Thresholds for Arterial Wall Inflammation Quantified by 18F-FDG PET Imaging Implications for Vascular Interventional Studies

AbstractObjectivesThis study assessed 5 frequently applied arterial 18fluorodeoxyglucose (18F-FDG) uptake metrics in healthy control subjects, those with risk factors and patients with cardiovascular disease (CVD), to derive uptake thresholds in each subject group. Additionally, we tested the reproducibility of these measures and produced recommended sample sizes for interventional drug studies.Background18F-FDG positron emission tomography (PET) can identify plaque inflammation as a surrogate endpoint for vascular interventional drug trials. However, an overview of 18F-FDG uptake metrics, threshold values, and reproducibility in healthy compared with diseased subjects is not available.Methods18F-FDG PET/CT of the carotid arteries and ascending aorta was performed in 83 subjects (61 ± 8 years) comprising 3 groups: 25 healthy controls, 23 patients at increased CVD risk, and 35 patients with known CVD. We quantified 18F-FDG uptake across the whole artery, the most-diseased segment, and within all active segments over several pre-defined cutoffs. We report these data with and without background corrections. Finally, we determined measurement reproducibility and recommended sample sizes for future drug studies based on these results.ResultsAll 18F-FDG uptake metrics were significantly different between healthy and diseased subjects for both the carotids and aorta. Thresholds of physiological 18F-FDG uptake were derived from healthy controls using the 90th percentile of their target to background ratio (TBR) value (TBRmax); whole artery TBRmax is 1.84 for the carotids and 2.68 in the aorta. These were exceeded by >52% of risk factor patients and >67% of CVD patients. Reproducibility was excellent in all study groups (intraclass correlation coefficient >0.95). Using carotid TBRmax as a primary endpoint resulted in sample size estimates approximately 20% lower than aorta.ConclusionsWe report thresholds for physiological 18F-FDG uptake in the arterial wall in healthy subjects, which are exceeded by the majority of CVD patients. This remains true, independent of readout vessel, signal quantification method, or the use of background correction. We also confirm the high reproducibility of 18F-FDG PET measures of inflammation. Nevertheless, because of overlap between subject categories and the relatively small population studied, these data have limited generalizability until substantiated in larger, prospective event-driven studies. (Vascular Inflammation in Patients at Risk for Atherosclerotic Disease; NTR5006

Guideline treatment results in regression of atherosclerosis in type 2 diabetes mellitus

Background: Efficacy of guideline cardiovascular disease prevention regimens may differ between patients with or without type II diabetes mellitus. We therefore compared change in carotid artery wall dimensions in type II diabetes mellitus and non-type II diabetes mellitus patients with a history of a major cardiovascular disease event, using magnetic resonance imaging. Methods: Thirty type II diabetes mellitus patients and 29 age- and sex-matched non-diabetes mellitus patients with a history of stroke or myocardial infarction and a carotid artery stenosis (15%70%) were included. In all patients, treatment was according to cardiovascular risk management guidelines. At baseline and follow-up, carotid artery vessel wall dimensions were measured using 1.5 T magnetic resonance imaging. Results: After 2 years of follow-up, total wall volume of the carotid artery in type II diabetes mellitus patients decreased by 9.6% (ρ = 0.016). In contrast, stabilization rather than regression of carotid artery wall dimensions was observed in nondiabetes mellitus patients over a 2-year period. Body mass index was identified as a predictor of total wall volume decrease. Conclusions: Guideline treatment arrests atherogenesis in non-diabetes mellitus patients and even decreases vessel wall dimensions in type II diabetes mellitus patients. Baseline body mass index predicts cardiovascular disease prevention efficacy expressed as decrease in total wall volume. These data emphasize the importance of optimal cardiovascularprevention, particularly in diabetes patients with a high body mass index

Thresholds for Arterial Wall Inflammation Quantified by 18F-FDG PET Imaging: Implications for Vascular Interventional Studies.

