Effects of ezetimibe/simvastatin 10/10 mg versus Rosuvastatin 10 mg on carotid atherosclerotic plaque inflammation.

BACKGROUND: Using 18F-fluorodeoxyglucose (18FDG) positron emission tomography-computed tomography (PET/CT) imaging, we examined the effects of ezetimibe/simvastatin 10/10 mg versus rosuvastatin 10 mg on carotid atherosclerotic plaque inflammation. Whether the combination therapy of ezetimibe with low-dose statin is as effective as potent statin monotherapy in attenuating carotid atherosclerotic plaque inflammation remains unclear. METHODS: In this 2-by-2 factorial trial, 50 patients with 18FDG uptake (target-to-background ratio [TBR] ≥1.6) in the carotid artery and acute coronary syndrome were randomized to receive either simvastatin/ezetimibe 10/10 mg or rosuvastatin 10 mg. 18FDG PET/CT examinations were performed at baseline and at 6 months. The percent change in the TBR of the index vessel at the most diseased segment (MDS) was the primary endpoint. RESULTS: Baseline characteristics of the two groups were largely similar. At 6-month follow-up, the MDS TBR of the index vessel and aorta significantly decreased in ezetimibe/simvastatin group and tended to decrease in rosuvastatin group. However, the percent change in the MDS TBR of the index vessel was similar between the 2 groups (- 10.22 ± 17.49% vs. -5.84 ± 15.78%, respectively, p = 0.357), as was the percent change in the whole vessel TBR of the index vessel. Likewise, the changes in the MDS TBR or whole vessel TBR of the aorta were similar in both groups. Total cholesterol and low-density lipoprotein cholesterol levels improved to a similar degree in both groups. CONCLUSION: Treatment with ezetimibe/simvastatin versus rosuvastatin resulted in a similar improvement of carotid atherosclerotic plaque inflammation, suggesting their equivalent anti-inflammatory effects. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov : NCT02378064, 3-4-2015. /IRB No. 2015-0194.

AnxA5 reduces plaque inflammation of advanced atherosclerotic lesions in apoE(-/-) mice.

Annexin A5 (AnxA5) exerts anti-inflammatory, anticoagulant and anti-apoptotic effects through binding cell surface expressed phosphatidylserine. The actions of AnxA5 on atherosclerosis are incompletely understood. We investigated effects of exogenous AnxA5 on plaque morphology and phenotype of advanced atherosclerotic lesions in apoE(-/-) mice. Advanced atherosclerotic lesions were induced in 12 weeks old Western type diet fed apoE(-/-) mice using a collar placement around the carotid artery. After 5 weeks mice were injected either with AnxA5 (n = 8) or vehicle for another 4 weeks. AnxA5 reduced plaque macrophage content both in the intima (59% reduction, P < 0.05) and media (73% reduction, P < 0.01) of advanced atherosclerotic lesions of the carotid artery. These findings corroborated with advanced lesions of the aortic arch, where a 67% reduction in plaque macrophage content was observed with AnxA5 compared to controls (P < 0.01). AnxA5 did not change lesion extension, plaque apoptosis, collagen content, smooth muscle cell content or acellular plaque composition after 4 weeks of treatment as determined by immunohistochemistry in advanced carotid lesions. In vitro, AnxA5 exhibited anti-inflammatory effects in macrophages and a flow chamber based assay demonstrated that AnxA5 significantly inhibited capture, rolling, adhesion as well as transmigration of peripheral blood mononuclear cells on a TNF-α-activated endothelial cell layer. In conclusion, short-term treatment with AnxA5 reduces plaque inflammation of advanced lesions in apoE(-/-) mice likely through interfering with recruitment and activation of monocytes to the inflamed lesion site. Suppressing chronic inflammation by targeting exposed phosphatidylserine may become a viable strategy to treat patients suffering from advanced atherosclerosis.

