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Investigating Vulnerable Atheroma Using Combined F-18-FDG PET/CT Angiography of Carotid Plaque with Immunohistochemical Validation
Abstract
Inflammation and angiogenesis are hypothesized to be important factors contributing to plaque vulnerability, whereas calcification is suggested to confer stability. To investigate this in vivo, we combined CT angiography and PET and compared the findings with immunohistochemistry for patients undergoing carotid endarterectomy.
Twenty-one consecutive patients (18 men, 3 women; mean age ± SD, 68.3 ± 7.3) undergoing carotid endarterectomy were recruited for combined carotid (18)F-FDG PET/CT angiography. Plaque (18)F-FDG uptake was quantified with maximum standardized uptake value, and CT angiography quantified percentage plaque composition (calcium and lipid). Surgical specimens underwent ex vivo CT aiding image registration, followed by immunohistochemical staining for CD68 (macrophage density) and vascular endothelial growth factor (angiogenesis). Relationships between imaging and immunohistochemistry were assessed with Spearman rank correlation and multivariable regression.
The mean (±SD) surgically excised carotid plaque (18)F-FDG metabolism was 2.4 (±0.5) versus 2.2 (±0.3) contralaterally (P = 0.027). There were positive correlations between plaque (18)F-FDG metabolism and immunohistochemistry with CD68 (ρ = 0.55; P = 0.011) and vascular endothelial growth factor (ρ = 0.47; P = 0.031). There was an inverse relationship between plaque (18)F-FDG metabolism and plaque percentage calcium composition on CT (ρ = -0.51; P = 0.018) and between calcium composition and immunohistochemistry with CD68 (ρ = -0.57; P = 0.007). Regression showed that maximum standardized uptake value and calcium composition were independently significant predictors of angiogenesis, and calcium composition was a predictor of macrophage density.
We provide in vivo evidence that increased plaque metabolism is associated with increased biomarkers of angiogenesis and inflammation, whereas plaque calcification is inversely related to PET and histologic biomarkers of inflammation.
... Kim et al. showed in a recent study that patients with high carotid FDG uptake are more prone to early recurrence of ischemic stroke [19], although a prior study by Arauz et al. was unable to demonstrate this prognostic trend [20]. In patients with symptomatic atherosclerosis, ipsilateral carotid FDG uptake correlated with the contralateral carotid FDG uptake [21,22], and such that the ipsilateral was higher than contralateral FDG uptake [12,[22][23][24][25]. In contrast, studies performed early after a cerebrovascular event (less than 10 days) showed no difference between ipsilateral and contralateral FDG uptake [26,27]. ...
... In histological studies performed on samples acquired during endarterectomy, it was shown that FDG uptake was associated with an increase in parameters reflecting inflammatory cell infiltration-e.g., percentage of inflammatory cells and absolute macrophage area [11,13,16,21,43,[48][49][50], neovascularization, and loose extracellular matrix [49]. On the other hand, FDG uptake correlated inversely with calcium deposition in histological studies [13,16,24,48,49] and fibrous tissue [49] in histological assessment. Regarding lipid deposition, Saito et al. concluded that FDG uptake correlates positively with lipid deposition [51], whereas Menezes et al. did not [24]. ...
... On the other hand, FDG uptake correlated inversely with calcium deposition in histological studies [13,16,24,48,49] and fibrous tissue [49] in histological assessment. Regarding lipid deposition, Saito et al. concluded that FDG uptake correlates positively with lipid deposition [51], whereas Menezes et al. did not [24]. NaF uptake was correlated with calcium deposition in histological assessment [28,30]. ...
Purpose:
To conduct a systematic review of articles on PET imaging of carotid atherosclerosis with emphasis on clinical usefulness and comparison with other imaging modalities.
Methods:
Research articles reporting carotid artery PET imaging with different radiotracers until 30 November 2018 were systematically searched for in Medline/PubMed, Scopus, Embase, Google Scholar, and Cochrane Library. Duplicates were removed, and editorials, case studies, and investigations on feasibility or reproducibility of PET imaging and of patients with end-stage diseases or immunosuppressive medications were omitted. After quality assessment of included articles using Joanna Briggs Institute checklists, all eligible articles were reviewed.
Results:
Of 1718 primary hits, 53 studies comprising 4472 patients, aged 47-91 years (78.8% males), were included and grouped under the following headlines: diagnostic performance, risk factors, laboratory findings, imaging modalities, and treatment. 18F-fluorodeoxyglucose (FDG) (49/53) and 18F-sodium fluoride (NaF) (5/53) were the most utilized tracers to visualize carotid wall inflammation and microcalcification, respectively. Higher carotid FDG uptake was demonstrated in patients with than without symptomatic carotid atherosclerosis. Normal carotid arteries presented with the lowest FDG uptake. In symptomatic atherosclerosis, carotid arteries ipsilateral to a cerebrovascular event had higher FDG uptake than the contralateral carotid artery. FDG uptake was significantly associated with age, male gender, and body mass index in healthy individuals, and in addition with arterial hypertension, hypercholesterolemia, and diabetes mellitus in patients. Histological assessment indicated a strong correlation between microcalcification and NaF uptake in symptomatic patients. Histological evidence of calcification correlated inversely with FDG uptake, which was associated with increased macrophage and CD68 count, both accounting for increased local inflammatory response.
Conclusion:
FDG-PET visualizes the inflammatory part of carotid atherosclerosis enabling risk stratification to a certain degree, whereas NaF-PET seems to indicate long-term consequences of ongoing inflammation by demonstrating microcalcification allowing discrimination of atherosclerotic from normal arteries and suggesting clinically significant carotid atherosclerosis.
... Despite lack of standardization of image acquisition, processing, and uptake measurements, several studies have shown that FDG uptake is not only associated with macrophage infiltration but it is also a predictor of plaque progression and cardiovascular events and a sensitive marker of therapeutic modulation of inflammation. [10][11][12][13] However, high cost and patient exposure to radiation limit the use of FDG-PET/CT imaging in everyday clinical practice as a screening method for the evaluation of vascular inflammation. Microwave radiometry (MWR) is a non-invasive and safe diagnostic modality, which allows in vivo evaluation of carotid inflammation by measuring internal temperatures of tissues. ...
... This is in agreement with a number of previous studies, which have shown a positive relationship between CD68 stain and FDG uptake in carotid disease. [10][11][12][13] Similarly with our previous study 19 where specimens with high VEGF expression exhibited higher DT values, in this study specimens with increased CD31 levels showed higher thermal heterogeneity. However, carotids with higher CD31 expression exhibited similar FDG uptake compared with those with lower CD31 expression. ...
... This bilateral symmetry is in agreement with prior studies illustrating the systemic nature of the atherosclerotic process. 12,14,17,30 Clinical implications ...
Aims To explore the relationship between temperature measurements derived by microwave radiometry (MWR) and carotid flurodeoxyglucose (FDG) uptake and assess their association with histological and immunohistochemistry findings in patients with high-grade carotid stenosis.Methods and results In 21 patients undergoing carotid endarterectomy, carotid inflammation was evaluated by both FDG positron emission/computed tomography (FDG-PET/CT) imaging and MWR measurements. Carotid inflammation was assessed by PET/CT as target-to-background ratio (TBR) by obtaining measurements in consecutive axial slices 2 cm below to 2 cm above the carotid bifurcation. Temperature difference (ΔT) by MWR was assigned as the maximum–minimum temperature measurements over the corresponding carotid segments. The extent of lipid core, calcification as well as CD68 and CD31 levels were also assessed. There was a significant correlation between ΔT values and FDG uptake (R = 0.40, P = 0.01), but no correlation between the degree of angiographic stenosis and ΔT values (R = −0.02, P = 0.91) or PET/CT measurements (R = −0.28, P = 0.86). Patients with plaques containing high lipid core extension or low calcification exhibited higher ΔT (P = 0.001 and P < 0.001, respectively) and FDG uptake values (P = 0.02 and P = 0.02, respectively). Patients with plaques containing increased CD68 expression exhibited higher ΔT and FDG uptake measurements.Conclusion Carotid plaque inflammation was evaluated by temperature measurements, which were correlated with FDG-PET/CT indices, confirmed by histopathology and immunohistochemistry findings. Structural changes did not predict inflammatory process. The implications of these findings in risk stratification and management of patients with carotid atherosclerosis and the precise algorithm for potential clinical utilization of MWR and PET/CT remain to be determined.
... Despite lack of standardization of image acquisition, processing, and uptake measurements, several studies have shown that FDG uptake is not only associated with macrophage infiltration but it is also a predictor of plaque progression and cardiovascular events and a sensitive marker of therapeutic modulation of inflammation. [10][11][12][13] However, high cost and patient exposure to radiation limit the use of FDG-PET/CT imaging in everyday clinical practice as a screening method for the evaluation of vascular inflammation. Microwave radiometry (MWR) is a non-invasive and safe diagnostic modality, which allows in vivo evaluation of carotid inflammation by measuring internal temperatures of tissues. ...
... This is in agreement with a number of previous studies, which have shown a positive relationship between CD68 stain and FDG uptake in carotid disease. [10][11][12][13] Similarly with our previous study 19 where specimens with high VEGF expression exhibited higher DT values, in this study specimens with increased CD31 levels showed higher thermal heterogeneity. However, carotids with higher CD31 expression exhibited similar FDG uptake compared with those with lower CD31 expression. ...
... This bilateral symmetry is in agreement with prior studies illustrating the systemic nature of the atherosclerotic process. 12,14,17,30 Clinical implications ...
Aims:
To explore the relationship between temperature measurements derived by microwave radiometry (MWR) and carotid flurodeoxyglucose (FDG) uptake and assess their association with histological and immunohistochemistry findings in patients with high-grade carotid stenosis.
Methods and results:
In 21 patients undergoing carotid endarterectomy, carotid inflammation was evaluated by both FDG positron emission/computed tomography (FDG-PET/CT) imaging and MWR measurements. Carotid inflammation was assessed by PET/CT as target-to-background ratio (TBR) by obtaining measurements in consecutive axial slices 2 cm below to 2 cm above the carotid bifurcation. Temperature difference (ΔT) by MWR was assigned as the maximum-minimum temperature measurements over the corresponding carotid segments. The extent of lipid core, calcification as well as CD68 and CD31 levels were also assessed. There was a significant correlation between ΔT values and FDG uptake (R = 0.40, P = 0.01), but no correlation between the degree of angiographic stenosis and ΔT values (R = -0.02, P = 0.91) or PET/CT measurements (R = -0.28, P = 0.86). Patients with plaques containing high lipid core extension or low calcification exhibited higher ΔT (P = 0.001 and P < 0.001, respectively) and FDG uptake values (P = 0.02 and P = 0.02, respectively). Patients with plaques containing increased CD68 expression exhibited higher ΔT and FDG uptake measurements.
Conclusion:
Carotid plaque inflammation was evaluated by temperature measurements, which were correlated with FDG-PET/CT indices, confirmed by histopathology and immunohistochemistry findings. Structural changes did not predict inflammatory process. The implications of these findings in risk stratification and management of patients with carotid atherosclerosis and the precise algorithm for potential clinical utilization of MWR and PET/CT remain to be determined.
... Attenuation correction was performed with the noncontrast CT. CTA was performed as published previously (32). ...
... There is no established method for quantification of 68 Ga-DOTATATE PET in this context. We drew on previous published carotid PET tracerhistologic validation studies for the 2 methods used (10,32,33). Images were analyzed using Xeleris (GE Healthcare). ...
... Plaque composition in individual pixels was assigned based on density (Hounsfield units of 20-60 were assigned as lipid, 60-130 as fibrous, and .130 as calcification) (32,34). Plaque components were expressed as percentage of overall plaque volume. ...
Background:
Ga68 labelled somatostatin receptor ligand PET imaging has recently been shown in preclinical and early human studies to have a potential role in the evaluation of vulnerable arterial plaques. We prospectively evaluated carotid plaque Ga68-DOTATATE uptake in patients with recent carotid events, assessed inter- and intra- observer variability of such measurements, and explored the mechanism of any plaque DOTATATE activity with immunohistochemistry in resected specimens.
Materials & methods:
20 consecutively consenting patients with recent symptomatic carotid events (transient ischaemic attack [TIA], stroke or amaurosis fugax), due for carotid endarterectomy were prospectively recruited. Ga68-DOTATATE PET/CT of the neck was performed prior to surgery. Ga68-DOTATATE uptake was measured by drawing regions of interest (ROI) along the carotid plaques and contralateral plaques/carotid arteries by experienced radionuclide radiologist and radiographer. Two PET quantification methods with inter- and Intra-observer variability were assessed. Resected carotid plaques were retrieved for sst-2 immunohistochemical stain.
Results:
Median time delay between research PET and surgery was 2days. SUV and TBR values for the symptomatic plaques and the asymptomatic contralateral carotid arteries/plaques show no significant difference (n = 19, p-value >0.10), regardless of quantification method. Intraclass correlation coefficient was >0.8 in all measures of carotid artery/plaque uptake (SUV) and >0.6 in almost all measures of target-to-background ratio (TBR). None of the excised plaques were shown to contain cells (macrophages, lymphocytes, vessel-associated cells) expressing sst2 on their cell membrane.
Conclusion:
Ga68 DOTATATE activity on PET in recently symptomatic carotid plaques is not significantly different to contralateral carotids/plaques. Any activity seen on PET is not shown to be from specific sst2 receptor-mediated uptake in-vitro. It is therefore unlikely that sst2 PET/CT imaging will have a role in the detection and characterization of symptomatic carotid plaques.
... [10][11][12] Although angiogenesis in acute ischemic stroke is known to be a critical intrinsic restoration mechanism and regarded as a potential treatment strategy, angiogenesis in chronic ICAD is less studied. 13,14 Animal studies of chronic cerebral hypoxia or hypoperfusion have identified angiogenesis by detecting increases in the serum vascular endothelial growth factor (VEGF) levels and the microvessel density. [15][16][17] In addition, investigators have found that patients with severe ICAD show increased level of serum endothelial progenitor cells, 14,18 which play an important role in angiogenesis. ...
... Integrin avb3 imaging has been proved to be a valuable tool for angiogenesis assessment in various diseases by previous studies. 13,28,29,33 The 68 Ga-labeled RGD dimer, 68 Ga-NOTA-PRGD2, has gained popularity for clinical application given its ease of preparation, in addition to its high specificity and affinity for integrin avb3. 23,34 Jeong et al. 29 showed that 68 Ga-RGD could be blocked by cold RGD both in an in vitro binding assay and in an animal model, which demonstrated its specific binding to integrin avb3. ...
