1. No category

First Cardiac PET Imaging Meeting
Manchester Royal Infirmary 8 November 2012
Why Choose Cardiac PET?
Gary V. Heller, MD PhD
Professor of Medicine University of Connecticut School of Medicine
Farmington, CT
Cardiac PET: New Horizons
• Limitations of SPECT
• Advantages of PET
• PET procedures
• Novel information from PET
• New developments 2012
Growth of PET in the US:
Rubidium Generators, Estimated
Pros and Cons of SPECT MPI
•
Extensively validated, useful for cost-effective risk stratification and
patient management
•
Widely available in outpatient settings; technology “inexpensive”
•
Standardized protocols
•
Excellent procedural and clinical utilization guidelines
•
ACCF/ASNC Appropriateness Criteria: identify 27 “appropriate”
clinical indications
But..
•
Radiotracers not optimal
•
Time inefficient
•
Radiation dose
•
Attenuation correction not as robust
Brindis RG, et al. J Am Coll Cardiol. 2005;46:1587-1605.
Why PET 2012?
ƒ Availability of PET cameras: oncology
ƒ Availability of radiopharmaceutical Rb-82,
NH-13 ammonia
ƒ Improvement in acquisition protocols
ƒ Ability to undergo ECG-gated imaging, stress
and rest
ƒ Improvement in cardiac processing
ƒ Improvement in cardiac display
ƒ Excitement in the industry (new
radiopharmaceuticals, camera systems)
Options for Cardiac PET
ƒ Myocardial perfusion imaging for diagnosis, risk
stratification, CAD
ƒ Vasodilator stress
ƒ Dobutamine stress
ƒ Exercise (limited, but routine for F-18 in future)
ƒ
ƒ
ƒ
ƒ
Agents available: Rb-82, N-13 ammonia, O-15 water
Myocardial viability: FDG/perfusion agent
Cardiac sarcoid identification
New developments: blood flow, F-18 tracers for
perfusion, CHF tracers
PET Radiotracers
Characteristic
Rubidium-82
N-13 ammonia
O-15 water
18F-FDG*
Supplied
Generator
Cyclotron
Cyclotron
Cyclotron
Half-life
76 sec
9:96 min
2.09 min
109.7 min
First-pass
extraction
65%
80%
100%
N/A
Stress
Pharm >
Exercise
Pharm or
exercise
Pharm
N/A
Positron range
1.6 mm
0.28 mm
0.5 mm
0.10
Image quality
Very good
Excellent
Uninterpretable
Excellent
FDA approval
Yes
Yes
No
Yes
*Also F-18 flurpiridaz – perfusion tracer in development:
will provide exercise protocol
Comparison of Myocardial Perfusion
PET and SPECT Image Quality
Several potential advantages of PET MPI compared to
SPECT• Higher spatial resolution
• Greater counting efficiencies
• Robust attenuation correction
• Lower radiation exposure
• Faster protocols
Image quality scores for PET and SPECT
perfusion and ECG-gated scans
Bateman et al. JNC 2006; 13(1): 24-33
Prevalence of artifacts: PET vs SPECT
SPECT
PET
P value
No artifact
Minor artifact
19(17%)
49(44%)
0.0001
26(23%)
28(25%)
0.75
Significant artifact
64(57%)
33(29%)
0.0003
Major artifact
3(3%)
2(2%)
0.32
No GI uptake
45(40%)
100(89%)
<0.001
Minor GI uptake
19(17%)
5(4%)
0.0002
Significant GI uptake 46(41%)
6(5%)
<0.001
1(1%)
0.32
Major GI uptake
2(2%)
Bateman et al. JNC 2006; 13(1): 24-33
Pharmacologic Stress Myocardial
Perfusion Imaging
SPECT
Rb-82 PET
Myocardial Perfusion PET in Patients
with a Non-Diagnostic SPECT
233 consecutive
pts with a nondiagnostic
SPECT followed
by MP PET <90
days
2% NonDiagnostic
Abnormal
25%
Normal
73%
64% were women
Mean BMI 32
Mean age 62 yrs
Bateman, Circulation 108: IV-454, 2003.