Atherosclerotic Coronary Plaque Features in Patients With Chronic Obstructive Pulmonary Disease and Acute Coronary Syndrome.

Previous studies reported a robust relation between chronic obstructive pulmonary disease (COPD) and coronary artery disease (CAD). Systemic inflammation has been proposed as possible pathogenetic mechanism linking these 2 entities, although data on atherosclerotic coronary features in COPD patients are lacking. We studied atherosclerotic coronary plaque features in COPD patients presenting with acute coronary syndrome (ACS) using optical coherence tomography (OCT). ACS patients who underwent intracoronary OCT imaging of the culprit vessel were enrolled. Coronary plaque characteristics and OCT-defined macrophage infiltration (MØI) were assessed by OCT. ACS patients were divided into 2 groups according to the presence of an established diagnosis of COPD, and plaque features at the culprit site and along the culprit vessel were compared between the groups. Of 146 ACS patients (mean age:66.1 ± 12.7 years, 109 men), 47 (32.2%) had COPD. Patients with COPD had significantly higher prevalence of MØI (78.7% vs 54.5%, p = 0.005) and thin cap fibroatheroma (TCFA) (48.9% vs 22.2%, p = 0.001) at the culprit site. In the multivariate logistic regression, COPD was independently associated with MØI (odds ratio [OR] 21.209, 95% confidence interval [CI] 1.679 to 267.910, p = 0.018) and TCFA at the culprit site (OR 5.345, 95% CI 1.386 to 20.616, p = 0.015). Similarly, COPD was independently associated with both MØI (OR 3.570, 95% CI 1.472 to 8.658, p = 0.005) and TCFA (OR 4.088, 95% CI 1.584 to 10.554, p = 0.004) along the culprit vessel. In conclusion, in ACS patients who underwent OCT imaging of the culprit vessel, COPD was an independent predictor of plaque inflammation and vulnerability. These results may suggest that a higher inflammatory milieu in COPD patients might enhance local coronary inflammation, promoting CAD development and plaque vulnerability.

sICAM-1 concentrations are associated with inflammation in contralateral carotid plaque in patients with ischemic stroke.

BACKGROUND: Atherosclerotic plaques in the internal carotid artery are responsible for more than 15% of ischemic strokes. Carotid 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) detects plaque inflammation. Plasma ICAM-1 and LRP1 concentrations have been associated with inflammation in ipsilateral carotid plaque. The aim of the present study was to test the association between the soluble (s) form of these biomarkers and contralateral carotid plaques. METHODS: Prospective study conducted in 53 patients with a recent ischemic stroke and at least one atherosclerotic plaque in both carotid arteries. All of the patients underwent an early carotid 18F-FDG PET, and a blood sample was obtained at 7±1 days. Several plasma inflammatory markers were evaluated by Multiplex and sLRP1 levels were measured by commercial ELISA. Bivariate and multivariable linear regression was used to assess the association between inflammatory markers and the clinical variables, including contralateral maximum standardized uptake value (SUVmax) and mean SUVmax (mean of contralateral and ipsilateral SUVmax) of 18F-FDG uptake. Hazard ratio (HR) was estimated with Cox models adjusted for potential confounding factors to evaluate recurrence. RESULTS: Multivariable linear regression analysis showed an independent association between sICAM-1 and sVCAM-1 and mean SUVmax (CI=-0.064-0.325, p=0.004; CI=0.079-0.554, p=0.010). In addition, in bivariate regression analysis, sICAM-1 was associated with contralateral SUVmax (CI=0.049-0.382, p=0.012). Cox regression showed that mean SUVmax was associated with stroke recurrence (HR=5.604, p=0.044). CONCLUSIONS: sICAM-1 was independently associated with mean carotid plaque inflammation and with inflammation in contralateral plaque. sICAM-1 could be an indicator of plaque inflammation even in asymptomatic plaques.

Endothelial NCK2 promotes atherosclerosis progression in male but not female Nck1-null atheroprone mice.

