1. Editorial Slides
VP Watch, October 23, 2002, Volume 2, Issue 42
Hot Plaque; Cool It, Kill It, Or Crush It?
Ward Casscells, M.D.
John Edward Tyson Distinguished Professorship of Medicine
University of Texas-Houston and Texas Heart Institute
Houston, Texas
2. Detection of vulnerable plaques has become
the holy grail of cardiology.
Atherosclerosis is an inflammatory disease.
Therefore it can be sought by signs of
inflammation.1
3. Cardinal Signs of Inflammation
PainPain
RednessRedness
HEATHEAT
SwellingSwelling
InflammationInflammation
4. Casscells et al. have hypothesized
that vascular inflammation and
plaque vulnerability can be
identified by the heat released from
activated macrophages in the
plaque.2
5. It is known that macrophages are metabolically
very active with a high turn-over rate of total ATP
content.
Newsholme P. Biochem J. 1989;261:211-8
This high metabolic rate can lead to increased
heat production in areas of macrophage
accumulation while it cannot be observed in
areas of smooth muscle cell accumulation in the
absence of inflammatory cell infiltration.
Bjornheden T. Arteriosclerosis. 1987;7:238-47
6. • In 1996, Casscells, Willerson, et al measured the
intimal surface temperatures at 20 sites in each
of 50 samples of carotid artery taken at
endarterectomy from 48 patients.2
• They found several regions in which the surface
temperatures varied reproducibly by 0.2-0.3
degrees C, but 37% of plaques had substantially
warmer regions. While macrophage/monocytes
density was related to higher temperature, such a
relation was not seen with smooth muscle cell
density. 2
7. Temperature Heterogeneity on the Surface
of An Endartherectomized Carotid Plaque
Casscells W et al. Lancet. 1996;347:1447-51
8. • They were also able to show temperature
heterogeneity of the surface of human carotid
plaques ex vivo by infrared camera. 2
• Later on, Naghavi et al. using a thermosensor
catheter showed in vivo temperature
heterogeneity of atherosclerotic arteries in dogs
and rabbits. Also he found ex vivo that areas
with high temperature have low pH.3
9. Infrared Thermography Confirmed Temperature
Heterogeneity of Atherosclerotic Plaques
Dog model of atherosclerosis develops
marked lesions in its coronary arteries (left
panel). Willerson et al observed significant
temperature heterogeneity along the
coronary arteries of these dogs using an
infrared camera (right panel). 4An infrared camera image
shows marked temperature
heterogeneity over the
surface of an atherosclerotic
carotid plaque
10. Inverse Correlation of pH and temperature (ºC)
in endartherectomized human carotid plaques
Naghavi et al. Atherosclerosis, 2002
11. Naghavi et al developed a
multi-channel thermography
basket catheter to measure
temperature heterogeneity over
vessel wall of atherosclerotic
animals. They observed higher
average temperature as well as
temperature heterogeneity in
femoral arteries of
atherosclerotic dogs
compared to their carotid
arteries which are free of
disease. 5
13. Temperature Heterogeneity in Aorta of
Watanabe vs. Normal Rabbits
Temperature heterogeneity in
aortae of atherosclerotic
Watanabe rabbits
No temperature heterogeneity
in aortas of normal New
Zealand rabbits
14. • Stefanadis and colleagues from Athens later used a
thermography catheter to demonstrate in vivo thermal
heterogeneity in human atherosclerotic coronary arteries.
• They observed that temperature was constant within the
arteries of the control subjects, whereas most
atherosclerotic plaques showed higher temperature
compared with the healthy vessel wall.
• Temperature differences between atherosclerotic plaque
and healthy vessel wall increased progressively from
patients with stable angina to those with acute myocardial
infarction. 6
Thermal Heterogeneity – Clinical SyndromeThermal Heterogeneity – Clinical Syndrome
16. • In subsequent studies, Stefanadis,
Diamantopoulos, and colleagues studied 60
patients with coronary heart disease (CHD) and
20 sex- and age-matched controls without
CHD.
• They found strong correlations between C-
reactive protein (CRP) and serum amyloid A
(SAA) with the temperature differences.7
17. • Toutozas, Stefanadis and colleagues also
reported a strong correlation between
remodeling index and temperature
difference (DT) between the
atherosclerotic plaque and the healthy
vessel wall in patients with acute
coronary syndromes. 8
• They also showed that serum MMP-9
concentration is correlated with
temperature difference in patients with
acute coronary syndromes. 9
18. • In another set of clinical studies on 86 patients
undergoing a successful percutaneous
intervention, Stefanadis et al found that during a
follow-up period of 17.88 +/- 7.16 months,
temperature difference between the
atherosclerotic plaque and the healthy vessel
wall was a strong predictor of adverse cardiac
events. 10
• Of clinical importance, Stefanadis et al. found
patients on statins show significantly less
temperature heterogeneity comparing to those
who did not receive statins. 11
19. As reported in this issue of VP Watch, Stefanadis et al
reported the effect of statin therapy on plaque
temperature. 12
They measured the temperature differences between the
atherosclerotic plaque and the proximal vessel wall
using a thermography catheter. 12
The statistical analysis showed that the mean value of
temperature differences was higher in the untreated
group compared to those who treated with statin. 12
20. • Stefanadis and colleagues also showed a
progressive increase in temperature
difference by type of clinical syndrome:
- Statin group
• effort angina: 0·24±0·15
• unstable angina: 0·26±0·26
• acute MI: 0·40±0·28
P<0·05
-Untreated group
- effort angina: 0·41±0·26
- unstable angina: 0·44±0·28
- acute MI: 0·84±0·52
21. Conclusion:
• Intravascular thermography is a novel approach
for detection of inflamed vulnerable plaques.
