SHAPE Society

1. Plaque Characterization with
PET-CT
Ahmed Tawakol, M.D.
Cardiology Division
Massachusetts General Hospital &
Harvard Medical School

2. Vascular inflammation is an
attractive target for the detection
of high-risk plaques.

3. Inflammatory Markers Predict Coronary Events
Ridker PM et al. N Engl J Med 2000;342:836
4
3
2
1
1
RelativeRiskofFuture
CoronaryEvents
Quartile of Inflammatory Marker
hs-CRP
2 3 4
SAA
IL-6
sICAM-1

4. Inflammation is an Important Participant in
All Phases of Atherothrombotic Disease
• Lesion initiation
• Lesion progression
• Plaque Rupture
• Thrombosis

5. Imaging technologies that
characterize plaque inflammation
may prove useful for assessment of
risk of an ischemic event.

6. Nuclear Methods to
Image Inflammation
• Nuclear probes long been used to non-invasively
localize inflammation in humans.
• Examples:
– 67
Ga citrate,
– 111
In- or 99m
Tc-labeled leukocytes,
– 111
In-labeled IgG.
• Perhaps the best clinically available method is FDG-
PET

7. FDG Uptake Reflects Glycolysis
Adapted from: Hughes: Thorax, Volume 51(2S) 16S-22S
K1
18
FDG 18
FDG 18
FDG
K2
18
FDG-6-phosphate
Glycogen
Glycolysis
Hexokinase
K3
Vessel
Cell
transporter protein
x
x

8. Metabolic Basis for Using FDG-PET
for Macrophage Imaging
• Macrophages:
– Have high basal metabolic rates,
– Rely on external glucose source as fuel (macrophages
do not store glycogen)
– Increase glucose consumption further when activated.
• FDG uptake by inflamed tissues is 10-20 times
that of most other tissues.
• FDG uptake is often higher in inflammatory tissue
than in tumor cells.

9. Increased FDG Uptake has
been Observed in Human
Atherosclerotic Plaques

10. Increased FDG Uptake in Vascular
Inflammatory Diseases
Increased FDG uptake has been reported in:
-Takayasu's arteritis,
-Giant cell arteritis,
-Polymyalgia rheumatica and
-Nonspecific aortitis
-Patients with atherosclerosis

11. Increased FDG Uptake Observed in
Symptomatic Carotid Disease
Symptomatic
CarotidStenosis
Asymptomatic
CarotidStenosis
PET CT Co-Registered Image
J.H.F. Rudd et al,. Circulation 2002

12. Can FDG uptake, (PET), be used
to measure vascular inflammation?
-Animal study

13. PET-FDG Methods
Histology3 hr
PET
ImagingFDG administered
(IV) to balloon-
injured,
cholesterol-fed
atherosclerotic
rabbits
+/- 16s CT Angiography

14. Rabbit Model: Histopathology
H&E Trichrome RAM-11
InflamedFibrous
Tawakol, JNC 2005

15. Co-Registered Control Rabbit Aorta ImagesPETCT
AxialSagittal

16. Co-Registered Atherosclerotic Rabbit Aorta Images
Axial
PETCT
Axial

17. P<0.001, r=0.79
FDG Uptake vs. Inflammation in Atherosclerotic Rabbits
Vessel Inflammation
(% RAM-11 Staining)
FDGUptake
(%ID/gm*103
)
0
20
40
60
80
100
120
140
0 >0-5 >5-15 >15Blood Activity

18. P<0.0001,
r =0.93
PET - SUV vs. Inflammation in Atherosclerotic Rabbits
Inflammation
(% RAM-11 Staining)
0 10 20 30
FDGUptake
(SUV)
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6

19. Plaque inflammation can
be characterized with
FDG-PET

20. Can FDG-PET be used to
measure vascular
inflammation in humans?

21. Carotid PET Study
Histologic
correlationCEA
17 patients
w carotid
stenosis
scheduled
for CEA
FDG-
PET
Merged
with MRI
or CT

22. Patient 1: Low FDG Uptake

23. Trichrome
Collagen-rich plaque
Thick Fibrous Cap
Low lipid content
CD68
<1% plaque area
composed of
inflammatory cells
Patient 1 Histology

24. Patient 2: High FDG Uptake

25. CD68 Stain
20-30% plaque area
composed of
inflammatory cells
Trichrome
Thin Fibrous Cap
(50 microns)
Large necrotic core
Patient 2 Histology

26. Carotid FDG Uptake

27. FDGUptake(T/B)
Macrophage Staining (% plaque area)
Inflammation vs. FDG Uptake (PET)
N=10
P<0.0001
r=0.82
J
J J
JJJ
JJJJJJJ JJJ JJ JJJ J JJJ
JJJ
J
J
J JJ
JJ J JJJ
JJ JJ J
J
J J JJJ
J
J JJ
J
JJ
JJ
J
J
J
J
J
J
J
J
J
J
J
J
J
J
0.5
1
2
3
0 5 10 15 20 25

28. FDGUptake(T/B)
Collagen Staining (% plaque area)
Collagen vs. FDG Uptake (PET)
J
J
J
J
J
J
J
J
JJ
J
J
0.5
1
2
3
50 60 70 80 90 100
P<0.01
r=-0.76

29. Smooth Muscle Cell Staining (%)
0 10 20 30 40 50
FDGUptake(T/B)
0.5
1.0
1.5
2.0
2.5
3.0
3.5
P=NS
Smooth Muscle Cells vs. FDG Uptake

30. Carotid FDG uptake
correlates with histological
evidence of inflammation.

31. Implications
• FDG-PET may be useful for non-invasive characterization of
vascular inflammation
• Technique has promise:
– for targeting therapies to patients at potentially higher risk for stroke
– as an end-point for drug testing
– to identify event-causing carotid plaques
• Findings warrant further verification in a larger patient
population.