A better understanding of endothelial dysfunction holds promise for more effective interventions for atherosclerosis prevention and treatment. Endothelial signaling by the non-catalytic region of the tyrosine kinase (NCK) family of adaptors, consisting of NCK1 and NCK2, has been implicated in cardiovascular development and postnatal angiogenesis but its role in vascular disease remains incompletely understood. Here, we report stage- and sex-dependent effects of endothelial NCK2 signaling on arterial wall inflammation and atherosclerosis development. Male and female Nck1-null atheroprone mice enabling inducible, endothelial-specific Nck2 inactivation were fed a high fat diet (HFD) for 8 or 16 weeks to model atherosclerosis initiation and progression, respectively. Analysis of aorta preparations en face during disease progression, but not initiation, showed a significant reduction in plaque burden in males, but not females, lacking endothelial NCK2 relative to controls. Markers of vascular inflammation were reduced by endothelial NCK2 deficiency in both males and females during atherosclerosis progression but not initiation. At advanced stages of disease, plaque size and severity of atherosclerotic lesions were reduced by abrogation of endothelial NCK2 signaling only in males. Collectively, our results demonstrate stage- and sex-dependent modulation of atherosclerosis development by endothelial NCK2 signaling.

Association Between 18-FDG Positron Emission Tomography and MRI Biomarkers of Plaque Vulnerability in Patients With Symptomatic Carotid Stenosis.

Purpose: Pathologic studies suggest that unstable plaque morphology and inflammation are associated with cerebrovascular events. 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) is a validated technique for non-invasive imaging of inflammation-related plaque metabolism, and MRI can identify morphologic features of plaque instability. The aim of this study was to investigate the association of selected imaging characteristics of plaque vulnerability measured with MRI and PET in patients with symptomatic carotid stenosis. Methods: Patients from the BIOVASC study were selected based on the following inclusion criteria: (1) age ≥ 50 years; (2) recent (<30 days) ischaemic stroke (modified Rankin scale ≤3) or motor/speech/vision TIA; (3) ipsilateral internal carotid artery stenosis (≥5 0% lumen-narrowing); (4) carotid PET/CTA and MRI completed. Semi-automated plaque analysis of MRI images was performed to quantify morphologic features of plaque instability. PET images were co-registered with CTA and inflammation-related metabolism expressed as maximum standardised uptake value (SUVmax). Results: Twenty-five patients met inclusion criteria (72% men, mean age 65 years). MRI-measured plaque volume was greater in men (1,708-1,286 mm3, p = 0.03), patients who qualified with stroke (1,856-1,440 mm3, p = 0.05), and non-statin users (1,325-1,797 mm3, p = 0.03). SUVmax was associated with MRI-measured plaque lipid-rich necrotic core (LRNC) in the corresponding axial slice (r s = 0.64, p < 0.001) and was inversely associated with whole-plaque fibrous cap thickness (r s = -0.4, p = 0.02) and calcium volume (r s = -0.4, p = 0.03). Conclusion: This study demonstrated novel correlations of non-invasive imaging biomarkers of inflammation-related plaque metabolism with morphological MRI markers of plaque instability. If replicated, our findings may support the application of combined MRI and PET to detect vulnerable plaque in future clinical practise and randomised trials.

Coronary plaque instability assessed by positron emission tomography and optical coherence tomography.

