Summary Background Dalcetrapib modulates cholesteryl ester transfer protein (CETP) activity to raise high-density lipoprotein cholesterol (HDL-C). After the failure of torcetrapib it was unknown if ...HDL produced by interaction with CETP had pro-atherogenic or pro-inflammatory properties. dal-PLAQUE is the first multicentre study using novel non-invasive multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary endpoints. Methods In this phase 2b, double-blind, multicentre trial, patients (aged 18–75 years) with, or with high risk of, coronary heart disease were randomly assigned (1:1) to dalcetrapib 600 mg/day or placebo for 24 months. Randomisation was done with a computer-generated randomisation code and was stratified by centre. Patients and investigators were masked to treatment. Coprimary endpoints were MRI-assessed indices (total vessel area, wall area, wall thickness, and normalised wall index average carotid) after 24 months and18 F-fluorodeoxyglucose (18 F-FDG) PET/CT assessment of arterial inflammation within an index vessel (right carotid, left carotid, or ascending thoracic aorta) after 6 months, with no-harm boundaries established before unblinding of the trial. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov , NCT00655473. Findings 189 patients were screened and 130 randomly assigned to placebo (66 patients) or dalcetrapib (64 patients). For the coprimary MRI and PET/CT endpoints, CIs were below the no-harm boundary or the adverse change was numerically lower in the dalcetrapib group than in the placebo group. MRI-derived change in total vessel area was reduced in patients given dalcetrapib compared with those given placebo after 24 months; absolute change from baseline relative to placebo was −4·01 mm2 (90% CI −7·23 to −0·80; nominal p=0·04). The PET/CT measure of index vessel most-diseased-segment target-to-background ratio (TBR) was not different between groups, but carotid artery analysis showed a 7% reduction in most-diseased-segment TBR in the dalcetrapib group compared with the placebo group (–7·3 90% CI −13·5 to −0·8; nominal p=0·07). Dalcetrapib did not increase office blood pressure and the frequency of adverse events was similar between groups. Interpretation Dalcetrapib showed no evidence of a pathological effect related to the arterial wall over 24 months. Moreover, this trial suggests possible beneficial vascular effects of dalcetrapib, including the reduction in total vessel enlargement over 24 months, but long-term safety and clinical outcomes efficacy of dalcetrapib need to be analysed. Funding F Hoffmann-La Roche Ltd.
Abstract Objectives This study sought to determine whether splenic activation after acute coronary syndrome (ACS) is linked to leukocyte proinflammatory remodeling and whether splenic activity ...independently predicts the risk of cardiovascular disease (CVD) events. Background Pre-clinical data suggest the existence of a cardiosplenic axis, wherein activation of hematopoietic tissues (notably in the spleen) results in liberation of proinflammatory leukocytes and accelerated atherosclerotic inflammation. However, it is presently unknown whether a cardiosplenic axis exists in humans and whether splenic activation relates to CVD risk. Methods18 F-fluorodeoxyglucose (18 FDG)–positron emission tomography (PET) imaging was performed in 508 individuals across 2 studies. In the first study, we performed FDG-PET imaging in 22 patients with recent ACS and 22 control subjects. FDG uptake was measured in spleen and arterial wall, whereas proinflammatory gene expression of circulating leukocytes was assessed by quantitative real-time polymerase chain reaction. In a second study, we examined the relationship between splenic tissue FDG uptake with subsequent CVD events during follow-up (median 4 years) in 464 patients who previously had undergone FDG-PET imaging. Results Splenic activity increased after ACS and was significantly associated with multiple indices of inflammation: 1) up-regulated gene expression of proinflammatory leukocytes; 2) increased C-reactive protein; and 3) increased arterial wall inflammation (FDG uptake). Moreover, in the second study, splenic activity (greater than or equal to the median) was associated with an increased risk of CVD events (hazard ratio HR: 3.3; 95% confidence interval CI: 1.5 to 7.3; p = 0.003), which remained significant after adjustment for CVD risk factors (HR: 2.26; 95% CI: 1.01 to 5.06; p = 0.04) and for arterial FDG uptake (HR: 2.68; 95% CI: 1.5 to 7.4; p = 0.02). Conclusions Our findings demonstrate increased splenic metabolic activity after ACS and its association with proinflammatory remodeling of circulating leukocytes. Moreover, we observed that metabolic activity of the spleen independently predicted risk of subsequent CVD events. Collectively, these findings provide evidence of a cardiosplenic axis in humans similar to that shown in pre-clinical studies.
