Christophe Lucatelli

Cardiac αVβ3 integrin expression following acute myocardial infarction in humans

Objective Maladaptive repair contributes towards the development of heart failure following myocardial infarction (MI). The αvβ3 integrin receptor is a key mediator and determinant of cardiac repair. We aimed to establish whether αvβ3 integrin expression determines myocardial recovery following MI. Methods 18F-Fluciclatide (a novel αvβ3-selective radiotracer) positron emission tomography (PET) and CT imaging and gadolinium-enhanced MRI (CMR) were performed in 21 patients 2 weeks after ST-segment elevation MI (anterior, n=16; lateral, n=4; inferior, n=1). CMR was repeated 9 months after MI. 7 stable patients with chronic total occlusion (CTO) of a major coronary vessel and nine healthy volunteers underwent a single PET/CT and CMR. Results 18F-Fluciclatide uptake was increased at sites of acute infarction compared with remote myocardium (tissue-to-background ratio (TBRmean) 1.34±0.22 vs 0.85±0.17; p<0.001) and myocardium of healthy volunteers (TBRmean 1.34±0.22 vs 0.70±0.03; p<0.001). There was no 18F-fluciclatide uptake at sites of established prior infarction in patients with CTO, with activity similar to the myocardium of healthy volunteers (TBRmean 0.71±0.06 vs 0.70±0.03, p=0.83). 18F-Fluciclatide uptake occurred at sites of regional wall hypokinesia (wall motion index≥1 vs 0; TBRmean 0.93±0.31 vs 0.80±0.26 respectively, p<0.001) and subendocardial infarction. Importantly, although there was no correlation with infarct size (r=0.03, p=0.90) or inflammation (C reactive protein, r=−0.20, p=0.38), 18F-fluciclatide uptake was increased in segments displaying functional recovery (TBRmean 0.95±0.33 vs 0.81±0.27, p=0.002) and associated with increase in probability of regional recovery. Conclusion 18F-Fluciclatide uptake is increased at sites of recent MI acting as a biomarker of cardiac repair and predicting regions of recovery. Trial registration number NCT01813045; Post-results.

Optimization and Reproducibility of Aortic Valve 18F-Fluoride Positron Emission Tomography in Patients With Aortic Stenosis

Background—18F-Fluoride positron emission tomography (PET) and computed tomography (CT) can measure disease activity and progression in aortic stenosis. Our objectives were to optimize the methodology, analysis, and scan–rescan reproducibility of aortic valve 18F-fluoride PET-CT imaging. Methods and Results—Fifteen patients with aortic stenosis underwent repeated 18F-fluoride PET-CT. We compared nongated PET and noncontrast CT, with a modified approach that incorporated contrast CT and ECG-gated PET. We explored a range of image analysis techniques, including estimation of blood-pool activity at differing vascular sites and a most diseased segment approach. Contrast-enhanced ECG-gated PET-CT permitted localization of 18F-fluoride uptake to individual valve leaflets. Uptake was most commonly observed at sites of maximal mechanical stress: the leaflet tips and the commissures. Scan–rescan reproducibility was markedly improved using enhanced analysis techniques leading to a reduction in percentage error from ±63% to ±10% (tissue to background ratio MDS mean of 1.55, bias −0.05, limits of agreement −0·20 to +0·11). Conclusions—Optimized 18F-fluoride PET-CT allows reproducible localization of calcification activity to different regions of the aortic valve leaflet and commonly to areas of increased mechanical stress. This technique holds major promise in improving our understanding of the pathophysiology of aortic stenosis and as a biomarker end point in clinical trials of novel therapies. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT02132026.

