This document discusses a novel approach using thermography to identify vulnerable plaques. It hypothesizes that vascular inflammation and plaque vulnerability can be identified by the heat released from activated macrophages in plaques. Studies in animal models and humans found significant temperature heterogeneity over atherosclerotic arteries that correlated with macrophage density and markers of inflammation. A thermography catheter was developed and initial studies suggest it may help identify high-risk plaques by detecting areas of increased heat from macrophage activity. Larger clinical studies are still needed but thermography shows promise as a new technique for detecting vulnerable plaques when combined with other imaging methods.

1. Thermography: a NovelThermography: a Novel
Approach for Identification ofApproach for Identification of
Vulnerable PlaquesVulnerable Plaques
Mohammad Madjid, MD,Mohammad Madjid, MD,
Ward Casscells, MD,Ward Casscells, MD,
James T. Willerson, MD,James T. Willerson, MD,
Morteza Naghavi, MDMorteza Naghavi, MD

2. Disclosure:Disclosure:
Volcano Therapeutics, Inc.Volcano Therapeutics, Inc.

3. Holy Grail of Cardiology
How can we identify vulnerable plaques?How can we identify vulnerable plaques?

4. Atherosclerosis:Atherosclerosis:
An inflammatory diseaseAn inflammatory disease

5. Cardinal Signs of InflammationCardinal Signs of Inflammation
PainPain
RednessRedness
HEATHEAT
SwellingSwelling
InflammationInflammation

6. HypothesisHypothesis
Vascular inflammation and plaqueVascular inflammation and plaque
vulnerability can be identified byvulnerability can be identified by
the heat released from activatedthe heat released from activated
macrophages in the plaque.macrophages in the plaque.

7. RationaleRationale
 Macrophages are metabolically very active withMacrophages are metabolically very active with
a high turn-over rate of total ATP content.a high turn-over rate of total ATP content.
Newsholme P.Newsholme P. Biochem JBiochem J. 1989;261:211-8. 1989;261:211-8
 This high metabolic rate can lead to increasedThis high metabolic rate can lead to increased
heat production in areas of macrophageheat production in areas of macrophage
accumulation while it cannot be observed inaccumulation while it cannot be observed in
areas of smooth muscle cell accumulation in theareas of smooth muscle cell accumulation in the
absence of inflammatory cell infiltration.absence of inflammatory cell infiltration.
Bjornheden T.Bjornheden T. ArteriosclerosisArteriosclerosis. 1987;7:238-47. 1987;7:238-47

8. Temperature heterogeneity over the surfaceTemperature heterogeneity over the surface
of an endartherectomized carotid plaqueof an endartherectomized carotid plaque
Casscells W et al. Lancet. 1996;347:1447-51

9. While macrophage/monocytes (with high metabolic rate) density wasWhile macrophage/monocytes (with high metabolic rate) density was
related to higher temperature, such a relation wasn’t seen with smoothrelated to higher temperature, such a relation wasn’t seen with smooth
muscle cell density (with less metabolic activity)muscle cell density (with less metabolic activity)

10. Inverse relation between temperatureInverse relation between temperature
difference and cap thicknessdifference and cap thickness

11. Infrared experiments showInfrared experiments show
temperature heterogeneitytemperature heterogeneity
Our dog model of atherosclerosis develops
marked lesions in its coronary arteries (left panel).
We observed significant temperature
heterogeneity along the coronary arteries of these
dogs using an infrared camera (right panel).
An infrared camera image shows
marked temperature
heterogeneity over the surface of
an atherosclerotic carotid plaque

12. Inverse correlation of pH and temperature (ºC) inInverse correlation of pH and temperature (ºC) in
endartherectomized human carotid artery plaquesendartherectomized human carotid artery plaques
Naghavi et al. Atherosclerosis, 2002, in press

13. In vivo StudiesIn vivo Studies

14. Thermosensor Basket CatheterThermosensor Basket Catheter

17. Basket CatheterBasket Catheter
Thermal Resolution 0.01 C
Thermal Accuracy 0.02 C
Size (2-4 F expandable)
 Spatial ResolutionSpatial Resolution 0.5 mm0.5 mm
 Sampling RateSampling Rate 5-25 per sec5-25 per sec
 Number of wall sensorsNumber of wall sensors 44
 Blood sensorBlood sensor 11

18. Dog Model of AtherosclerosisDog Model of Atherosclerosis
Femoral Artery
Atherosclerotic
With Temperature Heterogeneity
Carotid Artery
Non-Atherosclerotic
Without Temperature Heterogeneity

19. Higher absolute temperature as well as temperature heterogeneity in femoral
arteries of atherosclerotic dogs compared to their carotid arteries which are
free of disease.
P<0.05

20. Temperature heterogeneity inTemperature heterogeneity in
atherosclerotic lesions of Watabae rabbitsatherosclerotic lesions of Watabae rabbits
Temperature heterogeneity
In aortae of atherosclerotic mice
No temperature heterogeneity
In aortae of normal mice

21. Infrared angio-thermographyInfrared angio-thermography
cathetercatheter

22. Infrared angio-thermographyInfrared angio-thermography
cathetercatheter
 Thermal resolution of 0.01º CThermal resolution of 0.01º C
 Spatial resolution of 100 microns.Spatial resolution of 100 microns.
 Real-time image reconstruction softwareReal-time image reconstruction software
 1mm window1mm window
 Two-dimensional and virtual longitudinal color-Two-dimensional and virtual longitudinal color-
coded thermographic imagescoded thermographic images
 We have tested the catheter in our phantom modelWe have tested the catheter in our phantom model
simulating “hot plaques” with continuous flow ofsimulating “hot plaques” with continuous flow of
normal saline in a silicon tube with multiple hotnormal saline in a silicon tube with multiple hot
spotsspots
 In vivoIn vivo studies are under way to confirm our findingsstudies are under way to confirm our findings
fromfrom ex vivoex vivo studies.studies.

