Project

magnetic resonance imaging; inflammation; atherosclerosis; monitoring; perfluorocarbon

Lead
Le niveau d’inflammation de plaques d’athérome permettrait de déceler celles qui sont proches de la rupture et donc de déceler un potentiel risque d’accident vasculaire cérébral ou d’infarctus du myocarde. Cependant, il n’y a actuellement pas d’outils cliniques disponibles permettant d’évaluer cela de façon non-invasive.Le but de ce projet est donc d’implémenter, de tester et de valider une méthodologie d’imagerie par résonance magnétique pour quantifier l’inflammation d’une plaque d’athérome chez les souris atteintes d’athérosclérose.
Lay summary
Contexte scientifique et social Une rupture de plaques d’athérome conduit généralement à un infarctus du myocarde ou à un accident vasculaire cérébral, qui sont, à eux deux, la première cause de mortalité dans la société occidentale. Cependant, la progression des plaques d’athérome ne peut être prédite avec les moyens cliniques actuels basés sur des critères anatomiques. C’est pourquoi ce projet porte sur le développement  d’une nouvelle technique d’imagerie par résonance magnétique (IRM) permettant le contrôle de l’inflammation des plaques d’athérome.  Contenu et objectifs Comme un lien a été établi entre la probabilité de rupture d’une plaque d’athérome et le taux d’inflammation, nous proposons d’utiliser l’IRM pour la visualisation des nanoparticules de perfluorocarbures (PFC) qui auront été retenues par les cellules immunitaires présentes dans les plaques. L’IRM est une technique non-invasive, sûre et qui n’implique pas de rayonnement nocif, de même que les PFC sont des molécules sans danger qui ont déjà été injectées en doses conséquentes chez des humains. Les atomes de fluor (19F) présent dans les PFC peuvent être imagés par IRM, avec l’avantage que les PFC injectés sont les seules sources de signal 19F. L’intensité du signal d’IRM des PFC dans la plaque d’athérome indique alors directement le niveau d’inflammation. Le but de ce projet est donc d’implémenter, de tester et de valider une méthode d’IRM du 19F et d’optimiser cette méthodologie pour les études IRM utilisant le 19F concernant la progression et la régression de l’athérosclérose chez les souris. Dans ce but, la technique sera validée in vitro avec des solutions connues, et en déterminant de quelle façon le signal IRM du 19F dans les plaques d’athérome chez les souris est lié aux indices histologiques de référence. Enfin, nous vérifierons l’hypothèse que l’IRM 19F peut détecter les changements dans la progression des plaques en réponse à des changements de régime et un traitement utilisant des statines.

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Last update: 25.09.2014

Lead
The level of inflammation in atherosclerotic plaques might indicate which are likely to rupture and possibly cause stroke or myocardial infarction, but currently there are no clinical tools available that can assess this noninvasively. The goal of this project is therefore to implement, test and validate a magnetic resonance imaging methodology for the quantification of inflammation in atherosclerotic plaque in atherosclerosis in mice.
Lay summary
Scientific and Social Context The rupture of atherosclerotic plaque commonly leads to myocardial infarction and stroke, which together are the number one cause of death in Western society. However, the progression of atherosclerotic plaque cannot be predicted with current “anatomy-based” clinical tools. Therefore, this project focuses on the development of a new magnetic resonance imaging (MRI) technique that is capable of monitoring inflammation in plaque. Content and Objectives Since the likelihood for atherosclerotic plaque to rupture has been linked with inflammation and the recruitment of immune cells, we propose to use MRI for the visualization of perfluorocarbon nanoparticles (PFCs) that are taken up by plaque immune cells. MRI is non-invasive, safe and does not involve harmful radiation, while PFCs are safe molecules that have already been injected in high doses in humans. Once in the bloodstream, PFCs are internalized by immune cells and are actively transported to inflammation sites. The fluorine (19F) atoms in PFCs can then be imaged by MRI, with the critical advantage that the injected PFCs are the only source of signal, since the body does not naturally contain MRI-detectable fluorine concentrations. The 19F MR signal strength in an atherosclerotic plaque therefore directly indicates the level of inflammation. The goal of this project is therefore to implement, test and validate a 19F MR methodology on a human clinical MR scanner, and optimize this methodology for 19F MRI studies of inflammation progression and regression in atherosclerosis in mice. To this end, the methodology will be validated in vitro with known solutions, and by determining how the 19F MR signal in atherosclerotic plaques in mice relates to established gold-standard histological indices. Finally, we will test the hypothesis that 19F MRI can detect changes in the rate of plaque progression in response to diet changes and statin therapy.