Diagnostic Accuracy of PET Perfusion:
Meta Analysis of 19 Studies
n = 1442
Nandalur KR et al. Acad Radiol. 2008;15:444-451.
Diagnostic Accuracy, PET
Beanlands and Youssef JNC 2010;17:683
Diagnostic Accuracy: PET vs SPECT
DIAGNOSTIC ACCURACY BY BMI
DIAGNOSTIC ACCURACY BY GENDER
*P = 0.55
*P = 0.009
84%
69%
*P = 0.05
88%
87%
70%
67%
MVD SENSITIVITY
*P = 0.03
71%
SPECT
PET
Bateman TM et al. J Nucl Cardiol. 2006; 13:24-33.
48%
*P = 0.02
85%
67%
65 year old Male with Anginal symptoms
Courtesy, Berks Cardiologists, Reading PA
Pet study, Same Patient
Courtesy, Berks Cardiologists, Reading PA
Prognostic Value of Rb-82 Myocardial
Perfusion PET Using Dipyridamole
153 consecutive pts followed for 3.0 +/- 0.9 yrs
Cumulative
Death & MI
(%)
27%
17%
0
SSS
<4
4%
4-7
8-11
≥12
Yoshinaga, JACC 43: 338A
Risk Stratification: PET Summed
Stress Score Severity and Left
Ventricular Dysfunction
Lertsburapa et al JNC 2007;14:S124
PET Protocols
Positron Emission and Annihilation
Events
γ 511 keV
Positron range
e-
β+
180 °
γ 511 keV
E = mc2
Coincidence Detection
•
Annihilation photon pairs are
detected by opposing scintillation
detectors
•
If 2 photons are detected
simultaneously, annihilation must
have occurred along a line
connecting the detectors
•
Acquisition is 360 degrees,
continuous
22
Transmission Scan
• Specific density maps of thorax measured to correct for
photon attenuation
• Measured attenuation
• Before or after emission scans
• Constant table position
– Transmission and emission scans
• Types:
– CT, PET: Ge-68 or Ce-137
• Review images for registration of emission and
transmission images
Prescan Delay: Rubidium-82
• Radiotracer half-life: 76
seconds
• Prescan delay
– 70-120 sec (Rb-82)
Images
– 4-7 min (N-13 ammonia)
• Total acquisition time: 7
minutes
Vom Dahl J, et al. Circulation. 1996;93:238-245.
Rubidium-82
ƒ
ƒ
ƒ
ƒ
Short half-life (75 seconds)
Requires on-site generator
Line from generator to patient
Acquisition of data must be very
fast (2-3 minutes)
ƒ Because of rapid acquisition,
pharmacologic stress only (for
present)
ƒ Because of rapid acquisition, data
during hyperemia
ƒ More wall motion abnormalities
ƒ True LV cavity dilation
ƒ Sequence of rest/stress very rapid
Acquisition Times: Rb-82
• Acquisition times need to recognize the fast decay time
of Rb-82
• 95% theoretical maximum of all counts will be acquired
in the first five minutes
Rest/Stress SPECT Protocol, circa
1991-2012
Elapsed Time: 2 ½-4 hours
Imaging time: 30 minutes
Radiation exposure: 10-25 mSv
Rest Imaging
Time
(minutes)
0
Radiopharmaceutical
Injection
(rest)
45
60
Stress Imaging
90
120
Radiopharmaceutical
Injection
(peak exercise/pharm stress)
135
PET-CT Protocol, 2012
Rb-82
20-60 mCi
Rb-82
20-60 mCi
Pharmacologic
stress*
CT-transmission
Gated
stress
Gated
rest
70-90 sec
70-90 sec
Approx 1 min
Approx 7 min
Approx 6 min
Approx 7 min Approx 1 min
Elapsed Time: 25 Minutes
Radiation Exposure: 2-5 mSv
*Dipyridamole,
Dipyridamole, regadenoson, or dobutamine.