OBJECTIVES: This study assessed 5 frequently applied arterial 18fluorodeoxyglucose (18F-FDG) uptake metrics in healthy control subjects, those with risk factors and patients with cardiovascular disease (CVD), to derive uptake thresholds in each subject group. Additionally, we tested the reproducibility of these measures and produced recommended sample sizes for interventional drug studies. BACKGROUND: 18F-FDG positron emission tomography (PET) can identify plaque inflammation as a surrogate endpoint for vascular interventional drug trials. However, an overview of 18F-FDG uptake metrics, threshold values, and reproducibility in healthy compared with diseased subjects is not available. METHODS: 18F-FDG PET/CT of the carotid arteries and ascending aorta was performed in 83 subjects (61 ± 8 years) comprising 3 groups: 25 healthy controls, 23 patients at increased CVD risk, and 35 patients with known CVD. We quantified 18F-FDG uptake across the whole artery, the most-diseased segment, and within all active segments over several pre-defined cutoffs. We report these data with and without background corrections. Finally, we determined measurement reproducibility and recommended sample sizes for future drug studies based on these results. RESULTS: All 18F-FDG uptake metrics were significantly different between healthy and diseased subjects for both the carotids and aorta. Thresholds of physiological 18F-FDG uptake were derived from healthy controls using the 90th percentile of their target to background ratio (TBR) value (TBRmax); whole artery TBRmax is 1.84 for the carotids and 2.68 in the aorta. These were exceeded by >52% of risk factor patients and >67% of CVD patients. Reproducibility was excellent in all study groups (intraclass correlation coefficient >0.95). Using carotid TBRmax as a primary endpoint resulted in sample size estimates approximately 20% lower than aorta. CONCLUSIONS: We report thresholds for physiological 18F-FDG uptake in the arterial wall in healthy subjects, which are exceeded by the majority of CVD patients. This remains true, independent of readout vessel, signal quantification method, or the use of background correction. We also confirm the high reproducibility of 18F-FDG PET measures of inflammation. Nevertheless, because of overlap between subject categories and the relatively small population studied, these data have limited generalizability until substantiated in larger, prospective event-driven studies. (Vascular Inflammation in Patients at Risk for Atherosclerotic Disease; NTR5006).This work was supported by a European Framework Program 7 grant (ESS: FP7-Health 309820: Nano-Athero). Erik Stroes has received lecturing fees from Merck, Novartis, ISIS, Amgen - none of are related to the contents of this manuscript. All other authors declare that they have no conflict of interest and no relationships with industry relevant to this study. JHFR is part-supported by the NIHR Cambridge Biomedical Research Centre, the British Heart Foundation and the Wellcome Trust.This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Elsevier

Increased arterial wall inflammation in patients with ankylosing spondylitis is reduced by statin therapy

Ankylosing spondylitis (AS) is a chronic inflammatory disease with involvement of axial and sacroiliac joints. In addition, patients with AS have increased risk of cardiovascular disease (CVD), which might be attributed to enhanced inflammatory activity of the arterial wall. In the present study, we compared the level of carotid arterial wall inflammation in patients with AS with healthy controls using (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography with CT. As arterial wall inflammation is reduced by statin therapy, we subsequently assessed the effect of 3-month statin therapy on arterial wall inflammation in AS. We included 24 patients with AS (age 44±10, 72% males) without a history of CVD and 20 controls matched for age and gender. Patients with AS had lower high-density lipoprotein cholesterol and increased C reactive protein (CRP) compared with controls. The 10-year CVD risk was 2% in both groups. Notwithstanding, patients with AS had a 20% increase in arterial wall (18)F-FDG uptake compared with controls. Three-month atorvastatin 40 mg daily significantly lowered low-density lipoprotein cholesterol (baseline 3.55±1.15 mmol/L, -53%) and CRP (baseline 5.0 (1.5-9.3) mg/L, -58%) with a concomitant decrease of carotid arterial wall inflammation (maximum target-to-background ratio from 1.90±0.30 to 1.67±0.27; p=0.009). Patients with AS and without other CVD risk factors have increased arterial wall inflammation, which decreases upon statin therapy. These subjects are not identified as being at risk in current cardiovascular prevention guidelines. Our data support the need to revise CV disease management in AS, with perhaps a role for early statin therap

Increasing spatial resolution of 3T MRI scanning improves reproducibility of carotid arterial wall dimension measurements

To improve carotid 3T magnetic resonance imaging (MRI) dimension measurements in patients with overt atherosclerotic carotid artery disease. In 31 patients with advanced atherosclerotic carotid artery disease, two high resolution (0.25 × 0.25 mm(2); HR) and two routinely used low resolution (0.50 × 0.50 mm(2); LR) carotid 3T MRI scans were performed within 1 month. After manual delineation of carotid wall contours in a dedicated image analyses program in eight slices covering the atherosclerotic plaque, image reproducibility, as well as the within-reader and between-reader variability were determined. We found significantly higher intraclass correlation coefficients for total wall volume, mean wall area and mean wall thickness for the HR measurements (all p < 0.05). We found a significant lower signal-to-noise and contrast-to-noise ratio for the HR compared to the LR measurements. The carotid arterial wall dimension measurements of all parameters were significantly lower for the HR compared to the LR measurements. No significant differences were observed between the within-reader and between-reader reproducibility for HR versus LR measurements. Increasing the in-plane resolution improves the reproducibility of 3T MRI carotid arterial wall dimension measurements. The use of HR imaging will contribute to a reduced sample size needed in intervention trials using MRI scanning of the carotid artery as surrogate marker for atherosclerosis progressio

Superior in vivo compatibility of hydrophilic polymer coated prosthetic vascular grafts

