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040 center for vulnerable plaque research


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040 center for vulnerable plaque research

  1. 1. Center for Vulnerable Plaque Research CVPR UT- HoustonTexasHeart Institute
  2. 2. How the World Dies Today? YLLS: Yearsof LifeLost
  3. 3. Everybody has atherosclerosis, the question is who has vulnerable plaque Sudden Cardiac Death Acute MI Vulnerable Plaque(s)
  4. 4. PlaqueEruption (Volcano!)
  5. 5. Compensatory Enlargement of Human Atherosclerotic Coronary Arteries N Engl J Med 1987 May 28;316(22):1371-5 <50% stenosis Luminal area is not endangered until more than 40% of internal elastic lamina is destructed and occupied by plaque Coronary artery disease is a disease of arterial wall disease not lumen. PositiveRemodeling <80% stenosis
  6. 6. How important is detection of vulnerable plaque?
  7. 7. In 50-70% of cases the first symptom of having a vulnerable plaque is sudden death out-of- hospital. Kill It Before It Kills You!
  8. 8. Human Carotid Plaque Courtesy of Dr. Chun Yuan University of Washington
  9. 9. We need MRI with vulnerable plaque targeted contrast media that identifies: 1- Inflammation (macrophage infiltration), 2- Fissured/Permeable Cap, 3- Leaking Angiogenesis and 4- Intra-Plaque Hemorrhage 5- …?
  10. 10. SuperparamagneticSuperparamagnetic andand Ultra-superparamagneticUltra-superparamagnetic Iron OxideIron Oxide lBlood pool magnetic resonance (MR) imaging contrast media with a central core of iron oxide generally coated by a polysaccharide layer lShortening MR relaxation time lEngulfed by and accumulated in cells with phagocytic activity
  11. 11. Particle Core Size Particle Size Blood (nm) (nm) Half-life Combidex 5-6 20-30 8h Feridex 4-6 35-50 2.4±0.2h DDM 43/34/102 6.4 20-30 6h Clariscan MION 4-6 17 varies Feruglose --- --- --- --- Examples of commercially available SPIOs
  12. 12. Current applications of SPIO in MR imaging: -Detection of Hepatic Lesions (primary and metastatic cancers) -Experimental Nephritic syndrome in Laboratory animals -Monitoring rejection of transplanted heart or kidney in the animal model of allograft transplantation. -Experimental detection of CNS lesions in laboratory animals.
  13. 13. USPIOs Enter the AtheroscleroticUSPIOs Enter the Atherosclerotic Plaque ThroughPlaque Through l-Macrophages that engulfed them l-Fissured or thin cap l-Extensive angiogenesis l-vasa vasorum leakage l-Intra plaque hemorrhage
  14. 14. In-vitro Study of Macrophage SPIO Uptake  In a series of in-vitro studies we have tested the rate of SPIO uptake by human activated monocytes in different conditions regarding incubation time and concentration of SPIO. All SPIO were labeled by a fluorescent dye (DCFA).
  15. 15. FL-labeled SPIO Incubated Macrophages 24hr
  16. 16. Double DAPI Staining with Fluorescence-labeled SPIO Macrophages after 24hr Incubation
  17. 17. HypothesisHypothesis Active macrophages residing inside the inflamed vulnerable plaques can be visualized following injection of SPIO or USPIOs into the systemic circulation by virtue of a decrease in the magnetic resonance signal intensity of the plaque,and correlate with histopathologic characteristics of vulnerability to rupture.
