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Morteza Naghavi MD,
Tania Khan, Babs Soller PhD, Peter Melling PhD,
Mohammad Madjid MD, Ward Casscells MD,
James T. Willer...
 Casscells et al have previously
discovered that plaque temperature
correlates with other markers of
vulnerability and th...
Plaque temperature correlates with number of
macrophages
but not with smooth muscle cells
Our ex-vivo findings have been recently
corroborated by others in-vivo, suggesting that
increased plaque temperature comp...
Why should vulnerable plaque be Why should vulnerable plaque be hothot??
Vulnerable plaque is inflamed
and inflammation ge...
What else can be found in a site ofWhat else can be found in a site of
inflammation?inflammation?
Increased metabolic rate...
pHpH
Extra-cellular low pH or acidic environment is
characteristic of an inflamed site
This is mainly because of massive...
 Atherosclerotic plaques are known to be hypoxic due
to:
- Increased oxygen consumption by macrophages
- Decreased oxygen...
……why plaque pH or lactate?why plaque pH or lactate?
When incubated with Ox-LDL, macrophages are
seen to reduce their env...
What could be the significance ofWhat could be the significance of
an acidic plaque?an acidic plaque?
 Low pH can activat...
pH
9.00
8.88
8.75
8.63
8.50
8.38
8.25
8.13
8.00
7.88
7.75
7.63
7.50
7.38
7.25
7.13
7.00
6.88
6.75
6.63
Noofpointswiththesa...
PH
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
pH Heterogeneity Within and Between Plaques in 48 Human Carotid Specimens
Red box shows...
Watanabe Rabbit Aorta
pH
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
pH Heterogeneity in 9 Watanabe Rabbit Aortas
2220231717191026252428N =
11 human umbilical artery
pH
9.5
9.3
9.1
8.9
8.7
8.5
8.3
8.1
7.9
7.7
7.5
7.3
7.1
6.9
6.7
6.5
6.3...
calcified&thrombosedLipid Rich
pH
9.0
8.5
8.0
7.5
7.0
6.5
pH in Lipid Rich Yellow Areas vs. Calcified areas
Areas with lar...
Lipid Rich Yellow Areas (A and B) vs. Calcified Areas (C and D)
Lipid core
Calcification
H&E Movat
Correlation of pH and Temperature in Human Carotid Plaques Varied by the Areas
We see a marked inverse correlation between...
Correlation of ph and Temperature in 9 Watanabe Rabbit Aorta
A significant inverse correlation between temperature and pH
...
Correlation of pH and Temperature in 11 Human Umbilical Arteries
In contrast to human and rabbit plaques in human umbilica...
Fluorescence Ratio (dual emission) Imaging Microscopy of A
Predominantly Calcified Plaque Shows Significant Microscopic
pH...
Fluorescence Single-Emission Imaging Microscopy
of a Predominantly Lipid Rich Plaque Shows
Significant Microscopic pH Hete...
What else, besides Temp and pH?What else, besides Temp and pH?
Oxidized lipid and proteins
– Ox-LDL
– Ox-collagen
Nitrat...
How to measure
Temperature, pH
and the other factors
in plaque invivo?
Atherosclerotic plaque, temperature, ph and lactate
Atherosclerotic plaque, temperature, ph and lactate
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Atherosclerotic plaque, temperature, ph and lactate

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Atherosclerotic plaque, temperature, ph and lactate