23. Human StudiesHuman Studies
Our findings have been confirmedOur findings have been confirmed
in clinical settings by the Hellenicin clinical settings by the Hellenic
group of Stefandis andgroup of Stefandis and
colleagues, and also in Belgiumcolleagues, and also in Belgium
and the Netherlands.and the Netherlands.

24. In vivoIn vivo thermal heterogeneity within humanthermal heterogeneity within human
atherosclerotic coronary arteriesatherosclerotic coronary arteries
Stefanadis et al. Circulation. 1999;99:1965-71

25. The risk of an adverse cardiac event in patients with highThe risk of an adverse cardiac event in patients with high
temperature difference is significantly higher than that intemperature difference is significantly higher than that in
ACS patients with low temperature differenceACS patients with low temperature difference
Stefanadis et al. J Am Coll Cardiol. 2001;37:1277-83Stefanadis et al. J Am Coll Cardiol. 2001;37:1277-83

26. Stefanadis et al. J Mol Cell Cardiol. 2000;32:43-52
Strong correlation between C-reactive protein (CRP) (and serum
amyloid A (SAA) ) and the temperature differences

27. Administration of atorvastatin in patients with coronary arteryAdministration of atorvastatin in patients with coronary artery
disease results in less heat production from the culprit lesion anddisease results in less heat production from the culprit lesion and
less temperature difference.less temperature difference.
Stefanadis et al. Eur Heart J (in press)
StatinsNo statin
Temperaturedifference
2.5
2.0
1.5
1.0
.5
0.0
-.5
P<0,001

28.  Toutozas et al reported correlation betweenToutozas et al reported correlation between
temperature and expansive remodeling andtemperature and expansive remodeling and
MMP-9 concentrationMMP-9 concentration
 Verheye et al showed that temperatureVerheye et al showed that temperature
heterogeneity was reduced after change fromheterogeneity was reduced after change from
high to low-cholesterol diet in rabbits.high to low-cholesterol diet in rabbits.
Toutouzas et al. Circulation. 2000;102:II-707;
Toutouzas et al. J Am Coll Cardiol. 2001;37:356A
Verheye et al. Circulation Supple Oct. 2001;

29. FutureFuture
CombinationCombination with anatomical imaging methodswith anatomical imaging methods
to yield additional functional information aboutto yield additional functional information about
the lesionthe lesion

31. FutureFuture
A combination ofA combination of
ultrasound andultrasound and
thermography couldthermography could
provide thermal, andprovide thermal, and
structural datastructural data
valuable for detectingvaluable for detecting
and determination ofand determination of
functional status offunctional status of
plaques.plaques.

32. IVUS or OCT + ThermographyIVUS or OCT + Thermography
ActivityActivity ThermographyThermography
Anatomy (shape)Anatomy (shape) IVUS - OCTIVUS - OCT
ElasticityElasticity ElastographyElastography
Chemical compositionChemical composition Integrated RFIntegrated RF
BackscatteringBackscattering
SpectroscopySpectroscopy

33. Conclusion:Conclusion:
 As cardiology enters into the arena of vulnerable plaqueAs cardiology enters into the arena of vulnerable plaque
and vulnerable patient, along with the other emergingand vulnerable patient, along with the other emerging
diagnostic techniques such as OCT, elastography, anddiagnostic techniques such as OCT, elastography, and
near infrared spectroscopy,near infrared spectroscopy, thermographythermography catheter iscatheter is
ready to enter into cat labs.ready to enter into cat labs.
 Clinical studies in 2002 and 2003 will shed light on howClinical studies in 2002 and 2003 will shed light on how
we can utilize these emerging technologies to improvewe can utilize these emerging technologies to improve
our ability for identifying patients at extreme risk ofour ability for identifying patients at extreme risk of
coronary event, namely vulnerable patients.coronary event, namely vulnerable patients.
 The ultimate solution must be sought in non-invasiveThe ultimate solution must be sought in non-invasive
techniques where by developing a proper combination oftechniques where by developing a proper combination of
novel serum markers and non-invasive imaging tools thenovel serum markers and non-invasive imaging tools the
world of cardiology would be ready toworld of cardiology would be ready to attack the long-attack the long-
standing dilemma of out-of-hospital sudden heart attackstanding dilemma of out-of-hospital sudden heart attack
and coronary death.and coronary death.

34. ThermaStar Catheter
Not cleared by
the FDA and not
available for
commercial sale.

35. Center for Vulnerable Plaque ResearchCenter for Vulnerable Plaque Research
Houston, TexasHouston, Texas
Khawar Gul, MDKhawar Gul, MD
Said Siadaty, MDSaid Siadaty, MD
Sameh Naguib, MDSameh Naguib, MD
Bujin Gu, PhDBujin Gu, PhD
Reji John, MDReji John, MD
Basit Malik, MDBasit Malik, MD
KC Courian, MDKC Courian, MD
Roxana Grausu, MDRoxana Grausu, MD
Mohammad Madjid, MD, Ward Casscells, MD, James T. Willerson, MD, Morteza Naghavi, MDMohammad Madjid, MD, Ward Casscells, MD, James T. Willerson, MD, Morteza Naghavi, MD