Francis R. Joshi

PET imaging of inflammation in atherosclerosis

PET imaging of atherosclerosis can quantify several in vivo pathological processes occurring within the arterial system. 18F-fluorodeoxyglucose (FDG) is the most-commonly used PET tracer, with well-established roles in atherosclerosis imaging. In this context, the 18F-FDG signal largely reflects tracer uptake by plaque macrophages and, therefore, inflammation with smaller contributions from other resident cell types. As a marker of plaque vulnerability, the 18F-FDG PET signal can be used to help to identify patients at the highest risk of clinical events. 18F-FDG PET has also been used successfully as a surrogate end point in clinical trials of antiatherosclerotic therapies. Nonetheless, imaging atherosclerosis with 18F-FDG has several limitations. Most importantly, coronary artery imaging is problematic because 18F-FDG accumulates in all cells that metabolize glucose, and background myocardial uptake is generally greater than any signal originating from a plaque. To help to overcome these limitations, several novel PET tracers, which might be more-specifically targeted than 18F-FDG, have been tested in atherosclerosis imaging. These tracers are designed to track inflammation, hypoxia, neoangiogenesis, or active calcification, which are all precursors to plaque rupture and its clinical sequelae.

Anti-Tumor Necrosis Factor-α Therapy Reduces Aortic Inflammation and Stiffness in Patients With Rheumatoid Arthritis

Background—Rheumatoid arthritis (RA) is a systemic inflammatory condition associated with increased cardiovascular risk. This is not fully explained by traditional risk factors, but direct vascular inflammation and aortic stiffening may play a role. We hypothesized that patients with RA exhibit aortic inflammation, which can be reversed with anti-tumor necrosis factor-&agr; therapy and correlates with aortic stiffness reduction. Methods and Results—Aortic inflammation was quantified in 17 patients with RA, before and after 8 weeks of anti-tumor necrosis factor-&agr; therapy by using 18F-fluorodeoxyglucose positron emission tomography with computed tomography coregistration. Concomitantly, 34 patients with stable cardiovascular disease were imaged as positive controls at baseline. Aortic fluorodeoxyglucose target-to-background ratios (TBRs) and aortic pulse wave velocity were assessed. RA patients had higher baseline aortic TBRs in comparison with patients who have cardiovascular disease (2.02±0.22 versus 1.74±0.22, P=0.0001). Following therapy, aortic TBR fell to 1.90±0.29, P=0.03, and the proportion of inflamed aortic slices (defined as TBR >2.0) decreased from 50±33% to 33±27%, P=0.03. Also, TBR in the most diseased segment of the aorta fell from 2.51±0.33 to 2.05±0.29, P<0.0001. Treatment also reduced aortic pulse wave velocity significantly (from 9.09±1.77 to 8.63±1.42 m/s, P=0.04), which correlated with the reduction of aortic TBR (R=0.60, P=0.01). Conclusions—This study demonstrates that RA patients have increased aortic 18F-fluorodeoxyglucose uptake in comparison with patients who have stable cardiovascular disease. Anti-tumor necrosis factor-&agr; therapy reduces aortic inflammation in patients with RA, and this effect correlates with the decrease in aortic stiffness. These results suggest that RA patients exhibit a subclinical vasculitis, which provides a mechanism for the increased cardiovascular disease risk seen in RA.

Identifying active vascular microcalcification by (18)F-sodium fluoride positron emission tomography.

Vascular calcification is a complex biological process that is a hallmark of atherosclerosis. While macrocalcification confers plaque stability, microcalcification is a key feature of high-risk atheroma and is associated with increased morbidity and mortality. Positron emission tomography and X-ray computed tomography (PET/CT) imaging of atherosclerosis using 18F-sodium fluoride (18F-NaF) has the potential to identify pathologically high-risk nascent microcalcification. However, the precise molecular mechanism of 18F-NaF vascular uptake is still unknown. Here we use electron microscopy, autoradiography, histology and preclinical and clinical PET/CT to analyse 18F-NaF binding. We show that 18F-NaF adsorbs to calcified deposits within plaque with high affinity and is selective and specific. 18F-NaF PET/CT imaging can distinguish between areas of macro- and microcalcification. This is the only currently available clinical imaging platform that can non-invasively detect microcalcification in active unstable atherosclerosis. The use of 18F-NaF may foster new approaches to developing treatments for vascular calcification.

