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Molecular Imaging of Coronary Plaques

Daniel S. Berman, MDDirector, Cardiac Imaging

Cedars-Sinai Heart Institute

CSMC

Professor of MedicineDavid Geffen School of Medicine at UCLA

CSMC20113

Zahi A. Fayad, PhD, FAHA, FACCP f f R di l d M di i (C di l )Professor of Radiology and Medicine (Cardiology) 

Director, Translational and Molecular Imaging InstituteMount Sinai School of Medicine, New York, NY

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David Newby, MDM k D k MDMark Dweck, MD

University of Edinburgh

Understanding CAD is ChangingUnderstanding CAD is Changing

TCFA with Cap RuptureFibroatheroma: Stable Plaque

Narula & Virmani, 1999Narula & Willerson, JACC (ed)Narula & Willerson, JACC (ed)

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Anatomical level

Anatomical to Molecular ImagingTissue level

Cellular and molecular Level

Imaging Probes

Sensitivity

PET MRI CT

Payload required

RadioactiveSmall Molecules

ParamagneticSuperparamagnetic

Radiodense

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Imaging Probes

Sensitivity

PET MRI CT

Payload required

RadioactiveSmall Molecules

ParamagneticSuperparamagnetic

Radiodense

Orders of Magnitude in Drug (Contrast Agent) Dosing:Exploiting the Exploratory IND (eIND) Mechanism

Modality “Typical” Intravenous Human Dose (g)

CT 75 cc of 930 mM solution = 56 g

MRI 15 cc of 500 mM solution = 7 gMRI 15 cc of 500 mM solution 7 g

- - - - - - - - - - 2 Regular Strength Tylenol = 600 mg

Optical (NIR) 5 cc of a 1 mM solution = 5 mg

- - - - - - - - - - FDA definition of micro-dosing = 100 µg

SPECT 20 mCi (10,000 Ci/mmol) = 2 µgeIND‐

PET 20 mCi (10,000 Ci/mmol) = 2 µg Eligible

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FDG-PET CTa Fused

FDG accumulationRate/sec

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FDG Uptake in Carotid Artery Disease

Rate/sec

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P<0.01

symptomaticasymptomaticSymptomsNo symptoms

Weissberg P et al., Circulation 2004

Simvastatin Attenuates Plaque Inflammation

Tahara et al JACC 2006

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Tawakol et al JACC 2006

Measuring atherosclerosis FDG‐PET/CT

18F‐FDG‐PET/CT imaging5• Identifies cells with increased metabolic activity

• Measures plaque glycolysis (inflammation)

• Used to assess changes in plaque

CT

CT

Used to assess changes in plaque inflammation 

• Statins, anti‐inflammatory drugs, TZDs

• Predictor of future risk of atherothrombosis

PET/C

1Rudd et al. Circulation. 2002;105;2708–2711; 2Rudd et al. J Am Coll Cardiol. 2010;55:2527–2735; 3Tahara et al. J Am Coll Cardiol. 2006;48:1825–1831; 4Lee et al. J Nucl Med. 2008;49:1277–1282; 5Fayad et al. The Lancet 2011;378:1547‐1559.

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FDG Visualization of Inflamed Coronary Plaque

FDG Visualization of Inflamed Coronary Plaque

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Cheng, et al JNM in press 2012

• 27 PCI patients studied with FDG PET/CT1-6 days p PDI: 20 STEMI; 7 stable CAD• Increased uptake in: 12/20 STEMI; 1/7 Stable

Figure 3AXIALCORONAL SAGITTAL

LAD STEMI

FDG Uptake at Stent Site in Acute STEMI

RCA STEMI

LCX STEMI

Cheng, et al JNM in press 2012

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AXIALCORONAL SAGITTAL

RCA stent for stable CAD

Absence of FDG Uptake at Stent Site in Stable CAD

LAD stent for stable CAD

Cheng, et al JNM in press 2012

Sinusas lecture: ASNC 2009

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Direct Imaging of Myocardial Ischemia (FDG)

He et al, Narula, Jain. Circulation 2003

18Fluoro-Deoxy Glucose‘The ring of fire’

Aortic Ring InflammationDweck et al. Circulation 2012;125:in press

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Sodium 18FluorideAortic Stenosis

Dweck et al. Circulation 2012;125:76-86

18Fluoro-Deoxy Glucose‘The ring of fire’

Dweck et al. Circulation 2012;125:76-86

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Calcification more importantthan Inflammation

Dweck et al. Circulation 2012;125:76-86

Dweck et al JACC 2012

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F-18 NaF Uptake in Coronary Plaque

Dweck M…Newby D ACC 2012

10 year FRS for Controls and Patients with CAC who did and did

not have 18F-NaF uptake

Dweck et al JACC 2012

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binding followed by

Annexin V

Detection of theapoptotic cell

TNF orFas Ligand

Tc-99m Annexin V: Probe for Vulnerable Plaque

translocasescramblase

floppase

2D-crystallization

translocase

death domainsmediated signaling

activation of theexecutioner of apoptosis

floppase

?

TNFR orCD95 + +-

Courtesy Chris Reutlingsperger, Maastricht University

Old TIA Recent TIAA B

ANT

L

AnnexinAnnexin--V Imaging For ApoptosisV Imaging For Apoptosis

C D

Transverse

Coronal

AnnexinIHC inEndarterectomy

Keitselaar, Hofstra, Narula; NEJM 2004

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RGD tracer uptake is increased inatherosclerotic plaque

Oil Red O 18F RGD uptake αvβ3 Autoflour

Tamarappoo, et al 2010

Direct Imaging of Myocardial Ischemia (FDG)

He et al, Narula, Jain. Circulation 2003

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Molecular Imaging to Detect Vulnerable PlaqueClinial Applications Emerging in 2020

Langer et al. JACC 2008;52:1-12.

Molecular Imaging Across CAD Spectrum

Coronary Calcium/

Stenosis/Perfusion

FunctionGeometry

ConventionalImaging

Coronary Atherosclerosis

MyocardialIschemia/Infarction

HeartFailure

Plaque

MolecularImaging

Disease ActivityPlaque

VulnerabilityRemodeling

Guiding Specifictherapy

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