Improved detection of molecular markers of atherosclerotic plaques using sub-millimeter PET imaging

Since atherosclerotic plaques are small and sparse, their non-invasive detection via PET imaging requires both highly specific radiotracers as well as imaging systems with high sensitivity and resolution. This study aimed to assess the targeting and biodistribution of a novel fluorine-18 anti-VCAM-1 Nanobody (Nb), and to investigate whether sub-millimetre resolution PET imaging could improve detectability of plaques in mice. The anti-VCAM-1 Nb functionalised with the novel restrained complexing agent (RESCA) chelator was labelled with [F-18]AlF with a high radiochemical yield (>75%) and radiochemical purity (>99%). Subsequently, [F-18]AlF(RESCA)-cAbVCAM1-5 was injected in ApoE(-/-) mice, or co-injected with excess of unlabelled Nb (control group). Mice were imaged sequentially using a cross-over design on two different commercially available PET/CT systems and finally sacrificed for ex vivo analysis. Both the PET /CT images and ex vivo data showed specific uptake of [F-18]AlF(RESCA)-cAbVCAM1-5 in atherosclerotic lesions. Non-specific bone uptake was also noticeable, most probably due to in vivo defluorination. Image analysis yielded higher target-to-heart and target-to-brain ratios with the beta-CUBE (MOLECUBES) PET scanner, demonstrating that preclinical detection of atherosclerotic lesions could be improved using the latest PET technology

Targeting of vascular cell adhesion molecule-1 by18F-labelled nanobodies for PET/CT imaging of inflamed atherosclerotic plaques

Aims Positron emission tomography-computed tomography (PET-CT) is a highly sensitive clinical molecular imaging modality to study atherosclerotic plaque biology. Therefore, we sought to develop a new PET tracer, targeting vascular cell adhesion molecule (VCAM)-1 and validate it in a murine atherosclerotic model as a potential agent to detect atherosclerotic plaque inflammation. Methods and results The anti-VCAM-1 nanobody (Nb) (cAbVCAM-1-5) was radiolabelled with Fluorine-18 (F-18), with a radiochemical purity of >98%. In vitro cell-binding studies showed specific binding of the tracer to VCAM-1 expressing cells. In vivo PET/CT imaging of ApoE(-/-) mice fed aWestern diet or control mice was performed at 2h30 post-injection of [F-18]-FB-cAbVCAM-1-5 or F-18-control Nb. Additionally, plaque uptake in different aorta segments was evaluated ex vivo based on extent of atherosclerosis. Atherosclerotic lesions in the aortic arch of ApoE(-/-) mice, injected with [F-18]-FB-anti-VCAM-1 Nb, were successfully identified using PET/CT imaging, while background signal was observed in the control groups. These results were confirmed by ex vivo analyses where uptake of [F-18]-FB-cAbVCAM-1-5 in atherosclerotic lesions was significantly higher compared with control groups. Moreover, uptake increased with the increasing extent of atherosclerosis (Score 0: 0.68 +/- 0.10, Score 1: 1.18 +/- 0.36, Score 2: 1.49 +/- 0.37, Score 3: 1.48 +/- 0.38% ID/g, Spearman's r(2) = 0.675, P < 0.0001). High lesion-to-heart, lesion-to-blood, and lesion-to-control vessel ratios were obtained (12.4 +/- 0.4, 3.3 +/- 0.4, and 3.1 +/- 0.6, respectively). Conclusion The [F-18]-FB-anti-VCAM-1 Nb, cross-reactive for both mouse and human VCAM-1, allows non-invasive PET/CT imaging of VCAM-1 expression in atherosclerotic plaques in a murine model and may represent an attractive tool for imaging vulnerable atherosclerotic plaques in patients

MEDECINE NUCLEAIRE ET MALADIE CORONARIENNE : EVALUATION DE TRACEURS DE LA PERFUSION MYOCARDIQUE ET DE LA PLAQUE D'ATHEROME VULNERABLE