BACKGROUND: Non-ST-elevation myocardial infarction (NSTEMI) and unstable angina (UA) are caused often by destabilization of non-flow limiting inflamed coronary artery plaques. 18F-fluorodeoxyglucose (FDG) uptake with positron emission tomography/computed tomography (PET/CT) reveals plaque inflammation, while intracoronary optical coherence tomography (OCT) reliably identifies morphological features of coronary instability, such as plaque rupture or erosion. We aimed to prospectively compare these two innovative biotechnologies in the characterization of coronary artery inflammation, which has never been attempted before. METHODS: OCT and FDG PET/CT were performed in 18 patients with single vessel coronary artery disease, treated by percutaneous coronary intervention (PCI) with stent implantation, divided into 2 groups: NSTEMI/UA (n = 10) and stable angina (n = 8) patients. RESULTS: Plaque rupture/erosion recurred more frequently [100% vs 25%, p = 0.001] and FDG uptake was greater [TBR median 1.50 vs 0.87, p = 0.004] in NSTEMI/UA than stable angina patients. FDG uptake resulted greater in patients with than without plaque rupture/erosion [1.2 (0.86-1.96) vs 0.87 (0.66-1.07), p = 0.013]. Among NSTEMI/UA patients, no significant difference in FDG uptake was found between ruptured and eroded plaques. The highest FDG uptake values were found in ruptured plaques, belonging to patients with NSTEMI/UA. OCT and PET/CT agreed in 72% of patients [p = 0.018]: 100% of patients with plaque rupture/erosion and increased FDG uptake had NSTEMI/UA. CONCLUSION: For the first time, we demonstrated that the correspondence between increased FDG uptake with PET/CT and morphology of coronary plaque instability at OCT is high.

Should vascular wall 18F-FDG uptake be adjusted for the extent of atherosclerotic burden?

Vascular wall 18F-FDG uptake is often used as a surrogate marker of atherosclerotic plaque inflammation. A potential caveat is that vascular wall 18F-FDG uptake is higher simply because more atherosclerosis is present. To determine if the degree of inflammation is high or low relative to the extent of atherosclerosis, vascular wall 18F-FDG uptake may require statistical adjustment for a non-inflammatory marker reflecting the extent of atherosclerosis, e.g. calcification. Adjustments is probably needed if (1) vascular wall 18F-FDG uptake correlates sufficiently strongly with arterial calcification and (2) adjustment for extent of calcification affects determinants of vascular 18F-FDG uptake. This study addresses these questions. 18F-FDG PET/low-dose-CT scans of 99 patients were used. Cardiovascular risk factors were assessed and PET/CT scans were analysed for standardized 18F-FDG uptake values and calcification. ANOVA was used to establish the association between vascular 18F-FDG uptake and calcification. Multiple linear regression (with and without calcification as independent variable) was used to show whether determinants of vascular 18F-FDG uptake were affected by the degree of calcification. 18F-FDG uptake was related to increased calcification in the aortic arch, descending and abdominal aorta. However, 18F-FDG uptake showed considerable overlap between categories of calcification. Age and body mass index were main determinants of vascular 18F-FDG uptake. In multiple regression analyses, most standardized beta coefficients of these determinants were not affected by adjustment for the degree of calcification. Although vascular 18F-FDG uptake is related to total atherosclerotic burden, as reflected by vascular calcification, the association is weak and unlikely to affect the identification of determinants of atherosclerotic inflammation implicating no need for adjustment in future studies.

Comparison of High-Dose Rosuvastatin Versus Low-Dose Rosuvastatin Plus Ezetimibe on Carotid Atherosclerotic Plaque Inflammation in Patients with Acute Coronary Syndrome.

We compared the effects of ezetimibe/rosuvastatin 10/5 mg versus rosuvastatin 20 mg on carotid atherosclerotic plaque inflammation measured by 18FDG PET/CT. Fifty patients with acute coronary syndrome (ACS) were randomly assigned to the ezetimibe/rosuvastatin 10/5 mg and rosuvastatin 20 mg groups. The primary outcome was the percent change in the target-to-background ratio (TBR) of the index vessel in the most diseased segment (MDS), as assessed by 18FDG PET/CT at baseline and at 6 months. Forty-eight patients completed follow-up PET/CT. MDS TBR was - 6.2 ± 13.9% for patients in the ezetimibe/rosuvastatin group and - 10.8 ± 17.7% for those in the rosuvastatin group (difference, 4.6 percentage points; upper limitation of one-sided confidence interval = 13.8; p = 0.60 for noninferiority). In conclusion, combination therapy with ezetimibe 10 mg and rosuvastatin 5 mg compared with rosuvastatin 20 mg did not meet the criterion for non-inferiority for primary outcome, and the present study was not conclusive on whether the former was non-inferior to the latter. Graphical Abstract.