  1. 1. Morteza Naghavi MD, Tania Khan, Babs Soller PhD, Peter Melling PhD, Mohammad Madjid MD, Ward Casscells MD, James T. Willerson MD The University of Texas-HoustonTexas Heart Institute Functional Evaluation of Atherosclerotic Functional Evaluation of Atherosclerotic  Plaque, Temperature, pH and Lactate Plaque, Temperature, pH and Lactate 
  2. 2.  Casscells et al have previously discovered that plaque temperature correlates with other markers of vulnerability and that hot plaque may be a vulnerable plaque (The Lancet 1996) Introduction:Introduction:
  3. 3. Plaque temperature correlates with number of macrophages but not with smooth muscle cells
  4. 4. Our ex-vivo findings have been recently corroborated by others in-vivo, suggesting that increased plaque temperature compared to adjacent arterial wall correlates with patients’ clinical presentation. Stefanadis et al 1999
  5. 5. Why should vulnerable plaque be Why should vulnerable plaque be hothot?? Vulnerable plaque is inflamed and inflammation generates heat
  6. 6. What else can be found in a site ofWhat else can be found in a site of inflammation?inflammation? Increased metabolic rate namely increased oxygen and glucose consumption Free radical formation (ROS and RNS) Hypoxia ?
  7. 7. pHpH Extra-cellular low pH or acidic environment is characteristic of an inflamed site This is mainly because of massive lactate formation resulted from increased metabolic activity of inflammatory cells. These cells normally do not find enough oxygen to burn glucose therefore, go through anaerobic pathway and generate a large a mount of lactate
  8. 8.  Atherosclerotic plaques are known to be hypoxic due to: - Increased oxygen consumption by macrophages - Decreased oxygen diffusion through plaque fibrous cap Both result in anaerobic metabolism. (Bjornheden et al 1987)  Macrophages are also known to be metabolically very active. For example the ATP consumption of every 2 activated macrophages equals to one isolated maximally loaded cardiomyocyte. Back to old literature:Back to old literature:
  9. 9. ……why plaque pH or lactate?why plaque pH or lactate? When incubated with Ox-LDL, macrophages are seen to reduce their environmental pH to as low as 5.5. (De Vries et al 1998) Macrophages oxidize LDL in both neutral and acidic pH, but the LDL oxidation is more pronounced in an acidic environment. (Leake et al 1995)
  10. 10. What could be the significance ofWhat could be the significance of an acidic plaque?an acidic plaque?  Low pH can activate or increase activity of acidic matrix digesting enzymes resulting in plaque softening, weakening and rupture. Others recently reported presence of acidic enzymes in human atherosclerotic plaques (Libby et all, 1998)
  11. 11. pH 9.00 8.88 8.75 8.63 8.50 8.38 8.25 8.13 8.00 7.88 7.75 7.63 7.50 7.38 7.25 7.13 7.00 6.88 6.75 6.63 Noofpointswiththesameph 140 120 100 80 60 40 20 0 pH Distribution in 48 Human Carotid Plaques This histogram demonstrates distribution of pH measured in 858 points in 48 carotid plaques of 48 patients. A marked variation ranging from 6.5 to 8.9 is seen.
  12. 12. PH 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 pH Heterogeneity Within and Between Plaques in 48 Human Carotid Specimens Red box shows the middle quartiles, solid lines shows median, cross-bars show pH range and circles represents extreme values. This graph shows a significant pH variation within and between plaques. The variation within the plaque holds the majority of the total variation.
  13. 13. Watanabe Rabbit Aorta pH 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 pH Heterogeneity in 9 Watanabe Rabbit Aortas
  14. 14. 2220231717191026252428N = 11 human umbilical artery pH 9.5 9.3 9.1 8.9 8.7 8.5 8.3 8.1 7.9 7.7 7.5 7.3 7.1 6.9 6.7 6.5 6.3 6.1 5.9 5.7 5.5 pH Heterogeneity in 11 Human Umbilical Arteries
  15. 15. calcified&thrombosedLipid Rich pH 9.0 8.5 8.0 7.5 7.0 6.5 pH in Lipid Rich Yellow Areas vs. Calcified areas Areas with large lipid core exhibit higher temperature and lower pH p < 0.01
  16. 16. Lipid Rich Yellow Areas (A and B) vs. Calcified Areas (C and D) Lipid core Calcification H&E Movat
  17. 17. Correlation of pH and Temperature in Human Carotid Plaques Varied by the Areas We see a marked inverse correlation between temperature and pH of plaques that varies by macroscopic characteristics of plaques. p < 0.01
  18. 18. Correlation of ph and Temperature in 9 Watanabe Rabbit Aorta A significant inverse correlation between temperature and pH is seen these rabbits similar to human carotid plaques A significant inverse correlation between temperature and pH is seen these rabbits similar to human carotid plaques p < 0.01
  19. 19. Correlation of pH and Temperature in 11 Human Umbilical Arteries In contrast to human and rabbit plaques in human umbilical there is no relationship seen between temperature and pH p = 0.2
  20. 20. Fluorescence Ratio (dual emission) Imaging Microscopy of A Predominantly Calcified Plaque Shows Significant Microscopic pH Heterogeneity with Higher pH in Calcified Areas
  21. 21. Fluorescence Single-Emission Imaging Microscopy of a Predominantly Lipid Rich Plaque Shows Significant Microscopic pH Heterogeneity Mostly Acidic
  22. 22. What else, besides Temp and pH?What else, besides Temp and pH? Oxidized lipid and proteins – Ox-LDL – Ox-collagen Nitrated proteins – Nitrosyl hemoglobin – Nitrosyl tyrosine ?
  23. 23. How to measure Temperature, pH and the other factors in plaque invivo?

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