This project will overcome the current limitations of conventional CT imaging dedicated to cardiovascular disease (CVD) by developing a non-radioactive molecular imaging methodology using the SPCCT technology. This will be achievable with a high spatial resolution of 200 µm combined with newly developed contrast agents detected with high quality K-edge technique that can only be provided by SPCCT technology.
The specific objectives of the ATHERSPECTRAL-CT project are:<br />• To develop and perform, with already clinically available Gd nanosized particles a very high spatial resolution non-invasive angiography<br />• To perform quantitative myocardial perfusion evaluation using clinically available Gd nanosized or specifically tailored particles<br />• To extend this approach to optimize targeted new nanohybrid contrast agents for elastin and ICAM. To develop targeted nanosized particles in order to reach locally high concentrations of these heavy atoms for SPCCT detection and binding these atoms to the two above mentioned markers of inflammatory processes.<br />• To detect, quantify and monitor in vivo, non-invasively, the evolution of atheroma, and myocardial infarction using newly developed targeted new hybrid nano contrast agents.
Four main workpackages have been identified. WP0 concerns project management and dissemination; WP1 concerns contrast agent development; WP2 concerns image acquisition and reconstruction focused on development of dedicated protocols for atherosclerosis and myocardial perfusion; WP3 concerns image post-processing focused on denoizing algorithms and quantification of tissue perfusion.
WP1 - Contrast agent develoment. This WP concerning the development of new contrast agents for SPCCT imaging is divided in two tasks: (i) Task 1.1. Non-targeted contrast agents and (ii) Task 1.2. Targeted contrast agents
WP2 - in vitro and in vivo sensitivity evaluation for AGuIx nanoparticles. This WP will focus on in vitro acquisitions on tubes of varying concentrations of nanoparticles and simulated calcifications (hydroxyapatite mixture) and in vivo acquisitions of angiography and perfusion in healthy animals and disease models. The work is divided in three main tasks. The first two tasks will focus on in vitro and in vivo imaging in healthy animals with the AGuIX nanoparticles already in Phase I clinical trials (Task 2.1) and the novel contrast agents developed by WP1 (Task 2.2). Finally, the third task will focus on in vivo imaging in the two animal models in order to develop dedicated imaging protocols for all investigated contrast agents chosen based on results from Task 2.1 and Task 2.2
WP3 - development of dedicated image processing algorithms for element specific dynamic SPCCT images. This WP will involve research into algorithms dedicated to the element specific SPCCT images that will take advantage of the temporal information in the data in order to perform denosing and quantification of myocardial tissue perfusion.
This project will overcome the current limitations of available imaging modalities by developing a complete tool (acquisition system & specific probes) dedicated to CV imaging that will (1) improve early diagnosis of atherosclerosis: prevention of acute event (MI) and personalized preventive treatment; and (2) improve management of patients presenting with an acute CV event (MI). It aims to: better assessing atherosclerotic plaque components and the level of intra-plaque inflammation in order to adapt the preventive treatment for each patient; better and earlier detect perfusion defect in the ischemic zone in case of MI at acute phase. The new therapies targeting currently under evaluation will benefit from an accurate assessment of the perfusion defect process in order to reduce the final extension of the damage. This quantification of the perfusion defect with a fast examination will allow to correctly adapt the dose to each patient and to avoid side effects of these treatments. Thus a significant impact on clinical decisions in cardiovascular diseases is expected thanks to a relatively affordable and widely available imaging technique. It will also allow obtaining objective criteria of treatment efficacy in the framework of clinical studies, a task that cannot be handled by the current modalities. Furthermore, dose reduction is expected with this system. This is important as CT today contributes by 50% and more to the per capita exposure of the population to medical use of ionizing radiation. It is realistic to expect that by SPCCT the average effective CT dose will be halved by elimination of electronic and, Swank and scatter rejection (either complete or in part) by using optimal X-ray spectra for the different diagnostic tasks and thus enforcing the dissemination of this new technologies. Another important element of this project is that the concept can be later extended to other fields that need specificity and spatial resolution, in particular oncology.
The annual screening and prevention costs for atherosclerosis covered 4 million euros in Europe and the costs for imaging and non-invasive diagnostic procedures were 58 million euro health care costs annually. However, a description of the costs incurred does not provide any indication of quality of care or about whether money is being spent wisely. The diagnostic technologies to be developed and refined in this project can improve the average health gain and cost-effectiveness of costly treatments substantially. This improvement can be achieved at various points along the patient management pathway, from the time of diagnosis and on to point of treatment decision-making and the monitoring of the patient even after a clinical event or procedure has taken place. In all cases, an appropriate and good-quality test can improve the quality and cost-effectiveness of treatment decisions to improve a patient’s health and prolong life.
Scientific papers that are written in connection with the project will be submitted to relevant international peer-reviewed journals. Journals with the highest visibility and impact factors will be targeted, as well as open access journals, e.g. Radiology, Investigative Radiology, European Radiology, Contrast Media and Molecular Imaging, Value in Health, International Journal of Technology Assessment in Health Care. The most relevant journals that we are considering for the publication of our results are Medical Physics, Nanoscale, Physics in Medicine and Biology, for the technical aspects of the project, and Circulation, JACC, Atherosclerosis, Radiology for the cardiovascular applications. Journals with Gold Open Access policy will be targeted, such as Journal of Cardiac Failure, System, Reconstruction and Image Processing. Fees for publications in gold open access have been foreseen to ensure the Open Access of major publications. Green open access publication.
Atherosclerosis and its consequences remain the main cause of mortality in industrialized and developing nations. Spectral Photon Counting Computed Tomography (SPCCT) can detect and quantify accurately Gd by using the K-edge technique. AGuIX nanoparticles are composed of a polysiloxane matrix surrounded by Gd cyclic chelates. The regulatory toxicity tests have shown no evidence of toxicity on two different animal species and the nanoparticules have been accepted for a phase I clinical trial. Their easy functionalization by biomolecules can target Fibrin, VCAM or proto-elastin. The objective is to develop and perform, a very high spatial resolution non-invasive angiography, and quantitative myocardial perfusion evaluation using clinically available Gd nanosized and new developed particles based on the AGuIX platform. To increase the signal per nanoparticle, gadolinium and/or bismuth will be added on the nano-objectin order to detect, quantify and monitor in vivo non- invasively the evolution of atheroma and myocardial infarction. A comparison will be done between non targeted nanoparticles and nanoparticles functionalized to have an affinity for fibrin, VCAM or proto-elastin.
Monsieur Philippe Douek (CENTRE DE RECHERCHE EN ACQUISITION ET TRAITEMENT D'IMAGES POUR LA SANTE (CREATIS))
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
NHTherAguix NH THERAGUIX
CarMeN LABORATOIRE DE RECHERCHE EN CARDIOVASCULAIRE, METABOLISME, DIABETOLOGIE (CARMEN)
ILM Institut Lumière Matière
CREATIS CENTRE DE RECHERCHE EN ACQUISITION ET TRAITEMENT D'IMAGES POUR LA SANTE (CREATIS)
Help of the ANR 535,924 euros
Beginning and duration of the scientific project: - 48 Months