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Objectives Intraplaque angiogenesis and inflammation are key promoters of atherosclerosis and are mediated by the alpha-V beta-3 (αvβ3) integrin pathway. We investigated the applicability of the αvβ3-integrin receptor-selective positron emission tomography (PET) radiotracer 18F-fluciclatide in assessing human aortic atherosclerosis.Methods Vascular 18F-fluciclatide binding was evaluated using ex vivo analysis of carotid endarterectomy samples with autoradiography and immunohistochemistry, and in vivo kinetic modelling following radiotracer administration. Forty-six subjects with a spectrum of atherosclerotic disease categorised as stable (n=27) or unstable (n=19; recent myocardial infarction) underwent PET and CT imaging of the thorax after administration of 229 (IQR 217–237) MBq 18F-fluciclatide. Thoracic aortic 18F-fluciclatide uptake was quantified on fused PET-CT images and corrected for blood-pool activity using the maximum tissue-to-background ratio (TBRmax). Aortic atherosclerotic burden was quantified by CT wall thickness, plaque volume and calcium scoring.Results 18F-Fluciclatide uptake co-localised with regions of increased αvβ3 integrin expression, and markers of inflammation and angiogenesis. 18F-Fluciclatide vascular uptake was confirmed in vivo using kinetic modelling, and on static imaging correlated with measures of aortic atherosclerotic burden: wall thickness (r=0.57, p=0.001), total plaque volume (r=0.56, p=0.001) and aortic CT calcium score (r=0.37, p=0.01). Patients with recent myocardial infarction had greater aortic 18F-fluciclatide uptake than those with stable disease (TBRmax 1.29 vs 1.21, p=0.02).Conclusions In vivo expression of αvβ3 integrin in human aortic atheroma is associated with plaque burden and is increased in patients with recent myocardial infarction. Quantification of αvβ3 integrin expression with 18F-fluciclatide PET has potential to assess plaque vulnerability and disease activity in atherosclerosis.This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made.

Background: Fluorine-18–sodium fluoride (18F-NaF) uptake is a marker of active vascular calcification associated with high-risk atherosclerotic plaque.Objectives: In patients with abdominal aortic aneurysm (AAA), the authors assessed whether 18F-NaF positron emission tomography (PET) and computed tomography (CT) predicts AAA growth and clinical outcomes.Methods: In prospective case-control (n = 20 per group) and longitudinal cohort (n = 72) studies, patients with AAA (aortic diameter >40 mm) and control subjects (aortic diameter 18F-NaF PET-CT, CT angiography, and calcium scoring. Clinical endpoints were aneurysm expansion and the composite of AAA repair or rupture.Results: Fluorine-18-NaF uptake was increased in AAA compared with nonaneurysmal regions within the same aorta (p = 0.004) and aortas of control subjects (p = 0.023). Histology and micro-PET-CT demonstrated that 18F-NaF uptake localized to areas of aneurysm disease and active calcification. In 72 patients within the longitudinal cohort study (mean age 73 ± 7 years, 85% men, baseline aneurysm diameter 48.8 ± 7.7 mm), there were 19 aneurysm repairs (26.4%) and 3 ruptures (4.2%) after 510 ± 196 days. Aneurysms in the highest tertile of 18F-NaF uptake expanded 2.5× more rapidly than those in the lowest tertile (3.10 [interquartile range (IQR): 2.34 to 5.92 mm/year] vs. 1.24 [IQR: 0.52 to 2.92 mm/year]; p = 0.008) and were nearly 3× as likely to experience AAA repair or rupture (15.3% vs. 5.6%; log-rank p = 0.043).Conclusions: Fluorine-18-NaF PET-CT is a novel and promising approach to the identification of disease activity in patients with AAA and is an additive predictor of aneurysm growth and future clinical events. (Sodium Fluoride Imaging of Abdominal Aortic Aneurysms [SoFIA3]; NCT02229006; Magnetic Resonance Imaging [MRI] for Abdominal Aortic Aneurysms to Predict Rupture or Surgery: The MA3RS Trial; ISRCTN76413758)

