Thermography: a Novel Thermography: a Novel Approach for Identification of Approach 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, MD Morteza Naghavi, MD

Disclosure: Disclosure:

Volcano Therapeutics, Inc.Volcano Therapeutics, Inc.

Holy Grail of Cardiology

How can we identify vulnerable plaques?How can we identify vulnerable plaques?

Atherosclerosis:Atherosclerosis:

An inflammatory diseaseAn inflammatory disease

Cardinal Signs of InflammationCardinal Signs of Inflammation

Pain

Redness

HEAT

Swelling

Inflammation

HypothesisHypothesis

Vascular inflammation and plaque Vascular inflammation and plaque vulnerability can be identified by vulnerability can be identified by the heat released from activated the heat released from activated macrophages in the plaque.macrophages in the plaque.

RationaleRationale Macrophages are metabolically very active with Macrophages 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 increased This high metabolic rate can lead to increased heat production in areas of macrophage heat production in areas of macrophage accumulation while it cannot be observed in accumulation while it cannot be observed in areas of smooth muscle cell accumulation in the areas 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

Temperature heterogeneity over the surface Temperature heterogeneity over the surface of an endartherectomized carotid plaqueof an endartherectomized carotid plaque

Casscells W et al. Lancet. 1996;347:1447-51

While macrophage/monocytes (with high metabolic rate) density was While macrophage/monocytes (with high metabolic rate) density was related to higher temperature, such a relation wasn’t seen with smooth related 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)

Inverse relation between temperature Inverse relation between temperature difference and cap thicknessdifference and cap thickness

Infrared experiments show Infrared 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

Inverse correlation of pH and temperature (ºC) in Inverse correlation of pH and temperature (ºC) in endartherectomized human carotid artery plaques endartherectomized human carotid artery plaques

Naghavi et al. Atherosclerosis, 2002, in press

In vivo StudiesIn vivo Studies

Thermosensor Basket CatheterThermosensor Basket Catheter

Basket CatheterBasket CatheterThermal Resolution 0.01 CThermal Accuracy 0.02 CSize (2-4 F expandable) Spatial ResolutionSpatial Resolution 0.5 mm 0.5 mm Sampling RateSampling Rate 5-25 per sec 5-25 per sec Number of wall sensorsNumber of wall sensors 4 4 Blood sensorBlood sensor 1 1

Dog Model of AtherosclerosisDog Model of Atherosclerosis

Femoral Artery

Atherosclerotic

With Temperature Heterogeneity

Carotid Artery

Non-Atherosclerotic

Without Temperature Heterogeneity

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

Temperature heterogeneity in Temperature 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

Infrared angio-thermography Infrared angio-thermography catheter catheter

Infrared angio-thermography Infrared angio-thermography cathetercatheter

Thermal resolution of 0.01º C Thermal resolution of 0.01º C Spatial resolution of 100 microns. Spatial resolution of 100 microns. Real-time image reconstruction software Real-time image reconstruction software 1mm window 1mm window Two-dimensional and virtual longitudinal color-Two-dimensional and virtual longitudinal color-

coded thermographic images coded thermographic images We have tested the catheter in our phantom model We have tested the catheter in our phantom model

simulating “hot plaques” with continuous flow of simulating “hot plaques” with continuous flow of normal saline in a silicon tube with multiple hot normal saline in a silicon tube with multiple hot spotsspots

In vivo In vivo studies are under way to confirm our findings studies are under way to confirm our findings from from ex vivoex vivo studies. studies.

Human StudiesHuman Studies

Our findings have been confirmed Our findings have been confirmed in clinical settings by the Hellenic in clinical settings by the Hellenic group of Stefandis and group of Stefandis and colleagues, and also in Belgium colleagues, and also in Belgium and the Netherlands. and the Netherlands.

In vivo In vivo thermal heterogeneity within human thermal heterogeneity within human atherosclerotic coronary arteries atherosclerotic coronary arteries

Stefanadis et al. Circulation. 1999;99:1965-71

The risk of an adverse cardiac event in patients with high The risk of an adverse cardiac event in patients with high temperature difference is significantly higher than that in temperature difference is significantly higher than that in

ACS patients with low temperature difference ACS 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

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

Administration of atorvastatin in patients with coronary artery Administration of atorvastatin in patients with coronary artery disease results in less heat production from the culprit lesion and disease 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

Tem

pera

ture

diff

eren

ce

2.5

2.0

1.5

1.0

.5

0.0

-.5

P<0,001

Toutozas et al reported correlation between Toutozas et al reported correlation between temperature and expansive remodeling and temperature and expansive remodeling and MMP-9 concentration MMP-9 concentration

Verheye et al showed that temperature Verheye et al showed that temperature

heterogeneity was reduced after change from heterogeneity 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;37:356AVerheye et al. Circulation Supple Oct. 2001;

FutureFuture

CombinationCombination with anatomical imaging methods with anatomical imaging methods to yield additional functional information about to yield additional functional information about the lesionthe lesion

FutureFuture

A combination of A combination of ultrasound and ultrasound and thermography could thermography could provide thermal, and provide thermal, and structural data structural data valuable for detecting valuable for detecting and determination of and determination of functional status of functional status of plaques. plaques.

IVUS or OCT + ThermographyIVUS or OCT + Thermography

Activity Activity ThermographyThermographyAnatomy (shape)Anatomy (shape) IVUS - OCTIVUS - OCTElasticityElasticity ElastographyElastographyChemical compositionChemical composition Integrated RF Integrated RF

Backscattering Backscattering SpectroscopySpectroscopy

Conclusion:Conclusion: As cardiology enters into the arena of vulnerable plaque As cardiology enters into the arena of vulnerable plaque

and vulnerable patient, along with the other emerging and vulnerable patient, along with the other emerging diagnostic techniques such as OCT, elastography, and diagnostic techniques such as OCT, elastography, and near infrared spectroscopy, near infrared spectroscopy, thermographythermography catheter is catheter is ready to enter into cat labs.ready to enter into cat labs.

Clinical studies in 2002 and 2003 will shed light on how Clinical studies in 2002 and 2003 will shed light on how we can utilize these emerging technologies to improve we can utilize these emerging technologies to improve our ability for identifying patients at extreme risk of our 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-invasive The ultimate solution must be sought in non-invasive techniques where by developing a proper combination of techniques where by developing a proper combination of novel serum markers and non-invasive imaging tools the novel serum markers and non-invasive imaging tools the world of cardiology would be ready to world of cardiology would be ready to attack the long-attack the long-standing dilemma of out-of-hospital sudden heart attack standing dilemma of out-of-hospital sudden heart attack and coronary death.and coronary death.

ThermaStar Catheter

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

Center for Vulnerable Plaque ResearchCenter for Vulnerable Plaque ResearchHouston, TexasHouston, Texas

Khawar Gul, MDKhawar Gul, MDSaid Siadaty, MDSaid Siadaty, MDSameh Naguib, MDSameh Naguib, MDBujin Gu, PhDBujin Gu, PhDReji John, MDReji John, MDBasit Malik, MDBasit Malik, MDKC Courian, MD KC Courian, MD Roxana Grausu, MD Roxana 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