CORONARY ARTERY DISEASE IS ONE OF THE PRIMARY CAUSE OF MORTALITY WORLDWIDE. NUCLEAR MEDICINE IS THE MAJOR IMAGING TECHNIQUE FOR DIAGNOSIS AND FOLLOWING OF THIS DISEASE. PERFUSION : NOWADAYS, MAJOR RADIOACTIVE AGENTS USED IN CLINICAL PRACTICE ARE MYOCARDIAL PERFUSION TRACERS. THE REFERENCE TRACER IS THALLIUM-201. HOWEVER, 201TL PRESENTS SOME DRAWBACKS. 99MTCN-NOET HAS BEEN PROPOSED FOR ITS REPLACEMENT. THIS STUDY SHOWS THAT IN CONTRAST WITH PREVIOUS STUDIES REALIZED IN VITRO ON CARDIOMYOCYTES, VERAPAMIL, AN L-TYPE CALCIUM CHANNEL INHIBITOR, DOES NOT INHIBIT MYOCARDIAL FIXATION OF 99mTcN-NOET IN VIVO IN DOG. THIS DATA IS IN AGREEMENT WITH THE HYPOTHESIS OF A NON SPECIFIC ENDOTHELIAL FIXATION OF THIS TRACER. MOREOVER, THIS STUDY SHOWS THAT AS A PURE TRACER OF MYOCARDIAL PERFUSION, 99mTcN-NOET CAN ALSO BE USED TO ASSESS MYOCARDIAL VIABILITY ON A MODEL OF MYOCARDIAL CHRONIC INFARCTUS IN RAT. ATHEROSCLEROSIS : DISRUPTION OF VULNERABLE ATHEROSCLEROTIC PLAQUES IS THE MAIN EVENT LEADING TO CORONARY ACCIDENTS. THE SECOND PART OF THIS STUDY CONCERNS THE EVALUATION OF NEW POTENTIAL TRACERS OF THE VULNERABLE ATHEROSCLEROTIC PLAQUE IN AN EXPERIMENTAL MODEL OF RABBIT WITH AN INHERITABLE HYPERCHOLESTEROLEMIA. THE FOUR TRACERS EVALUATED (B2702(R), B2702-I, B2702-TC AND TC-RAFT-B2702) ARE SYNTHETIC PEPTIDES COMPRISING THE RESIDUES 75-84 OF HLA-B2702, A MOLECULE KNOWN TO LINK VCAM-1, AN ADHESION MOLECULE EXPRESSED IN VULNERABLE ATHEROSCLEROTIC PLAQUE. THE AUTORADIOGRAPHY STUDIES SHOW THAT ALL TRACERS ACCUMULATE WITHIN ATHEROSCLEROTIC PLAQUE EXPRESSING VCAM- AND THAT. I-B2702 SHOWS THE BEST PLAQUE/CONTROL FIXATION RATIO.LA MALADIE CORONARIENNE REPRESENTE L'UNE DES PREMIERES CAUSES DE MORTALITE DANS LE MONDE. LA MEDECINE NUCLEAIRE CONSTITUE LA PRINCIPALE MODALITE D'IMAGERIE POUR LE DIAGNOSTIC ET LA PRISE EN CHARGE DE CETTE PATHOLOGIE. PERFUSION : ACTUELLEMENT, LES RADIOTRACEURS UTILISES EN PRATIQUE CLINIQUE SONT DES TRACEURS DE LA PERFUSION MYOCARDIQUE. LE THALLIUM-201, TRACEUR DE REFERENCE, PRESENTE UNE DOSIMETRIE ELEVEE. 99mTcN-NOET A ETE PROPOSE POUR SON REMPLACEMENT. CONTRAIREMENT AUX RESULTATS PRECEDEMMENT OBTENUS IN VITRO SUR DES CARDIOMYOCYTES, LE VERAPAMIL, UN INHIBITEUR CALCIQUE, N'INHIBE PAS LA FIXATION MYOCARDIQUE DE 99mTcN-NOET IN VIVO CHEZ LE CHIEN. CE RESULTAT EST EN ACCORD AVEC L'HYPOTHESE D'UNE FIXATION ENDOTHELIALE DE CE TRACEUR. D'AUTRE PART, LES ETUDES INDIQUENT QU'EN TANT QUE TRACEUR PUR DU DEBIT, 99MTCN-NOET PEUT ETRE UTILISE POUR APPRECIER LA VIABILITE TISSULAIRE MYOCARDIQUE SUR UN MODELE D'INFARCTUS CHRONIQUE DU MYOCARDE CHEZ LE RAT. ATHEROME : LA RUPTURE D'UNE PLAQUE D'ATHEROME VULNERABLE EST L'EVENEMENT RESPONSABLE DE LA MAJORITE DES ACCIDENTS CORONARIENS. LA SECONDE PARTIE DE CETTE THESE PORTE SUR L'EVALUATION DE NOUVEAUX RADIOTRACEURS POTENTIELS DE CES PLAQUES SUR UN MODELE EXPERIMENTAL DE LAPIN GENETIQUEMENT HYPERCHOLESTEROLEMIQUE. LES 4 TRACEURS EVALUES (B2702(R), B2702-I, B2702-TC ET TC-RAFT-B2702) SONT DERIVES D'UN PEPTIDE ISSU D'UNE MOLECULE DE CMH-I DECRIT POUR LIER VCAM-1, UNE MOLECULE D'ADHESION EXPRIMEE AU NIVEAU DES PLAQUES VULNERABLES. LES ETUDES AUTORADIOGRAPHIQUES INDIQUENT QUE LES 4 TRACEURS S'ACCUMULENT DANS LES PLAQUES D'ATHEROME EXPRIMANT VCAM-1 ET QUE C'EST I-B2702 QUI PRESENTE LE MEILLEUR RAPPORT DE FIXATION PLAQUE/REGION SAINE