The authors submit the following corrections. A mislabeling of the units was found in Figure 2D. The y-axes of both graphs should read: "concentration of gold (ng gold/L)" not "(ng gold/mL)". Similarly, in Supplementary Figure S4 the urine concentration on the yaxis should also read: "concentration of gold (ng gold/L)". This error affects the estimate of % mass translocation in the Discussion, which also contained inconsistencies. We have now corrected these errors and refined our exposure estimates for this calculation. Thus, we would like to revise the following text on page 4546: "Based on the exposure characteristics of our first study (2 h exposure of ∼116 μg/m3 under light exercise), we calculate the total inhaled dose of particulate to be ∼690 mg. If ∼80 μg of gold was cleared by the kidneys over 24 h (average volume of urine collected: 2.4 L containing 35 ng/mL), and, therefore, if this was the sole route of clearance, we estimate that at least 0.2% of inhaled gold nanoparticles translocated from the lung into circulation". This should be replaced with: "Based on the exposure characteristics of our first study (2 h exposure of ∼116 μg/m3 intermittent rest [6 L/min for 4 × 15 min] and moderate exercise [47.5 L/min for 4 × 15 min]), we calculate the total inhaled dose of the particulate to be ∼383 μg. If ∼84 ng of gold was cleared by the kidney over 24 h (average volume or urine collected: 2.4 L containing 35 ng/L; Figure 1D), we estimate that at least 0.02% of inhaled gold nanoparticles translocated from the lung into the circulation". We emphasize that this calculation is for illustrative purposes and represents only a defined 24 h period in time. The estimate is likely to be conservative and does not take into account the proportion of alveolar deposition and the slow return of respiratory rate to resting levels after exercise and is based on the assumption that the urine is the sole route of clearance. While this estimate is an order of magnitude lower than that stated in the original manuscript, the proportion of translocated particles still fits with prior findings. Early studies in rodents provided rough estimates that

The development of engineered nanomaterials is growing exponentially, despite concerns over their potential similarities to environmental nanoparticles that are associated with significant cardiorespiratory morbidity and mortality. The mechanisms through which inhalation of nanoparticles could trigger acute cardiovascular events are emerging, but a fundamental unanswered question remains: Do inhaled nanoparticles translocate from the lung in man and directly contribute to the pathogenesis of cardiovascular disease? In complementary clinical and experimental studies, we used gold nanoparticles to evaluate particle translocation, permitting detection by high-resolution inductively coupled mass spectrometry and Raman microscopy. Healthy volunteers were exposed to nanoparticles by acute inhalation, followed by repeated sampling of blood and urine. Gold was detected in the blood and urine within 15 min to 24 h after exposure, and was still present 3 months after exposure. Levels were greater following inhalation of 5 nm (primary diameter) particles compared to 30 nm particles. Studies in mice demonstrated the accumulation in the blood and liver following pulmonary exposure to a broader size range of gold nanoparticles (2-200 nm primary diameter), with translocation markedly greater for particles

BACKGROUND: Phenotypic switching of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic state is implicated in diverse vascular pathologies including atherogenesis, plaque stabilisation, and neointimal hyperplasia. However, very little is known as to the role of long non coding RNA (lncRNA) during this process. Here we investigated a role for long non-coding (lnc)RNAs in VSMC biology and pathology.METHODS AND RESULTS: Using RNA sequencing, we identified >300 lncRNAs whose expression was altered in human saphenous vein vascular smooth muscle cells following stimulation with interleukin-1α and platelet-derived growth factor. We focused on a novel lncRNA (Ensembl: RP11-94A24.1), which we termed smooth muscle–induced lncRNA enhances replication (SMILR). Following stimulation, SMILR expression was increased in both the nucleus and cytoplasm, and was detected in conditioned media. Furthermore, knockdown of SMILR markedly reduced cell proliferation. Mechanistically, we noted that expression of genes proximal to SMILR was also altered by interleukin-1α/platelet-derived growth factor treatment, and HAS2 expression was reduced by SMILR knockdown. In human samples, we observed increased expression of SMILR in unstable atherosclerotic plaques and detected increased levels in plasma from patients with high plasma C-reactive protein.CONCLUSIONS: These results identify SMILR as a driver of vascular smooth muscle cell proliferation and suggest that modulation of SMILR may be a novel therapeutic strategy to reduce vascular pathologies.