• Patients on statin treatment produce less heat
from the culprit coronary plaque than those not
treated.
• Statins have a favorable effect on heat release
from hot plaques.
22. Questions:
• How accurate is the measurement of vessel wall
temperature in the presence of flowing blood?
• Is thermography per se enough to make clinical decision
or it has to be combined with other anatomical imaging
information about plaque?
• Once a “hot plaque” is found, how can we know if it is an
inflamed plaque at risk of rupture or an inflamed plaque
which is already ruptured?
• What would be the treatment of choice once “hot plaques”
are found? Stenting with drug-eluting stent? Heating?
Cooling? Killing macrophages with PDT? or aggressive
systemic therapy?
23. References
1. Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999;340:115-26.
2. Casscells W, Hathorn B, David M, Krabach T, Vaughn WK, McAllister HA, Bearman G, Willerson JT. Thermal detection of cellular
infiltrates in living atherosclerotic plaques: possible implications for plaque rupture and thrombosis. Lancet. 1996;347:1447-51.)
3. Naghavi et al. pH Heterogeneity of human and rabbit atherosclerotic plaques; a new insight into detection of vulnerable plaque.
Atherosclerosis. 2002 Sep;164(1):27-35.
4. Thermography: A Novel Approach to Identify Plaques at Risk of Rupture and/or Thrombosis. Mohammad Madjid, Morteza Naghavi,
James T. Willerson, Ward Casscells, In “The Vulnerable Atherosclerotic Plaque: Understanding, Identification and Modification” edited
by Valentin Fuster, Futura Co., NY, 2002
5. Gul K, O'Brien T, Siadaty S, Madjid M, Mohammadi RM, Tewatia T, Willerson JT, Casscells W, Naghavi M. Coronary thermosensor
basket catheter with thermographic imaging software for thermal detection of vulnerable atherosclerotic plaques. J Am Coll Cardiol.
2001;37:18A.
6. Stefanadis C, Diamantopoulos L, Vlachopoulos C, Tsiamis E, Dernellis J, Toutouzas K, Stefanadi E, Toutouzas P. Thermal
heterogeneity within human atherosclerotic coronary arteries detected in vivo: A new method of detection by application of a special
thermography catheter. Circulation. 1999;99:1965-71.
7. Stefanadis C, Diamantopoulos L, Dernellis J, Economou E, Tsiamis E, Toutouzas K, Vlachopoulos C, Toutouzas P. Heat production of
atherosclerotic plaques and inflammation assessed by the acute phase proteins in acute coronary syndromes. J Mol Cell Cardiol.
2000;32:43-52.
8. Toutouzas MK, Stefanadis CM, Vavuranakis MM, Tsiamis ME, Tsioufis MC, Pitsavos CM, P.M. T. Arterial remodeling in acute coronary
syndromes: correlation of IVUS characteristics with temperature of the culprit lesion. Circulation. 2000;102:II-707.
9. Toutouzas K, Stefanadis C, Tsiamis E, Vavuranakis M, Tsioufis C, Tsekoura D, Vaina S, P. T. The temperature of atherosclerotic
plaques is correlated with matrix metalloproteinases concentration in patients with acute coronary syndromes. J Am Coll Cardiol.
2001;37:356A.
10. Stefanadis C, Toutouzas K, Tsiamis E, Stratos C, Vavuranakis M, Kallikazaros I, Panagiotakos D, Toutouzas P. Increased local
temperature in human coronary atherosclerotic plaques: an independent predictor of clinical outcome in patients undergoing a
percutaneous coronary intervention. J Am Coll Cardiol. 2001;37:1277-83.
11. Stefanadis C, Toutouzas K, Tsiamis E, Vavouranakis M, Kallikazaros I, Toussoulis D, Vaina S, Voutsas A, Pitsavos C, Toutouzas P.
Patients with coronary artery disease under statin treatment have decreased heat release from culprit lesions: new insights in the
nonlipid effects of statins. Eur Heart J. 2001;22:28 C.
12. C. Stefanadis et al. Statin treatment is associated with reduced thermal heterogeneity in human atherosclerotic plaques; European
Heart Journal 2002;23(21):1664-1669