Angiogenesis is a critical compensation route, which has been demonstrated in the brain following ischemic stroke; however, few studies have investigated angiogenesis in chronic intracranial atherosclerosis disease (ICAD). We used ⁶⁸Ga-NOTA-PRGD2 positron emission tomography/computed tomography based imaging to detect angiogenesis in chronic ICAD and to explore the factors that may have affected it. A total of 21 participants with unilateral severe chronic ICAD were included in the study. Of the 21 participants, 19 were men; the mean (SD) age was 52 (15) years. In 18 participants, we observed elevated ⁶⁸Ga-NOTA-PRGD2 uptake in the peri-infarct, subcortical, and periventricular regions of the lesioned side, with a higher ⁶⁸Ga-NOTA-PRGD2 SUVmax compared to that in the contralateral hemisphere (0.15 vs. 0.06, p=0.001). The ¹⁸F-FDG PET SUVmax was significantly lower on the lesioned side (11.28 vs. 13.92, p=0.001). Subgroup analyses revealed that the recent group (<6 months) had a higher lesion-to-contralateral region ratio SUVmax than the remote group (>6 months) (6.73 vs. 2.36, p<0.05). Our results provide molecular imaging evidence of angiogenesis in patients with severe chronic ICAD. Furthermore, the extent of angiogenesis in chronic ICAD may be affected by the post-qualified event time interval, and not by infarction itself or the severity of the arterial lesion.
... However, TBR values depend on the time between FDG injection and imaging acquisition, which have varied between study protocols [62]. Moreover, different cardiovascular imaging biomarkers may describe different stages of the atherosclerotic disease progression with not necessarily a strict overlap, which may cause discrepancy between the results found in the observational studies and the RCT [63,64]. Indeed, vascular inflammation and, e.g., calcifications in the arterial wall most likely represent different phases of atherosclerosis [65]. ...
Psoriasis is an immune-mediated inflammatory disease associated with an increased risk of cardiovascular disease (CVD). The risk of CVD increases with the severity of psoriasis, and exposure to systemic inflammation may partly explain the increased risk of CVD in these patients. This raises the question of whether anti-psoriatic treatment, in addition to treating the skin lesions, also lowers the risk of developing CVD. Different types of studies have examined the impact of systemic anti-psoriatic treatments on the risk of CVD in patients with psoriasis and epidemiological observational studies with, e.g., myocardial infarction and stroke as outcomes, and clinical studies investigating circulating inflammatory biomarkers in the blood indicate that anti-psoriatic therapy has a protective effect; however, no randomized controlled trial (RCT) has examined the impact of systemic anti-psoriatic treatment on future hard cardiovascular endpoints. This narrative review provides an overview of the clinical cardiovascular imaging studies examining the effect of systemic anti-psoriatic treatment on the risk of subclinical CVD in patients with psoriasis. We found a total of 24 clinical imaging studies, where 16 of these were observational cohort studies and eight were RCTs. The observational studies suggest an improvement in the risk of subclinical CVD based on different cardiovascular imaging biomarkers; however, the RCTs showed inconsistent results and mainly included vascular inflammation as the outcome. Future RCTs including other imaging biomarkers as surrogates for subclinical CVD, with longer follow-up and with hard cardiovascular endpoints are warranted to address whether systemic anti-psoriatic treatments reduce the risk of CVD.
... In a study of patients undergoing carotid endarterectomy (CEA) after FDG-PET/CT, SUVmax was associated with an increased CD68 concentration, a marker of macrophage activity [176]. Tawakol et al. also found higher CD68 staining in plaques with high SUV compared to those with low SUV [167]. ...
Carotid artery disease has traditionally been assessed based on the degree of luminal narrowing. However, this approach, which solely relies on carotid stenosis, is currently being questioned with regard to modern risk stratification approaches. Recent guidelines have introduced the concept of the “vulnerable plaque,” emphasizing specific features such as thin fibrous caps, large lipid cores, intraplaque hemorrhage, plaque rupture, macrophage infiltration, and neovascularization. In this context, imaging-based biomarkers have emerged as valuable tools for identifying higher-risk patients. Non-invasive imaging modalities and intravascular techniques, including ultrasound, computed tomography, magnetic resonance imaging, intravascular ultrasound, optical coherence tomography, and near-infrared spectroscopy, have played pivotal roles in characterizing and detecting unstable carotid plaques. The aim of this review is to provide an overview of the evolving understanding of carotid artery disease and highlight the significance of imaging techniques in assessing plaque vulnerability and informing clinical decision-making.
... F-FDG too49 . This retrospective analysis of clinical data combined with the in vitro ...
... При воспалении сосудов интенсивное поглощение 18 F-FDG происходит в макрофагах, гладкомышечных и эндотелиальных клетках [57]. Повышенное поглощение 18 F-FDG при каротидном и коронарном атеросклерозе свидетельствует о нестабильности бляшек и гистологических признаках их уязвимости [58,59], включая повышенную плотность CD68-позитивных макрофагов [60]. ...
Atherosclerosis is a chronic immunomodulated disease that affects multiple vascular beds and results in a significant worldwide disease burden. Conventional imaging modalities focus on the morphological features of atherosclerotic disease such as the degree of stenosis caused by a lesion. Modern CT, MR and positron emission tomography scanners have seen significant improvements in the rapidity of image acquisition and spatial resolution. This has increased the scope for the clinical application of these modalities. Multimodality imaging can improve cardiovascular risk prediction by informing on the constituency and metabolic processes within the vessel wall. Specific disease processes can be targeted using novel biological tracers and smart contrast agents. These approaches have the potential to inform clinicians of the metabolic state of atherosclerotic plaque.
This review will provide an overview of current imaging techniques for the imaging of atherosclerosis and how various modalities can provide information that enhances the depiction of basic morphology.
This publication is the reprint with Russian translation from original: Syed MB, Fletcher AJ, Forsythe RO, Kaczynski J, Newby DE, Dweck MR, van Beek EJ. Emerging techniques in atherosclerosis imaging. Br J Radiol. 2019;92(1103):20180309. doi: 10.1259/bjr.20180309.
... CTA can be used to diagnose LVV based on morphological vessel wall abnormalities, showing concentric thickening stretching a long segment of an artery [33]. Atherosclerotic non-calcified plaques and vulnerability can also be assessed using CTA, showing eccentric and focal thickening of the arterial wall [34]. Although there is little evidence on the combined use of FDG-PET and CTA in LVV, its combined use may reliably diagnose LVV while also showing morphological changes to the vessel wall. ...
Imaging is becoming increasingly important for the diagnosis of large vessel vasculitis (LVV). Atherosclerosis may be difficult to distinguish from LVV on imaging as both are inflammatory conditions of the arterial wall. Differentiating atherosclerosis from LVV is important to enable optimal diagnosis, risk assessment, and tailored treatment at a patient level. This paper reviews the current evidence of ultrasound (US), 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET), computed tomography (CT), and magnetic resonance imaging (MRI) to distinguish LVV from atherosclerosis. In this review, we identified a total of eight studies comparing LVV patients to atherosclerosis patients using imaging—four US studies, two FDG-PET studies, and two CT studies. The included studies mostly applied different methodologies and outcome parameters to investigate vessel wall inflammation. This review reports the currently available evidence and provides recommendations on further methodological standardization methods and future directions for research.
... It allows for the visualisation of angiogenesis and macrophage infiltration, and can discriminate lipid-rich plaque from fibrous plaque (94) but failed so far to identify IPH. Several contrast agents have been developed, but fluorodeoxyglucose (FDG) contrast agents targeting macrophages appear to be the most used; they detect inflammation and present good association with histology on carotid and aorta (94) giving details on plaque metabolism. It remains to be demonstrated that the PET signal can reliably predict future longterm cardiovascular events on carotid imaging. ...
Vulnerable carotid atherosclerotic plaques are characterised by several risk factors, such as inflammation, neovascularization and intraplaque haemorrhage (IPH). Vulnerable plaques can lead to ischemic events such as stroke. Many studies reported a relationship between IPH, plaque rupture, and ischemic stroke. Histology is the gold standard to evaluate IPH, but it required carotid endarterectomy (CEA) surgery to collect the tissue sample. In this context, several imaging methods can be used as a non-invasive way to evaluate plaque vulnerability and detect IPH. Most imaging studies showed that IPH is associated with plaque vulnerability and stroke, with magnetic resonance imaging (MRI) being the most sensitive and specific to detect IPH as a predictor of ischemic events. These conclusions are however still debated because of the limited number of patients included in these studies; further studies are required to better assess risks associated with different IPH stages. Moreover, IPH is implicated in plaque vulnerability with other risk factors which need to be considered to predict ischemic risk. In addition, MRI sequences standardization is required to compare results from different studies and agree on biomarkers that need to be considered to predict plaque rupture. In these circumstances, IPH detection by MRI could be an efficient clinical method to predict stroke. The goal of this review article is to first describe the pathophysiological process responsible for IPH, its histological detection in carotid plaques and its correlation with plaque rupture. The second part will discuss the benefits and limitations of imaging the carotid plaque, and finally the clinical interest of imaging IPH to predict plaque rupture, focusing on MRI-IPH.
... As such, it accumulates in tissues with high metabolic activities, including inflammatory cells, and has been employed to provide an index of leukopoietic tissue activity (e.g., the bone marrow or BM) and of the presence of inflammation within a variety of tissues, including the arterial wall (ArtI), in atherosclerosis. 1 ArtI can be measured reliably in the aorta and carotid arteries and has repeatedly been associated with macrophage density in atherosclerotic plaques (Table 1). [2][3][4][5][6][7][8][9][10][11] Nevertheless, ArtI presents several challenges. It is not specific for macrophage infiltration alone (as it is also trapped in smooth muscle and other components of the arterial wall), and measurement of uptake cannot reliably be performed in the coronary arteries (due to high uptake by background myocardium and inadequate resolution). ...
Positron emission tomography (PET) imaging can yield unique mechanistic insights into the pathophysiology of atherosclerosis. 18F-fluorodeoxyglucose (18F-FDG), a radiolabeled glucose analog, is retained by cells in proportion to their glycolytic activity. While 18F-FDG accumulates within several cell types in the arterial wall, its retention correlates with macrophage content, providing an index of arterial inflammation (ArtI) which predicts subsequent cardiovascular disease (CVD) events. Furthermore, 18F-FDG-PET imaging allows the simultaneous assessment of metabolic activity in several tissues (e.g., brain, bone marrow) and is performed in conjunction with cross-sectional imaging that enables multi-organ structural assessments. Accordingly, 18F-FDG-PET/computed tomography (CT) imaging facilitates evaluation of disease pathways that span multiple organ systems. Within this paradigm, 18F-FDG-PET/CT imaging has been implemented to study the mechanism linking chronic stress to CVD. To evaluate this, stress-associated neural activity can be quantified (as metabolic activity of the amygdala (AmygA)), while leukopoietic activity, ArtI, and coronary plaque burden are assessed concurrently. Such simultaneous quantification of tissue structures and activities enables the evaluation of multi-organ pathways with the aid of mediation analysis. Using this approach, multi-system 18F-FDG-PET/CT imaging studies have demonstrated that chronically heightened stress-associated neurobiological activity promotes leukopoietic activity and systemic inflammation. This in turn fuels more ArtI and greater non-calcified coronary plaque burden, which result in more CVD events. Subsequent studies have revealed that common stressors, such as chronic noise exposure and income disparities, drive the front end of this pathway to increase CVD risk. Hence, multi-tissue multimodality imaging serves as a powerful tool to uncover complex disease mechanisms.
... To demonstrate the utility of TIP-based tracer mapping, we conducted ex-vivo PET scans and autoradiography of atherosclerotic minipig aortas, following in-vivo injection of FDG. FDG is reported to accumulate predominantly in metabolically active macrophages in atherosclerotic plaques [14,15], although other arterial cell types, including vascular smooth muscle cells, have also been implicated in FDG accumulation [16]. The prevailing view is that FDG accumulates preferentially in plaques compared with normal arterial wall in both humans and animals [17]. ...
Autoradiography using phosphor imaging screens is often used to characterize tissue distribution of positron emission tomography (PET) radiotracers. PET tracers emit positrons with limited penetration range, and valid quantitative autoradiography can therefore only be achieved in thin tissue slices. However, in some settings, quantitative tracer profiling in thick tissues is required. Our aim was to develop a reliable method for this purpose. In this paper, we present a method based on total intensity projections (TIPs) of PET and computed tomography (CT) images. We show theoretically and experimentally that tissue total activity and tissue volume maps can be derived from the TIPs of PET and CT images, respectively. We also show that these maps are free of signal displacement artifacts in the direction of projection. To demonstrate the utility of the approach, we obtain and compare TIP-based maps and autoradiography of ex-vivo atherosclerotic minipig aortas following in-vivo injection of 18F-fluorodeoxyglucose. We show that autoradiography of the thick aortas yields distorted results due to positron range effects, whereas TIP-mapping is free from such bias. The TIP-based maps may, thus, provide a low-resolution alternative to autoradiography, when tracer accumulation profiling in thick tissues is required.
... Subsequent clinical studies of FDG PET/CT showed that CT-derived vascular calcification and PET metabolic activity in fact were detecting potentially different stages of plaque development. 15 Additionally, high-risk plaque morphology by CT corresponded with the inflammation burden detected by FDG PET. 16 Inflammatory vascular conditions also show extensive FDG PET uptake in blood vessel walls. ...
Fluorodeoxyglucose-PET/computed tomography combines the high sensitivity of PET with the excellent spatial resolution provided by computed tomography, making it a potentially powerful tool for capturing and quantifying early vascular diseases. Patients with chronic inflammatory states have an increased risk of cardiovascular events; there is also increased vascular fluorodeoxyglucose uptake seen compared with healthy controls. This review examines the use of fluorodeoxyglucose-PET/computed tomography in assessing low-grade vascular inflammation in chronic inflammation and then reviews fluorodeoxyglucose-PET/computed tomography as a tool in monitoring the efficacy of various treatments known to modulate cardiovascular disease.
... Thrombogenic Conditions Atherosclerotic plaques are vulnerable sites for rupture mostly because of their lipi-rich cores as well as thin fibrous cap formation around the plaque [58]. Diabetic patients have systemic inflammation and more severe endothelial dysfunction meaning more platelets and increased vascular stasis resulting in a thrombogenic milieu [59]. ...
Purpose of Review
Diabetes is a common and prevalent medical condition as it affects many lives around the globe. Specifically, type-2 diabetes (T2D) is characterized by chronic systemic inflammation alongside hyperglycemia and insulin resistance in the body, which can result in atherosclerotic legion formation in the arteries and thus progression of related conditions called diabetic vasculopathies. T2D patients are especially at risk for vascular injury; adjunct in many of these patients, their cholesterol and triglyceride levels reach dangerously high levels and accumulate in the lumen of their vascular system.
Recent Findings
Microvascular and macrovascular vasculopathies as complications of diabetes can accentuate the onset of organ illnesses; thus, it is imperative that research efforts help identify more effective methods for prevention and diagnosis of early vascular injuries. Current research into vasculopathy identification/treatment will aid in the amelioration of diabetes-related symptoms and thus reduce the large number of deaths that this disease accounts annually.
Summary
This review aims to showcase the evolution and effects of diabetic vasculopathy from development to clinical disease as macrovascular and microvascular complications with a concerted reference to sex-specific disease progression as well.
... On PET imaging, evidence has shown that hypercaptation corresponds to inflammation in the plaque (Figures 3 and 4). [41][42][43][44] Perfusion or rather postcontrast imaging since dynamic imaging at the moment would provide a too low resolution is possible also with CT and MR. One example where enhanced imaging has been of help is the so-called carotid ring sign that helps to differentiate acute from chronic occlusions. ...
