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4th vulnerable plaque symposium

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4th vulnerable plaque symposium

  1. 1. Plaque temperature heterogeneity is associated with macrophage accumulation and metalloproteinase activity R. Krams, LCA van Damme Dept. Experimental Cardiology, Thoraxcenter, Rotterdam, The Netherlands
  2. 2. Background • Plaque rupture has been related to a high MMP activity and macrophage (Mø) accumulation Galis et al, J. Clin. Invest. 1994 • Recently, regional temperature heterogeneity has been observed in atherosclerotic plaques in vivo Verheye et al, Circulation 2002
  3. 3. Aim of this study • To test the hypothesis that temperature heterogeneity is associated not only with macrophage accumulation but also with MMP-activity in atherosclerotic plaques in vivo.
  4. 4. Methods In 6 NZW rabbits: • Endothelium was removed (denudation) of the infra renal aorta • 2 months 2% cholesterol diet • Temperature measurement after 2 months of follow up • Immunohistochemistry for the detection of mø (RAM11, Dako), smooth muscle cells (1A4), histology for collagen amount (picro-serious red) and lipid contents (oil red o) and MMP activity in a zymogram
  5. 5. start end 3F Fogarty 50 mm Infra renal aorta Renal artery Denudation area
  6. 6. Thermography • Intravascular thermography • Catheter: Thermocore Medical Systems • Accuracy: ± 0.01 °C • Pullback speed: 0.2 mm/sec • Measurement of temperature difference from a reference area
  7. 7. Analysis I •Thermography with / without blood flow -pull back over 6 cm -mean of 4 thermistors -mean of 2 pull backs -reference area set at 0 °C
  8. 8. Analysis II • Histological analysis: -Mø % of plaque area -Lipid % of plaque area -Collagen % of plaque area -Smooth Muscle Cell(SMC) % of plaque area • Vulnerability Index (VI-index): VI = Mø% + Lipid% Collagen% + SMC% Shiomi et al, Atherosclerosis 2001
  9. 9. Analysis III • MMP activity in a zymogram -SDS PAGE gel electroforese -separation on molecular weight -substrate: gelatin
  10. 10. Protocol Inducing atherosclerosis Perform thermography after 2 months Hot Cold Isolate area Isolate area MMP-activity / cel distribution MMP-activity / cel distribution Compare
  11. 11. Distance (mm) from renal artery 0 5 10 15 20 25 30 35 40 45 50 55 ∆T(°C)fromreference 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 ∆T(°C)fromreference -0.2 -0.1 0.0 0.1 length (mm) vs Mean without blood flow length (mm) vs Mean with blood flow Results I Thermograph (with and without blood flow) Hot spot 1 Hot spot 2 Cold area Example 1
  12. 12. Length from renal artery (mm) 0 5 10 15 20 25 30 35 40 45 50 55 ∆T(°C)fromreferencearea -0.1 0.0 0.1 0.2 0.3 0.4 0.5 ∆T(°C)fromreferencearea -0.01 0.00 0.01 0.02 0.03 length (mm) vs Mean without blood flow length (mm) vs Mean with blood flow Example 2 Results I Thermograph (with and without blood flow)
  13. 13. ∆T (°C) from reference 0.1 0.2 0.3 0.4 0.5 0.6 0.7 VI-index 0 1 2 3 VI-index Regression between VI-index and ∆T R=0.8, p=0.013 Results II
  14. 14. Results II ∆T (°C) from reference 0.1 0.2 0.3 0.4 0.5 0.6 0.7 Mø(%)intheplaque 0 5 10 15 20 25 30 mø Regression between mø(%) and ∆T (°C), R = 0.7 p = 0.020
  15. 15. Results III MMP-9 Pro-MMP-2 MMP-2 active MMP-9 Pro-MMP-2 MMP-2 active MMP-9 Pro-MMP-2 MMP-2 active Length (mm) from renal artery 0 10 20 30 40 50 60 ∆T(°C)fromreference 0.00 0.25 0.50 0.75
  16. 16. MMP2activeproMMP2 MMP9 MMPactivity(pixels/mm2) 0 5000 10000 Hot regions Reference rgeions * * * p<0.05 Results III
  17. 17. Summary • We found that temperature has a positive correlation between mø% and VI-index • We found more pro-MMP2 and active MMP2 inside the hot area’s compared to the cold area’s •We found almost no rise in temperature in presence of blood flow
  18. 18. Conclusion I • Temperature heterogeneity is associated with a VI-index • The underlying mechanism of this association is mø accumulation • The high MMP-activity suggests that active mø are detected by temperature changes
  19. 19. Conclusion II • We have seen in our model that it is almost impossible to measure temperature differences in presence of blood flow
  20. 20. Discussion • Blood has a cooling effect on the vessel wall, and blood flow is high in the rabbit’s abdominal aorta (twice human coronary flow). • Therefore to exclude a dominant flow effect on our measurements, we stopped the flow with a balloon
  21. 21. Co-operation • Catherization laboratory Prof. Dr. PW Serruys Dr. W. van der Giessen • Experimental Cardiology Rotterdam L.C.A van Damme C. van Pelt B. Mousavi Gourabi W. Maat D. Segers C. Cheng Dr. R. Krams Dr. D.J. Duncker • Experimental Cardiology Utrecht Dr. G. Pasterkamp C. Snijder A. Schoneveld • Thermocore Medical Systems Dr. G. Van Langenhove Dr. T. Flint Dr. Y. Yianni • Middelheim Hospital Antwerpen S. Verheye M. Kockx M. Knaapen

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