Detection of Atherosclerotic Inflammation by 68Ga-DOTATATE PET Compared to [18F]FDG PET Imaging

Background Inflammation drives atherosclerotic plaque rupture. Although inflammation can be measured using fluorine-18-labeled fluorodeoxyglucose positron emission tomography ([18F]FDG PET), [18F]FDG lacks cell specificity, and coronary imaging is unreliable because of myocardial spillover. Objectives This study tested the efficacy of gallium-68-labeled DOTATATE (68Ga-DOTATATE), a somatostatin receptor subtype-2 (SST2)-binding PET tracer, for imaging atherosclerotic inflammation. Methods We confirmed 68Ga-DOTATATE binding in macrophages and excised carotid plaques. 68Ga-DOTATATE PET imaging was compared to [18F]FDG PET imaging in 42 patients with atherosclerosis. Results Target SSTR2 gene expression occurred exclusively in “proinflammatory” M1 macrophages, specific 68Ga-DOTATATE ligand binding to SST2 receptors occurred in CD68-positive macrophage-rich carotid plaque regions, and carotid SSTR2 mRNA was highly correlated with in vivo 68Ga-DOTATATE PET signals (r = 0.89; 95% confidence interval [CI]: 0.28 to 0.99; p = 0.02). 68Ga-DOTATATE mean of maximum tissue-to-blood ratios (mTBRmax) correctly identified culprit versus nonculprit arteries in patients with acute coronary syndrome (median difference: 0.69; interquartile range [IQR]: 0.22 to 1.15; p = 0.008) and transient ischemic attack/stroke (median difference: 0.13; IQR: 0.07 to 0.32; p = 0.003). 68Ga-DOTATATE mTBRmax predicted high-risk coronary computed tomography features (receiver operating characteristics area under the curve [ROC AUC]: 0.86; 95% CI: 0.80 to 0.92; p < 0.0001), and correlated with Framingham risk score (r = 0.53; 95% CI: 0.32 to 0.69; p <0.0001) and [18F]FDG uptake (r = 0.73; 95% CI: 0.64 to 0.81; p < 0.0001). [18F]FDG mTBRmax differentiated culprit from nonculprit carotid lesions (median difference: 0.12; IQR: 0.0 to 0.23; p = 0.008) and high-risk from lower-risk coronary arteries (ROC AUC: 0.76; 95% CI: 0.62 to 0.91; p = 0.002); however, myocardial [18F]FDG spillover rendered coronary [18F]FDG scans uninterpretable in 27 patients (64%). Coronary 68Ga-DOTATATE PET scans were readable in all patients. Conclusions We validated 68Ga-DOTATATE PET as a novel marker of atherosclerotic inflammation and confirmed that 68Ga-DOTATATE offers superior coronary imaging, excellent macrophage specificity, and better power to discriminate high-risk versus low-risk coronary lesions than [18F]FDG. (Vascular Inflammation Imaging Using Somatostatin Receptor Positron Emission Tomography [VISION]; NCT02021188)

Non-invasive imaging of atherosclerosis

Atherosclerosis is an inflammatory disease that causes most myocardial infarctions, strokes, and acute coronary syndromes. Despite the identification of multiple risk factors and widespread use of drug therapies, it still remains a global health concern with associated costs. It is well known that the risks of atherosclerotic plaque rupture are not well correlated with stenosis severity. Lumenography has a central place for defining the site and severity of vascular stenosis as a prelude to intervention for relief of symptoms due to blood flow limitation. Atherosclerosis develops within the arterial wall; this is not imaged by lumenography and hence it provides no information regarding underlying processes that may lead to plaque rupture. For this, we must rely on other imaging modalities such as ultrasound, computed tomography, magnetic resonance imaging, and nuclear imaging methods. These are capable of reporting on the underlying pathology, in particular the presence of inflammation, calcification, neovascularization, and intraplaque haemorrhage. Additionally, non-invasive imaging can now be used to track the effect of anti-atherosclerosis therapy. Each modality alone has positives and negatives and this review will highlight these, as well as speculating on future developments in this area.

Vascular imaging with positron emission tomography.

Joshi F, Rosenbaum D, Bordes S, Rudd JHF (University of Cambridge, Cambridge, UK; Groupe Hospitalier Pitié‐Salpêtrière, Assistance Publique‐Hôpitaux de Paris, Paris, France; and Instituto Cardiovascular, Madrid, Spain). Vascular imaging with positron emission tomography (Review). J Intern Med 2011; 270: 99–109.

Does Vascular Calcification Accelerate Inflammation?: A Substudy of the dal-PLAQUE Trial