In great part due to recent advances in medical technology, ischemic cerebral stroke has become an increasingly treatable condition, which requires urgent measures and which rely on pharmacological and/or interventional measures. Due to its high prevalence, preventive measures should also be undertaken, and this is a situation where the use of advanced neuroimaging techniques could be helpful in certain underlying diseases. What is proposed here is to discuss how modern neuroimaging techniques (advanced magnetic resonance (MR) techniques and/or nuclear medicine techniques such as positron emission tomography (PET)) could help in situations that would otherwise lead to a stroke. Since both primary and secondary prevention measures are often required, we see that the techniques can be helpful in both situations. The diseases that cause stroke that can be investigated are, among others, carotid stenosis; transient ischemic attacks (TIAs) may also be followed by a major stroke if nothing is undertaken. It has been established that carotid stenosis is to be treated in the presence of a significant lesion that has neurological symptoms. The question of how to deal with these patients often arises when the relationship between the stenosis and symptoms is not significant or the symptomatology unclear. In such situations, either PET and/or fat-saturated T1 images of the carotids can help to demonstrate the embolic nature of the plaque. We have seen that carotid plaque vulnerability, which can cause embolism, can be associated with plaque inflammation (seen on PET) or plaque haemorrhage (seen on MR images). Also, while PET and MRI will demonstrate different stages of plaque vulnerability, they can both help to demonstrate vascular lesions that are at risk of causing significant ischemic events. Diffusion-weighted imaging (DWI) has shown that some TIAs may indeed be ischemic brain lesions with a transient symptomatology. The early use of DWI can thus help treat these patients more acutely. Based on this, we have seen that newer imaging techniques can provide additional knowledge about conditions that may lead to stroke and be treated. This should have a major impact on patient outcomes and ultimately on healthcare costs related to this condition.
... Concerning non-neoplastic diseases, immunohistochemical findings, using a CD68 marker for macrophage density and vascular endothelial growth factor, were used for patients undergoing carotid endarterectomy after an initial FDG PET/CT uptake determination. Increased plaque metabolism was demonstrated to correlate with increased inflammation and angiogenesis, whereas the histological and PET markers were shown to be inversely related in plaque calcifications [2]. Modern research practices in neurodegenerative diseases still make use, and demonstrate, the invaluable nature of histopathologic confirmation in this study of Aβ plaques being highlighted by [18F]flutemetamol PET [3]. ...
Purpose:
This review provides an overview of some of the most recent clinical trials which investigated various types of cancer and other diseases, through the use of PET-CT imaging, highlighting the use of immunohistochemical stains or conventional histopathology for the validation or contradiction of their hypothesis. Furthermore, we investigate a potential new direction of research by analyzing the upcoming role of microRNAs in disease confirmation.
Methods:
An extensive search of MEDLINE/PubMed and SCOPUS electronic databases was made, using the MeSH terms "positron emission tomography computed tomography" and "immunohistochemistry" as well as "SUV" and "immunohistochemistry", restricting the search by clinical trials and time period. Further searches were made for articles regarding Ki-67 and microRNAs in correlation with metabolic PET-CT uptake.
Results:
Out of all 389 initial search results, 27 original articles were found relevant to the topic. Their contents were synthesized and discussed regarding the matter at hand. No relevant clinical trials involving microRNAs were found.
Conclusions:
Immunohistochemical and histopathologic results remain widely used and indispensable in modern research, concerning PET-CT validation. Possible candidates for diagnosis confirmation, in future research, may reside in the further development of microRNAs.
... 16 Interestingly, in patients with recent ischemic stroke and complicated plaques on MRI, a global increase of the vascular FDG signal was detected in both carotid arteries. Several studies 14,17,18 have confirmed that, in patients with recent ischemic stroke, the FDG signal is increased in atherosclerotic plaques ipsilateral but also contralateral to the side of stroke and is higher than in carotid plaques of asymptomatic patients, with patients imaged in the first 90 days after ischemic stroke showing higher FDG signal in carotid plaques compared with patients imaged at later time points. 19 Accordingly, carotid plaques contralateral to culprit lesions in symptomatic patients cannot be classified as stable from a biological point of view. ...
Noninvasive imaging technologies offer to identify several anatomic and molecular features of high-risk plaques. For the noninvasive molecular imaging of atherosclerotic plaques, nuclear medicine constitutes one of the best imaging modalities, thanks to its high sensitivity for the detection of probes in tissues. 18F-fluorodeoxyglucose (FDG) is currently the most widely used radiopharmaceutical for molecular imaging of atherosclerotic plaques with positron emission tomography. The intensity of FDG uptake in the vascular wall correlates closely with the degree of macrophage infiltration in atherosclerotic plaques. FDG positron emission tomographic imaging has become a powerful tool to identify and monitor noninvasively inflammatory activities in atherosclerotic plaques over time. This review examines how FDG positron emission tomographic imaging has given us deeper insight into the role of inflammation in atherosclerotic plaque progression and discusses perspectives for alternative radiopharmaceuticals to FDG that could provide a more specific and simple identification of high-risk lesions and help improve risk stratification of atherosclerotic patients.
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... A different approach could have been to evaluate intervention effect on most-diseased segment as previously reported [32,33]. Significant correlations between ex vivo molecular markers of plaque inflammation and in vivo tracer uptake were observed, consistent with what has been shown from endarterectomy specimens from human patients [8,34]. The porcine aortic expression of the scavenger receptor (CD68) correlated well with FDG-uptake as well as immunohistochemical staining of CD68-positive cells (R 2 = 0.59, p = 0.0008; data not shown). ...
Background and aims:
The advantage of combining molecular and morphological imaging, e.g. positron emission tomography and magnetic resonance imaging (PET/MRI), is reflected in the increased use of these modalities as surrogate end-points in clinical trials. This study aimed at evaluating plaque inflammation using 18F-fluorodeoxyglucose (18F-FDG)-PET/MRI, and gene expression in a minipig model of atherosclerosis.
Methods:
Göttingen Minipigs were fed for 60 weeks with fat/fructose/cholesterol-rich diet (FFC), chow (Control) or FFC-diet changed to chow midway (diet normalization group; DNO). In all groups, 18F-FDG-PET/MRI of the abdominal aorta was assessed midway and at study-end. The aorta was analyzed using histology and gene expression.
Results:
At study-end, FFC had significantly higher FDG-uptake compared to Control (target-to-background maximal uptake, TBRMax (95% confidence interval) CITBRMax: 0.092; 7.32) and DNO showed significantly decreased uptake compared to FFC (CITBRMax: -5.94;-0.07). No difference was observed between DNO and Control (CITBRMax: -2.71; 4.11). FFC displayed increased atherosclerosis and gene expression of inflammatory markers, including vascular cell adhesion molecule 1 (VCAM-1), cluster of differentiation 68 (CD68), matrix metalloproteinase 9 (MMP9), cathepsin K (CTSK) and secreted phosphoprotein 1 (SPP1) compared to Control and DNO (all, p < 0.05). FDG-uptake correlated with gene expression of inflammatory markers, including CD68, ρs = 0.58; MMP9, ρs = 0.46; SPP1, ρs = 0.44 and CTSK, ρs = 0.49; (p ≤ 0.01 for all).
Conclusions:
In a model of atherosclerosis, 18F-FDG-PET/MRI technology allows for detection of inflammation in atherosclerotic plaques, consistent with increased inflammatory gene expression. Our findings corroborate clinical data and are important in pre-clinical drug development targeting plaque inflammation.
... 18-fluorodeoxyglucose ( 18 FDG) is the main tracer used in PET examinations in clinical practice; it is a sugar marked with radioactive fluorine, and it accumulates inside of active metabolic cells, like inflammatory cells. This feature can be exploited in order to evidence plaque inflammation [58]; in fact, plaque inflammation is accompanied by anarchic neovascularization promoted by molecules like Vascular Endothelial Growth Factor (VEGF), and high uptake of 18 FDG could be considered a marker of plaque neovascularization. ...
Intraplaque hemorrhage (IPH) is one of the main factors involved in atherosclerotic plaque (AP) instability. Its recognition is crucial for the correct staging and management of patients with carotid artery plaques to limit ischemic stroke. Imaging plays a crucial role in identifying IPH, even if the great variability of intraplaque vascularization and the limitations of our current imaging technologies make it difficult. The intent of this review is to give a general overview of the main features of intraplaque vascularization and IPH on Ultrasound (US), Computed Tomography (CT), Magnetic Resonance (MR) and Nuclear Medicine, and a brief description on the future prospectives.
... e ability of DANBIRT to assess and quantify in vivo inflammation presents an opportunity to functionally characterize developing atheroma and atherosclerosis. Current molecular imaging techniques such as FDG-PET/CT localize general metabolic activity but lack specificity for molecular events associated with inflammatory cell activation [5,47]. ...
Atherosclerosis-related morbidity and mortality remain a global concern. Atherosclerotic disease follows a slow and silent progression, and the transition from early-stage lesions to vulnerable plaques remains difficult to diagnose. Inflammation is a key component of the development of atherosclerotic plaque and consequent life-threatening complications. This study assessed ¹¹¹ In-DANBIRT as an in vivo , noninvasive SPECT/CT imaging probe targeting an inflammatory marker, Lymphocyte Function Associated Antigen-1 (LFA-1), in atherosclerotic plaques. Methods . Selective binding of ¹¹¹ In-DANBIRT was assessed using Sprague-Dawley rats exposed to filtered air and ozone (1 ppm) by inhalation for 4 hours to induce a circulating leukocytosis and neutrophilia in peripheral blood. After 24 hours, whole blood was collected and incubated with radiolabeled DANBIRT ( ⁶⁸ Ga-DANBIRT and ¹¹¹ In-DANBIRT). Isolated cell component smeared slides using cytospin technique were stained with Wright-Giemsa stain. Apolipoprotein E-deficient (apoE −/− ) mice were fed either a normal diet or a high-fat diet (HFD) for 8 weeks. Longitudinal SPECT/CT imaging was performed 3 hours after administration at baseline, 4, and 8 weeks of HFD diet, followed by tissue harvesting for biodistribution, serum lipid analysis, and histology. 3D autoradiography was performed in both groups 24 hours after administration of ¹¹¹ In-DANBIRT. Results . Increased specific uptake of radiolabeled DANBIRT by neutrophils in the ozone-exposed group was evidenced by the acute immune response due to 4-hour ozone exposure. Molecular imaging performed at 3 hours using SPECT/CT imaging evidenced an exponential longitudinal increase in ¹¹¹ In-DANBIRT uptake in atherosclerosis lesions in HFD-fed mice compared to normal-diet-fed mice. Such results were consistent with increased immune response to vascular injury in cardiovascular and also immune tissues, correlated by 24 hours after administration of 3D autoradiography. Histologic analysis confirmed atherosclerotic disease progression with an increased vascular lesion area in HFD-fed mice compared to normal-diet-fed mice. Conclusion . ¹¹¹ In-DANBIRT is a promising molecular imaging probe to assess inflammation in evolving atheroma and atherosclerotic plaque.
... Macrophages are the primary constituents of high-risk plaque that undergoes erosion and rupture [7]. Consequently, it has been hypothesized that 18 FDG uptake may serve as an indirect marker of carotid macrophage metabolic activity, given that macrophages have high metabolic rates [9,10,[15][16][17][18][19]. Early studies suggested the extent of 18 FDG uptake in carotid . ...
Background:
[18F]-fluorodeoxyglucose (18FDG) uptake imaged with positron emission tomography (PET) and computed tomography (CT) may serve as a biomarker of plaque inflammation. This study evaluated the relationship between carotid plaque 18FDG uptake and a) intraplaque expression of macrophage and macrophage-like cellular CD68 immunohistology; b) intraplaque inflammatory burden using leukocyte-sensitive CD45 immunohistology; c) symptomatic patient presentation; d) time from last cerebrovascular event.
Methods:
54 patients scheduled for carotid endarterectomy underwent 18FDG PET/CT imaging. Maximum 18FDG uptake (SUVmax) and tissue-to-blood ratio (TBRmax) was measured for carotid plaques. Quantitative immunohistological analysis of macrophage-like cell expression (CD68) and leukocyte content (CD45) was performed.
Results:
18FDG uptake was related to CD68 macrophage expression (TBRmax: r = 0.51, p < 0.001), and total-plaque leukocyte CD45 expression (TBRmax: r = 0.632, p = 0.009, p < 0.001). 18FDG TBRmax uptake in carotid plaque associated with patient symptoms was greater than asymptomatic plaque (3.58 ± 1.01 vs. 3.13 ± 1.10, p = 0.008). 18FDG uptake differed between an acuity threshold of <90 days and >90 days (SUVmax:3.15 ± 0.87 vs. 2.52 ± 0.45, p = 0.015).
Conclusions:
In this CAIN cohort, 18FDG uptake imaged with PET/CT serves a surrogate marker of intraplaque inflammatory macrophage, macrophage-like cell and leukocyte burden. 18FDG uptake is greater in plaque associated with patient symptoms and those with recent cerebrovascular events. Future studies are needed to relate 18FDG uptake and disease progression.
... PET on the other hand, has proven to be more useful in detecting early inflammatory stages of vasculitis [37][38][39]. 18 F-FDG PET signal intensity has been found to be strongly associated with macrophage density [40][41][42]. Activated macrophages and lymphocytes overexpress glucose transporters (Glut-1 and Glut-5) and undergo a switch to glycolysis. Based on this principle, 18 F-FDG, a radiolabelled glucose analog, is highly taken up by infiltrating immune cells (including macrophages) in active vasculitic lesions. ...
Macrophages are key players in the pathogenesis of large-vessel vasculitis (LVV) and may serve as a target for diagnostic imaging of LVV. The radiotracer, 18F-FDG has proven to be useful in the diagnosis of giant cell arteritis (GCA), a form of LVV. Although uptake of 18F-FDG is high in activated macrophages, it is not a specific radiotracer as its uptake is high in any proliferating cell and other activated immune cells resulting in high non-specific background radioactivity especially in aging and atherosclerotic vessels which dramatically lowers the diagnostic accuracy. Evidence also exists that the sensitivity of 18F-FDG PET drops in patients upon glucocorticoid treatment. Therefore, there is a clinical need for more specific radiotracers in imaging GCA to improve diagnostic accuracy. Numerous clinically established and newly developed macrophage targeted radiotracers for oncological and inflammatory diseases can potentially be utilized for LVV imaging. These tracers are more target specific and therefore may provide lower background radioactivity, higher diagnostic accuracy and the ability to assess treatment effectiveness. However, current knowledge regarding macrophage subsets in LVV lesions is limited. Further understanding regarding macrophage subsets in vasculitis lesion is needed for better selection of tracers and new targets for tracer development. This review summarizes the development of macrophage targeted tracers in the last decade and the potential application of macrophage targeted tracers currently used in other inflammatory diseases in imaging LVV.
... cancer cells, macrophages). Because atherosclerotic plaques that are prone to rupture have a high concentration of macrophages, 18 F-FDG has been used to identify areas of high metabolic activity [8,9,10,11]. The largest uptake of 18 F-FDG occurs in small regions located at the site of active plaque and that uptake is distinctly different compared to adjacent tissues [12]. ...
... La tomographie par émission de positons avec utilisation du 18-FDG est une méthode validée et reproductible pour détecter les plaques instables [43]. La consommation de FDG est corrélée à la vascularisation, à l'inflammation et/ou à la présence d'une hypoxie dans la plaque [44,45]. Il Tableau 3 Comparaison entre la présence de microbulles intraplaque et la densité de microvaisseaux (DMV) constatée en immunohistologie. ...