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Last update: 25.09.2014

Active participation

Title	Year

Number	Title	Start	Funding scheme

The rupture of atherosclerotic plaque commonly leads to myocardial infarction and stroke, which together are the number one cause of death in Western society, with women overtaking men in recent years. The progression of atherosclerotic plaque is impossible to predict with current clinical tools, but results in clinical events that affect millions of people worldwide each year. It has recently become clear that current “anatomy-based” medical imaging approaches do not provide specific or clinically useful predictors of the vulnerability of atherosclerotic plaque. For these reasons, the availability of a clinical modality that is capable of predicting impending plaque rupture would be of utmost importance and socioeconomic value.Since the likelihood for plaque to rupture has been linked with inflammation and the recruitment of immune cells, we propose to use magnetic resonance imaging (MRI) for the visualization of perfluorocarbon nanoparticles (PFCs) that are phagocytosed by plaque immune cells. PFCs are safe and inert particles that have been injected in high doses in humans and have already passed several clinical trials as blood volume expanders (although they have not been used for imaging in patients), while MRI is non-invasive, safe and does not involve harmful ionizing radiation. Once in the bloodstream, PFCs are internalized by immune cells and are actively transported to inflammation sites such as atherosclerotic plaques. The fluorine (19F) atoms in PFCs can then be imaged by MRI, with the critical advantage that the injected PFCs are the only source of signal, since the body does not naturally contain MRI-detectable fluorine concentrations. The 19F MR signal strength in an atherosclerotic plaque therefore directly and quantitatively represents the PFC concentration, and represents an exclusive indicator of the level of inflammation. PFCs furthermore have the unique property compared to previously proposed inflammation contrast agents that they clear rapidly out of a tissue once released by their phagocytosing immune cell; this means that PFC-generated MR signals will accurately reflect inflammation changes over time. The combination of PFCs and MRI is thus ideal for monitoring inflammation progression over time.In preparation for this proposal, the PI has conducted preliminary studies in which he successfully tested this molecular imaging concept in atherosclerotic mice on an animal high-field MR scanner. To our best knowledge, this is the first and only demonstration of 19F MRI of atherosclerosis in vivo. As a logical next step and considering the favorable safety profile of PFCs, we now propose to mechanistically translate this tested approach to the clinical setting with a more potent PFC to maximize sensitivity. As a first step, we will establish by which immune cells the nanoparticles are internalized, as well as implement, test and validate the 19F MR methodology on a human clinical MR scanner, and optimize this methodology for 19F MRI studies of inflammation progression and regression in atherosclerosis in mice.To this end, recently purchased 19F MRI hardware - funded through a seed grant secured by the PI - and an advanced acceleration technique - in-house developed compressed sensing - will be combined on a clinical MR scanner. In a tried network of collaborators that was established by the PI (evidenced by common papers and successful grant applications), the technique will subsequently be validated in vitro and by determining how the 19F MR signal in atherosclerotic plaques in mice relates to established gold-standard histological indices. Immunofluorescent histology and flow cytometry will be used to determine the types and populations of immune cells that internalize the PFC nanoparticles, thus giving new insights into the recruitment of immune cells in atherosclerosis. Finally, we will test the hypothesis that 19F MRI can detect changes in the rate of plaque progression in response to diet changes and statin therapy.Consistent with prior work of the PI, we plan to disseminate the related findings at conferences and as publications in peer-reviewed journals, and take our methods to the next level by sharing them with international collaborators. Furthermore, the PI will mentor a PhD student whom he will teach the imaging methodology as well as how to conduct translational and interdisciplinary research. In conclusion, this translational interdisciplinary proposal addresses one of the major needs in contemporary medicine, and builds on strong preliminary studies as well as an established network of collaborators. Should it be funded, this grant will lead to new knowledge on inflammation mechanisms in atherosclerosis as well as unique new technology to quantitatively monitor inflammation in atherosclerosis over time.