Systemic atherosclerotic plaque vulnerability in patients with Coronary Artery Disease with a single Whole Body FDG PET-CT scan.

OBJECTIVES: 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<0.05) and a gradient was observed (ascending > descending > aortic arch), and were also higher in the carotids in female patients (1.43±0.07) versus controls (p<0.05). A tendency for higher levels of plaque inflammation in the abdominal aorta was noted in all groups, but no significant FDG uptake was found either in the iliac or femoral arteries in any group. Plaque inflammation was also higher in the LAD in males but with large variations. Higher levels of calcifications were noted in the LAD, infra-renal abdominal aorta and common iliac arteries, but without significant correlation with plaque inflammation except sporadic overlapping. CONCLUSION: Patients with advanced CAD are at risk for vulnerable inflamed atheromas in other territories such as the thoracic aorta and carotid arteries, underpinning the systemic nature of the atherosclerotic disease. Coexistence with calcifications is rare, suggesting a different functional status of the plaques and different stages of the disease. Evaluation of subclinical systemic plaque vulnerability in CAD with a Whole Body [FDG] PET-CT scan is feasible and a potentially useful biomarker to assess subclinical vascular risk for risk stratification and treatment optimization, but further studies are needed.

IL-7R blockade reduces post-myocardial infarction-induced atherosclerotic plaque inflammation in ApoE-/- mice.

Modulating inflammation by targeting IL-1ß reduces recurrent athero-thrombotic cardiovascular events without lipid lowering. This presents an opportunity to explore other pathways associated with the IL-1ß signaling cascade to modulate the inflammatory response post-myocardial infarction (MI). IL-7 is a mediator of the inflammatory pathway involved in monocyte trafficking into atherosclerotic plaques and levels of IL-7 have been shown to be elevated in patients with acute MI. Recurrent athero-thrombotic events are believed to be mediated in part by index MI-induced exacerbation of inflammation in atherosclerotic plaques. The objective of the study was to assess the feasibility of IL-7R blockade to modulate atherosclerotic plaque inflammation following acute MI in ApoE-/- mice. Mice were fed Western diet for 12 weeks and then subjected to coronary occlusion to induce an acute MI. IL-7 expression was determined using qRT-PCR and immuno-staining, and IL-7R was assessed using flow cytometry. Plaque inflammation was evaluated using immunohistochemistry. IL-7R blockade was accomplished with monoclonal antibody to IL-7R. IL-7 mRNA expression was significantly increased in the cardiac tissue of mice subjected to MI but not in controls. IL-7 staining was observed in the coronary artery. Plaque macrophage and lipid content were significantly increased after MI. IL-7R antibody treatment but not control IgG significantly reduced macrophage and lipid content in atherosclerotic plaques. The results show that IL-7R antibody treatment reduces monocyte/macrophage and lipid content in the atherosclerotic plaque following MI suggesting a potential new target to mitigate increased plaque inflammation post-MI.

Comparison of fimasartan and amlodipine therapy on carotid atherosclerotic plaque inflammation.