L’échographie en mode harmonique avec injection de produit de contraste ultrasonore permet de visualiser des microbulles mobiles dans la plaque carotidienne, témoin d’une néovascularisation secondaire à une inflammation ou à une hypoxie. Ces néovaisseaux pourraient constituer un marqueur « précurseur » de la plaque vulnérable. L’objectif de ce travail est de faire une mise au point sur la technique d’acquisition de l’imagerie de contraste ultrasonore dans l’exploration des carotides aussi bien pour les lésions athéromateuses que pour les vascularites des gros vaisseaux. Un descriptif précis du matériel à utiliser, de la méthodologie d’acquisition des images et des conditions environnementales est abordé. Nous insisterons notamment sur les pièges à éviter ainsi que sur les bons réflexes à avoir pour interpréter cette imagerie. La présence de microbulles dans une plaque est associée de façon significative à une augmentation des événements cardiovasculaires (infarctus et syndrome coronaire aigu) mais aussi des accidents ischémiques cérébraux ipsilatéraux. La détection d’irrégularités de parois, de microfissures et de niches ulcérées est facilitée par l’utilisation du contraste en comparaison avec le scanner. Aucune étude n’a pour l’instant validé l’échographie de contraste dans l’exploration de la sténose carotidienne asymptomatique. L’échographie de contraste permet aussi de détecter les phases actives des vascularites des gros vaisseaux par la présence des microbulles dans les parois et d’en surveiller la régression sous traitement médical approprié. De futures études de validation voire des registres sont souhaitables pour permettre de mieux utiliser cet outil en pratique clinique quotidienne.
... 18 Ffluorodeoxyglucose ( 18 F-FDG)-positron emission tomography (PET) is a molecular non invasive imaging technique that has been suggested as a biomarker to report on the metabolic activity of atherosclerosis since glucose is the major substrate for macrophages resident in plaque [6,7]. Indeed, the relationship between arterial 18 F-FDG signal and plaque inflammation has been reported both in animal models [8] and humans, especially at the level of carotid plaques, aorta and iliacfemoral arteries [9][10][11][12][13]. Identification of metabolically active plaques in the coronary tree would be desirable since this might allow the implementation of preventative strategies. ...
Purpose:
To evaluate the relationship between aortic inflammation as assessed by (18)F-fluorodeoxyglucose-positron emission tomography ((18)F-FDG-PET) and features of plaque vulnerability as assessed by frequency domain-optical coherence tomography (FD-OCT).
Methods:
We enrolled 30 consecutive non-ST-segment elevation acute coronary syndrome patients undergoing percutaneous coronary intervention. All patients underwent three-vessel OCT before intervention and (18)F-FDG-PET before discharge. Univariable and C-reactive protein (CRP)-adjusted linear regression analyses were performed between features of vulnerability [namely:lipid-rich plaques with and without macrophages and thin cap fibroatheromas (TCFA)] and (18)F-FDG uptake in both ascending (AA) and descending aorta (DA) [measured either as averaged mean and maximum target-to-blood ratio (TBR) or as active slices (TBRmax ≥ 1.6)].
Results:
Mean age was 62 years, and 26 patients were male. On univariable linear regression analysis TBRmean and TBRmax in DA was associated with the number of lipid-rich plaques (β = 4.22; 95%CI 0.05-8.39; p = 0.047 and β = 3.72; 95%CI 1.14-6.30; p = 0.006, respectively). TBRmax in DA was also associated with the number of lipid-rich plaques containing macrophages (β = 2.40; 95%CI 0.07-4.72; p = 0.044). A significant CRP adjusted linear association between the TBRmax in DA and the number of lipid-rich plaques was observed (CRP-adjusted β = 3.58; 95%CI -0.91-6.25; p = 0.01). TBRmax in DA showed a trend towards significant CRP-adjusted association with number of lipid-rich plaques with macrophages (CRP-adjusted β = 2.30; 95%CI -0.11-4.71; p = 0.06). We also observed a CRP-adjusted (β = 2.34; 95%CI 0.22-4.47; p = 0.031) linear association between the number of active slices in DA and the number of lipid-rich plaques. No relation was found between FDG uptake in the aorta and the number of TCFAs.
Conclusions:
In patients with first NSTEACS(, 18)F-FDG uptake in DA is correlated with the number of OCT detected lipid-rich plaques with or without macrophages. This association may be independent from CRP values.
... In addition, coronary CTA was performed at a single time point, thereby precluding longitudinal assessment of changes or stability of coronary plaques at 12 weeks (after treatment). However, the reduction in both the coronary and extracoronary artery FDG signals, which has been validated histopathologically as an inflammatory marker, 12,26,29,30 suggests that the underlying inflammation-mediated high-risk plaque features may have been favorably modified. Although the image analyses in our study were prespecified before initiation of any study procedures, future studies are warranted to confirm our findings. ...
Background—
Nonobstructive coronary plaques manifesting high-risk morphology (HRM) associate with an increased risk of adverse clinical cardiovascular events. We sought to test the hypothesis that statins have a greater anti-inflammatory effect within coronary plaques containing HRM.
Methods and Results—
In this prospective multicenter study, 55 subjects with or at high risk for atherosclerosis underwent ¹⁸F-fluorodeoxyglucose positron emission tomographic/computed tomographic imaging at baseline and after 12 weeks of treatment with atorvastatin. Coronary arterial inflammation (¹⁸F-fluorodeoxyglucose uptake, expressed as target-to-background ratio) was assessed in the left main coronary artery (LMCA). While blinded to the PET findings, contrast-enhanced computed tomographic angiography was performed to characterize the presence of HRM (defined as noncalcified or partially calcified plaques) in the LMCA. Arterial inflammation (target-to-background ratio) was higher in LMCA segments with HRM than those without HRM (mean±SEM: 1.95±0.43 versus 1.67±0.32 for LMCA with versus without HRM, respectively; P=0.04). Moreover, atorvastatin treatment for 12 weeks reduced target-to-background ratio more in LMCA segments with HRM than those without HRM (12 week-baseline Δtarget-to-background ratio [95% confidence interval]: −0.18 [−0.35 to −0.004] versus 0.09 [−0.06 to 0.26]; P=0.02). Furthermore, this relationship between coronary plaque morphology and change in LMCA inflammatory activity remained significant after adjusting for baseline low-density lipoprotein and statin dose (β=−0.27; P=0.038).
Conclusions—
In this first study to evaluate the impact of statins on coronary inflammation, we observed that the anti-inflammatory impact of statins is substantially greater within coronary plaques that contain HRM features. These findings suggest an additional mechanism by which statins disproportionately benefit individuals with more advanced atherosclerotic disease.
Clinical Trial Registration—
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00703261.
... Apart from preclinical studies, most of the evidence comes from studies in large arterial beds, such as the carotid, aortic, femoral, and iliac arteries, where FDG PET has proven feasibility for atherosclerosis imaging in humans. FDG PET results also have high reproducibility and correlation with macrophages and biomarkers of angiogenesis [9][10][11] (Fig. 1). The feasibility of FDG imaging of coronary plaques and especially of the left main coronary artery (because this vessel is larger, more remote from myocardium, and less mobile) has also been found in humans [12]. ...
Objective:
The purposes of this article are to review the common biologic features of cancer and coronary artery disease assessed with PET tracers, focusing on those already used in the clinic and those with translational potential, and to discuss the current value and expected contribution of PET in diagnosis, risk stratification, and treatment monitoring.
Conclusion:
PET using a wide variety of radiotracers enhances understanding of pathophysiologic changes shared by cancer and coronary artery disease, helps establish an accurate diagnosis, and aids in prognostic assessment and management decisions. It is likely that with the evolution of therapeutic strategies for blocking the development and progression of both diseases and with the introduction of novel, specific ligands in clinical practice, PET will play an ever stronger role in diagnosis, risk stratification, and monitoring of therapy.
... Hypoxia is a prominent feature of the atherosclerotic milieu and associates strongly with the burden of macrophage infiltration and inflammation (41). Animal (42)(43)(44)(45)(46)(47)(48) and human (33,(49)(50)(51) studies have consistently demonstrated a correlation between 18 F-FDG uptake and the presence and density of macrophages in atherosclerosis. 18 F-FDG PET vascular imaging in humans was first described in 1999 in Takayasu's arteritis, before being investigated in other vasculitides (52)(53)(54). ...
Atherosclerosis is characterized by the formation of complex atheroma lesions (plaques) in arteries that pose risk by their flow-limiting nature and propensity for rupture and thrombotic occlusion. It develops in the context of disturbances to lipid metabolism and immune response, with inflammation underpinning all stages of plaque formation, progression and rupture. As the primary disease process responsible for myocardial infarction, stroke and peripheral vascular disease, atherosclerosis is a leading cause of morbidity and mortality on a global scale. A precise understanding of its pathogenic mechanisms is therefore critically important. Integral to this is the role of vascular wall imaging. Over recent years, the rapidly evolving field of molecular imaging has begun to revolutionize our ability to image beyond just the anatomical substrate of vascular disease, and more dynamically assess its pathobiology. Nuclear imaging by positron emission tomography (PET) can target specific molecular and biological pathways involved in atherosclerosis, with the application of (18)Fluoride PET imaging being widely studied for its potential to identify plaques that are vulnerable or high risk. In this review, we discuss the emergence of (18)Fluoride PET as a promising modality for the assessment of coronary atherosclerosis, focusing on the strengths and limitations of the two main radionuclide tracers that have been investigated to date: 2-deoxy-2-((18)F)fluoro-D-glucose ((18)F-FDG) and sodium (18)F-fluoride ((18)F-NaF).
... An extensive body of literature, with excellent review articles (22), is available on the use of 18 F-FDG PET imaging as a marker of macrophage infiltration to identify inflammatory vascular plaques. In one study, 18 F-FDG uptake was found to correlate positively with macrophage density (23). TSPO ligands such as 125 I-DPA-713 (N,N-diethyl-2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide) (24) and 11 C-PK11195 (25), as well as labeled DOTATATE ( 68 Ga and 64 Cu) (Fig. 3) (26), have also been used in the evaluation of plaques. ...
The ability to image inflammation in vivo can improve our understanding of the pathophysiology underlying various disease etiologies including cancer, atherosclerosis and neurodegeneration. A great wealth of preclinical and translational research has been and is currently being developed to help decipher the involvement of the immune system in disease pathophysiology, quantify disease course as well as visualize the potential detrimental effects of excessive inflammation. Down the road, the ultimate goal is to have clinical non-invasive in vivo imaging biomarkers of inflammation that will help diagnose disease, establish prognosis and gauge response to preventative and therapeutic strategies.
... The authors measured the SUV in the volume of the plaque corresponding to the site of the CEUS measurement. Previous studies have shown a correlation between 18 F-FDG plaque uptake with plaque vascularization assessed histologically and with plaque inflammation and/or hypoxia (34)(35)(36). Our study evaluated for the first time the correlation between PET/CT scan and CEUS carotid examination in patients with LVV. ...
Objective:
To assess the findings of contrast-enhanced ultrasound (CEUS) of carotid arteries in patients with large vessel vasculitis (LVV) and to compare them with those observed using 18F-FDG positron emission tomography (FDG-PET).
Methods:
31 consecutive patients with LVV (14 with Takayasu, 17 with giant cell arteritis with large vessel involvement) underwent both PET/CT and carotid artery colour Doppler ultrasonography (CDUS) for a total of 35 combined assessments. Right carotid artery CEUS was performed after CDUS in all assessments. Kerr's criteria, complete clinical examination and acute phase reactants were simultaneously evaluated. Intensity of vascular uptake and vascularization of carotid artery wall were compared.
Results:
Ten FDG/PET scans showed active vascular 18F-FDG uptake (visual grade ≥2) in the right carotid artery. CEUS demonstrated severe vascularization (grade 2) within the right carotid artery wall in 12 examinations. Carotid CEUS vascularization grade significantly correlated with vascular 18F-FDG uptake (p<0.001) and max standardized uptake value (SUV) in right carotid artery/mean SUV in superior vena cava (p=0.001). When active vascular 18F-FDG uptake (≥2) was considered the gold standard for defining vascular inflammation, carotid CEUS had a sensitivity of 100% (95%CI 65%,100%) and a specificity of 92% (95%CI 72%, 99%). The positive LR was 12.5 (95%CI 3.3, 47.2). Severe vascularization at CEUS and active vascular 18F-FDG uptake were significantly more frequent in active disease according to Kerr's criteria compared to inactive (p = 0.001 and p = 0.002, respectively).
Conclusions:
Carotid CEUS vascularization grade and grade of vascular inflammation on FDG-PET were correlated in patients with LVV. This article is protected by copyright. All rights reserved.
Stroke or cerebrovascular disease is one of the main causes of death globally. The incidence of stroke is linked to the persistent rise in the prevalence of risk factors like obesity, diabetes, hypertension, and hyperlipidemia. As a significant risk factor for stroke, this chapter discussed the impact of diabetes on stroke events. It summarises the pathophysiology of hyperglycaemia and additional other co-existing common risk factors leading to stroke events. Likewise, this chapter discusses the clinical implications, management approach to diabetes with stroke events and preventive strategies to reduce stroke risk. The comprehensive medical intervention of diabetes, alongside other associated risk factors management, together with effective healthy lifestyle changes, is an essential and effective strategy to lower the risk of stroke in patients with T2DM.
Nanotechnology is the newer form of technology using nanoparticles, leading to better and more precise diagnosis. The role of nanoimaging is also important in the different applications of infectious and inflammatory diseases. The important aspect will be the use of different nanomaterials, which will have different characteristics concerning the various drug-loaded nanocarriers, and also the newer concept for various infectious and inflammatory diseases. These include different pathologies like immunodeficiency syndromes, hepatitis, tuberculosis, and various associated inflammatory conditions.
Background:
Calcification and progression of atheromatous disease (AD) both have been independently related with the risk of stroke. However, the link between the two phenomena is still unclear. The main objective of this study was to analyze the temporal evolution of Ca content of carotid atheromatous plaques and its relation with the progression of carotid AD using quantitative CT Angiography (CTA).
Methods:
Forty-three asymptomatic patients with stenosis of the internal carotid artery (ICA)>50% completed the study. Contrast mold volume and calcium (Ca) content by quantitative CTA and Modified Agatston Score (Ca volume x radiological density) were assessed at baseline and after 12±2 months. Biochemical parameters, including main markers of Ca/Phosphorus (P) metabolism, were determined.
Results:
CTA measurement showed an increase of volumetric stenosis (volume decrease of the contrast mold), compared to baseline (475.45 (155.6) mm3 x U.H vs 501.3 (171.9) mm3 x U.H; p=0.04) as well as an increase of intra-plaque Ca (64.58 (57.8) mm3x U.H. vs 56.8 (52.3) p=0.002). An inverse correlation between baseline Ca content and volumetric stenosis progression (r= - 0.481; p<0.001), as well as between the increase of carotid Ca and plasma levels of vitamin D (r= 0.4; p=0.025) were also found. Multiple regression analysis found a model with baseline intra-plaque Ca, adjusted by body mass index (BMI) as most predictive of carotid AD progression.