18F–Sodium Fluoride Uptake in Abdominal Aortic Aneurysms: The SoFIA3 Study

Background Fluorine-18–sodium fluoride (18F-NaF) uptake is a marker of active vascular calcification associated with high-risk atherosclerotic plaque. Objectives In patients with abdominal aortic aneurysm (AAA), the authors assessed whether 18F-NaF positron emission tomography (PET) and computed tomography (CT) predicts AAA growth and clinical outcomes. Methods In prospective case-control (n = 20 per group) and longitudinal cohort (n = 72) studies, patients with AAA (aortic diameter >40 mm) and control subjects (aortic diameter <30 mm) underwent abdominal ultrasound, 18F-NaF PET-CT, CT angiography, and calcium scoring. Clinical endpoints were aneurysm expansion and the composite of AAA repair or rupture. Results Fluorine-18-NaF uptake was increased in AAA compared with nonaneurysmal regions within the same aorta (p = 0.004) and aortas of control subjects (p = 0.023). Histology and micro-PET-CT demonstrated that 18F-NaF uptake localized to areas of aneurysm disease and active calcification. In 72 patients within the longitudinal cohort study (mean age 73 ± 7 years, 85% men, baseline aneurysm diameter 48.8 ± 7.7 mm), there were 19 aneurysm repairs (26.4%) and 3 ruptures (4.2%) after 510 ± 196 days. Aneurysms in the highest tertile of 18F-NaF uptake expanded 2.5× more rapidly than those in the lowest tertile (3.10 [interquartile range (IQR): 2.34 to 5.92 mm/year] vs. 1.24 [IQR: 0.52 to 2.92 mm/year]; p = 0.008) and were nearly 3× as likely to experience AAA repair or rupture (15.3% vs. 5.6%; log-rank p = 0.043). Conclusions Fluorine-18-NaF PET-CT is a novel and promising approach to the identification of disease activity in patients with AAA and is an additive predictor of aneurysm growth and future clinical events. (Sodium Fluoride Imaging of Abdominal Aortic Aneurysms [SoFIA3]; NCT02229006; Magnetic Resonance Imaging [MRI] for Abdominal Aortic Aneurysms to Predict Rupture or Surgery: The MA3RS Trial; ISRCTN76413758)

18F-Fluoride and 18F-Fluorodeoxyglucose Positron Emission Tomography After Transient Ischemic Attack or Minor Ischemic Stroke: Case-Control Study.

Background— Combined positron emission tomography (PET) and computed tomography (CT) can assess both anatomy and biology of carotid atherosclerosis. We sought to assess whether 18F-fluoride or 18F-fluorodeoxyglucose can identify culprit and high-risk carotid plaque. Methods and Results— We performed 18F-fluoride and 18F-fluorodeoxyglucose PET/CT in 26 patients after recent transient ischemic attack or minor ischemic stroke: 18 patients with culprit carotid stenosis awaiting carotid endarterectomy and 8 controls without culprit carotid atheroma. We compared standardized uptake values in the clinically adjudicated culprit to the contralateral asymptomatic artery, and assessed the relationship between radiotracer uptake and plaque phenotype or predicted cardiovascular risk (ASSIGN score [Assessing Cardiovascular Risk Using SIGN Guidelines to Assign Preventive Treatment]). We also performed micro PET/CT and histological analysis of excised plaque. On histological and micro PET/CT analysis, 18F-fluoride selectively highlighted microcalcification. Carotid 18F-fluoride uptake was increased in clinically adjudicated culprit plaques compared with asymptomatic contralateral plaques (log10standardized uptake valuemean 0.29±0.10 versus 0.23±0.11, P=0.001) and compared with control patients (log10standardized uptake valuemean 0.29±0.10 versus 0.12±0.11, P=0.001). 18F-Fluoride uptake correlated with high-risk plaque features (remodeling index [r=0.53, P=0.003], plaque burden [r=0.51, P=0.004]), and predicted cardiovascular risk [r=0.65, P=0.002]). Carotid 18F-fluorodeoxyglucose uptake appeared to be increased in 7 of 16 culprit plaques, but no overall differences in uptake were observed in culprit versus contralateral plaques or control patients. However, 18F-fluorodeoxyglucose did correlate with predicted cardiovascular risk (r=0.53, P=0.019), but not with plaque phenotype. Conclusions— 18F-Fluoride PET/CT highlights culprit and phenotypically high-risk carotid plaque. This has the potential to improve risk stratification and selection of patients who may benefit from intervention.

PET Cell Tracking Using 18 F-FLT is Not Limited by Local Reuptake of Free Radiotracer

Assessing the retention of cell therapies following implantation is vital and often achieved by labelling cells with 2′-[18F]-fluoro-2′-deoxy-D-glucose (18F-FDG). However, this approach is limited by local retention of cell-effluxed radiotracer. Here, in a preclinical model of critical limb ischemia, we assessed a novel method of cell tracking using 3′-deoxy-3′-L-[18F]-fluorothymidine (18F-FLT); a clinically available radiotracer which we hypothesise will result in minimal local radiotracer reuptake and allow a more accurate estimation of cell retention. Human endothelial cells (HUVECs) were incubated with 18F-FDG or 18F-FLT and cell characteristics were evaluated. Dynamic positron emission tomography (PET) images were acquired post-injection of free 18F-FDG/18F-FLT or 18F-FDG/18F-FLT-labelled HUVECs, following the surgical induction of mouse hind-limb ischemia. In vitro, radiotracer incorporation and efflux was similar with no effect on cell viability, function or proliferation under optimised conditions (5 MBq/mL, 60 min). Injection of free radiotracer demonstrated a faster clearance of 18F-FLT from the injection site vs. 18F-FDG (p ≤ 0.001), indicating local cellular uptake. Using 18F-FLT-labelling, estimation of HUVEC retention within the engraftment site 4 hr post-administration was 24.5 ± 3.2%. PET cell tracking using 18F-FLT labelling is an improved approach vs. 18F-FDG as it is not susceptible to local host cell reuptake, resulting in a more accurate estimation of cell retention.