CT-transmission:
(optional)
Unique Aspects, New Developments,
in PET Perfusion: 2012
ƒ Transient ischemic cavity dilation, reversible wall
motion abnormalities
ƒ Quantitation of regional blood flow:
ƒ Reality, 2012: Rubidium-82, N13 Ammonia
ƒ Culprit lesion, eliminate false negative
ƒ New at risk population
ƒ New Perfusion agents, F-18
ƒ two in FDA Phase 2, 3
ƒ Ischemic memory agent, neuronal imaging agent in
development
ƒ Radiation exposure
Novel Information From PET
Transient Cavity Dilation in Rest/Dipyridamole
Stress Rb-82 PET Myocardial Perfusion*
123 Catheterized patients
%
32%
*Imaging during stress with PET
Bateman TM. American Heart Association Scientific Sessions; 2005.
39%
Impact of TID in Predicting Outcomes in Patients
Undergoing Rb-82 PET Imaging
P < 0.01
12
10.7
P < 0.01
10
7.6
8
6
4
Annual All‐Cause Mortality
4.1
2
0
No Perfusion Defect, No TID
Perfusion Defect, No TID
Both Perfusion Defect and TID
TID = transient ischemic dilatation.
Padala A, et al. American College of Cardiology Annual Scientific Session; Orlando, FL; March 29-31, 2009.
Presentation 0908-7.
Wall Motion During Stress: PET
vs SPECT
• Reversible wall motion with SPECT
• Associated with high-grade stenosis
• Associated with identification of MVD
• Reversible wall motion with PET
• More common than with SPECT, due to rapid acquisition
• Significance with accuracy, high grade stenosis, MVD
LVEF Reserve Is Inversely Related to the
Magnitude of Jeopardized Myocardium
P < 0.001
P = 0.07
15
P < 0.0001
15
P = 0.003
10
P = 0.05
5.3
4.4
5
0
3.6
-0.2
n = 353
n = 24
n = 104
n = 28
-5
-10
Normal
Scar
82Rb
Mild-mod
reversibility
Severe
reversibility
PET scan results
Dorbala S, et al. J Nucl Med. 2007;48:349-358.
Left ventricular ejection fraction
reserve (%)
Left ventricular ejection fraction
reserve (%)
P < 0.0001
10
7.6
5.6
5
2.5
0
1
-5
- 6.7
-10
-15
-20
0-vessel
CAD
n = 15
1-vessel
CAD
n = 23
2-vessel
CAD
n = 13
Left main or
3-vessel CAD
n = 17
Angiographic disease extent
Impact of LVEF Reserve in Predicting
Cardiac Events
Dorbala S, et al. JACC Cardiovasc Imaging. 2009;2:846854.
Flow Quantification
Why Can’t We Be Certain That This Normal Myocardial
Perfusion PET Scan Rules Out Extensive CAD?
1. Non-responder to vasodilation
stress
2. Antagonists to vasodilation stress
3. Epicardial CAD with balanced flow
reduction
4. Diffuse small-vessel CAD
Flow Quantification: How It Is Changing MPI
2 Themes:
1. Spatially-relative MPI is not as good as we would like
2. There is much more to coronary anatomy than the
coronary arteries
Micro-Circulation
Epicardial
Camici PG, Rimoldi OE. J Nucl Med. 2009;50:1076-1087.
epicardial
MBF Quantification: PET
• Dynamic acquisition
30
SEC
35
SEC
40
SEC
45
SEC
50
SEC
55
SEC
• Kinetic analysis
• MBF estimated in mL/g/min
60
SEC
65
SEC
70
SEC
80
SEC
90
100
Right ventricle
Activity
Left ventricle
Myocardium
Time (sec)
El Fakhri G, et al. J Nucl Med. 2005;46:1264-1271.