Conclusions:
These results suggest that a higher content of Ca confers greater stability against the progression of carotid AD and, eventually, its ability to generate symptomatology.
Background and aims
Urokinase-type plasminogen activator receptor (uPAR) is associated with extracellular matrix (ECM) degradation and cancer aggressiveness. Its role in arterial atherogenesis as a molecular imaging target is not well-established. The aim of this study was to non-invasively visualize uPAR expression in atherosclerosis by a novel uPAR-targeting positron emission tomography (PET) tracer [⁶⁴Cu]Cu-DOTA-AE105.
Methods
We used molecular biology to investigate uPAR expression by analyzing human atherosclerotic plaques and cultured cells. A retrospective analysis was performed on patients, who underwent combined PET/CT (n = 10) to measure [⁶⁴Cu]Cu-DOTA-AE105 uptake in five large arteries, divided into a high and low-risk group based on coronary artery calcium score (CAC score).
Results
The in vitro assay for THP-1 monocytes displayed a significantly upregulated uPAR expression upon stimulation (5.2-fold upregulation, p < 0.0001 by a one-way ANOVA followed by Tukey's test) by single-cell flowcytometric analysis. Freshly excised human atherosclerotic plaques underwent flow cytometric and microarray analyses manifesting 73.9 ± 2.9% of mononuclear phagocyte system (MPS) cells expressing uPAR and had a greater than 7-fold higher gene expression of plasminogen activator urokinase receptor (PLAUR, p = 0.002), integrin subunit alpha X (ITGAX, p = 0.0008), and cluster of differentiation 163 (CD163, p < 0.0001). The tissue-to-background ratios (TBRmax) in five large arteries showed a higher [⁶⁴Cu]Cu-DOTA-AE105 uptake in the group with high CAC score compared to the group with low CAC score (2.4 ± 0.1 vs 1.7 ± 0.1, p = 0.057), significantly higher in the ascending aorta (2.7 ± 0.1 vs 2.0 ± 0.1, p = 0.038) and the abdominal aorta (3.2 ± 0.2 vs 2.0 ± 0.2, p = 0.038) by a non-parametric Mann-Whitney test.
Conclusions
uPAR is abundantly expressed by MPS cells in atherosclerotic plaques and can be visualized by the novel PET tracer [⁶⁴Cu]Cu-DOTA-AE105 that may non-invasively detect extracellular matrix remodeling during atherogenesis.
Objectives
Although studies have demonstrated that inflammatory and lipid/ lipoproteins-related biomarkers, genetic mutations, and epigenetic mechanisms could be candidates for diagnosis and prognosis of ischemic stroke, there is still no consensus on how to identify vulnerable plaques based on circulating biomarkers.
Materials and methods
Histological and immunohistochemical staining were performed in the aorta sections of ApoE⁻/⁻ and WT mice. Eighty-nine patients who underwent CTA were included in this study. The degree of carotid stenosis and the wall features of plaque components were quantitatively analyzed. And the serum concentration of FKN and PDGF-BB were measured.
Results
(1) The type V vulnerable atherosclerotic plaques deposited on the aortas of ApoE⁻/⁻ mice after feeding with western diet for 16 weeks. And the expression of CX3CR1 and PDGFR-β increased in the areas of atherosclerotic plaques, especially inside the fibrous cap of plaque. (2) Patients with symptomatic carotid stenosis showed larger LNRC, smaller calcified plaques and more plaque ulceration detected by CTA than asymptomatic stenosis patients. Plaque ulceration and size of LNRC were high risk factors for stroke while plaque calcification was less frequently associated with cerebrovascular ischemia. (3) The serum concentration of FKN was lower and of PDGF-BB was higher in the patients with carotid artery stenosis. Correlation analysis suggested that FKN and PDGF-BB correlated positively with carotid plaque calcification and LNRC respectively.
Conclusions
For prediction it is recommended to combine circulating biomarkers (FKN and PDGF-BB) and imaging biomarkersfor comprehensive diagnosis and risk stratification in carotid atherosclerotic stroke.
Background18F-NaF PET/CT identifies high-risk plaques due to active calcification in coronary arteries with potential to characterize plaques in ST-elevation myocardial infarction (MI) and chronic stable angina (CSA) patients.Methods
Twenty-four MI and 17 CSA patients were evaluated with 18F-NaF PET/CTCA for SUVmax and TBR values of culprit and non-culprit plaques in both groups (inter-group and intra-group comparison), and pre- and post-interventional MI plaques sub-analysis.ResultsCulprit plaques in MI patients had significantly higher SUVmax (1.6; IQR 0.6 vs 1.3; IQR 0.3, P = 0.03) and TBR (1.4; IQR 0.6 vs 1.1; IQR 0.4, P = 0.006) than culprit plaques of CSA. Pre-interventional culprit plaques of MI group (n = 11) revealed higher SUVmax (P = 0.007) and TBR (P = 0.008) values than culprit CSA plaques. Culprit plaques showed significantly higher SUVmax (P = 0.006) and TBR (P = 0.0003) than non-culprit plaques in MI group, but without significant difference between culprit and non-culprit plaques in CSA group. With median TBR cutoff value of 1.4 in MI culprit plaques, 6/7 plaques (85.7%) among the event prone non-culprit lesions had TBR values > 1.4 in CSA group.Conclusion
The study shows higher SUVmax and TBR values in MI culprit plaques and comparable TBR values for event prone plaques of CSA group in identifying high-risk plaques.
Die PET (Positronen-Emissions-Tomographie) ist ein bildgebendes Verfahren, welches die räumliche Verteilung eines mit einem Positronenstrahler markierten Radiopharmakons im Organismus darstellt. Die im Vergleich zur konventionellen Gammakameratechnik höhere räumliche Auflösung beruht auf der Messung der beim Zerfall eines Positrons emittierten beiden Gammaquanten in einem engen Zeitfenster. Die derzeit erreichbare Auflösung liegt bei 4–6 mm. Moderne PET Scanner werden als kombinierte PET/CT-Geräte betrieben. Durch die sequenzielle Akquisition von CT und PET kann die räumliche Verteilung biochemischer Prozesse bzw. physiologischer und pathologischer Stoffwechselvorgänge im Organismus in ihrem anatomischen Bezug sichtbar gemacht werden. Die CT-Komponente ist außerdem zur Berechnung der Absorptionskorrektur und damit zur Quantifizierung der PET (Berechnung der Aktivitätskonzentration des Radiopharmakons im Gewebe) erforderlich. Die CT kann als hochauflösendes CT mit Kontrastmittel erfolgen und damit auch zusätzlich zum PET die Möglichkeiten einer umfassenden CT-Diagnostik ausschöpfen.
Atherosclerosis is a chronic and most often progressive disease with a long clinically apparently silent period, and can become unstable at any time, due to a plaque rupture or erosion, leading to an acute atherothrombotic event. Atherosclerosis has a progression rate that is highly variable among patients and in the same patient. The progression of atherosclerotic plaque from asymptomatic to symptomatic phase depends on its structure and composition in which inflammation plays an essential role. Prototype of the ruptured plaque contains a large, soft, lipid-rich necrotic core with intraplaque hemorrhage that accounts for more than half of the volume of the plaque covered by a thin and inflamed fibrous cap with few smooth muscle cells, and a heavy infiltrate of inflammatory cells. Noninvasive imaging modalities might provide an assessment of the atherosclerotic disease process through the exploration of these plaque features. Computed tomography angiography and magnetic resonance imaging can characterize plaque morphology, whereas molecular imaging, owing to the high sensitivity of nuclear medicine for the detection of radiopharmaceuticals in tissues, allows to explore plaque biology. During the last 2 decades, FDG-PET imaging has also emerged as a powerful tool to explore noninvasively inflammatory activities in atherosclerotic plaques providing new insights on the evolution of metabolic activities in the vascular wall over time. This review highlights the role of PET imaging for the exploration of metabolic activities in atherosclerotic plaques. It will resume the evidence that have been gathered from clinical studies using FDG-PET and will discuss the perspectives of new radiopharmaceuticals for vulnerable plaque imaging.
Objective(s): Cardiovascular disease is a leading cause of morbimortality with over half cardiovascular events occurring in the asymptomatic population by traditional risk stratification. This preliminary study aimed to evaluate systemic plaque vulnerability in patients with prior Coronary Artery Disease (CAD) with a single Whole Body [FDG] PET-CT scan in terms of plaque inflammation and calcifications.
Methods: Twenty-two patients referred for oncological evaluation and with prior history of advanced CAD or age and gender matched controls without cardiovascular disease, underwent a Whole Body PET-CT scan 90 min after injection of 18F-FDG. A total of 975 transaxial PET images were retrospectively analysed to assess plaque inflammation using a standardized method of analysis with averaged Target-to-Background Ratios (TBRs) at different levels, in the thoracic and abdominal aorta, carotids, LAD, common iliac and femoral arteries, and were correlated with calcium scores from the CT images.
Results: TBRs from the thoracic aorta were higher in male patients than controls (1.49±0.11, p descending > aortic arch), and were also higher in the carotids in female patients (1.43±0.07) versus controls (p
Atherosclerosis is a chronic immunomodulated disease that affects multiple vascular beds and results in a significant worldwide disease burden. Conventional imaging modalities focus on the morphological features of atherosclerotic disease such as the degree of stenosis caused by a lesion. Modern CT, MR and positron emission tomography scanners have seen significant improvements in the rapidity of image acquisition and spatial resolution. This has increased the scope for the clinical application of these modalities. Multimodality imaging can improve cardiovascular risk prediction by informing on the constituency and metabolic processes within the vessel wall. Specific disease processes can be targeted using novel biological tracers and “smart” contrast agents. These approaches have the potential to inform clinicians of the metabolic state of atherosclerotic plaque. This review will provide an overview of current imaging techniques for the imaging of atherosclerosis and how various modalities can provide information that enhances the depiction of basic morphology.
PET-based cardiac nuclear imaging plays a large role in the management of ischemic heart disease. Compared with conventional single-photon emission CT myocardial perfusion imaging, PET provides superior accuracy in diagnosis of coronary artery disease and, with the incorporation of myocardial blood flow and coronary flow reserve, adds value in assessing prognosis for established coronary and microvascular disease. This review describes these and other uses of PET in ischemic heart disease, including assessing myocardial viability in ischemic cardiomyopathy. Developments in novel PET flow tracers and molecular imaging tools to assess atherosclerotic plaque vulnerability, vascular calcification, and vascular remodeling also are described.
Les maladies cardiovasculaires représentent la première cause de morbidité et mortalité dans le monde. L'athérosclérose, qui conduit à l'obstruction des artères, est à l'origine de 50% des décès dans les sociétés industrialisées. La rupture d'une plaque d'athérosclérose dite vulnérable entraîne de nombreuses complications qui, en fonction du territoire artériel considéré, vont de l'accident vasculaire cérébral à l'infarctus du myocarde. Pour pallier ce problème de santé publique majeur, l'enjeu clinique et en particulier diagnostic repose sur la prévention de ces complications cardiovasculaires dans une population à haut risque comme à l'île de la Réunion, qui se caractérise par une incidence élevée d'atteintes vasculaires et de mortalité associée. Or, il n'existe aucune technique d'imagerie permettant la détection précoce des plaques d'athérosclérose vulnérables. La médecine nucléaire possède une grande sensibilité et pourrait offrir des outils diagnostics performants permettant d'évaluer la formation de ces plaques. Parmi tous les biomarqueurs tissulaires et circulants produits lors de l'athérogenèse, nous avons choisi la Lp-PLA2 (phospholipase A2 associée aux lipoprotéines), enzyme associée aux processus inflammatoires (produite par les monocytes et macrophages) et transportée par les lipoprotéines, comme cible de l'athérosclérose en imagerie TEP (Tomographie par Émission de Positons). Nos travaux ont permis la synthèse puis le radiomarquage d'un puissant inhibiteur cette enzyme : le Darapladib, ainsi que d'analogues. Nous avons réussi à obtenir le 18F-Darapladib afin d'étudier son accumulation dans des modèles murin et ex vivo humain de plaques d’athérome.
Die PET (Positronen-Emissions-Tomographie) ist ein bildgebendes Verfahren, welches die räumliche Verteilung eines mit einem Positronenstrahler markierten Radiopharmakons im Organismus darstellt. Die im Vergleich zur konventionellen Gammakameratechnik höhere räumliche Auflösung beruht auf der Messung der beim Zerfall eines Positrons emittierten beiden Gammaquanten in einem engen Zeitfenster. Die derzeit erreichbare Auflösung liegt bei 4–6 mm. Moderne PET Scanner werden als kombinierte PET/CT-Geräte betrieben. Durch die sequenzielle Akquisition von CT und PET kann die räumliche Verteilung biochemischer Prozesse bzw. physiologischer und pathologischer Stoffwechselvorgänge im Organismus in ihrem anatomischen Bezug sichtbar gemacht werden. Die CT-Komponente ist außerdem zur Berechnung der Absorptionskorrektur und damit zur Quantifizierung der PET (Berechnung der Aktivitätskonzentration des Radiopharmakons im Gewebe) erforderlich. Die CT kann als hochauflösendes CT mit Kontrastmittel erfolgen und damit auch zusätzlich zum PET die Möglichkeiten einer umfassenden CT-Diagnostik ausschöpfen.
Objective:
Reference values of fluorine-18-fluorodeoxyglucose (F-FDG) and fluorine-18-sodium fluoride (F-NaF) uptake in human arteries are unknown. The aim of this study was to determine age-specific and sex-specific reference values of arterial F-FDG and F-NaF uptake.
Participants and methods:
Uptake of F-FDG and F-NaF was determined in the ascending aorta, aortic arch, and descending thoracic aorta. In addition, F-FDG uptake was determined in the carotid arteries and F-NaF uptake was determined in the coronary arteries. Arterial F-FDG and F-NaF uptake were quantified as the blood pool subtracted maximum activity concentration in kBq/ml (BSF-FDGmax and BSF-NaFmax, respectively). In addition to determining reference values, we evaluated the influence of age and sex on BSF-FDGmax and BSF-NaFmax.
Results:
Arterial F-FDG and F-NaF uptake was assessed in 89 healthy adults aged 21-75 years (mean age: 44±14 years, 53% men). Both BSF-FDGmax and BSF-NaFmax increased with age. BSF-FDGmax increased with age in the descending aorta (β=0.28; P=0.003), whereas BSF-NaFmax increased with age in the ascending aorta (β=0.18; P<0.001), aortic arch (β=0.19; P=0.006), descending aorta (β=0.33; P<0.001), and coronary arteries (β=0.20; P=0.009), respectively. BSF-FDGmax and BSF-NaFmax were not influenced by sex, except for BSF-FDGmax in the ascending aorta.
Conclusion:
Prospective evaluation of 89 healthy adults generated age-specific and sex-specific reference values of arterial F-FDG and F-NaF uptake. Our findings indicate that arterial F-FDG and F-NaF uptake tend to increase with age.
Background:
(18)F-fluorocholine ((18)F-FCH) uptake is associated with cell proliferation and activity in tumor patients. We hypothesized that (18)F-FCH could similarly be a valuable imaging tool to identify vulnerable plaques and associated intraplaque inflammation and atheroma cell proliferation.
