magnetic resonance imaging; inflammation; atherosclerosis; monitoring; perfluorocarbon
Bouchoucha Meryem, van Heeswijk Ruud B, Gossuin Yves, Kleitz Freddy, Fortin Marc-André (2017), Fluorinated Mesoporous Silica Nanoparticles for Binuclear Probes in 1H and 19F Magnetic Resonance Imaging, in Langmuir
, 33(40), 10531.
van Heeswijk Ruud B, Gonzales Christine, Schwitter Juerg (2017), Cardiac Disease, in Ahrens Eric T, Flögel Ulrich (ed.), Pan Stanford Publishing, Singapore, 191.
Colotti Roberto, Bastiaansen Jessica AM, Wilson Anne, Flögel Ulrich, Gonzales Christine, Schwitter Juerg, Stuber Matthias, van Heeswijk Ruud B (2017), Characterization of Perfluorocarbon Relaxation Times and their Influence on the Optimization of Fluorine-19 MRI at 3 Tesla, in Magn Reson Med
, 77(6), 2263.
Messroghli Daniel R, Moon James C, Ferreira Vanessa, Grosse-Wortmann Lars, He Taigang, Kellman Peter, Macherbauer Julia, Nezafat Reza, Salerno Michael, Schelbert Erik B, Taylor Andrew J, Thompson Richard, Ugander Martin, van Heeswijk Ruud B, Friedrich Matthias G (2017), Clinical recommendations for cardiac mapping of T1, extracellular volume, T2, and T2*: A consensus statement by the Society for Cardiovascular Magnetic Resonance (SCMR) endorsed by the European Associ, in J Cardiovasc Magn Reson
, 19, 75.
van Heeswijk Ruud B, Piccini Davide, Tozzi Pier-Giorgio, Rotman Samuel, Meyer Pierre, Schwitter Juerg, Stuber Matthias, Hullin Roger (2017), Three-dimensional self-navigated T2 mapping for the detection of acute cellular rejection after orthotopic heart transplantation, in Transpl Dir
, 3(4), e149.
Ludwig Kai D, Hernando Diego, Roberts Nate T, van Heeswijk Ruud B, Fain Sean B, A Chemical Shift Encoding (CSE) Approach for Spectral Selection in Fluorine-19 MRI, in Magn Reson Med
van Heeswijk Ruud B, Colotti Roberto, Darçot Emeline, Delacoste Jean, Pellegrin Maxime, Piccini Davide, Hernando Diego, Chemical shift encoding (CSE) for sensitive fluorine-19 MRI of perfluorocarbons with complex spectra, in Magn Reson Med
Coristine Andrew J, Chaptinel Jerome, Ginami Giulia, Bonanno Gabriele, Coppo Simone, van Heeswijk Ruud B, Piccini Davide, Stuber Matthias, Improved respiratory self-navigation for 3D radial acquisitions through the use of a "pencil-beam" 2D-T2-Prep for free-breathing, whole-heart coronary MRA, in Magn Reson Med
Colotti Roberto, Omoumi Patrick, Bonanno Gabriele, Ledoux Jean-Baptiste, van Heeswijk Ruud B, Isotropic Three-Dimensional T2 Mapping of Knee Cartilage: Development and Validation, in J Magn Reson Imaging
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.