Images Appear Normal Visually – So What
Does Normal Myocardial Flow Reserve Add?
1. Confirms that vasodilation occurred
– Non-responder
– Caffeine or other antagonist
2. Excludes balanced flow reduction
3. Excludes flow-limiting epicardial CAD
4. Excludes endothelial dysfunction
5. Excludes small-vessel CAD
6. Infers a better prognosis
Survival Curves Showing Added Value of CFR in
Predicting Outcome Up to 3 Years After a
Normal MPI PET Scan
Herzog BA, et al. J Am Coll Cardiol. 2009;54:150-156.
CACS > 1000
Risk Stratification and Calcium
Score and PET MPI
Schenker MO, et al. Circulation. 2008;117:1693-1700.
New Perfusion Tracers: PET
Ideal PET MPI Imaging Agent
• High cardiac uptake with minimal redistribution
• Near linear myocardial uptake vs. flow up to 5
mL/min/g or more (high first pass extraction fraction)
• High target to non-target ratio (vs. lung, liver, bowel)
• Usable for both exercise and pharmacologic stress
• Usable for quantitation of absolute myocardial flow
• Available as unit dose (18F-labeled compound)
Adapted from: Glover, D and Gropler, R., J. Nucl. Card 14:6 p765-8
Chemical Structure of Flurpiridaz F 18
Mitochondrial Complex 1 (MC-1) Inhibitor
2-tert-Butyl-4-chloro-5-[4-(2- (18F)fluoro-ethoxymethyl)-benzyloxy]-2H-pyridazin-3-one
Yu, et al., J Nucl Cardiol. 2007;14(6):789-98
47
Ver. 18Aug 09
First Pass Uptake in Isolated Rabbit
Hearts
Flurpiridaz F 18 (n=4)
3
201Tl
Uptake
(n=3)
99mTc-sestamibi
2
* p<0.05
(n=3)
*
*
1
0
0
1
2
3
4
Coronary perfusion flow (ml/min/g)
5
Yu, et al., J Nucl Cardiol. 2007;14(6):789-98
48
Ver. 18Aug 09
Quality Control
Stress
Rest
Short Axis
Stress
Rest
Vertical-Long Axis
Stress
Rest
Horizontal-Long Axis
F18DC
Stress
Rest
Short Axis
Stress
Rest
Vertical-Long Axis
Stress
Rest
Horizontal-Long Axis
F18DP
Second agent in Phase 2 Trial
JACC Imaging2012;5:285-92
Resting 60 Minute Image: BFPET
Phase 2 Study
Courtesy, Thjis Spoor, Fluropharma Inc
Radiation Dosimetry
Radiation Dosimetry
• Growing public concern in US
• Average annual exposure 6.2 mSv1 (3.2 mSv in 1980)
• 25% of annual exposure is from medical imaging
• ~22% of medical imaging exposure is from nuclear
cardiology!2
• Conclusion: Need to consider dosimetry in imaging
test selection
1. National Council on Radiation Protection and Measurements. Report No.160—Ioninizing Radiation Exposure of
the Population of the United States. 2009. www.ncrppublications.org/Reports/160.
2. Fazel R, et al. N Engl J Med. 2009;361:849-857.
Recommendations for Reducing Radiation
Exposure in Myocardial Perfusion Imaging
Favorable dosimetry (20 mCi Rb-82 ~ 0.9 mSv)
Senthamizhchelvan S, et al. J Nucl Med. 2010;51:1592-1599.
Senthamizhchelvan S, et al. J Nucl Med. 2011;52:485-491.
Cerqueira MD, et al. J Nucl Cardiol. 2010;17:709-718.
Conclusions: Cardiac PET in
2012
• Differences between PET and SPECT
• Unique aspects to PET perfusion
• Myocardial flow with PET
• New perfusion tracers: PET
• Radiation exposure: PET
Sunset, Cape Cod MA USA