Protein adsorption, cell adhesion and graft patency was compared in hydrophilic versus hydrophobic polymer-coated prosthetic vascular grafts. We hypothesize that in vivo compatibility of hydrophilic polymer-coated prosthetic vascular grafts is superior to in vivo compatibility of hydrophobic grafts. A pairwise side-to-side common carotid artery interposition graft was placed eight female landrace goats (mean weight 55 kg). Protein adsorption was assessed using Western Blot in two hydrophilic and two hydrophobic grafts harvested after three days. Graft patency was monitored for 28 days in six goats with continuous wave Doppler ultrasonography. Adherence of endothelial cells, leukocytes and platelets was determined with ELISA and compared between the two graft types after 28 days. After three days, more ApoA-I, albumin and VEGF and less fibrin adsorbed to hydrophilic grafts. After 28 days, compared to hydrophobic grafts, higher numbers of endothelial cells were present on hydrophilic grafts (P=0.016), and less thrombocytes and leukocytes (P=0.012 and 0.024, respectively). Two out of eight hydrophobic grafts lost patency, while none of the hydrophilic grafts failed (P=0.157). Hydrophilic polymer-coated vascular grafts have superior in vivo compatibility when compared to hydrophobic grafts as characterized by reduced platelet and leukocyte adherence as well as higher endothelializatio

Unexpected arterial wall and cellular inflammation in patients with rheumatoid arthritis in remission using biological therapy: a cross-sectional study

Increasing numbers of patients (up to 40 %) with rheumatoid arthritis (RA) achieve remission, yet it remains to be elucidated whether this also normalizes their cardiovascular risk. Short-term treatment with TNF inhibitors lowers arterial wall inflammation, but not to levels of healthy controls. We investigated whether RA patients in long-term remission are characterized by normalized inflammatory activity of the arterial wall and if this is dependent on type of medication used (TNF-inhibitor versus nonbiological disease-modifying antirheumatic drugs (DMARDs)). Arterial wall inflammation, bone marrow and splenic activity (index of progenitor cell activity) was assessed with (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) in RA patients in remission (disease activity score (DAS28) <2.6 for >6 months) and healthy controls. We performed ex vivo characterization of monocytes using flow cytometry and a transendothelial migration assay. Overall, arterial wall inflammation was comparable in RA patients (n = 23) in long-term remission and controls (n = 17). However, RA subjects using current anti-TNF therapy (n = 13, disease activity score 1.98[1.8-2.2]) have an almost 1.2-fold higher (18)F-FDG uptake in the arterial wall compared to those using DMARDs (but with previous anti-TNF therapy) (n = 10, disease activity score 2.24[1.3-2.5]), which seemed to be predominantly explained by longer duration of their rheumatic disease in a multivariate linear regression analysis. This coincided with increased expression of pro-adhesive (CCR2) and migratory (CD11c, CD18) surface markers on monocytes and a concomitant increased migratory capacity. Finally, we found increased activity in bone marrow and spleen in RA patients using anti-TNF therapy compared to those with DMARDs and controls. A subset of patients with RA in clinical remission have activated monocytes and increased inflammation in the arterial wall, despite the use of potent TNF blocking therapies. In these subjects, RA disease duration was the most important contributor to the level of arterial wall inflammation. This increased inflammatory state implies higher cardiovascular risk in these patients, who thus may require more stringent CV risk managemen

Effect of Anti-ApoA-I Antibody-Coating of Stents on Neointima Formation in a Rabbit Balloon-Injury Model

Since high-density lipoprotein (HDL) has pro-endothelial and anti-thrombotic effects, a HDL recruiting stent may prevent restenosis. In the present study we address the functional characteristics of an apolipoprotein A-I (ApoA-I) antibody coating in vitro. Subsequently, we tested its biological performance applied on stents in vivo in rabbits.The impact of anti ApoA-I- versus apoB-antibody coated stainless steel discs were evaluated in vitro for endothelial cell adhesion, thrombin generation and platelet adhesion. In vivo, response to injury in the iliac artery of New Zealand white rabbits was used as read out comparing apoA-I-coated versus bare metal stents.ApoA-I antibody coated metal discs showed increased endothelial cell adhesion and proliferation and decreased thrombin generation and platelet adhesion, compared to control discs. In vivo, no difference was observed between ApoA-I and BMS stents in lumen stenosis (23.3±13.8% versus 23.3±11.3%, p=0.77) or intima surface area (0.81±0.62 mm2 vs 0.84±0.55 mm2, p=0.85). Immunohistochemistry also revealed no differences in cell proliferation, fibrin deposition, inflammation and endothelialization.ApoA-I antibody coating has potent pro-endothelial and anti-thrombotic effects in vitro, but failed to enhance stent performance in a balloon injury rabbit model in vivo

Scan parameters for the HR and LR carotid arterial wall dimension measurements.

<p>* Scan times at heart rate of 60 min^-1</p><p>HR = high resolution; LR = low resolution; TSE = turbo spin-echo, FFE = fast field echo, FOV = field of view, DIR = double inversion-recovery, NEX = number of excitations.</p