Objectives A prospective, multicenter18 fluorine-fluorodeoxyglucose (18 F-FDG) positron emission tomography (PET)/computed tomography (CT) imaging study was performed to estimate the correlations ...among arterial FDG uptake and atherosclerotic plaque biomarkers in patients with peripheral artery disease. Background Inflammation within atherosclerotic plaques is associated with instability of the plaque and future cardiovascular events. Previous studies have shown that18 F-FDG-PET/CT is able to quantify inflammation within carotid artery atherosclerotic plaques, but no studies to date have investigated this correlation in peripheral arteries with immunohistochemical confirmation. Methods Thirty patients across 5 study sites underwent18 F-FDG-PET/CT imaging before SilverHawk atherectomy (FoxHollow Technologies, Redwood City, California) for symptomatic common or superficial femoral arterial disease. Vascular FDG uptake (expressed as target-to-background ratio) was measured in the carotid arteries and aorta and femoral arteries, including the region of atherectomy. Immunohistochemistry was performed on the excised atherosclerotic plaque extracts, and cluster of differentiation 68 (CD68) level as a measure of macrophage content was determined. Correlations between target-to-background ratio of excised lesions, as well as entire arterial regions, and CD68 levels were determined. Imaging was performed during the 2 weeks before surgery in all cases. Results Twenty-one patients had adequate-quality18 F-FDG-PET/CT peripheral artery images, and 34 plaque specimens were obtained. No significant correlation between lesion target-to-background ratio and CD68 level was observed. Conclusions There were no significant correlations between CD68 level (as a measure of macrophage content) and FDG uptake in the peripheral arteries in this multicenter study. Differences in lesion extraction technique, lesion size, the degree of inflammation, and imaging coregistration techniques may have been responsible for the failure to observe the strong correlations with vascular FDG uptake observed in previous studies of the carotid artery and in several animal models of atherosclerosis.
dal-PLAQUE is a placebo-controlled multicenter study designed to assess the effect of dalcetrapib on imaging measures of plaque inflammation and plaque burden. dal-PLAQUE is a multimodality imaging ...study in the context of the large dal-HEART Program. Decreased high-density lipoprotein cholesterol is linked to increased risk of coronary heart disease (CHD). Dalcetrapib, a compound that increases high-density lipoprotein cholesterol by modulating cholesteryl ester transfer protein, is being studied to assess if it can reduce the progression of atherosclerotic disease and thereby decrease cardiovascular morbidity and mortality. Patients with CHD or CHD-risk equivalents were randomized to receive 600 mg dalcetrapib or placebo daily for 24 months, in addition to conventional lipid-lowering medication and other medications for cardiovascular risk factors. The primary outcomes are the effect of dalcetrapib on 18F-fluorodeoxyglucose positron emission tomography target-to-background ratio after 6 months and magnetic resonance imaging (MRI) plaque burden (wall area, wall thickness, total vessel area, and wall area/total vessel area ratio) after 12 months. Secondary objectives include positron emission tomography target-to-background ratio at 3 months and MRI plaque burden at 6 and 24 months; plaque composition at 6, 12, and 24 months; and aortic compliance at 6 months. A tertiary objective is to examine the dynamic contrast-enhanced MRI parameters of plaque neovascularization. In total, 189 subjects entered screening, and 130 were randomized. dal-PLAQUE will provide important information on the effects of dalcetrapib on markers of inflammation and atherosclerotic plaque burden and, thereby, on the safety of cholesteryl ester transfer protein modulation with dalcetrapib. Results are expected in 2011.