Methods and results:
Ten consecutive stroke patients (90% men, median age 66.5 years, range, 59.4-69.7) with ipsilateral >70% carotid artery stenosis and who underwent carotid endarterectomy were included in the study. Before carotid endarterectomy, all patients underwent positron emission tomography to assess maximum (18)F-FCH uptake in ipsilateral symptomatic carotid plaques and contralateral asymptomatic carotid arteries, which was corrected for background activity, resulting in a maximum target-to-background ratio (TBRmax). Macrophage content was assessed in all carotid endarterectomy specimens as a percentage of CD68(+)-staining per whole plaque area (plaqueCD68(+)) and as a maximum CD68(+) percentage (maxCD68(+)) in the most inflamed section/plaque. Dynamic positron emission tomography imaging demonstrated that an interval of 10 minutes between (18)F-FCH injection and positron emission tomography acquisition is appropriate for carotid plaque imaging. TBRmax in ipsilateral symptomatic carotid plaques correlated significantly with plaqueCD68(+) (Spearman's ρ=0.648, P=0.043) and maxCD68(+) (ρ=0.721, P=0.019) in the 10 corresponding carotid endarterectomy specimens. TBRmax was significantly higher (P=0.047) in ipsilateral symptomatic carotid plaques (median: 2.0; interquartile range [Q1-Q3], 1.5-2.5) compared with the contralateral asymptomatic carotid arteries (median: 1.4; Q1-Q3, 1.3-1.6). TBRmax was not significantly correlated to carotid artery stenosis (ρ=0.506, P=0.135).
Conclusions:
In vivo uptake of (18)F-FCH in human carotid atherosclerotic plaques correlated strongly with degree of macrophage infiltration and recent symptoms, thus (18)F-FCH positron emission tomography is a promising tool for the evaluation of vulnerable plaques.
Clinical trial registration:
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01899014.
The use of 2-deoxy-2-[ 18 F] fluoro-D-glucose (FDG) and positron emission tomogra-phy/computed tomography (PET/CT) is increasing rapidly – and the list of emerging and evolving applications is ever-expanding in a multitude of clinical settings. In this anniversary review celebrating four decades of FDG, we will outline an overview of the present status of FDG imaging with emphasis on clinical implementation in the main indications of FDG-PET/CT, i.e. neurology and psychiatry, oncology, cardiovascular diseases, and infectious and inflammatory diseases , including some general considerations towards clinical benefit and potential future directions.
Les pathologies cardio-vasculaires d’origine athéroscléreuse, premières causes de mortalité dans les pays occidentaux, sont insuffisamment prises en charge par les outils de dépistage et de suivi thérapeutique actuels. La Tomographie par Emission de Positons (TEP) est susceptible d’apporter au clinicien des outils puissants pour le diagnostic et le suivi thérapeutique des patients, en particulier grâce au traceur Fluorodésoxyglucose marqué au fluor 18 ([18F]-FDG). Cependant, l’Effet de Volume Partiel (EVP), dû notamment à la résolution spatiale limitée dans les images (plusieurs millimètres) en regard des faibles dimensions (de l’ordre du millimètre) des VOlumes d’Intérêt (VOIs), et les fluctuations statistiques du signal mesuré présentent des défis pour une quantification fiable.Un modèle original de lésion athéromateuse, paramétré par ses dimensions et sa concentration d’activité, a été développé et des simulations Monte-Carlo d’acquisitions TEP au [18F]-FDG de 36 lésions ont été produites. A partir des acquisitions simulées, nous avons montré que le nombre d’itérations des reconstructions itératives, le post-filtrage appliqué et le moyennage dans le VOI,paramètres relevés comme hautement variables dans une revue de la littérature dédiée, peuvent induire des variations des valeurs de fixation mesurées d’un facteur 1.5 à 4. Nous avons montré qu’une modélisation de la réponse du tomographe pouvait réduire le biais de mesure d’environ 10% par rapport au biais mesuré sur une image reconstruite avec un algorithme itératif standard et pour un niveau de bruit comparable. Sur les images reconstruites, nous avons montré que la fixation mesurée reste très biaisée (sous-estimation de plus de 50% du SUV réel) et dépend fortement des dimensions de la lésion à cause de l’EVP. Un contraste minimum de 4 par rapport à l’activité sanguine est nécessaire pour qu’une lésion soit détectée. Sans correction d’EVP, la mesure présente une corrélation faible avec la concentration d’activité, mais est très corrélée à l’activité totale dans la lésion. L’application d’une correction d’EVP fournit une mesure moins sensible à la géométrie de la lésion et plus corrélée à la concentration d’activité mais réduit la corrélation à l’activité totale dans la lésion.En conclusion, nous avons montré que l’intégralité de la fixation du [18F]-FDG dans les lésions athéromateuses inflammatoires totale peut être caractérisée sur les images TEP. Cette estimée ne requiert pas de correction de l’EVP. Lorsque la concentration d’activité dans la lésion est estimée, les mesures sont très biaisées à cause de l’EVP. Ce biais peut être réduit en mesurant le voxel d’intensité maximale, dans les images reconstruites sans post-filtrage avec au moins 80 itérations incluant un modèle de réponse du détecteur. La mise en œuvre d’une correction d’EVP facilite la détection des changements d’activité métabolique indépendamment de changements de dimensions de la zone siègede l’inflammation. Une quantification absolue exacte de la concentration d’activité dans les lésions ne sera possible que via une amélioration substantielle de la résolution spatiale des détecteurs TEP.
Advances in basic cardiovascular sciences have enhanced our understanding of disease pathogenesis at the genomic, transcriptional and proteomic level. Translation of basic research into clinical practice has played a major role in prevention, diagnosis and therapy of cardiovascular diseases (CVD), and in this context, the contribution of non invasive imaging (PET, SPECT, MRI, CT, US, optical imaging and hybrid modalities) has been instrumental. In the years to come, evaluation of myocardial perfusion and ventricular function by non invasive techniques will remain important for diagnosis and management of patients investigated for CVD, but such information will be augmented by an understanding of the contribution of other parameters such as myocardial metabolism, innervation, inflammation, angiogenesis, apoptosis, thrombosis and extracellular matrix alterations of the vessel wall or the myocardium. Suitable imaging probes for those targets may provide tools for early identification of individuals who are at risk of cardiovascular events, refining prediction based on current risk scoring models and existing non invasive tools.
Identifying patients at high risk for an acute cardiovascular event such as myocardial infarction or stroke and assessing the total atherosclerotic burden are clinically important. Currently available imaging modalities can delineate vascular wall anatomy and, with novel probes, target biologic processes important in plaque evolution and plaque stability. Expansion of the vessel wall involving remodeling of the extracellular matrix can be imaged, as can angiogenesis of the vasa vasorum, plaque inflammation, and fibrin deposits on early nonocclusive vascular thrombosis. Several imaging platforms are available for targeted vascular imaging to acquire information on both anatomy and pathobiology in the same imaging session using either hybrid technology (nuclear combined with CT) or MRI combined with novel probes targeting processes identified by molecular biology to be of importance. This article will discuss the current state of the art of these modalities and challenges to clinical translation.
This article is not available through ChesterRep. It can be accessed at http://circ.ahajournals.org/cgi/content/full/105/23/2708 This study demonstrates that atherosclerotic plaque inflammation can be imaged with 18FDG-PET, and that symptomatic, unstable plaques accumulate more 18FDG than asymptomatic lesions. This article was submitted to the RAE2008 for the University of Chester - Allied Health Professions and Studies.
We prospectively investigated the ideal imaging time to measure vascular uptake after injection of (18)F-FDG.
A total of 17 patients with atherosclerotic abdominal aortic aneurysm underwent dynamic abdominal PET/CT using 2-min frames between 45 and 53, 57 and 65, 115 and 123, and 175 and 183 min after injection of (18)F-FDG. For each period of dynamic imaging, vessel wall and lumen uptake were measured using the maximum standardized uptake value (SUV(max)) and target-to-background ratio (TBR).
No significant difference in TBR across all time points (repeated measures ANOVA, P = 0.206) was observed, despite a significant difference in aortic wall and lumen uptake with time (repeated measures ANOVA, P = 0.02 and P < 0.001, respectively). There was no significant difference between aortic wall uptake at 60 min (SUV(max), 2.15 +/- 0.11 SE) and 180 min (SUV(max), 1.99 +/- 0.18 SE) (paired t test, P = 0.367). There was a significant difference in lumen uptake at 60 min (SUV(max), 2.4 +/- 0.11 SE) and 180 min (SUV(max), 1.7 +/- 0.1 SE) (paired t test, P = 0.001). There was no significant difference in TBR between 60 min (0.91 +/- 0.03) and 180 min (1.01 +/- 0.06 SE) (paired t test, P = 0.131). With increasing delayed imaging, there was increasing variability (SE) in the SUV(max) for the aortic wall and TBRs.
There was no significant advantage in imaging at 3 h over 1 h after (18)F-FDG injection.
Atherosclerosis is recognised as an inflammatory disease, and new diagnostic tools are warranted to evaluate plaque inflammatory activity and risk of cardiovascular events. We investigated [18]-fluorodeoxyglucose (FDG) uptake in vulnerable carotid plaques visualised by positron emission tomography (PET). Uptake was correlated to quantitative gene expression of known markers of inflammation and plaque vulnerability.
Ten patients with recent transient ischaemic attack and carotid artery stenosis (>50%) underwent combined FDG-PET and computed tomography angiography (CTA) the day before carotid endarterectomy. Plaque mRNA expression of the inflammatory cytokine interleukin 18 (IL-18), the macrophage-specific marker CD68 and the two proteinases, Cathepsin K and matrix metalloproteinase 9 (MMP-9), were quantified using real-time quantitative polymerase chain reaction.
Consistent up-regulation of CD68 (3.8-fold+/-0.9; mean+/-standard error), Cathepsin K (2.1-fold+/-0.5), MMP-9 (122-fold+/-65) and IL-18 (3.4-fold+/-0.7) were found in the plaques, compared to reference-artery specimens. The FDG uptake by plaques was strongly correlated with CD68 gene expression (r=0.71, P=0.02). Any correlations with Cathepsin K, MMP-9 or IL-18 gene expression were weaker.
FDG-PET uptake in carotid plaques is correlated to gene expression of CD68 and other molecular markers of inflammation and vulnerability.
Vascular endothelial growth factor (VEGF), a potent growth factor for endothelial cells and inducer of angiogenesis, is important for endothelial integrity and thus for vascular function. On the other hand, VEGF may enhance the pathophysiologic mechanism of plaque formation and plaque destabilization. In this review we discuss the data available so far for VEGF as angiogenic and/or inflammatory cytokine in the vulnerable atherosclerotic plaque.
Atherosclerotic plaque characteristics play an important role in the development of coronary events. We investigated coronary plaque characteristics on multi-slice computed tomography (MSCT) and virtual histology intravascular ultrasound (VH IVUS) in patients with acute coronary syndromes (ACS) and stable coronary artery disease (CAD).
Fifty patients (25 with ACS, 25 with stable CAD) underwent 64-slice MSCT followed by VH IVUS in 48 (96%) patients. In ACS patients, 32% of plaques were non-calcified on MSCT and 59% were mixed [corresponding odds ratio (95% confidence intervals): 3.9 (1.6-9.5), P = 0.003 and 3.4 (1.6-6.9), P = 0.001, respectively]. In patients with stable CAD, completely calcified lesions were more prevalent (61%). On VH IVUS, the percentage of necrotic core was higher in the plaques of ACS patients (11.16 +/- 6.07 vs. 9.08 +/- 4.62% in stable CAD, P = 0.02). In addition, thin cap fibroatheroma was more prevalent in ACS patients (32 vs. 3% in patients with stable CAD, P < 0.001) and was most frequently observed in mixed plaques on MSCT. Plaque composition both on MSCT and VH IVUS was identical between culprit and non-culprit vessels of ACS patients.
On MSCT, differences in plaque characterization were demonstrated between patients with ACS and stable CAD. Plaques of ACS patients showed features of vulnerability to rupture on VH IVUS. Potentially, MSCT may be useful for non-invasive identification of atherosclerotic plaque patterns associated with higher risk.
Glucose metabolic activity expressed as (18)F-FDG uptake may be increased in active atherosclerotic plaque. Calcium depositions are often increased in mature atherosclerotic plaque. The purpose of the present study was to assess the patterns of vascular-wall (18)F-FDG uptake and CT calcifications using combined PET/CT.
One hundred twenty-two consecutive patients over the age of 50 (47 women and 75 men; mean age, 66 +/- 9 y) undergoing whole-body (18)F-FDG PET/CT for tumor assessment were retrospectively evaluated. PET, CT, and PET/CT slices were generated for review. Abnormal vascular findings in major arteries in the chest and abdomen were categorized as PET positive (PET+), PET negative (PET-), CT positive (CT+), or CT negative (CT-). The topographic relationship between increased vascular-wall (18)F-FDG uptake on PET and the presence of calcifications on CT was assessed on PET/CT fused images, with abnormal sites further classified as PET+/CT+, PET+/CT-, or PET-/CT+. The presence of CT calcifications and increased vascular-wall (18)F-FDG uptake was correlated with age, sex, presence of cardiovascular risk factors, and cardiovascular disease.
Abnormal findings were identified at 349 sites. CT calcifications (CT+) were observed at 320 sites (92%) of 100 patients (82%), more commonly in men (P < 0.03), in older patients (P < 0.0001), in patients with hypertension (P < 0.003) or hyperlipidemia (P < 0.04), and in smokers (P < 0.008). Increased vascular-wall (18)F-FDG uptake (PET+) was observed at 52 sites (15%) of 38 patients (31%), more commonly in men (P < 0.02), in older patients (P < 0.0001), and in patients with hypertension (P < 0.02), and was borderline in patients with cardiovascular disease (P = 0.057). PET+ and CT+ findings correlated in 12 patients, a PET+/CT- pattern was found in 18 patients, and 8 patients had increased vascular-wall (18)F-FDG uptake in sites with and without calcifications (PET+/CT+, CT-). Twenty-two patients (18%) had a PET-/CT- pattern.
Hybrid PET/CT can be used to identify and to correctly localize vascular-wall (18)F-FDG activity. Increased vascular-wall (18)F-FDG activity was found in 15% of sites and CT calcifications were noted in 92% of sites, with congruent findings in 7%. The clinical significance of the relationship between vascular-wall (18)F-FDG uptake and CT calcifications needs to be assessed by further prospective studies with long-term follow up.
In a previous in vitro study we have demonstrated that atherosclerotic plaque components can be characterized with multidetector computed tomography (MDCT) based on differences in Hounsfield values (HV). Now we evaluated the use of MDCT in vivo to characterize and quantify atherosclerotic carotid plaque components compared with histology as reference standard.
Fifteen symptomatic patients with carotid stenosis (>70%) underwent MDCT angiography before carotid endarterectomy (CEA). From each CEA specimen 3 histological sections and corresponding MDCT images were selected. The HV of the major plaque components were assessed. The measured HV were: 657+/-416HU, 88+/-18HU, and 25+/-19HU for calcifications, fibrous tissue, and lipid core, respectively. The cut-off value to differentiate lipid core from fibrous tissue and fibrous tissue from calcifications was based on these measurements and set at 60 HU and 130 HU, respectively. Regression plots showed good correlations (R2>0.73) between MDCT and histology except for lipid core areas, which had a good correlation (R2=0.77) only in mildly calcified (0% to 10%) plaques.
