SPECT/CT for Atherosclerosis Imaging: The Future is Clear

Daniel S. Berman, MDDirector, Cardiac Imaging

Cedars-Sinai Medical Center

Professor of MedicineDavid Geffen School of Medicine at UCLA

DISCLOSUREDaniel S. Berman, M.D.

declares the following relationships:

Grant Support: BMS Medical Imaging, Astellas, GE Amersham, Mallinckrodt-Tyco Speakers Bureau: Astellas Consultant: Mallinckrodt-Tyco

Spectrum Dynamics Royalties: Cedars-Sinai Medical Center Stockholder: Spectrum Dynamics

MDCT Technical Parameters 2005

Four major manufacturers with 64 slice CT

• ~.4-.5 mm3 isotropic voxels

• Temporal resolution: 165-210 ms for 180 (330-420 ms rotation time)

• Cardiac study in 5-10 beats

76 M #3311-1526

Sx: ASYMPTOMATICRISK FACTORS: CHOLESTEROLRESTING ECG: NORMAL

RESULTS OF EXERCISE:DURATION: 9:39HR: 131 (91% MPHR) BP: 134/74 150/72CLINICAL RESPONSE: NONISCHEMICECG RESPONSE: NONISCHEMIC

73 M #3311-1526EBT RESULTS

Location # Calcified Lesions

Calcified Plaque Volume (mm3)

Calcium Score

LAD 3 97 126

* 32th percentile

76 M #3311-1526CTA

76 M 11/3/05 #3311-1526Stress MIBI

Rest Tl

Stress MIBI

Rest Tl

Stress MIBI

Rest Tl

Stress MIBI

Rest Tl

76 M #3311-1526

A B C D

Calcification Soft Plaque

D2

Lesion

76 M #3311-1526

Limitations of Anatomic Imaging Little information regarding disease activity

• Two patients: with mild coronary calcium, score ~100 discovered on screening 1 yr ago and placed on statin, ASA, and ACE

• Patient A: recently symptomatic• Patient B: still asymptomatic• Both undergo CT coronary angiography, and

are found to have 75% mid LAD stenosis by CT angio AND extensive non-calcified plaque by IVUS

• Should the treatment be the same?

It will be!

Why not catheterize all suspected CAD patients?

Occulo-stenotic reflex*: unnecessary PCI• Immediate Risk – Death (rare)– Clinical MI (uncommon)– Subclinical MI (more frequent)– Branch occlusion (frequent)

• Late risk– Possible higher mortality risk than medical therapy in patients without ischemia

• Costs

• Objective measurements of perfusion and function• Accurate for assessing risk of cardiac death (CD)• Relationship of degree of abnormality to risk• Identifies likely to benefit from revascularization• Proven as cost effective “gatekeeper” to the cath labLimitations• Cannot detect early atherosclerosis• May underestimate extent of CAD

*Topol

Cardiac CT

Limitations• Densely calcified plaques: nondiagnostic• Dependence on low HR and regular rhythm• Radiation, iodinated contrast• Overestimation of stenosis• No information regarding plaque “activity”

• No Hx CAD• Known CAD • Post-PTCA• Post-CABG • Men and Women• Sx and Asx • DM• Elderly

SPECT: Risk Increases as a Function of Stress Perfusion Abnormality

Extent/Severity of Perfusion Defects

Ris

k*

*Adjusted or unadjusted

Guidelines for Clinical Use of Cardiac Radionuclide Imaging 2003

Data from over 50,000 patients

log

Haz

ard

Rat

io0

12

34

56

% Myocardium Ischemic0 12.5% 25% 32.5% 50%

Medical Rx

Revasc*

*

*p<0.001

Adjusted† Risk of Cardiac Death vs MPS ischemiaRevascularization vs Medical Rx

Hachamovitch, et al Circulation 2003

†Adjusted for predictorsof revascularization as well asclinical, hx, stress SPECT data

VISUAL SSSSTANDARDTPD

stenosis ≥ 50%

1.00.75.50.250.00

1.00

.75

.50

.25

0.00

1 - Specificity

Sens

itivi

ty

Changes in Analytic SoftwareAutomatic Total Perfusion Deficit

**

* P < 0.05

Slomka, et al J Nucl Cardiol 2005;12:66-77

When was the last fundamental change in the detector technology?