18F-Fluoride and 18F-Fluorodeoxyglucose Positron Emission Tomography After Transient Ischemic Attack or Minor Ischemic StrokeCLINICAL PERSPECTIVE: Case–Control Study

Background— Combined positron emission tomography (PET) and computed tomography (CT) can assess both anatomy and biology of carotid atherosclerosis. We sought to assess whether 18F-fluoride or 18F-fluorodeoxyglucose can identify culprit and high-risk carotid plaque. Methods and Results— We performed 18F-fluoride and 18F-fluorodeoxyglucose PET/CT in 26 patients after recent transient ischemic attack or minor ischemic stroke: 18 patients with culprit carotid stenosis awaiting carotid endarterectomy and 8 controls without culprit carotid atheroma. We compared standardized uptake values in the clinically adjudicated culprit to the contralateral asymptomatic artery, and assessed the relationship between radiotracer uptake and plaque phenotype or predicted cardiovascular risk (ASSIGN score [Assessing Cardiovascular Risk Using SIGN Guidelines to Assign Preventive Treatment]). We also performed micro PET/CT and histological analysis of excised plaque. On histological and micro PET/CT analysis, 18F-fluoride selectively highlighted microcalcification. Carotid 18F-fluoride uptake was increased in clinically adjudicated culprit plaques compared with asymptomatic contralateral plaques (log10standardized uptake valuemean 0.29±0.10 versus 0.23±0.11, P=0.001) and compared with control patients (log10standardized uptake valuemean 0.29±0.10 versus 0.12±0.11, P=0.001). 18F-Fluoride uptake correlated with high-risk plaque features (remodeling index [r=0.53, P=0.003], plaque burden [r=0.51, P=0.004]), and predicted cardiovascular risk [r=0.65, P=0.002]). Carotid 18F-fluorodeoxyglucose uptake appeared to be increased in 7 of 16 culprit plaques, but no overall differences in uptake were observed in culprit versus contralateral plaques or control patients. However, 18F-fluorodeoxyglucose did correlate with predicted cardiovascular risk (r=0.53, P=0.019), but not with plaque phenotype. Conclusions— 18F-Fluoride PET/CT highlights culprit and phenotypically high-risk carotid plaque. This has the potential to improve risk stratification and selection of patients who may benefit from intervention.

Cardiac Alpha-V Beta-3 Integrin Expression Following Acute Myocardial Infarction in Humans

The study and MRD, WJ and DEN are supported by the British Heart Foundation (FS/12/84, FS/10/026, CH/09/002, R M/13/2/30158, RE/13/3/30183). DEN is the recipient of a Wellcome Trust Senior Investigator Award (WT103782AIA). JHFR is part-funded by the NIHR Cambridge Biomedical Research Centre. The Wellcome Trust Clinical Research Facility and Clinical Research Imaging Centre are supported by NHS Research Scotland (NRS) through NHS Lothian.

YIA4 The Novel Alpha-V Beta-3 Integrin Positron Emission Tomography Radiotracer 18F-Fluciclatide is a Marker of Aortic Atherosclerosis Activity

Introduction Intra-plaque angiogenesis and inflammation are key promoters of plaque vulnerability. Angiogenic endothelial cells and macrophages express the integrin αvβ3. The novel RGD-based radiotracer 18F-Fluciclatide has high affinity for αvβ3 integrin and therefore may act as a surrogate marker of the unstable atherosclerotic plaque. Methods Forty-six subjects with a mixture of ischaemic heart disease and aortic stenosis, including 9 healthy subjects underwent CT-coronary angiography (CTCA) and combined PET/CT imaging of the thorax 40 min after the administration of 226 ± 13 mBq 18F-fluciclatide. Regions of interest were drawn around the thoracic aorta using serial axial slices on fused PET/CT images. 18F-Fluciclatide uptake in these regions was normalised for blood-pool activity in the superior vena cava using tissue to background ratio [TBR]. Reproducibility of this technique was assessed on 10 image-sets by two observers. Quantification and analysis of descending thoracic aortic atheroma on CTCA was performed using plaque analysis software. Results There was a close correlation between 18F-fluciclatide uptake and the extent of atherosclerosis within the aorta on CTCA, as measured by wall thickness (r = 0.62 [0.31–0.81], p= <0.001] and total plaque burden (r = 0.60 [0.27–0.80], p = 0.001). Furthermore, aortic 18F-fluciclatide uptake (expressed as mean TBRmax) correlated with total aortic calcium score (AU) (r = 0.36 [0.05–0.60], p = 0.02) and was significantly greater in subjects with ischaemic heart disease (1.34 ± 0.03 vs 1.25 ± 0.03; p = 0.02) and hypercholesterolaemia (1.35 ± 0.03 vs 1.25 ± 0.03; p = 0.01). There were no significant age (r = 0.20(–0.12–0.47), p = 0.21) or sex related differences (1.34 ± 0.05 vs 1.29 ± 0.02, p = 0.24) and reproducibility analysis showed no fixed or proportional bias (0.07[–0.13–0.27]) with excellent intra-class correlation (0.98[0.92–1.0]). Conclusion The quantification of αvβ3 integrin expression within the aorta using 18F-fluciclatide is a highly reproducible marker of atherosclerotic burden. This supports further work in establishing its role in the assessment of the unstable plaque.