MDCT is able to quantify total plaque area, calcifications, and fibrous tissue in atherosclerotic carotid plaques in good correlation with histology. Lipid core can only be adequately quantified in mildly calcified plaques.
Plaque morphologic features have been suggested as a complement to luminal narrowing measurements for assessing the risk of stroke associated with carotid atherosclerotic disease, giving rise to the concept of "vulnerable plaque." The purpose of this study was to evaluate the ability of multidetector-row CT angiography (CTA) to assess the composition and characteristics of carotid artery atherosclerotic plaques with use of histologic examination as the gold standard.
Eight patients with transient ischemic attacks who underwent carotid CTA and "en bloc" endarterectomy were enrolled in a prospective study. An ex vivo micro-CT study of each endarterectomy specimen was obtained, followed by histologic examination. A systematic comparison of CTA images with histologic sections and micro-CT images was performed to determine the CT attenuation associated with each component of the atherosclerotic plaques. A computer algorithm was subsequently developed that automatically identifies the components of the carotid atherosclerotic plaques, based on the density of each pixel. A neuroradiologist's reading of this computer analysis was compared with the interpretation of the histologic slides by a pathologist with respect to the types and characteristics of the carotid plaques.
There was a 72.6% agreement between CTA and histologic examination in carotid plaque characterization. CTA showed perfect concordance for calcifications. A significant overlap between densities associated with lipid-rich necrotic core, connective tissue, and hemorrhage limited the reliability of individual pixel readings to identify these components. However, CTA showed good correlation with histologic examination for large lipid cores (kappa = 0.796; P < .001) and large hemorrhages (kappa = 0.712; P = .102). CTA performed well in detecting ulcerations (kappa = 0.855) and in measuring the fibrous cap thickness (R(2) = 0.77; P < .001).
The composition of carotid atherosclerotic plaques determined by CTA reflects plaque composition defined by histologic examination.
Atherosclerosis imaging with 18F-FDG PET is useful for tracking inflammation within plaque and monitoring the response to drug therapy. Short-term reproducibility of this technique in peripheral artery disease has not been assessed, and the optimal method of 18F-FDG quantification is still debated. We imaged 20 patients with vascular disease using 18F-FDG PET twice, 14 d apart, and used these data to assess reproducibility measures and compare 2 methods of 18F-FDG uptake measurement. We also reviewed the literature on quantification methods to determine the optimal measures of arterial 18F-FDG uptake for future studies.
Twenty patients with vascular disease underwent PET/CT of the iliac, femoral, and carotid arteries 90 min after 18F-FDG administration. In 19 patients, repeat testing was performed at 2 wk. Coregistration and attenuation correction were performed with CT. Vessel 18F-FDG uptake was measured as both the mean and maximum blood-normalized standardized uptake value (SUV), known as the target-to-background ratio (TBR). We assessed interscan, interobserver, and intraobserver agreement.
Nineteen patients completed both imaging sessions. The carotid and peripheral arteries all have excellent short-term reproducibility of the 18F-FDG signal, with intraclass correlation coefficients all greater than 0.8 for all measures of reproducibility. Both mean and maximum TBR measurements for quantifying 18F-FDG uptake are equally reproducible. 18F-FDG uptake was significantly higher in the carotid arteries than in both iliac and femoral vessels (P < 0.001 for both).
We found that both mean and maximum TBR in the carotid, iliac, and femoral arteries were highly reproducible. We suggest the mean TBR be used for tracking systemic arterial therapies, whereas the maximum TBR is optimal for detecting and monitoring local, plaque-based therapy.
Both calcification and FDG uptake have been advocated as indicators of atheroma. Atheromas calcify as cells in the lesion undergo apoptosis and necrosis during evolution of the lesion and at the end stage of the lesion. FDG concentrates in lesions due to the relatively dense cellularity in regions of inflammation of active atheromas. This investigation examines the geographic relationship of focal vascular F-18-FDG uptake, as a marker of atherosclerotic inflammation, to arterial calcification detected by contemporaneous CT. Methods: We reviewed PET/CT images from 78 patients who were referred for tumor staging for the presence of vascular 18F-FDG uptake and vascular calcification. Arterial wall 18F-FDG accumulation greater than adjacent blood-pool activity was considered inflammation. Arterial attenuation of > 130 Hounsfield units was considered calcification. Sites in the ascending and descending aorta, the carotid and iliac arteries, and the coronary territories were examined on the emission, CT, and fusion images on a point-by-point basis. When lesions were seen, we evaluated whether they were overlapping or discrete. Results: The 18F-FDG arterial distribution was consistent with established atherosclerotic topography, with increased uptake in the thoracic aorta, at the carotid bifurcation, and in the proximal coronary vessels. Arteries typically displayed a patchwork of normal vessel, focal inflammation, or calcification; inflammation and calcification overlapped in < 2% of cases. Arterial inflammation preceded calcification, in terms of mean patient age. Coronary inflammation was more prevalent in patients with more cardiovascular risk factors. Conclusion: Vascular calcification and vascular metabolic activity rarely overlap, suggesting these findings represent different stages in the evolution of atheroma.
The number of blood vessels correlates with metastasis in solid tumors, including oral squamous cell carcinoma (OSCC). Hypoxia inducible factor-1alpha (HIF-1alpha) could play a role in tumor lymphangiogenesis by regulating the lymphatic expression of vascular endothelial growth factor-C (VEGF-C). HIF-1alpha protein expression, VEGF-C protein expression, lymphatic vessel density (LVD) and blood vessel density (BVD) in OSCC were investigated.
HIF-1alpha and VEGF-C protein expression were investigated by means of immunohistochemistry in samples from 65 cases of OSCC. The density of the lymphatic microvessels and blood microvessels immunohistochemically stained by LYVE-1 and CD34 antibody, respectively, was calculated. The association between the HIF-1alpha expression and the clinicopathological parameters was evaluated.
HIF-1alpha overexpression occurred in 43 out of the 65 tumor samples (66.2%), while VEGF-C overexpression was observed in 34 out of the 65 tumor samples (52.3%). Higher LVD was found in both high HIF-1alpha and high VEGF-C expression cases. HIF-1alpha overexpression was significantly correlated with VEGF-C overexpression (p = .018, Chi-square test), higher LVD (p < 0.001, Mann-Whitney U-test), and regional lymph nodal involvement (p = 0.004, Chi-square test) as well as UICC TMN classification (p = 0.043, Chi-square test), respectively. In addition, higher BVD existed in the high HIF-1alpha and VEGF-C expression groups (p < 0.001, Mann-Whitney U-test).
HIF-1alpha might play a crucial role in regional lymph node metastasis as a regulator of lymphangiogenesis and angiogenesis in OSCC with a possible novel pathway involving VEGF-C. Therefore, HIF-1alpha might be a particularly promising target for controlling regional lymph node metastases by a combination of antiangiogenic and anti-lymphangiogenic effects in OSCC.
To investigate the diagnostic performance of (18)F-fludeoxyglucose ((18)F-FDG) positron emission tomography (PET)/CT in patients with suspected large-vessel vasculitis and its potential to evaluate the extent and activity of disease.
78 consecutive patients (mean age 63 years; 53 females) with suspected large-vessel vasculitis were evaluated with (18)F-FDG PET/CT.( 18)F-FDG uptake in the aorta and major branches was visually graded using a four-point scale and quantified with standardised uptake values (SUV(max)). According to clinical diagnosis, patients were classified into three groups: (a) steroid-naïve, large-vessel vasculitis (16 patients), (b) vasculitis on steroid treatment (18 patients) and (c) no evidence of vasculitis (44 patients). Analysis of variance and linear regression were used to investigate the association of (18)F-FDG uptake with clinical diagnosis and inflammatory markers.
(18)F-FDG PET/CT was positive (visual uptake ≥ 2; equal to or greater than liver) in all patients with steroid-naïve, large-vessel vasculitis. The thoracic aorta, the carotid and the subclavian arteries were most frequently involved. In these patients, SUV(max) values were significantly higher than in the other groups (analysis of variance; p<0.05). Linear regression showed a significant positive association (b-coefficients: 0.018-0.02; p<0.05) between SUV(max) of the thoracic aorta and inflammatory markers in patients with vasculitis (Groups a and b). Patients on steroid treatment showed low visual scores (uptake <2) and significantly lower SUV(max) values than steroid-naïve patients.
(18)F-FDG PET/CT can detect the extent and activity of large-vessel vasculitis in untreated patients and is unreliable in diagnosing vasculitis in patients on steroids.
The identification of asymptomatic individuals at risk for near-term atherothrombotic events to ensure optimal preventive treatment remains a challenging goal. In the BioImage Study, novel approaches are tested in a typical health-plan population. Based on certain demographic and risk characteristics on file with Humana Inc, a total of 7,687 men 55 to 80 years of age and women 60 to 80 years of age without evidence of atherothrombotic disease but presumed to be at risk for near-term atherothrombotic events were enrolled between January 2008 and June 2009. Those who met the prespecified eligibility criteria were randomized to a telephonic health survey only (survey only: n = 865), standard risk assessment (Framingham only: n = 718), or comprehensive risk assessment in a dedicated mobile facility equipped with advanced imaging tools (n = 6,104). Baseline examination included assessment of cardiovascular risk factors and screening for subclinical (asymptomatic) atherosclerosis with quantification of coronary artery calcification by computed tomography (CT), measurement of intima-media thickness, presence of carotid atherosclerotic plaques and abdominal aortic aneurysm by ultrasound, and ankle brachial index. Participants with one or more abnormal screening test results underwent advanced imaging with contrast-enhanced magnetic resonance imaging for carotid and aortic plaques, contrast-enhanced coronary CT angiography for luminal stenosis and noncalcified plaques, and 18F-fluorodeoxyglucose-positron emission tomography/CT for carotid and aortic plaque inflammation. Plasma, PAXgene RNA, and DNA samples were obtained, frozen, and stored for future biomarker discovery studies. All individuals will be followed until 600 major atherothrombotic events have occurred in those undergoing imaging. The BioImage Study will help identify those patients with subclinical atherosclerosis who are at risk for near-term atherothrombotic events and enable a more personalized management of care.
Increased uptake of 18F-fluorodeoxyglucose (18F-FDG) in atherosclerotic plaque on Positron Emission Tomography (PET), predicts vulnerability. Recent studies have shown that the PET signal is reproducible over a 2-week period and as a result drug trials are underway. However, the natural history of these lesions is unknown. The aim of this study is determine the natural history of increased vascular wall uptake of 18F-fluorodeoxyglucose (18F-FDG).
Following institutional ethics committee approval, we retrospectively examined PET/CT images of patients from our Institution that had at least 4 examinations in the last 5 years. This represented 205 studies in total, from 50 patients (29 men, 21 women, mean age 49.4+/-12.1 years, mean 5.1+/-1.7 studies/patient). The mean follow-up was 27.2+/-11.8 months. The carotids and the aorta were evaluated for increased 18F-FDG uptake with a maximum Standardized Uptake Value (SUVmax)>2.5, and >3.0, and calcification. Plots of SUVmax and Hounsfield units (HU) were made versus time.
The initial prevalence of increased focal arterial 18F-FDG uptake was 17/50 patients and of arterial calcification 19/50. 132 sites of 18F-FDG uptake in total were observed longitudinally. 18F-FDG vascular uptake did not persist with time. There was no correlation between 18F-FDG uptake and HU. No calcifications developed at sites of focal increased 18F-FDG uptake.
Arterial lesions with increased 18F-FDG uptake represent transient phenomena. This data is important for the interpretation of findings of clinical trials using arterial 18F-FDG uptake as an imaging biomarker to monitor pharmacological intervention.
This study's objective was to compare (18)F-fluoro-2-deoxyglucose positron emission tomography ((18)F-FDG PET), CT, and MRI of carotid plaque assessment. Materials and
Fifty patients with symptomatic carotid atherosclerosis underwent (18)F-FDG PET/CT and MRI. Correlations and agreement between imaging findings were assessed by Spearman and Pearson rank correlation tests, t tests, and Bland-Altman plots.
Spearman rho between plaque (18)F-FDG standard uptake values and CT/MRI findings varied from -0.088 to 0.385. Maximum standard uptake value was significantly larger in plaques with intraplaque hemorrhage (1.56 vs 1.47; P=0.032). Standard uptake values did not significantly differ between plaques with an intact and thick fibrous cap and plaques with a thin or ruptured fibrous cap on MRI. (1.21 vs 1.23; P=0.323; and 1.45 vs 1.54; P=0.727). Pearson rho between CT and MRI measurements varied from 0.554 to 0.794 (P<0.001). For lipid-rich necrotic core volume, the CT-MRI correlation was stronger in mildly (<or=10%) than in severely (>10%) calcified plaques (Pearson rho 0.730 vs 0.475). Mean difference in measurement +/-95% limits of agreement between CT and MRI for minimum lumen area, volumes of vessel wall, lipid-rich necrotic core, calcifications, and fibrous tissue were 0.4+/-18.1 mm(2) (P=0.744), -41.9 +/-761.7 mm(3) (P=0.450), 78.4+/-305.0 mm(3) (P<0.001), 180.5+/-625.7 mm(3) (P=0.001), and -296.0+/-415.8 mm(3) (P<0.001), respectively.
Overall, correlations between (18)F-FDG PET and CT/MRI findings are weak. Correlations between CT and MRI measurements are moderate to strong, but there is considerable variation in absolute differences.
Fluorodeoxyglucose positron-emission tomography (FDG PET) imaging of atherosclerosis has been used to quantify plaque inflammation and to measure the effect of plaque-stabilizing drugs. We explored how atherosclerotic plaque inflammation varies across arterial territories and how it relates to arterial calcification. We also tested the hypotheses that the degree of local arterial inflammation measured by PET is correlated with the extent of systemic inflammation and presence of risk factors for vascular disease.
Forty-one subjects underwent vascular PET/computed tomography imaging with FDG. All had either vascular disease or multiple risk factors. Forty subjects underwent carotid imaging, 27 subjects underwent aortic, 24 subjects iliac, and 13 subjects femoral imaging. Thirty-three subjects had a panel of biomarkers analyzed. We found strong associations between FDG uptake in neighboring arteries (left versus right carotid, r=0.91, P<0.001; ascending aorta versus aortic arch, r=0.88, P<0.001). Calcification and inflammation rarely overlapped within arteries (carotid artery FDG uptake versus calcium score, r=-0.42, P=0.03). Carotid artery FDG uptake was greater in those with a history of coronary artery disease (target-to-
<0.01) and in males versus females (target-to-
<0.05). Similar findings were also noted in the aorta and iliac arteries. Subjects with the highest levels of FDG uptake also had the greatest concentrations of inflammatory biomarkers (descending aorta target-to-
=0.53, P=0.01; carotid target-to-
=0.50, P=0.01). Nonsignificant positive trends were seen between FDG uptake and levels of interleukin-18, fibrinogen, and C-reactive protein. Finally, we found that the atheroprotective biomarker adiponectin was negatively correlated with the degree of arterial inflammation in the descending aorta (r=-0.49, P=0.03).
