J H F Rudd

Assessment of calcification and inflammation with positron emission tomography in aortic stenosis and atherosclerosis

Abstract Background Calcification and inflammation are key pathological processes in aortic stenosis and atherosclerosis. Using combined positron emission tomography and computed tomography (PET/CT), we sought to investigate their contribution to disease progression in aortic stenosis and to help identify vulnerable atherosclerotic plaque. Methods In the first part of the study patients with calcific aortic valve disease stenosis were prospectively compared with age-matched and sex-matched controls with normal valves. Aortic valve severity was determined at baseline and 1 year by echocardiography and CT calcium scoring. Calcification and inflammation in the valve were assessed by sodium 18-fluoride (NaF) and 18-fluorodeoxyglucose (FDG) uptake with PET. In the second part of the study NaF and FDG activity was assessed in the coronary arteries both in patients with stable coronary disease and in patients after myocardial infarction. Findings 101 patients with aortic stenosis were compared with 20 controls. Tracer activity (target to background ratio [TBR]) was higher in patients with aortic stenosis than in controls (mean NaF 2·87 [SD 0·82] vs 1·55 [0·17], FDG 1·58 [0·21] vs 1·30 [0·13]; both p r 2 =0·540) with a more modest increase observed for FDG ( r 2 =0·218). Baseline NaF correlated closely with alkaline phosphatase staining on immunohistochemistry ( r 2 =0·79) and was a better predictor of disease progression at 1 year ( r 2 =0·44, n=20) than was FDG ( r 2 =0·02) or baseline calcium score ( r 2 =0·36, current best predictor). Increased NaF activity was observed in 45 (42%) of 106 patients with stable coronary atherosclerosis and was localised to individual coronary plaques. These patients had higher rates of previous major adverse cardiovascular events (p=0·016) and higher Framingham risk scores (p=0·011) than did patients without increased uptake. In patients after myocardial infarction (n=15) intense NaF activity was observed at the site of the culprit lesion, with increased uptake compared with the maximum uptake elsewhere in the coronary arteries (TBR median 1·56 [IQR 1·49–1·82] vs 1·23 [1·15–1·48], p=0·02). Interpretation In the valve, NaF holds promise in predicting aortic stenosis progression. In the coronary arteries it identifies culprit plaque post myocardial infarction and stable patients at elevated cardiac risk. Funding British Heart Foundation.

P540Zero coronary artery calcium score in patients with stable chest pain is associated with a good prognosis despite risk of non-calcified plaques

Division of Cardiovascular Medicine, University of Cambridge, Addenbrookes Hospital, Cambridge, UK Department of Clinical Radiology, Imperial College Hospitals NHS Trust, St Marys Hospital, London, UK Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Cambridge, UK Department of Radiology, Addenbrookes Hospital, Cambridge, UK Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, UK

POSITRON EMISSION TOMOGRAPHY TO IDENTIFY RUPTURED AND VULNERABLE CORONARY PLAQUES

Background Non-invasive imaging to identify vulnerable or ruptured coronary artery plaque would represent a major clinical advance. Using positron emission tomography (PET) and computed tomography (CT), we investigated coronary uptake of 18F-fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) in patients with acute myocardial infarction or stable angina. Methods Forty patients with acute myocardial infarction and 40 with stable angina underwent electrocardiogram-gated 18F-NaF and 18F-FDG PET-CT and invasive coronary angiography. 18F-NaF uptake was compared with virtual histology intravascular ultrasound in patients with stable angina, and with histology in 12 carotid endartectomy specimens. Results Intense focal 18F-NaF uptake occurred at the site of plaque rupture in 37 (93%) patients with myocardial infarction (tissue-to-background ratio [TBR], 1.66 [1.40–2.25] versus 1.24 [1.06–1.38]; culprit versus maximal non-culprit, P<0.001). In patients with stable angina, 18 (45%) had focal plaque 18F-NaF uptake (2.10 [1.71–2.81]) that, compared to plaques without uptake, had more high-risk features: positive remodeling (vessel area 24 [17–27] versus 14 [12–18] mm2; P=0.002), necrotic core (24.6% [20.5–28.8] verses 18.0% [14.0–22.4], P=0.001) and microcalcification (73 versus 21%, P=0.002). Carotid plaque rupture also co-localized with ex vivo 18F-NaF uptake and was associated with areas of apoptosis, necrosis and active calcification. Myocardial uptake markedly hampered 18F-FDG assessment in most patients (55%) and even where coronary uptake was discernible, there were no differences between culprit and non-culprit lesions (1.71 [1.40–2.13] versus 1.58 [1.28–2.01]; P=0.34). Conclusions 18F-NaF holds major promise as a novel biomarker of coronary plaque vulnerability and rupture with implications for the diagnosis, investigation and treatment of coronary artery disease.

