Multimodal Cardiovascular Imaging
- Klinikum rechts der Isar der Technischen Universität München
- Markus Schwaiger
The aim of this project is to develop multimodal imaging strategies with a focus on inflammatory processes in atherosclerosis and in the sub-acute phase after myocardial infarction. For this purpose tracers targeting inflammatory processes (such as activated macrophages) are being developed. One such example is the tracer Tilmanocept which binds specifically to mannose-receptors on the surface of macrophages. Tilmanocept has originally been developed to image sentinel lymph nodes and was therefore labeled with radionuclides ideal for conventional gamma cameras. In our research group Tilmanocept is being modified so that positron emitting radionuclides, particularly Gallium-68, can be attached to Tilmanocept. Furthermore, the structure of Tilmanocept is being adapted to improve the affinity and biodistribution of this tracer. First biodistribution data in Apo-E-mice demonstrated an increased uptake in atherosclerotic plaques. Another focus of our research is the evaluation of Ga-68-pentixafor a PET-tracer binding with nanomolar affinity to the chemokine receptor 4 (CXCR4). CXCR4 is known to be overexpressed on activated, hypoxic macrophages therefor CXCR4 seems to be a very promising target to image inflammatory processes in atherosclerosis. In a rabbit model of atherosclerosis this approach has already been evaluated. New Zealand White rabbits fed with a high cholesterol diet received an endothelial abrasion of the right carotid artery and of the abdominal aorta to induce atherosclerotic plaque formation. Studies were performed using Ga-68-pentixafor (for imaging studies) and I-125-pentixafor (for biodistribution studies). We were able to demonstrate that tracer uptake was increased in atherosclerotic lesions and could be blocked efficiently by AMD3100 a CXCR4-inhibitor. CXCR4-immunohistochemistry staining showed a high correlation with tracer uptake in autoradiography. These results are the basis for a DZHK-funded project with the aim to evaluate Ga-68-pentixafor in humans with carotid plaques in comparison to F-18-FDG. Besides these experiments to study inflammatory processes in atherosclerotic plaques, a large number of clinical studies to investigate the post-ischemic inflammatory response after myocardial infarction have been conducted. Patients were imaged in the first few days after myocardial infarction on an integrated PET/MR scanner using F-18-FDG as radiotracer. Patients had to fast for >12 hours and received heparin before tracer injection in order to suppress physiological F-18 FDG uptake in remote myocardium. The area of F-18 FDG uptake showed a high correlation with the area at risk and was significantly larger than the infarcted area (the latter was determined by late gadolinium enhancement MRI). Interestingly, the intensity of F-18 FDG uptake as a measure of post-ischemic inflammation correlated inversely with left ventricular function after 6 months, i.e. the higher the inflammatory signal the more likely an increase in endsystolic/end-diastolic volume and a decrease in ejection fraction was observed. While preclinical rodent studies clearly suggest that the F-18 FDG uptake reflects the invasion of inflammatory cells into the post-ischemic myocardium, no large animal study has proven this hypothesis. That is the reason why our group initiated first large animal studies with the aim to further breakdown this novel biosignal.
- imaging atherosclerotic plaques, macrophage infiltration, Tilmanocept plaque inflammation, tracer development, CXCR4, Ga-68-pentixafor, acute myocardial infarction, post-ischemic inflammation, FDG-PET/MRI
- € 392.617,58