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186 4th vulnerable plaque symposium
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. 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. 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. 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
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. 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. 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. Analysis III
• MMP activity in a zymogram
-SDS PAGE gel electroforese
-separation on molecular weight
-substrate: gelatin
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. 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. ∆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. 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
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. 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. Conclusion II
• We have seen in our model that it is almost
impossible to measure temperature differences
in presence of blood flow
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. 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