B Assessment of valvular calcification and inflammation by positron emission tomography

Background The pathophysiology of aortic stenosis is incompletely understood and the relative contributions of valvular calcification and inflammation to disease progression are unknown. Methods Patients with aortic sclerosis and mild, moderate and severe stenosis were prospectively compared to age and sex-matched control subjects. Aortic valve severity was determined by echocardiography. Calcification and inflammation in the aortic valve were assessed by sodium 18-fluoride (18F-NaF) and 18-fluorodeoxyglucose (18F-FDG) uptake using positron emission tomography. Histological analysis was performed on the valves of five patients who subsequently underwent aortic valve replacement. Results 121 subjects (20 controls; 20 aortic sclerosis; 25 mild, 33 moderate and 23 severe aortic stenosis) were administered both 18F-NaF and 18F-FDG. Quantification of tracer uptake within the valve demonstrated excellent inter-observer repeatability with no fixed or proportional biases and limits of agreement of ±0.21 (18F-NaF) and ±0.13 (18F-FDG) for maximum tissue-to-background ratios. Activity of both tracers was higher in patients with aortic stenosis than control subjects (18F-NaF: 2.87±0.82 vs 1.55±0.17; 18F-FDG: 1.58±0.21 vs 1.30±0.13; both p<0.001). 18F-NaF uptake displayed a progressive rise with valve severity (r2=0.540, p<0.001) and colocalised to osteocalcin staining on histology. Uptake was observed both in the presence and absence of underlying calcium on CT with the latter predominating. 18F-FDG displayed a more modest increase in activity with valve severity (r2=0.218; p<0.001) and mapped to areas of macrophage accumulation. Among patients with aortic stenosis, 91% had increased 18F-NaF (>1.97) and 35% increased 18F-FDG (>1.63) uptake. A weak correlation between the activities of these tracers was observed (r2=0.174, p<0.001) and while 18F-NaF activity was higher in the aortic valve than aortic atheroma (2.68±0.84 vs 2.07±0.30; p<0.001) the reverse was true for 18F-FDG (1.56±0.21 vs 1.80±0.25; p<0.001). Conclusions Positron emission tomography is a novel, feasible and repeatable approach to the evaluation of valvular calcification and inflammation in patients with aortic stenosis. Calcification appears to be the predominant process that is particular to the valve and disproportionate to the degree of inflammation, indicating it to be a more attractive target for therapeutic intervention.

095 Plaque mapping based on contrast ratios permits identification of unstable coronary plaque and quantification of coronary atherosclerosis by coronary CT angiography

Background Previous attempts to characterise coronary components using CT have relied on fixed Hounsfield unit (HU) ranges which do not correct for the effect of inter-patient variation of contrast intensity on plaque attenuation. We examine the utility of using HU-ranges derived from contrast attenuation ratios. Methods 57 patients underwent coronary CT and Virtual Histology IVUS examination. Attenuation was sampled in over 1000 plaque areas co-registered with VH-IVUS and compared to contrast attenuation to create contrast ratios for each plaque component. These ratios were used to create a colour map of the plaque based on the HU of its constituents and used to test: (A) Classification of plaque components against histology in 10 post-mortem human coronary arteries. (B) Quantification of plaque geometry and composition compared with VH-IVUS in 30 coronary segments