BACKGROUND: The renin-angiotensin system plays an important role in promoting atherosclerotic plaque inflammation, which may be inhibited by angiotension-II receptor blockers. HYPOTHESIS: We investigated the effects of fimasartan and amlodipine therapy on carotid atherosclerotic plaque inflammation using 18 F-fluorodeoxyglucose (18 FDG) positron emission tomography (PET) imaging. METHODS: Fifty patients with acute coronary syndrome (ACS) and at least one lesion with 18 FDG uptake in the carotid artery (target-to-background ratio [TBR] ≥ 1.6) were randomly assigned to receive either fimasartan (60 mg once a day) or amlodipine (5 mg once a day). 18 FDG PET examinations were performed in all patients at baseline and 6 months. The primary endpoint was the percent change in the index vessel TBR for the most diseased segment (MDS TBR). RESULTS: The two groups had similar baseline characteristics. At the 6-month follow-up, index vessel and aorta MDS TBR significantly decreased in both groups. However, the percent change in index vessel MDS TBR was similar between the two groups (-9.33 ± 14.2% vs -7.73 ± 19.1%, respectively, P = 0.9). No significant difference was found for the percent change in the whole vessel TBR for the index vessel between the two groups, with similar findings for changes in MDS TBR or whole vessel TBR for the aorta. Total cholesterol, low-density lipoprotein cholesterol levels, and blood pressure improved to a similar degree in both groups. CONCLUSIONS: Fimasartan and amlodipine reduce carotid atherosclerotic plaque inflammation similarly in patients with ACS, offering the same level of effectiveness.

Vascular Inflammation in Subclinical Atherosclerosis Detected by Hybrid PET/MRI.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease, but data on arterial inflammation at early stages is limited. OBJECTIVES: The purpose of this study was to characterize vascular inflammation by hybrid 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/magnetic resonance imaging (PET/MRI). METHODS: Carotid, aortic, and ilio-femoral 18F-FDG PET/MRI was performed in 755 individuals (age 40 to 54 years; 83.7% men) with known plaques detected by 2-/3-dimensional vascular ultrasound and/or coronary calcification in the PESA (Progression of Early Subclinical Atherosclerosis) study. The authors evaluated the presence, distribution, and number of arterial inflammatory foci (increased 18F-FDG uptake) and plaques with or without inflammation (coincident 18F-FDG uptake). RESULTS: Arterial inflammation was present in 48.2% of individuals (24.4% femorals, 19.3% aorta, 15.8% carotids, and 9.3% iliacs) and plaques in 90.1% (73.9% femorals, 55.8% iliacs, and 53.1% carotids). 18F-FDG arterial uptakes and plaques significantly increased with cardiovascular risk factors (p < 0.01). Coincident 18F-FDG uptakes were present in 287 of 2,605 (11%) plaques, and most uptakes were detected in plaque-free arterial segments (459 of 746; 61.5%). Plaque burden, defined by plaque presence, number, and volume, was significantly higher in individuals with arterial inflammation than in those without (p < 0.01). The number of plaques and 18F-FDG uptakes showed a positive albeit weak correlation (r = 0.25; p < 0.001). CONCLUSIONS: Arterial inflammation is highly prevalent in middle-aged individuals with known subclinical atherosclerosis. Large-scale multiterritorial PET/MRI allows characterization of atherosclerosis-related arterial inflammation and demonstrates 18F-FDG uptake in plaque-free arterial segments and, less frequently, within plaques. These findings suggest an arterial inflammatory state at early stages of atherosclerosis. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318).

[18F]-Fluorodeoxyglucose PET/CT imaging as a marker of carotid plaque inflammation: Comparison to immunohistology and relationship to acuity of events.

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 ±â€¯1.01 vs. 3.13 ±â€¯1.10, p = 0.008). 18FDG uptake differed between an acuity threshold of <90 days and >90 days (SUVmax:3.15 ±â€¯0.87 vs. 2.52 ±â€¯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.

Head-to-Head Comparison of Inflammation and Neovascularization in Human Carotid Plaques: Implications for the Imaging of Vulnerable Plaques.