BACKGROUND Atherosclerosis is an inflammatory condition with calcification apparent late in the disease process. The extent and progression of coronary calcification predict cardiovascular events. Relatively little is known about noncoronary vascular calcification. OBJECTIVES This study investigated noncoronary vascular calcification and its influence on changes in vascular inflammation. METHODS A total of 130 participants in the dal-PLAQUE (Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging) study underwent fluorodeoxyglucose positron emission tomography/computed tomography at entry and at 6 months. Calcification of the ascending aorta, arch, carotid, and coronary arteries was quantified. Cardiovascular risk factors were related to arterial calcification. The influences of baseline calcification and drug therapy (dalcetrapib vs. placebo) on progression of calcification were determined. Finally, baseline calcification was related to changes in vascular inflammation. RESULTS Age >65 years old was consistently associated with higher baseline calcium scores. Arch calcification trended to progress more in those with calcification at baseline (p = 0.055). There were no significant differences between progression of vascular calcification with dalcetrapib compared to that with placebo. Average carotid target-to-background ratio indexes declined over 6 months if carotid calcium was absent (single hottest slice [p = 0.037], mean of maximum target-to-background ratio [p = 0.010], and mean most diseased segment [p < 0.001]), but did not significantly change if calcification was present at baseline. CONCLUSIONS Across multiple arterial regions, higher age is consistently associated with higher calcium scores. The presence of vascular calcification at baseline is associated with progressive calcification; in the carotid arteries, calcification appears to influence vascular inflammation. Dalcetrapib therapy did not affect vascular calcification.

Noninvasive imaging in cardiovascular therapy: the promise of coronary arterial ¹⁸F-sodium fluoride uptake as a marker of plaque biology.

The majority of myocardial infarctions are caused by atherosclerotic plaque rupture. However, identifying lesions at risk of rupture, so-called vulnerable plaques, is challenging. Most are not flow-limiting [1,2] and will therefore not be detected by conventional stress testing or invasive coronary angiography. Other methods are therefore required to improve the prediction of adverse coronary events. The presence of calcium in the coronary arteries is pathognomic of atherosclerosis and can be quantified using computed tomography (CT) and the Agatston score. This provides a surrogate of the coronary atherosclerotic burden and offers powerful cardiovascular risk prediction [3], presumably because with an increasing number of plaques, more are likely to be vulnerable. Vulnerable plaques are known to have certain pathological characteristics, which include inflammation and spotty calcification. Activated macrophages infiltrate the thin fibrous cap, secreting matrix metalloproteinases, which predispose the plaque to rupture [4]. Spotty calcification represents the very earliest stage of the vascular calcific process and is frequently not resolved by CT. Unlike the confluent calcification observed later in the disease process, microcalcif ication increases wall stress, predisposing the plaque to microfractures and rupture [5–7]. We have recently investigated the feasibility of using PET to image these two processes in the coronary arteries [8]. In a cohort of 119 patients, we performed PET/ CT imaging using F-fluorodeoxyglucose (F-FDG) to detect plaque inflammation and F-sodium f luoride (F-NaF) to image calcification. Both tracers are easy to manufacture in modern cyclotrons and are commercially available. F-FDG has become well established as a measure of vascular inflammation [9,10], whereas F-NaF has been used to image new bone formation, primarily cancer metastases, for 50 years. Fluoride ions exchange with hydroxyl ions in exposed hydroxyapatite, a key structural crystal that is deposited in both bone matrix and in the initial stages of vascular calcium formation. Retrospective data derived from the use of F-NaF in cancer imaging have previously suggested that vascular uptake may identify novel or developing regions of arterial calcification [11–13]. In our study results for F-FDG were disappointing, being hampered by myocardial uptake from which it was difficult to isolate activity in the coronary Noninvasive imaging in cardiovascular therapy: the promise of coronary arterial 18F-sodium fluoride uptake as a marker of plaque biology

PET imaging of atherosclerosis

Atherosclerosis is a chronic, progressive, multifocal disease of the arterial wall, which is mainly fuelled by local and systemic inflammation, often resulting in acute ischemic events following plaque rupture and vessel occlusion. When assessing the cardiovascular risk of an individual patient, we must consider both global measures of disease activity and local features of plaque vulnerability, in addition to anatomical distribution and degree of established atherosclerosis. These parameters cannot be measured with conventional anatomical imaging techniques alone, which are designed primarily to identify the presence of organic intraluminal obstruction in symptomatic patients. However, molecular imaging with PET, using specifically targeted radiolabeled probes to track active in vivo atherosclerotic mechanisms noninvasively, may potentially provide a method that is better suited for this purpose. Vascular PET imaging can help us to further understand aspects of plaque biology, and current evidence supports a future role as an emerging clinical tool for the quantification of cardiovascular risk in order to guide and monitor responses to antiatherosclerosis treatments and to distinguish high-risk plaques.

Vascular Imaging With

This study was funded by a programme grant (RG/10/007/28300) from the British Heart Foundation (BHF). Dr. Joshi was supported by a BHF Clinical Research Training Fellowship (FS/12/29/29463), a British Atherosclerosis Society Binks Trust Travel Award, and a Raymond and Beverly Sackler PhD Studentship. Dr. Manavaki is funded by the NIHR Cambridge Biomedical Research Centre. Dr. Rudd is partially supported by the NIHR Cambridge Biomedical Research Centre, the BHF, The Wellcome Trust, and the EPSRC Cambridge Centre for Mathematical Imaging in Healthcare.