06 Dual Energy CT has the Potential to Improve Non-Invasive Identification Of Necrotic Core

Background CT can classify plaque based on its x-ray attenuation. However, identifying vulnerable plaque is limited by overlap between the attenuation of necrotic core and fibrous plaque. Changes in attenuation of plaque components to x-rays of differing energies may allow better discrimination. We tested whether Dual Energy CT (DECT) (simultaneous image acquisition at two energies) improved identification of necrotic core, both in-vivo and ex-vivo. Methods 20 patients underwent DECT and 3-vessel Virtual Histology-IVUS (VH-IVUS). Attenuation was sampled in 1088 plaque areas co-registered with VH-IVUS and used to define dual energy indices (changes in attenuation of plaque components at 100 kV and 140kV). 42 plaques were analysed by DECT to determine whether DECT increased sensitivity to detect VH-IVUS defined necrotic core. 10 post-mortem coronary arteries were also examined with DECT prior to histological analysis to determine whether DECT increased sensitivity to detect histologically proven necrotic core. Results Dual energy indices of necrotic core and fibrous plaque were significantly different (mean: 0.0071 vs. 0.0283, p<0.05). Utilising these increased diagnostic accuracy for DECT to detect necrotic core in 87 segments of post-mortem arteries (sensitivity-64%, specificity-96%) compared with single energy CT (sensitivity-54%, specificity-92%). Sensitivity to detect necrotic core was lower in plaques analysed in-vivo due to the impact of temporal resolution on moving coronaries. However, DECT still provided marginal improvements in sensitivity (45%) compared with single energy CT (39%). Conclusions Dual Energy CT has the potential to improve the differentiation of necrotic core and fibrous plaque allowing more accurate non-invasive identification of vulnerable plaque.

113 Dual energy ct improves differentiation of coronary atherosclerotic plaque components compared to conventional single energy CT

Introduction Vulnerable plaques have a relatively high necrotic core area and low fibrous tissue content. Although CT can identify plaque components on the basis of their x-ray attenuation, there is significant overlap between their attenuation ranges, most crucially between necrotic core and fibrous plaque. Recently introduced dual energy CT (DECT) permits acquisition of 2 different energy data sets simultaneously, with the change in attenuation of plaque components to different energies depending upon their material composition. We therefore examined whether DECT was better than single energy CT in determining plaque components defined by virtual histology IVUS. Methods 20 patients underwent DECT and 3-vessel VH-IVUS. CT data was obtained at peak voltages of 100u2005kV and 140u2005kV. 52 plaques were chosen with either homogenous fibrous plaque or confluent areas of calcified plaque or necrotic core as defined by VH-IVUS. VH-IVUS images were co-registered and orientated with the corresponding CT images using distance from coronary ostia and fiduciary markers (Abstract 113 figure 1). Multiple regions of interest (ROI) were placed within the plaque components or in lumen on cross sectional CT images pre-classified by VH-IVUS (Abstract 113 figure 1). ROI densities were measured (in Hounsfield Units) and assigned to the plaque component. A dual energy index (DEI) was created for each component, defined as the ratio of the difference in attenuation at 2 different energies / sum of attenuation with 1000 added to each attenuation value to avoid negatives.Abstract 113 Figure 1 Demonstration of plaque co-registration between VH-IUS and 140kV/100kV CT data sets. Calcified plaque is identified 5mm from side branch adjacent to characteristic calcification (yellow line). Cross section taken through this plaque (blue arrow) and following orientation with VH-IVUS cross section HU region of interest sampling is performed in calcified plaque. Results Attenuation values for 1088 ROIs were measured from 70 paired data sets at 100u2005kV and 140u2005kV creating 70 DEIs (12 necrotic core, 11 fibrous plaque, 29 calcified plaques and 18 lumen). Values obtained using a single energy data set showed good differentiation between calcified plaque and all others (p<0.05), but considerable overlap between necrotic core and fibrous plaque (p=ns) (Abstract 113 figure 2A) (Abstract 113 table 1). In DECT, lumen (iodinated contrast) showed the greatest change in attenuation and hence had the highest DEI. Necrotic core had the lowest DEI and could be distinguished from all other components (p<000.1) Importantly, in contrast to the single energy data, DEI derived from both energy data sets permitted resolution of necrotic core and fibrous plaque without overlap (Abstract 113 figure 2B).Abstract 113 Figure 2 (A) Defined CT attenuation spectra of plaque components using a single energy (140kV), calcified plaque is distinguishable from all others but necrotic core and fibrous plaque overlap. (B) The use of dual energy index from the attenuation data at 2 energies (100/140kV) allows significant separation of necrotic core and fibrous plaque (p<0.05) (Tukeys multiple comparison test).Abstract 113 Table 1 Plaque Component 100u2009kV mean HU (SD) 140u2009kV mean HU (SD) Mean Difference (100–140u2009kV) Dual Energy Index (mean) Necrotic Core 57.26 (42.20) 42.69 (31.51) 14.57 0.0071 Fibrous Plaque 148.30 (49.47) 84.60 (30.34) 63.69 0.0283 Calcified Plaque 733.10 (226.7) 582.20 (194.9) 150.9 0.0450 Lumen 411.5 (82.27) 282.90 (55.93) 128.6 0.0483 Conclusions The additional attenuation data provided by DECT improves the differentiation of plaque components when compared to conventional single energy CT. In particular, DECT may allow better differentiation of necrotic core and fibrous plaque, a weakness of conventional cardiac CT, allowing for more accurate non-invasive identification of vulnerable plaques.