32. Structural imaging (CT or
MR) is needed for PET
measurements

33. CT is useful for detection
and characterization of
coronary plaques

34. MPR of LAD in Cross SectionThin MIP
Detection of Plaque
Compared w IVUS:
Sensitivity 82%, Specificity 88%
Achenbach et al. Circulation 2004

35. r = 0.64, p < 0.001
Moselewski et al. AJC 2004
Plaque Area
Potential to detect and quantify coronary plaque

36. Plaque CompositionPlaque Composition
Leber et al JACC

37. MDCT Plaque Remodeling:
0.34 cm² 0.43 cm²
Achenbach et al. JACC 2004

38. Coronary CT is here now…

39. Coronary CT is here now…
Are we ready for Coronary PET-CT ?

40. PET-CT Characterization of Coronary Plaques:
Additional Technical Challenges
•Cardiac and respiratory motion
•Myocardial uptake of FDG
•Smaller volume of coronary plaques.

41. •Cardiac and respiratory motion
Gating
PET-CT Characterization of Coronary Plaques:
Additional Technical Challenges

42. •Cardiac and respiratory motion
Gating
•Myocardial uptake of FDG
PET-CT Characterization of Coronary Plaques:
Additional Technical Challenges

43. •Cardiac and respiratory motion
Gating
•Myocardial uptake of FDG
Suppression of myocardial FDG uptake
PET-CT Characterization of Coronary Plaques:
Additional Technical Challenges

44. Suppression of Myocardial FDG Uptake
• Relatively simple
• Healthy myocardium prefers lipids to
glucose
• High fat, low glucose diet results in
suppression of myocardial FDG uptake

45. Suppression of Myocardial FDG Uptake
after Atkins-Type Diet for 24 Hrs

46. •Cardiac and respiratory motion
Gating
•Myocardial uptake of FDG
Requires suppression
•Smaller volume of coronary plaques.
PET-CT Characterization of Coronary Plaques:
Additional Technical Challenges

47. •Cardiac and respiratory motion
Gating
•Myocardial uptake of FDG
Requires suppression
•Smaller volume of coronary plaques.
Are we limited by PET’s spatial resolution?
PET-CT Characterization of Coronary Plaques:
Additional Technical Challenges

48. •Cardiac and respiratory motion
Gating
•Myocardial uptake of FDG
Requires suppression
•Smaller volume of coronary plaques.
Not necessarily-
With PET, it’s about target-to-background ratio
PET-CT Characterization of Coronary Plaques:
Additional Technical Challenges

49. •Cardiac and respiratory motion
Gating
•Myocardial uptake of FDG
Requires suppression
•Smaller volume of coronary plaques.
Not necessarily-
With PET, it’s about target-to-background ratio
Lighthouse effect
PET-CT Characterization of Coronary Plaques:
Additional Technical Challenges

50. •Cardiac and respiratory motion
Gating
Myocardial uptake of FDG
Requires suppression
•Smaller volume of coronary plaques.
Higher target to background
•More specific tracers
PET-CT Characterization of Coronary Plaques:
Additional Technical Challenges

51. Novel Tracers
Potential Targets:
– Inflammation
• Scavenger receptor
• P2 purine receptors
• others
– Apoptosis
– Thrombus
– Neovascularization
– Others

52. Purine Receptor Imaging
18
F-Meth-Ap4A
Sagittal
Aorta
Transverse
Aorta
Coronal
Spine
Aorta
Micro-PET

53. P<0.001
r=0.87
AP4AUptake
(%ID/cc)
0.00
0.02
0.04
0.06
0.08
0.10
0-7 8-16 >16
Plaque Inflammation
(% Ram-11 Staining)
Ap4A uptake vs. Inflammation

54. Annexin V
Kietselaer BL, NEJM 2004

55. ConjugatedF
FreeF
ConjugatedF
FreeF
0
10
20
30(molce6equivalent/gmtissuex10-10
)
FlurochromeConcentration
Inflamed Ao
Control Ao
Targeting Scavenger Receptor-A:
Increased Uptake By Inflamed Plaques
P<0.001

56. •Cardiac and respiratory motion
Gating
Myocardial uptake of FDG
Requires suppression
•Smaller volume of coronary plaques.
Higher target to background
More specific tracers
•Improved instrumentation
PET-CT Characterization of Coronary Plaques:
Additional Technical Challenges

57. Improved Instrumentation
• Intravascular positron detectors
• Improved PET and PET-CT
• PET-MRI

58. Volume CT System
Canine heart
150 micron isotropic resolution
VCT Lab in Bldg 149
Detector
Tube

59. Crossflex 3 x 18 mm
Stent
VCT MDCT
150 x 150 x 150µ 650 x 650 x 1250µ

60. Case:
Middle Aged Woman w CP

64. Could we have intervened and prevented the MI?
What if… we also detected a high degree of plaque inflammation?

65. Acknowledgements
Cardiology
• Kusai Aziz, MD
• Gregory Bashian, MD
• Henry Gewirtz, MD
• Alex Morss, MD
• James Muller, MD
• Raymond Migrino, MD
• Jane Sherwood, RN
• Jeffrey Swanson, BS
Neurology
• Karen Furie, MD
Radiology
• Suhny Abbara, M.D.
• Nathaniel Alpert, PhD
• Ali Bonab, PhD
• Thomas Brady, MD
• Ricardo Curry, MD
• Maros Ferencik, MD
• Alan Fischman, MD, PhD
• Denise Hinton, PhD
• Udo Hoffmann, MD
• Koen Nieman, MD
Pathology
• Shahinaz Bedri, MD
• Stuart Houser, MD
• James Stone, MD