Médecine nucléaire et maladie coronarienne (évaluation de traceurs de la perfusion myocardique et de la plaque d'athérome vulnérable)

LA MALADIE CORONARIENNE REPRESENTE L UNE DES PREMIERES CAUSES DE MORTALITE DANS LE MONDE. LA MEDECINE NUCLEAIRE CONSTITUE LA PRINCIPALE MODALITE D IMAGERIE POUR LE DIAGNOSTIC ET LA PRISE EN CHARGE DE CETTE PATHOLOGIE. PERFUSION : ACTUELLEMENT, LES RADIOTRACEURS UTILISES EN PRATIQUE CLINIQUE SONT DES TRACEURS DE LA PERFUSION MYOCARDIQUE. LE THALLIUM-201, TRACEUR DE REFERENCE, PRESENTE UNE DOSIMETRIE ELEVEE. 99mTcN-NOET A ETE PROPOSE POUR SON REMPLACEMENT. CONTRAIREMENT AUX RESULTATS PRECEDEMMENT OBTENUS IN VITRO SUR DES CARDIOMYOCYTES, LE VERAPAMIL, UN INHIBITEUR CALCIQUE, N INHIBE PAS LA FIXATION MYOCARDIQUE DE 99mTcN-NOET IN VIVO CHEZ LE CHIEN. CE RESULTAT EST EN ACCORD AVEC L HYPOTHESE D UNE FIXATION ENDOTHELIALE DE CE TRACEUR. D AUTRE PART, LES ETUDES INDIQUENT QU EN TANT QUE TRACEUR PUR DU DEBIT, 99MTCN-NOET PEUT ETRE UTILISE POUR APPRECIER LA VIABILITE TISSULAIRE MYOCARDIQUE SUR UN MODELE D INFARCTUS CHRONIQUE DU MYOCARDE CHEZ LE RAT. ATHEROME : LA RUPTURE D UNE PLAQUE D ATHEROME VULNERABLE EST L EVENEMENT RESPONSABLE DE LA MAJORITE DES ACCIDENTS CORONARIENS. LA SECONDE PARTIE DE CETTE THESE PORTE SUR L EVALUATION DE NOUVEAUX RADIOTRACEURS POTENTIELS DE CES PLAQUES SUR UN MODELE EXPERIMENTAL DE LAPIN GENETIQUEMENT HYPERCHOLESTEROLEMIQUE. LES 4 TRACEURS EVALUES (B2702(R), B2702-I, B2702-TC ET TC-RAFT-B2702) SONT DERIVES D UN PEPTIDE ISSU D UNE MOLECULE DE CMH-I DECRIT POUR LIER VCAM-1, UNE MOLECULE D ADHESION EXPRIMEE AU NIVEAU DES PLAQUES VULNERABLES. LES ETUDES AUTORADIOGRAPHIQUES INDIQUENT QUE LES 4 TRACEURS S ACCUMULENT DANS LES PLAQUES D ATHEROME EXPRIMANT VCAM-1 ET QUE C EST I-B2702 QUI PRESENTE LE MEILLEUR RAPPORT DE FIXATION PLAQUE/REGION SAINE.GRENOBLE1-BU Sciences (384212103) / SudocSudocFranceF

Equivocal usefulness of FDG for the noninvasive imaging of abdominal aortic aneurysms

International audienc

Identifying the leukocyte uptake pattern of inflammation imaging agents: Current limitations and potential impact

International audienc

First magnetic resonance coronary artery imaging of bioresorbable vascular scaffold in-patient

International audienc

Mapping elasticity moduli of atherosclerotic plaque in situ via atomic force microscopy.