111 Single centre prospective cardiac CT study to determine the prevalence of patients with coronary artery disease with a zero coronary artery calcium score and associated non-cardiac incidental findings

Introduction Cardiac CT, incorporating coronary artery calcium (CAC) scoring and angiography, is being increasingly used to evaluate patients with chest pain and exclude coronary artery disease (CAD), as recommended in the recent NICE guidelines. Calcification of the coronary arteries is an excellent marker of underlying atherosclerosis, but a zero CAC score does not completely exclude the diagnosis as potentially significant non-calcified plaques will not be detected by CAC scoring. CT imaging may also identify non-cardiac incidental findings that can lead to further downstream testing and medical expense. Objectives (1) To evaluate the probability of CAD in patients with a CAC score of zero. (2) To determine the incidence of non-cardiac incidental findings on cardiac CT and to quantify resulting investigations. Methods 116 symptomatic patients undergoing cardiac CT to exclude CAD from November 2009 to October 2010 were prospectively enrolled. Patients underwent CAC scoring and had contrast-enhanced, 128-slice, dual source CT coronary angiography (CTCA―Siemens Flash). Scans were dual-reported by a cardiac radiologist and a cardiologist. Statistical analysis was performed using GraphPadPrism. Results 62/116 patients had a CAC score of zero. Of these, 57 (91.9%) patients had normal coronary arteries, 4 (6.5%) patients had non-obstructive CAD (stenosis <50%), and 1 patient (1.6%) had significant obstructive CAD (stenosis>50%). This patient with obstructive CAD had a high grade lesion in the proximal left anterior descending artery that required intervention. 54/116 had non-zero CAC scores. Of these, 13 (24%) had obstructive CAD and 41 (76%) non-obstructive CAD. 42/116 (36%) patients had incidental findings on cardiac CT that are summarised in Abstract 111 table 1. These incidental findings resulted in further investigations, documented in Abstract 111 table 2. The mean radiation dose (± SEM) for CAC scoring was 0.61±0.03u2005mSv. The mean radiation dose (± SEM) for subsequent CTCA was 2.66 ± 0.32u2005mSv in high pitch “flash” mode (n=27), 5.86±0.50u2005mSv in prospective mode (n=64) and 17.15±1.68u2005mSv in the retrospective mode (n=25).Abstract 111 Table 1 Incidental findings on cardiac CT Area Structure Incidental Finding n Chest (n=27) Lung parenchyma Nodule <1u2009cm 5 Emphysema 3 Atelectasis 6 Fibrosis 4 Tumour recurrence 1 Bronchiectasis 2 Pleura Effusion 2 Calcification 2 Lymph node Adenopathy 2 Abdomen (n=7) Liver Cyst/Nodules 6 Adernal Adenoma/metastasis 1 Diaphragm (n=5) Hiatus Hernia 5 Vasculature (n=11) Aorta Dilatation 8 Aneurysm 1 Renal Stenosis 1 Coeliac Stenosis 1Abstract 111 Table 2 Further investigation of incidental findings on Cardiac CT Investigation n Bone scintigraphy 1 Chest clinic referral 2 CT chest 4 DMSA 1 MR adrenals 1 MRA renal 1 Nephrology clinic referral 1 Pleural fluid aspiration 1 Ultrasound kidneys 1 Ultrasound liver 3 Conclusions Despite 62 patients having a reassuring CAC score of zero, 8% of this group had evidence of non-calcified plaque, with one patient having obstructive CAD that required intervention. We conclude that if strong clinical suspicion remains in patients with a CAC score of zero further coronary investigation may be warranted. Incidental findings are common, and can result in multiple further investigations for patients. Further research is needed to evaluate the added cost, clinical benefits and radiation exposure created by investigation of such incidental findings in the context of cardiac CT.Abstract 111 Table 3 Investigations and referrals generated by incidental findings Investigations or referrals Number Bone scintigraphy 1 Chest clinic referral 2 CT chest 4 DMSA 1 MR adrenals 1 MR cardiac 2 MRA renal 1 Nephrology clinic referral 1 Pleural fluid aspiration 1 Ultrasound kidneys 1 Ultrasound liver 3

