AG Cardiovascular Imaging and Immunology
Overview
Areas of interest
I - Cardiovascular Imaging
Non-invasive imaging using target specific contrast agents allows visualization of disease specific structures of interest, adding functional information and increasing sensitivity of detection. Targeted contrast agents consist of a specific ligand, either antibody or peptide, conjugated to a signal element, which can be a radionuclide, paramagnetic substrate or microbubble, subsequently used for PET/SPECT, magnetic resonance or ultrasound imaging. In our group, we are primarily interested in targeting activated platelets. Activated platelets are involved in atherosclerotic plaques progression. Especially during erosion or rupture of inflamed lesions, platelets are activated on the endothelial surface. Detection of areas with increased platelet activation could thus be facilitated to identify unstable coronary atherosclerotic plaques. Further cardiovascular diseases that involve platelet activation include myocardial infarction, pulmonary embolism and infective endocarditis. Non-invasive imaging of activated platelets may provide information about inflammation as well as extent and activity of disease. Our goal is to investigate how molecular cardiovascular imaging can be facilitated for diagnostics and clinical decision making to ultimately help the physician in guiding the patient.
Figure I Left Schematic construct of a targeted contrast agent. Conjugation of a contrast-giving element (e.g. gadolinium, iron oxide, radionuclide or microbubble) to a specific ligand (antibody or peptide) allows binding of contrast agents at cellular targets of interest. Right Example of a contrast agent application, showing the detection of a vascular thrombosis in the murine carotid artery. Above Contrast enhanced CT of the murine aorta and carotid arteries. Below Signal of a thrombosis in the right carotid artery after injection of an In-111-labelled contrast agent targeting activated platelets.
II - Cardiovascular Immunology
Innate immunity has been recognized to be an important player in wound healing and cardiac remodeling following myocardial infarction. After ischemic tissue injury, a burst of pro-inflammatory factors and cytokines is released from the infarct tissue into the blood to trigger recruitment of inflammatory immune cells (e.g. neutrophils, monocyte/macrophages). These immune cells locally orchestrate break down and removal of necrotic tissue as well as wound healing and tissue remodeling. For this reason, inflammation is an indispensable requirement for adequate myocardial recovery. On the other hand, exaggerated inflammation after myocardial infarction can also have detrimental consequences, leading to larger infarcts, progression of adverse cardiac remodeling and the development of heart failure. Modulation of the immune response following myocardial infarction thus may be an intriguing target for improving myocardial recovery. As a consequence, modulation of inflammation in cardiovascular disease demands thorough understanding of the underlying pathophysiology. Our group is especially interested in cross talk and signaling cascades that trigger leukocyte recruitment to the injured myocardium after myocardial infarction. Besides local recruitment from the blood, leukocyte supply via increased leukocyte production in the bone marrow is of mayor relevance for post-ischemic myocardial inflammation, but little is known about the pathways that carry the signals for increased leukocyte demands from the site of injury to the hematopoietic system. How do danger signals get into contact with the hematopoietic niche? How do hematopoietic stem and progenitor cells receive information about leukocyte demand? Do danger signals directly interact with hematopoietic stem cells or do they mediate cross talk to supply cells in the hematopoietic niche, e.g. endothelial cells? Exaggerated or prolonged leukocyte supply has been shown to increase adverse cardiac remodeling and increase the risk for secondary cardiovascular events due to atherosclerotic plaque inflammation.
Figure II Myocardial infarction triggers the release of a burst of pro-inflammatory danger signals from the infarct tissue into the blood. These cytokines may be involved in local immunoregulatory functions and the recruitment and transmigration of inflammatory leukocytes from the blood into the injured myocardium. Next to involvement in local recruitment, danger signals travel in the blood or via blood-independent routes for long-distance signaling. Leukocyte production by the hematopoietic system is responsible for constant supply of inflammatory cells. Increased hematopoiesis in the bone marrow and via extramedullary hematopoiesis replenishes the exhausting blood pool. However, exaggerated or prolonged leukocyte supply has been shown to increase adverse cardiac remodeling and increase the risk for secondary cardiovascular events due to atherosclerotic plaque inflammation. Graphics adopted from Servier art.
PD Dr. med Timo Heidt