International audienceSeveral studies have suggested that evolving mechanical stresses and strains drive atherosclerotic plaque development and vulnerability. Especially, stress distribution in the plaque fibrous capsule is an important determinant for the risk of vulnerable plaque rupture. Knowledge of the stiffness of atherosclerotic plaque components is therefore of critical importance. In this work, force mapping experiments using atomic force microscopy (AFM) were conducted in apolipoprotein E-deficient (ApoE(-/-)) mouse, which represents the most widely used experimental model for studying mechanisms underlying the development of atherosclerotic lesions. To obtain the elastic material properties of fibrous caps and lipidic cores of atherosclerotic plaques, serial cross-sections of aortic arch lesions were probed at different sites. Atherosclerotic plaque sub-structures were subdivided into cellular fibrotic, hypocellular fibrotic and lipidic rich areas according to histological staining. Hertz's contact mechanics were used to determine elasticity (Young's) moduli that were related to the underlying histological plaque structure. Cellular fibrotic regions exhibit a mean Young modulus of 10.4±5.7kPa. Hypocellular fibrous caps were almost six-times stiffer, with average modulus value of 59.4±47.4kPa, locally rising up to ∼250kPa. Lipid rich areas exhibit a rather large range of Young's moduli, with average value of 5.5±3.5kPa. Such precise quantification of plaque stiffness heterogeneity will allow investigators to have prospectively a better monitoring of atherosclerotic disease evolution, including arterial wall remodeling and plaque rupture, in response to mechanical constraints imposed by vascular shear stress and blood pressure

Pre-clinical and clinical evaluation of nuclear tracers for the molecular imaging of vulnerable atherosclerosis: an overview.: Nuclear tracers for vulnerable atherosclerosis imaging

International audienceCardiovascular diseases (CVD) are the leading cause of mortality worldwide. Despite major advances in the treatment of CVD, a high proportion of CVD victims die suddenly while being apparently healthy, the great majority of these accidents being due to the rupture or erosion of a vulnerable coronary atherosclerotic plaque. A non-invasive imaging methodology allowing the early detection of vulnerable atherosclerotic plaques in selected individuals prior to the occurrence of any symptom would therefore be of great public health benefit. Nuclear imaging could allow the identification of vulnerable patients by non-invasive in vivo scintigraphic imaging following administration of a radiolabeled tracer. The purpose of this review is to provide an overview of radiotracers that have been recently evaluated for the detection of vulnerable plaques together with the biological rationale that initiated their development. Radiotracers targeted at the inflammatory process seem particularly relevant and promising. Recently, macrophage targeting allowed the experimental in vivo detection of atherosclerosis using either SPECT or PET. A few tracers have also been evaluated clinically. Targeting of apoptosis and macrophage metabolism both allowed the imaging of vulnerable plaques in carotid vessels of patients. However, nuclear imaging of vulnerable plaques at the level of coronary arteries remains challenging, mostly because of their small size and their vicinity with unbound circulating tracer. The experimental and pilot clinical studies reviewed in the present paper represent a fundamental step prior to the evaluation of the efficacy of any selected tracer for the early, non-invasive detection of vulnerable patients

Elucidating atherosclerotic vulnerable plaque rupture by modeling cross substitution of ApoE-/- mouse and human plaque components stiffnesses.

International audienceThe structure of mouse atherosclerotic lesions may differ from that of humans, and mouse atherosclerotic plaques do not rupture except in some specific locations such as the brachiocephalic artery. Recently, our group was the first to observe that the amplitudes of in vivo stresses in ApoE-/- mouse aortic atherosclerotic lesions were much lower and differed from those found in a previous work performed on human lesions. In this previous preliminary work, we hypothesized that the plaque mechanical properties (MP) may in turn be responsible for such species differences. However, the limited number of human samples used in our previous comparative study was relevant but not sufficient to broadly validate such hypothesis. Therefore, in this study, we propose an original finite element strategy that reconstructs the in vivo stress/strain (IVS/S) distributions in ApoE-/- artherosclerotic vessels based on cross substitution of ApoE-/- mouse and human plaque components stiffnesses and including residual stress/strain (RS/S). Our results: (1) showed that including RS/S decreases by a factor 2 the amplitude of maximal IVS/S, and more importantly, (2) demonstrated that the MP of the ApoE-/- plaque constituents are mainly responsible for the low level-compared with human-of intraplaque stress in ApoE-/- mouse aortic atherosclerotic lesions (8.36 ± 2.63 kPa vs. 182.25 ± 55.88 kPa for human). Our study highlights that such differences in the distribution and amplitude of vessel wall stress might be one key feature for explaining for the difference in lesion stability between human coronary and mouse aortic lesions