076 Dual source computed tomography for characterisation of coronary atherosclerotic plaques. A comparison with virtual histology intravascular ultrasound

Background Non invasive plaque characterisation is important for risk stratification. Dual Source CT (DSCT) offers a significant improvement in temporal resolution over single source CT and may be a non invasive method to classify plaque components. Although CT plaque images have previously been compared with greyscale IVUS they have not been validated against virtual histology intravascular ultrasound (VH-IVUS), a technology which involves spectral analysis of IVUS radiofrequency signals. VH-IVUS is the gold standard for in vivo plaque classification, with proven validation against histology. Our aim was to show that DSCT could distinguish between plaque components as defined by VH-IVUS on the basis of their attenuation values in Hounsfield units (HU). Methods Twenty-one patients underwent DSCT and VH-IVUS prior to coronary stenting. Twenty-six plaques with VH-IVUS plaque burden >40% were chosen. Plaques were either homogenous for fibrous plaque or contained large confluent areas of calcified plaque or a necrotic core. The VH- IVUS images were co-registered with the corresponding CT image by an unblinded observer. Accurate matching of lesions was performed by using measurements of distance from the coronary ostia. The images were orientated using fiduciary markers (side branches or characteristic calcifications). Multiple regions of interest (ROI) were placed within the plaque components and lumen on the cross sectional CT images in areas that had been pre-classified on the VH-IVUS images (Abstract 76 Figure 1). The density of these ROIs were measured (expressed in HU) and assigned to the relative plaque type or lumen. Abstract 76 Figure 1 Co-registered VH IVUS (left) and DSCT (right) demonstrating ROI sampling of necrotic core (top) and calcified plaque (bottom). Results Attenuation values for 171 ROIs (necrotic core 28, fibrous plaque 38, calcified plaque 29 and lumen 76) were measured from the 26 plaques. Mean and standard deviation attenuation values were 35+/−17u2005HU, 128+/−49u2005HU, 719+/−237u2005HU and 362+/−51 respectively (Abstract 76 Table 1). There were statistically highly significant differences in the attenuation values among the four groups (necrotic core, fibrous plaque, calcified plaque and lumen) by nonparametric Kruskal–Wallis test (p<0.0001) (Abstract 76 Figure 2). Abstract 76 Table 1 Attenuation values derived from the ROIs placed in the plaque components and lumen expressed as means with ranges and standard deviation Plaque subtype Mean HU (range) Standard deviation Necrotic core 35 (3–73) 17 Fibrous plaque 128 (45–256) 49 Lumen 362 (246–486) 51 Calcified plaque 719 (358–1326) 237 Abstract 76 Figure 2 Box-and-whiskers plot of the CT density of the IVUS defined plaque types and lumen showing statistically significant differences between 4 groups (P<0.0001 Kruskal-Wallis). Conclusions VH-IVUS-defined plaque components have characteristic attenuation values that differ significantly enough to be differentiated by DSCT. This classification may facilitate non-invasive coronary plaque characterisation using DSCT for both therapeutic drug trials and assessment of vascular risk.