BACKGROUND: Inflammation and intraplaque neovascularization are acknowledged to be 2 features of plaque vulnerability, although their temporal expression and their respective value in predicting clinical events are poorly understood. To determine their respective temporal associations, we conducted a comprehensive assessment of inflammation and intraplaque neovascularization in the carotid plaque of symptomatic and asymptomatic patients. METHODS AND RESULTS: Thirty patients with severe carotid stenosis underwent 18F-fluorodeoxyglucose-positron emission tomography/computed tomographic imaging. Plaque 18F-fluorodeoxyglucose-uptake, indicative of inflammation, was measured by calculating the target:background ratio. The presence of intraplaque neovascularization during contrast-enhanced ultrasound was judged semiquantitatively; low-grade contrast enhancement (CE) suggested its absence, and high-grade CE, the presence of neovascularization. Carotid surgery was performed 1.6±1.8 days after completing both imaging modalities in all patients, and the presence of macrophages and neovessels was quantified by immunohistochemistry. We identified a significant correlation between the target:background ratio and macrophage quantification (R=0.78; P<0.001). The number of vessels was also significantly higher in carotid plaque with high-CE (P<0.001). Surprisingly, immunohistochemistry showed that high-CE and vessel number were neither associated with an elevated target:background ratio (P=0.28 and P=0.60, respectively) nor macrophage infiltration (P=0.59 and P=0.40, respectively). Finally, macrophage infiltration and target:background ratio were higher in the carotid plaque of symptomatic patients (P=0.021 and P=0.05, respectively), whereas CE grade and the presence of neovessels were not. CONCLUSIONS: Inflammation and intraplaque neovascularization are not systematically associated in carotid plaques, suggesting a temporal separation between the 2 processes. Inflammation seems more pronounced when symptoms are present. These data highlight the challenges that face any imaging strategy designed to assess plaque vulnerability.

CD80 Is Upregulated in a Mouse Model with Shear Stress-Induced Atherosclerosis and Allows for Evaluating CD80-Targeting PET Tracers.

PURPOSE: A shear stress-induced atherosclerosis mouse model was characterized for its expression of inflammation markers with focus on CD80. With this model, we evaluated two positron emission tomography (PET) radiotracers targeting CD80 as well as 2-deoxy-2-[18F]fluoro-D-mannose ([18F]FDM) in comparison with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). PROCEDURE: A flow constrictive cuff implanted around the common carotid artery in apolipoprotein E knockout mice resulted in plaque formation. CD80 expression levels and plaque histopathology were evaluated. Serial PET/X-ray computed tomography scans were performed to follow inflammation. RESULTS: Plaque formation with increased levels of CD80 was observed. Histologically, plaques presented macrophage-rich and large necrotic areas covered by a thin fibrous cap. Of the CD80-specific tracers, one displayed an increased uptake in plaques by PET. Both [18F]FDG and [18F]FDM accumulated in atherosclerotic plaques. CONCLUSION: This mouse model presented, similar to humans, an increased expression of CD80 which renders it suitable for non-invasively targeting CD80-positive immune cells and evaluating CD80-specific radiotracers.

Cannabinoid receptor type 2 (CB2) as one of the candidate genes in human carotid plaque imaging: Evaluation of the novel radiotracer [11C]RS-016 targeting CB2 in atherosclerosis.