  18. 18. vasa vasorum Over magnification is a major advantage of SPIO Darkening property of SPIO in the white background of fat and water of plaque is another advantage
  19. 19. SPIO and T2 Effect In-vitro study to show the effect of macrophage SPIO uptake on their T2 relaxation time
  20. 20. 0 10 20 30 40 50 60 70 80 90 50 250 control 20 min 60 min 6 hours 24 hours Macrophage Uptake of Feridex with Time and Concentration Shown by T2 Reduction Concentration µmol/ml
  21. 21. Histopathologic study of the Mouse injected With SPIO (Thoracic Aorta) ApoE KO mouse, Movat staining, proximal aorta Coronary Cross section Atherosclerosis plaque
  22. 22. Histopathologic study of ApoE KO Mouse injected With SPIO (Thoracic Aorta) CD68 staining (aortic plaque) Iron Staining (aortic plaque) Iron Staining (coronary section) Iron particles Iron particles
  23. 23. Histopathologic study of ApoE KO Mouse injected With SPIO (Abdominal Aorta) H&E staining Iron Staining CD 68 staining Iron particles
  24. 24. Histopathologic study of wild type Mouse injected With SPIO (Thoracic Aorta) H&E staining CD68 stainingIron staining
  25. 25. Comparison of the Number of the Iron Particles (per HPF) in ApoE KO Mice Plaque vs. Normal Wall 0 5 10 15 Atherosclerotic Aorta Average number of iron particles per sample P <0.001
  26. 26. Iron Staining H&E Staining Apo E-deficient mouse injected with SPIO Cytokines added
  27. 27. MR Image of Abdominal Aorta After SPIO Injection in ApoE and Control Mice ApoE deficien t mouse C57B1 (control) mouse Before Injection After Injection (5 Days ) Dark (negatively enhanced) aortic wall, full of iron particles Bright aortic lumen and wall without negative enhancement and no significant number of iron particles
  28. 28. Typical in vivo MR images of a live mouse at the heart (left) and renal level (right). Various vessels and aortic arch can easily e seen in these images. The slice thickness is 0.5 mm and the in-plane resolution is 50 µm (7.1 T MR system).
  29. 29. We chose Watanabe Hereditary Hypercholesterolemic rabbits (WHHR) and New Zealand White rabbits (NZW) for this study. We injected them with SPIO (Feridex) 1 mMol Fe/kg and obtained baseline as well as 5-day post-SPIO injection MR images of the aorta (1.5 Tesla MRI system at the University of Texas, MD Anderson,Houston,Texas). Then we compared the images in hypercholesterolemic rabbits with the normal,wild type NZW rabbits. Rabbit ex-vivo MRI studies: After the in-vivo MR images, we sacrificed the animals and excised the aorta. Then we put the isolated aorta in a gel medium, clamped both ends and any side branches and injected gadolinium inside the lumen. We did the same procedure for all rabbits. We also used 2 more rabbits, one WHHR and one NZW that were not injected with SPIO, as control, in the ex-vivo MR study. SPIO-Enhanced MRI study in rabbits
  30. 30. Histopathologic studies of Thoracic aorta in Watanabe Hereditary Hypercholesterolemic rabbit after SPIO injection H&E staining Iron staining Iron staining
  31. 31. Histopathologic studies of Thoracic aorta in Watanabe Hereditary Hypercholesterolemic rabbit after SPIO injection H&E staining Iron staining Iron staining Iron particles
  32. 32. Plaque Cell Density vs SPIO 0 10 20 30 40 50 60 0 10 20 30 40 50 60 70 Cell Denity in H&E staining SPIOpositivecell-Iron staining Series1 R=0.956 Correlation between Iron positive cells in Iron staining and cell density in H&E staining in rabbit atherosclerotic aorta.
  33. 33. MR Angiography 3D with Gadolinium-DTPA in Watanabe Rabbit Before SPIO injection After SPIO injection
  34. 34. Ex-vivo MR study of the thoracic aorta in Watanabe and Wild type rabbit after SPIO injection compared to control. 3D MR Angiography with Gadolinium-DTPA Watanabe rabbit Post-SPIO Watanabe rabbit control NZW rabbit control NZW rabbit Post-SPIO
  35. 35. Ex-vivo MR study of the thoracic aorta in Watanabe and Wild type rabbit after SPIO injection compared to control. (Gradient echo) Watanabe rabbit Post-SPIO Watanabe rabbit control NZW rabbit Post-SPIO NZW rabbit control