr−/−Apob100/100).

    Ldlr−/−Apob100/100 mice were fed a high-fat diet (HFD) for 12 weeks and then divided into 3 groups to receive HFD, chow diet (Chow), or HFD plus atorvastatin (HFD + A), respectively, for another 12 weeks. In addition to aortic histopathology, [18F]FDG uptake was studied in vivo using PET/computed tomography, and ex vivo by gamma counting of excised aorta.

    The authors found total cholesterol levels to be lower in the Chow and HFD + A groups than in the HFD group, with the Chow group also showing a lower plaque burden and lower numbers of macrophages in the lesions. In both in vivo and ex vivo analyses, [18F]FDG uptake in the aorta was lower in the Chow group compared to the HFD group, whereas atorvastatin had no effect on the uptake. [18F]FDG uptake correlated with plasma total cholesterol levels.

    In conclusion, while a cholesterol-lowering diet intervention was effective in reducing plasma cholesterol, plaque size and inflammation, there was no evidence that atorvastatin therapy has cholesterol-independent effects on inflammation in atherosclerotic lesions in Ldlr−/−Apob100/100 mice.

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