This study shows that FDG PET imaging can increase our knowledge of how atherosclerotic plaque inflammation relates to calcification, serum biomarkers, and vascular risk factors. Plaque inflammation and calcification rarely overlap, supporting the theory that calcification represents a late, burnt-out stage of atherosclerosis. Inflammation in one arterial territory is associated with inflammation elsewhere, and the degree of local arterial inflammation is reflected in the blood levels of several circulating biomarkers. We suggest that FDG PET imaging could be used as a surrogate marker of both atherosclerotic disease activity and drug effectiveness. Prospective, event-driven studies are now underway to determine the role of this technique in clinical risk prediction.
Despite modern CT systems and expert evaluators, the diagnostic performance of coronary CT angiography is limited by overestimation of vessel stenosis which reduces the positive predictive value (PPV) of the test. The aim of this study was to evaluate the performance of combined cardiac PET/64-detector CT angiography.
Included in this retrospective study were 33 consecutive patients (5 women, 28 men; mean age 61.6 years, range 47-87 years, mean BMI 27.3+/-5.2 kg/m(2)) with clinically suspected flow-limiting coronary artery disease who underwent combined cardiac PET/64-detector CT angiography and invasive angiography. Combined PET/CT images were reported by an experienced dual-accredited radiologist/nuclear physician. An experienced cardiac CT radiologist re-read the CT images without PET. Stenotic disease was defined as >50% vessel narrowing. Invasive coronary angiography was used as a reference standard. Local ethics committee approval and patient consent were obtained.
CT angiography (without PET data) was concordant with invasive angiography in 31/33 patients and at a patient level, the sensitivity in detecting significant coronary artery lesions was 100%, the specificity was 82%, the PPV was 92% and the negative predictive value (NPV) was 100%. Using combined PET/CT angiography the findings were concordant with invasive angiography in 32/33 patients and at a patient level, the sensitivity was 96%, the specificity was 100%, the PPV was 100% and the NPV was 91%.
The use of integrated cardiac PET/64-detector CT angiography is feasible and appears to improve some aspects of the diagnostic performance of 64-detector coronary artery angiography in detecting coronary artery disease.
To evaluate the relationship between atherosclerotic plaque inflammation, as assessed by FDG-positron emission tomography/computed tomography (FDG-PET/CT), and plaque morphology and composition, as assessed by magnetic resonance imaging (MRI), in the carotid and femoral arteries.
Sixteen patients underwent FDG-PET/CT and MRI (T2-weighted (T2W) and proton density weighted (PDW)) of the carotid and femoral arteries. For every image slice, two observers determined the corresponding regions of the FDG-PET/CT and MRI image sets by matching CT and T2W axial images. Each plaque was then classified into one of three groups according to the CT appearance and T2W/PDW signal: (1) collagen, (2) lipid-necrotic core and (3) calcium. Arterial FDG uptake was measured for each plaque and normalized to vein FDG activity to produce a blood-normalized artery activity called the target to background ratio (TBR). The vessel wall thickness (VWT), the vessel wall area and the total vessel wall area were measured from the T2W MR images.
The TBR value was higher in the lipid-necrotic core group compared to the collagen and calcium groups, (p<0.001). The lipid-necrotic core group demonstrated a significant TBR variation according to the median of the VWT (TBR=1.26+/-0.25 vs. 1.50+/-0.12). There was no correlation with other morphological MR parameters.
This study demonstrates the complementary value of non-invasive FDG-PET/CT and MR imaging for the evaluation of atherosclerotic plaque composition and activity. Lipid-rich plaques are more inflamed than either calcified or collagen-rich plaques.
Inflammation is a major risk factor for atherosclerotic plaque rupture and clinical events. Previous studies have shown that plaque [(18)F]fluorodeoxyglucose (FDG) uptake correlates with macrophage content. In this study we examined the reproducibility of 3 methods of quantifying plaque FDG uptake in the carotid arteries using positron emission tomography (PET). The correlation between 2 simplified uptake parameters (standardized uptake value [SUV], vessel wall-to-blood ratio [VBR]) and a gold standard technique (influx rate [K(i)]) was also determined. We used MRI to correct carotid plaque FDG uptake for partial volume error.
Seven patients with a recent carotid territory transient ischemic attack underwent imaging twice within 8 days using MR and FDG-PET. MR coregistered to PET was used to delineate regions of interest, and to facilitate partial volume correction (PVC).
SUV was the most reproducible parameter irrespective of whether it was normalized by body surface area (BSA), lean body mass, or weight (intraclass correlation coefficient=0.85, 0.88, and 0.90, respectively). VBR correlated better to K(i) than SUV (r=0.58 VBR, r=0.46 SUV(BSA)). PVC improved these correlations to r=0.81 VBR and r=0.76 SUV(BSA), and only slightly degraded the reproducibility of SUV (intraclass correlation coefficient=0.83-0.85).
MR-guided FDG-PET is a highly reproducible technique in the carotid artery and the excellent anatomic detail provided by MR facilitates PVC. Of the methods examined, SUV(BSA)(PVC) appears to represent the best compromise between reproducible and accurate determination of FDG metabolism in carotid artery vessel wall.
To apply magnetic resonance (MR) imaging of intraplaque hemorrhage (IPH), as compared with histologic analysis as the reference standard, to detect T1 hyperintense intraplaque signal and to test the hypothesis that T1 hyperintense material represents blood products (methemoglobin).
Institutional review board approval and patient informed consent were obtained. Eleven patients undergoing carotid endarterectomy were examined with MR imaging of IPH, and MR images were assessed for T1 hyperintense intraplaque signal. A total of 160 images per patient were available for coregistration with corresponding histologic slices. Because of endarterectomy specimen size and degradation and processing artifacts, only 97 images were coregistered to corresponding histologic slices. A grid that consisted of 16 segments was overlaid on images for correlation of MR images and histologic slices. Only one of 16 segments was chosen randomly per slide and used in the analysis. Agreement between MR images and histologic slices was measured with the Cohen kappa statistic.
Strong agreement was seen between MR images and histologic slices, with T1-weighted high signal intensity corresponding to hemorrhagic material (kappa = 0.7-0.8). There was a low 2% false-negative rate for the detection of hemorrhage on the basis of T1-weighted hyperintensity (two of 97 measured segments). The results of diagnostic tests for T1 hyperintense detection of hemorrhage were as follows: sensitivity of 100%, specificity of 80%, positive predictive value of 70%, and negative predictive value of 100% for reader 1 and sensitivity of 94%, specificity of 88%, positive predictive value of 78%, and negative predictive value of 97% for reader 2.
With its high spatial resolution, MR imaging of IPH permits detection of plaque hemorrhage location, resulting in strong agreement between imaging and histologic findings.
Paul Dudley White was an astute observer of ischemic heart disease who emphasized the unity of acute myocardial infarction and chronic exertional angina as facets of the clinical expression of coronary atherosclerosis. He knew that plaque ulceration was a precipitator of thrombosis, but in the days before angiography was widely used, he reasoned that thrombosis occurred at sites of previous high-grade stenosis. He would be fascinated by the explosion of knowledge concerning the mechanisms of the two major expressions of coronary heart disease that has occurred since his death in 1973.
Any consideration of how symptoms arise in coronary atherosclerosis must begin with plaque. By early adult life, most individuals in developed countries will have some coronary plaques that, in pathological terms, are advanced. This simply means that within the plaque there has been considerable accumulation of extracellular lipid, lipid within foam cells of macrophage origin, and collagen produced by smooth muscle cells.
Plaques occupy space; yet, as pathology studies have shown in the past, the arterial lumen is not necessarily compromised, implying that the angiogram would be a poor tool to assess atherosclerosis in living subjects, however good it might be at detecting high-grade stenosis that causes symptoms. The insensitivity of angiography in the detection of plaques has been amply demonstrated by intravascular ultrasound.1 2 The landmark work of Glagov et al,3 which showed that the arterial wall is not a static, immutable structure but rather can remodel itself by increasing its external diameter to accommodate the plaque without narrowing the lumen, is one explanation of angiographically silent plaques. This process has been confirmed by intravascular ultrasound.4 5 A second explanation is the occurrence of medial atrophy confined to the area immediately behind the plaque.6 This allows the plaque to bulge outward rather than inward …
Acute myocardial infarction is believed to be caused by rupture of an unstable coronary-artery plaque that appears as a single lesion on angiography. However, plaque instability might be caused by pathophysiologic processes, such as inflammation, that exert adverse effects throughout the coronary vasculature and that therefore result in multiple unstable lesions.
To document the presence of multiple unstable plaques in patients with acute myocardial infarction and determine their influence on outcome, we analyzed angiograms from 253 patients for complex coronary plaques characterized by thrombus, ulceration, plaque irregularity, and impaired flow.
Single complex coronary plaques were identified in 153 patients (60.5 percent) and multiple complex plaques in the other 100 patients (39.5 percent). As compared with patients with single complex plaques, those with multiple complex plaques were less likely to undergo primary angioplasty (86.0 percent vs. 94.8 percent, P = 0.03) and more commonly required urgent bypass surgery (27.0 percent vs. 5.2 percent, P < or = 0.001). During the year after myocardial infarction, the presence of multiple complex plaques was associated with an increased incidence of recurrent acute coronary syndromes (19.0 percent vs. 2.6 percent, P < or = 0.001); repeated angioplasty (32.0 percent vs. 12.4 percent, P < or = 0.001), particularly of non-infarct-related lesions (17.0 percent vs. 4.6 percent, P < or = 0.001); and coronary-artery bypass graft surgery (35.0 percent vs. 11.1 percent, P < or = 0.001).
Patients with acute myocardial infarction may harbor multiple complex coronary plaques that are associated with adverse clinical outcomes. Plaque instability may be due to a widespread process throughout the coronary vessels, which may have implications for the management of acute ischemic heart disease.
Atherosclerotic plaque rupture is usually a consequence of inflammatory cell activity within the plaque. Current imaging techniques provide anatomic data but no indication of plaque inflammation. The glucose analogue [18F]-fluorodeoxyglucose (18FDG) can be used to image inflammatory cell activity non-invasively by PET. In this study we tested whether 18FDG-PET imaging can identify inflammation within carotid artery atherosclerotic plaques.
Eight patients with symptomatic carotid atherosclerosis were imaged using 18FDG-PET and co-registered CT. Symptomatic carotid plaques were visible in 18FDG-PET images acquired 3 hours post-18FDG injection. The estimated net 18FDG accumulation rate (plaque/integral plasma) in symptomatic lesions was 27% higher than in contralateral asymptomatic lesions. There was no measurable 18FDG uptake into normal carotid arteries. Autoradiography of excised plaques confirmed accumulation of deoxyglucose in macrophage-rich areas of the plaque.
This study demonstrates that atherosclerotic plaque inflammation can be imaged with 18FDG-PET, and that symptomatic, unstable plaques accumulate more 18FDG than asymptomatic lesions.
Neovasculature within atherosclerotic plaques is believed to be associated with infiltration of inflammatory cells and plaque destabilization. The aim of the present investigation was to determine whether the amount of neovasculature present in advanced carotid plaques can be noninvasively measured by dynamic, contrast-enhanced MRI.
A total of 20 consecutive patients scheduled for carotid endarterectomy were recruited to participate in an MRI study. Images were obtained at 15-second intervals, and a gadolinium contrast agent was injected coincident with the second of 10 images in the sequence. The resulting image intensity within the plaque was tracked over time, and a kinetic model was used to estimate the fractional blood volume. For validation, matched sections from subsequent endarterectomy were stained with ULEX and CD-31 antibody to highlight microvessels. Finally, all microvessels within the matched sections were identified, and their total area was computed as a fraction of the plaque area. Results were obtained from 16 participants, which showed fractional blood volumes ranging from 2% to 41%. These levels were significantly higher than the histological measurements of fractional vascular area. Nevertheless, the 2 measurements were highly correlated, with a correlation coefficient of 0.80 (P<0.001).
Dynamic contrast-enhanced MRI provides an indication of the extent of neovasculature within carotid atherosclerotic plaque. MRI therefore provides a means for prospectively studying the link between neovasculature and plaque vulnerability.
Both calcification and FDG uptake have been advocated as indicators of atheroma. Atheromas calcify as cells in the lesion undergo apoptosis and necrosis during evolution of the lesion and at the end stage of the lesion. FDG concentrates in lesions due to the relatively dense cellularity in regions of inflammation of active atheromas. This investigation examines the geographic relationship of focal vascular (18)F-FDG uptake, as a marker of atherosclerotic inflammation, to arterial calcification detected by contemporaneous CT.
We reviewed PET/CT images from 78 patients who were referred for tumor staging for the presence of vascular (18)F-FDG uptake and vascular calcification. Arterial wall (18)F-FDG accumulation greater than adjacent blood-pool activity was considered inflammation. Arterial attenuation of >130 Hounsfield units was considered calcification. Sites in the ascending and descending aorta, the carotid and iliac arteries, and the coronary territories were examined on the emission, CT, and fusion images on a point-by-point basis. When lesions were seen, we evaluated whether they were overlapping or discrete.
The (18)F-FDG arterial distribution was consistent with established atherosclerotic topography, with increased uptake in the thoracic aorta, at the carotid bifurcation, and in the proximal coronary vessels. Arteries typically displayed a patchwork of normal vessel, focal inflammation, or calcification; inflammation and calcification overlapped in <2% of cases. Arterial inflammation preceded calcification, in terms of mean patient age. Coronary inflammation was more prevalent in patients with more cardiovascular risk factors.
Vascular calcification and vascular metabolic activity rarely overlap, suggesting these findings represent different stages in the evolution of atheroma.
The purpose of this study was to assess morphology and composition of culprit and stable coronary lesions by multidetector computed tomography (MDCT).
Noninvasive identification of culprit lesions has the potential to improve noninvasive risk stratification in patients with acute chest pain.
Thirty-seven patients with acute coronary syndrome (ACS) or stable angina underwent coronary 16-slice MDCT and invasive selective angiography. In all significant coronary lesions two observers measured the degree of stenosis, plaque area at stenosis, and remodeling index and assessed plaque composition. Differences between culprit lesions in patients with ACS and stable lesions in patients with ACS or stable angina were determined.
We analyzed 40 lesions with excellent image quality in 14 patients with ACS and 9 patients with stable angina. Culprit lesions in patients with ACS (n = 14) had significantly greater plaque area and a higher remodeling index than both stable lesions in patients with ACS (n = 13) and in patients with stable angina (n = 13) (17.5 +/- 5.9 mm2 vs. 9.1 +/- 4.8 mm2 vs. 13.5 +/- 10.7 mm2, p = 0.02; and 1.4 +/- 0.3 vs. 1.0 +/- 0.4 vs. 1.2 +/- 0.3, p = 0.04, respectively). The prevalence of non-calcified plaque was 100%, 62%, and 77%, respectively, and the prevalence of calcified plaque was 71%, 92%, and 85%, respectively, in culprit lesions in patients with ACS and in stable lesions in patients with ACS or stable angina.
We introduce the concept of noninvasive detection and characterization of coronary atherosclerotic lesions in patients with ACS by MDCT. We identified differences in lesion morphology and plaque composition between culprit lesions in ACS and stable lesions in ACS or stable angina, consistent with previous intravascular ultrasound studies.