Background—Phenotypic switching of vascular smooth muscle cells from a contractile to a synthetic state is implicated in diverse vascular pathologies, including atherogenesis, plaque stabilization, and neointimal hyperplasia. However, very little is known about the role of long noncoding RNA (lncRNA) during this process. Here, we investigated a role for lncRNAs in vascular smooth muscle cell biology and pathology.\ud \ud Methods and Results—Using RNA sequencing, we identified >300 lncRNAs whose expression was altered in human saphenous vein vascular smooth muscle cells following stimulation with interleukin-1α and platelet-derived growth factor. We focused on a novel lncRNA (Ensembl: RP11-94A24.1), which we termed smooth muscle–induced lncRNA enhances replication (SMILR). Following stimulation, SMILR expression was increased in both the nucleus and cytoplasm, and was detected in conditioned media. Furthermore, knockdown of SMILR markedly reduced cell proliferation. Mechanistically, we noted that expression of genes proximal to SMILR was also altered by interleukin-1α/platelet-derived growth factor treatment, and HAS2 expression was reduced by SMILR knockdown. In human samples, we observed increased expression of SMILR in unstable atherosclerotic plaques and detected increased levels in plasma from patients with high plasma C-reactive protein.\ud \ud Conclusions—These results identify SMILR as a driver of vascular smooth muscle cell proliferation and suggest that modulation of SMILR may be a novel therapeutic strategy to reduce vascular pathologies.

Vascular calcification powerfully predicts mortality and morbidity from cardiovascular disease. Men have a greater risk of cardiovascular disease, compared to women of a similar age. These gender disparities suggest an influence of sex hormones. Testosterone is the primary and most well-recognised androgen in men. Therefore, we addressed the hypothesis that exogenous androgen treatment induces vascular calcification. Immunohistochemical analysis revealed expression of androgen receptor (AR) in the calcified media of human femoral artery tissue and calcified human valves. Furthermore, in vitro studies revealed increased phosphate (Pi)-induced mouse vascular smooth muscle cell (VSMC) calcification following either testosterone or dihydrotestosterone (DHT) treatment for 9 days. Testosterone and DHT treatment increased tissue non-specific alkaline phosphatase (Alpl) mRNA expression. Testosterone-induced calcification was blunted in VSMC-specific AR-ablated (SM- ARKO) VSMCs compared to WT. Consistent with these data, SM-ARKO VSMCs showed a reduction in Osterix mRNA expression. However, intriguingly, a counter- intuitive increase in Alpl was observed. These novel data demonstrate that androgens play a role in inducing vascular calcification through the AR. Androgen signalling may represent a novel potential therapeutic target for clinical intervention.

Ischaemic vascular events occur in relation to an underlying vulnerable plaque. The pathological hallmarks of high-risk plaques are well described and include inflammation and microcalcification. To date, non-invasive imaging modalities have lacked the spatial resolution to detect these processes with the necessary precision to facilitate clinical utility. Positron emission tomography (PET) using targeted radiopharmaceuticals affords a highly sensitive tool for identifying features of interest and has been in use for several decades in oncological practice. Recent developments have created hybrid scanning platforms which add the detailed spatial resolution of computed tomography (CT) and, for the first time, made imaging of individual coronary plaques feasible. In this study we compared the utility of PET-CT using (18)F-fluoride and (18)F-fluorodeoxglucose ((18)F-FDG) to detect high-risk or ruptured atherosclerotic plaques in vivo. (18)F-fluoride localized to culprit and vulnerable plaques as determined by a combination of invasive imaging and histological tissue examination. In contradistinction, (18)F-FDG analysis was compromised by non-specific myocardial uptake that obscured the coronary arteries. We discuss the findings of this study, the limitations of the current approach of vulnerable plaque assessment and some on-going developments in cardiovascular imaging with (18)F-fluoride.