Nuclear Cardiology: Single Photon Imaging

When was the last fundamental change in the detector technology? 1958: Hal Anger patented the current NaI (Tl) detector/photomultiplier array configuration (#3011057)

Nuclear Cardiology: Single Photon Imaging

Resolution & Contrast - a Comparison

Total counts: 2,500K Total counts: 2,500K

Spectrum-Dynamics

Coronal

Sagittal

Transverse

Net acquisition time: 9 minutesFrame angle: 3°, positions:60, 9sec per position

Net acquisition time: 1 minutepositions:40, 1.5sec per position

Millennium VG a

Spectrum Dynamics Measured Contrast

Target A: 1.6

Target B: 2.2

Millenium Measured Contrast

Target A: unseen

Target B:1.3

3:12:1

Cardiac Phantom

Conventional• No AC• Acquisition time 12.5 m

Spectrum Dynamics• No AC• Acquisition time 1.25 m

•Tc99m

•Heart : .5mCi•Background : 2mCi (.19mCi/l)•Liver : .23mCi (.19mCi/liter)

Cardiac SPECT ImprovementsImplications for CHD and Atherosclerosis Testing

• Increased sensitivity: reduced acquisition time – Dynamic cardiac SPECT:

• time-activity curves for blood and myocardium• Compartment modeling results in:

– Absolute blood flow (voxel)– Coronary Flow Reserve: a region compared to itself– Coronary endothelial function (CPT)

• Increased resolution:– Potential to directly image plaque

• quantify “activity” of atherosclerosis

SPECT/CT

Philips Precedence Siemens Simbia

Dynamic SPECT for Molecular Imaging

• Noninvasive biopsy• Specific diagnosis

CT for Structure

DynaQ™ hybrid scanner

Who needs PET/CT or SPECT/CT

• Equivocal nuclear• Follow-up studies after initial CT (or

nuclear)• Why simultaneous: molecular imaging

Comparative Spatial Resolution and Tracer Concentration

SPECT PET ECHO MRI CT

Resolution (mm)

7-15 3-10 < 1 < 1 < 1

Tracer Concentration

pM-nM* pM-nM* 10-100 μM

10-100 μM

10-100 μM

*picomolar-nanomolar concentrations employed are key advantage of the radionuclide methods

translocasedeath domains

mediated signaling

activation of theexecutioner of apoptosis

scramblase floppase

?

binding followed by2D-crystallization

Annexin VDetection of the

apoptotic cellTNF or

Fas Ligand

TNFR orCD95 + +-

Courtesy Chris Reutlingsperger, Maastricht University

Tc-99m Annexin V: Probe for Vulnerable Plaque

Old TIA Recent TIAA B

C D

Transverse

Coronal

ANT

L

AnnexinIHC inEndarterectomy

Keitselaar, Hofstra, Narula; NEJM 2004

Annexin-V Imaging For ApoptosisAnnexin-V Imaging For Apoptosis

Annexin V-Tc99mautoradiograph

Digital photographdissected apoE-/- aorta

H & E

Histological AHA classificationStage IVa (vulnerable plaque)

Tc-99m Annexindissected aorta apoE -/- mouse

C. MoriStanford, 2005

99mTc-Annexin V SPECT for In Vivo Detection of Atherosclerotic Lesions in Porcine Coronary Arteries

Johnson et al. J Nucl Med 2005;46:1186-93

Scan positive

Scan negative

Imaging of Atherosclerotic Plaques Using a Human Antibody Against the Extra-Domain B of Fibronectin

Matter et al. Circ Res 2004;95:1225-33

125I-labeled L19 to atherosclerotic plaques in ApoE-/- mice.

OxLDL AB uptake reflects plaque burden

R=0.95P<0.001

0.00

0.05

0.10

0.15

0.20

0.25

0 500 1000 1500 2000Aortic weight (mg)

(%ID

)

MDA2

125I-MDA2 Uptake in Mouse and Rabbit Atherosclerotic Plaques

Tsimikas J Nucl Cardiol 1999, ATVB 2001

IL2 SPECT in 2 pts with bi-lateral carotid plaques

A Annovazzi e A Signore ACC 2005

IL2 SPECT: Carotid T/B ratios in patients from LS before and after 3

month treatment

1

1,5

2

2,5

3

3,5

Before therapy After therapy

99m

Tc-

IL2

upta

ke (C

/B r

atio

s)

Atorvastatin

1

1,5

2

2,5

3

3,5

Before diet After dietHypocholesterole

mic diet

SPECT for imaging vulnerable plaquePotential to Image Multiple Molecular

Processes Simulaneously • Apoptosis

• IK-17

• Oxidized LDL

• Interleukin 2

• Thrombus

• Activated platelets

• Neovascularization

Molecular ImagingNeeded Developments

• Discovery in molecular biology

• New probes (with FDA approval)

• Multimodality technology

– Structure/function

Post-processing software

• Reimbursement

SPECT/CT for Atherosclerosis Imaging• CT: quantify plaque volume

• SPECT or PET:

– quantify plaque activity

– Potential to quantify rest/stress blood flow

Advantage of SPECT

• Multiple tracers simlutaneously

• Possible wider availability of tracers and cameras

• Potential of SPECT• Increased sensitivity and resolution need to be realized