18 18F-flouride pet MR in valvular and coronary heart disease; a pilot investigational study

Introduction Recently, PET-MR has emerged as a novel imaging technique capable of assessing myocardial disease, inflammation and microcalcification. We aimed to investigate aortic valve and coronary 18F-NaF activity in subjects with aortic stenosis (AS) and coronary disease. Methods 25 patients underwent 18F-NaF PET-MR scanning. PET data was acquired in list mode with a standard Dixon attenuation correction technique. MR angiography was performed following infusion of Gadolinium. PET activity was quantified by calculating standardised uptake values (SUV) and tissue to background ratios (TBR) on fused PET-MR images. Culprit arteries were identified during preceding invasive coronary angiography. Results 22 of 25 patients completed the protocol. Patients with aortic stenosis had higher aortic valve SUVmax and TBRmax (Valve SUV max/left atrial SUV mean) than those without (SUVmax 1.89±0.60 vs 1.15±0.38, p=0.001 and TBRmax 2.87±0.98 vs 1.77±0.43, p=0.001). 13/13 patients with MI had focal 18F-NaF uptake in the culprit vessel with an SUV max and TBR max greater than the proximal referent vessel (SUV max 1.05±0.26 vs 0.74±0.13, p=0.002 and TBRmax 1.64±0.47 vs 1.16±0.26, p=0.004). Conclusion Similar to previous 18F-NaF PET CT studies, 18F-NaF PET-MR uptake is significantly greater in those with confirmed AS than those without. 18F-NaF uptake also accurately identifies culprit arteries in those with recent MI. The results share similarities with recently published valvular and coronary 18F-NaF PET-CT studies and thus promote further research into the utility of cardiovascular PET-MR as a complementary hybrid imaging technique.

18F-Fluoride and 18F-Fluorodeoxyglucose Positron Emission Tomography After Transient Ischemic Attack or Minor Ischemic StrokeCLINICAL PERSPECTIVE

Background— Combined positron emission tomography (PET) and computed tomography (CT) can assess both anatomy and biology of carotid atherosclerosis. We sought to assess whether 18F-fluoride or 18F-fluorodeoxyglucose can identify culprit and high-risk carotid plaque. Methods and Results— We performed 18F-fluoride and 18F-fluorodeoxyglucose PET/CT in 26 patients after recent transient ischemic attack or minor ischemic stroke: 18 patients with culprit carotid stenosis awaiting carotid endarterectomy and 8 controls without culprit carotid atheroma. We compared standardized uptake values in the clinically adjudicated culprit to the contralateral asymptomatic artery, and assessed the relationship between radiotracer uptake and plaque phenotype or predicted cardiovascular risk (ASSIGN score [Assessing Cardiovascular Risk Using SIGN Guidelines to Assign Preventive Treatment]). We also performed micro PET/CT and histological analysis of excised plaque. On histological and micro PET/CT analysis, 18F-fluoride selectively highlighted microcalcification. Carotid 18F-fluoride uptake was increased in clinically adjudicated culprit plaques compared with asymptomatic contralateral plaques (log10standardized uptake valuemean 0.29±0.10 versus 0.23±0.11, P=0.001) and compared with control patients (log10standardized uptake valuemean 0.29±0.10 versus 0.12±0.11, P=0.001). 18F-Fluoride uptake correlated with high-risk plaque features (remodeling index [r=0.53, P=0.003], plaque burden [r=0.51, P=0.004]), and predicted cardiovascular risk [r=0.65, P=0.002]). Carotid 18F-fluorodeoxyglucose uptake appeared to be increased in 7 of 16 culprit plaques, but no overall differences in uptake were observed in culprit versus contralateral plaques or control patients. However, 18F-fluorodeoxyglucose did correlate with predicted cardiovascular risk (r=0.53, P=0.019), but not with plaque phenotype. Conclusions— 18F-Fluoride PET/CT highlights culprit and phenotypically high-risk carotid plaque. This has the potential to improve risk stratification and selection of patients who may benefit from intervention.