Inflammation is a determinant of atherosclerotic plaque rupture, the event leading to most myocardial infarctions and strokes. Although conventional imaging techniques identify the site and severity ...of luminal stenosis, the inflammatory status of the plaque is not addressed. Positron emission tomography imaging of atherosclerosis using the metabolic marker fluorodeoxyglucose allows quantification of arterial inflammation across multiple vessels. This review sets out the background and current and potential future applications of this emerging biomarker of cardiovascular risk, along with its limitations.
Objectives This study sought to determine the effects of a p38 mitogen-activated protein kinase inhibitor, losmapimod, on vascular inflammation, by18 F-fluorodeoxyglucose (FDG) positron emission ...tomography/computed tomography imaging. Background The p38 mitogen-activated protein kinase cascade plays an important role in the initiation and progression of inflammatory diseases, including atherosclerosis. Methods Patients with atherosclerosis on stable statin therapy (n = 99) were randomized to receive losmapimod 7.5 mg once daily (lower dose LD), twice daily (higher dose HD) or placebo for 84 days. Vascular inflammation was assessed by FDG positron emission tomography/computed tomography imaging of the carotid arteries and aorta; analyses focused on the index vessel (the artery with the highest average maximum tissue-to-background ratio TBR at baseline). Serum inflammatory biomarkers and FDG uptake in visceral and subcutaneous fat were also measured. Results The primary endpoint, change from baseline in average TBR across all segments in the index vessel, was not significantly different between HD and placebo (ΔTBR: −0.04 95% confidence interval CI: −0.14 to +0.06, p = 0.452) or LD and placebo (ΔTBR: −0.02 95% CI: −0.11 to +0.06, p = 0.579). However, there was a statistically significant reduction in average TBR in active segments (TBR ≥1.6) (HD vs. placebo: ΔTBR: −0.10 95% CI: −0.19 to −0.02, p = 0.0125; LD vs. placebo: ΔTBR: −0.10 95% CI: −0.18 to −0.02, p = 0.0194). The probability of a segment being active was also significantly reduced for HD when compared with placebo (OR: 0.57 95% CI: 0.41 to 0.81, p = 0.002). Within the HD group, reductions were observed in placebo-corrected inflammatory biomarkers including high-sensitivity C-reactive protein (% reduction: −28% 95% CI: −46 to −5, p = 0.023) as well as FDG uptake in visceral fat (ΔSUV: −0.05 95% CI: −0.09 to −0.01, p = 0.018), but not subcutaneous fat. Conclusions Despite nonsignificant changes for the primary endpoint of average vessel TBR, HD losmapimod reduced vascular inflammation in the most inflamed regions, concurrent with a reduction in inflammatory biomarkers and FDG uptake in visceral fat. These results suggest a systemic anti-inflammatory effect. (A Study to Evaluate the Effects of 3 Months Dosing With GW856553, as Assessed FDG-PET/CT Imaging; NCT00633022 )
Background The presence of subclinical atherosclerosis is a likely predictor of cardiovascular events; however, factors associated with the early stages and progression of atherosclerosis are poorly ...defined. Objective The PESA study examines the presence of subclinical atherosclerosis by means of noninvasive imaging and prospectively analyzes the determinants associated with its development and progression in a middle-aged population. Methods The PESA study is an observational, longitudinal and prospective cohort study in a target population of 4000 healthy subjects (40-54 years old, 35% women) based in Madrid (Spain). Recruitment began in June 2010 and will be completed by the end of 2013. Baseline examination consists of (1) assessment for cardiovascular risk factors (including lifestyle and psychosocial factors); (2) screening for subclinical atherosclerosis using 2D/3D ultrasound in carotid, abdominal aorta and iliofemoral arteries, and coronary artery calcium score (CACS) by computed tomography; and (3) blood sampling for determination of traditional risk factors, advanced “omics” and biobanking. In addition, a subgroup of 1300 participants with evidence of atherosclerosis on 2D/3D ultrasound or CACS will undergo a combined18 F-fluorodeoxyglucose–positron emission tomography/magnetic resonance imaging (18 FDG PET/MRI) study of carotid and iliofemoral arteries. Follow-up at 3 and 6 years will include a repetition of baseline measurements, except for the18 FDG PET/MRI study, which will be repeated at 6 years. Conclusions The PESA study is expected to identify new imaging and biological factors associated with the presence and progression of atherosclerosis in asymptomatic people and will help to establish a more personalized management of medical care.