INTRODUCTION: Endarterectomized human atherosclerotic plaques are a valuable basis for gene expression studies to disclose novel imaging biomarkers and therapeutic targets, such as the cannabinoid receptor type 2 (CB2). In this work, CB2 is expressed on activated immune cells, which are abundant in inflamed plaques. We evaluated the CB2-specific radiotracer [11C]RS-016 for imaging vascular inflammation in human and mouse atherosclerotic lesions. METHODS: The differential gene expression of microscopically classified human carotid plaques was evaluated using quantitative polymerase chain reaction. In addition, CB2 expression levels in human plaques were investigated by in vitro autoradiography. As an appropriate animal model we used apolipoprotein E knockout mice (ApoE KO) with shear stress-induced atherosclerosis to evaluate CB2 levels in vivo. Positron emission tomography (PET) was performed with both the CB2 radioligand [11C]RS-016 and the metabolic radiotracer [18F]fluorodeoxyglucose ([18F]FDG) at various time points. Retrospectively, carotids were dissected for histopathology and gene expression analysis. RESULTS: We identified 28 human genes differentially expressed in atherosclerotic plaques compared to normal arteries of which 12 were upregulated preferentially in vulnerable plaques. The latter group included members of matrix metalloproteinase family and the T-lymphocyte activation antigens CD80 and CD86. CB2 was upregulated by 2-fold in human atherosclerotic plaques correlating with CD68 expression levels. Specific in vitro binding of [11C]RS-016 was predominantly observed to plaques. In vivo PET imaging of ApoE KO mice revealed accumulation of [11C]RS-016 and [18F]FDG in atherosclerotic plaques. Development of advanced plaques with elevated CB2 and CD68 levels were found in vitro in ApoE KO mice resembling human vulnerable plaques. CONCLUSION: We identified human genes associated with plaque vulnerability, which potentially could serve as novel imaging or therapeutic targets. The CB2-specific radiotracer [11C]RS-016 detected human plaques by in vitro autoradiography and accumulated in vivo in plaques of ApoE KO mice, however not exclusively in vulnerable plaques.

Similar Impact of Clopidogrel or Ticagrelor on Carotid Atherosclerotic Plaque Inflammation.

BACKGROUND: Platelets play an important role in inflammation. Inhibitors of the P2Y12 receptor, which is involved in platelet activation, may have a direct effect on carotid atherosclerotic plaque inflammation. HYPOTHESIS: We compared the effects of clopidogrel and ticagrelor therapy for carotid atherosclerotic plaque inflammation using 18 F-fluorodeoxyglucose ( 18 FDG) positron emission tomography (PET) imaging. METHODS: Fifty patients with acute coronary syndrome and ≥1 18 FDG uptake in the carotid artery (target-to-background ratio [TBR] ≥1.6) were randomized to either clopidogrel or ticagrelor groups. Of these, 46 completed PET examinations at baseline and at 6 months. The primary endpoint was the percent change in TBR of the index vessel at the most diseased segment (MDS). RESULTS: Baseline characteristics were similar between the 2 groups. At 6-month follow-up, low-density lipoprotein cholesterol and C-reactive protein significantly decreased in both groups (P < 0.001). The TBR of the index vessel and aorta significantly decreased in both groups (P < 0.01). The percent change in the MDS TBR of the index vessel was numerically but not significantly lower in the clopidogrel group than in the ticagrelor group (-9.5 ± 14.6% vs -13.5 ± 19.3%; P = 0.427). Likewise, the percent change in the whole-vessel TBR of the index vessel was not different between the 2 groups (P = 0.166). Similar findings were observed for changes in the MDS TBR (P = 0.412) or whole-vessel TBR of the aorta (P = 0.363). CONCLUSIONS: Carotid atherosclerotic plaque inflammation significantly decreases to a similar degree following 6 months of either clopidogrel or ticagrelor treatment.

Detection of Vulnerable Plaque in Patients with Cryptogenic Stroke.

In up to 40% of ischemic stroke cases the etiology remains unknown. A substantial proportion of these patients has non- or only mildly stenosing carotid artery plaques not fulfilling common criteria for large artery stroke, but beeing suspicious for arterio-arteriell embolism. Several imaging techniques allow the non-invasive analysis of plaque features. Nevertheless, carotid MRI might be best suited to assess the key features of vulnerable plaques. This review article discusses potential causes of cryptogenic stroke, the role of plaque imaging in non-stenosing plaques and the association of vulnerable plaques and specific plaque features with stroke risk and stroke recurrence.

Plaque Inflammation Imaging in Severe Carotid Stenosis and Recurrent Cerebral Ischemia.

A strong relationship exists between the severity of carotid stenosis and early stroke risk. Inflammation is believed to be an important event for atherosclerotic plaque destabilization and subsequent thromboembolism. (18)F-FDG can image atherosclerotic inflammation, providing information about plaque biology, which may serve as a useful biomarker for the assessment of early stroke risk.