Abstract Background Identifying vulnerable coronary plaque with coronary CT angiography is limited by overlap between attenuation of necrotic core and fibrous plaque. Using x-rays with differing ...energies alters attenuation values of these components, depending on their material composition. Objectives We sought to determine whether dual-energy CT (DECT) improves plaque component discrimination compared with single-energy CT (SECT). Methods Twenty patients underwent DECT and virtual histology intravascular ultrasound (VH-IVUS). Attenuation changes at 100 and 140 kV for each plaque component were defined, using 1088 plaque areas co-registered with VH-IVUS. Hounsfield unit thresholds that best detected necrotic core were derived for SECT (conventional attenuation values) and for DECT (using dual-energy indices, defined as difference in Hounsfield unit values at the 2 voltages/their sum). Sensitivity of SECT and DECT to detect plaque components was determined in 77 segments from 7 postmortem coronary arteries. Finally, we examined 60 plaques in vivo to determine feasibility and sensitivity of clinical DECT to detect VH-IVUS–defined necrotic core. Results In contrast to conventional SECT, mean dual-energy indices of necrotic core and fibrous tissue were significantly different with minimal overlap of ranges (necrotic core, 0.007 95% CI, –0.001 to 0.016; fibrous tissue, 0.028 95% CI, 0.016–0.050; P < .0001). DECT increased diagnostic accuracy to detect necrotic core in postmortem arteries (sensitivity, 64%; specificity, 98%) compared with SECT (sensitivity, 50%; specificity, 94%). DECT sensitivity to detect necrotic core was lower when analyzed in vivo, although still better than SECT (45% vs 39%). Conclusions DECT improves the differentiation of necrotic core and fibrous plaque in ex vivo postmortem arteries. However, much of this improvement is lost when translated to in vivo imaging because of a reduction in image quality.
Objectives The aim of this feasibility study was to evaluate 18 F-2-Fluoro-A85380 for in vivo imaging of arterial nicotinic acetylcholine receptors (nAChRs) in humans. Furthermore, potentially ...different vascular uptake patterns of this new tracer were evaluated in healthy volunteers and in patients with neurodegenerative disorders. Background 18 F-2-Fluoro-A85380 was developed for in vivo positron emission tomography (PET) imaging of nAChR subunits in the human brain. These nAChRs are also found in arteries and seem to mediate the deleterious effects of nicotine as a part of tobacco smoke in the vasculature. It has been previously shown that uptake patterns of the radiotracer in the brain differs in patients with neurodegenerative disorders compared with healthy controls. Methods 18 F-2-Fluoro-A85380 uptake was quantified in the ascending and descending aorta, the aortic arch, and the carotids in 5 healthy volunteers and in 6 patients with either Parkinson's disease or multiple system atrophy, respectively, as the maximum target-to-background ratio. The maximal standardized uptake value values, the single hottest segment, and the percent active segments of the 18 F-2-Fluoro-A85380 uptake in the arteries were also assessed. Results 18 F-2-Fluoro-A85380 uptake was clearly visualized and maximum target-to-background ratio uptake values corrected for the background activity of the tracer showed specific tracer uptake in the arterial walls. Significantly higher uptake values were found in the descending aorta. Comparison between volunteers and patients revealed significant differences, with lower 18 F-2-Fluoro-A85380 uptake in the patient group when comparing single arterial territories but not when all arterial territories were pooled together. Conclusions 18 F-2-Fluoro-A85380 can provide specific information on the nAChR distribution in human arteries. Vascular nAChR density seems to be lower in patients with Parkinson's disease or multiple system atrophy. Once confirmed in larger study populations and in the experimental setting, this approach might provide insights into the pathogenic role of nAChRs in the human vasculature.
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