Why Choose Cardiac PET?Why Choose Cardiac PET?
Gary V. Heller, MD PhD
Professor of Medicine University of Connecticut School of Medicine
Farmington, CT
First Cardiac PET Imaging Meeting
Manchester Royal Infirmary 8 November 2012
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
• 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.
Pros and Cons of SPECT MPIPros and Cons of SPECT MPI
Why PET 2012?Availability of PET cameras: oncologyAvailability of radiopharmaceutical Rb-82, NH-13 ammoniaImprovement in acquisition protocolsAbility to undergo ECG-gated imaging, stress and restImprovement in cardiac processingImprovement in cardiac displayExcitement in the industry (new radiopharmaceuticals, camera systems)
Options for Cardiac PETMyocardial perfusion imaging for diagnosis, risk stratification, CAD
Vasodilator stressDobutamine stressExercise (limited, but routine for F-18 in future)
Agents available: Rb-82, N-13 ammonia, O-15 waterMyocardial viability: FDG/perfusion agentCardiac sarcoid identificationNew developments: blood flow, F-18 tracers for perfusion, CHF tracers
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 Un-interpretable Excellent
FDA approval Yes Yes No Yes
PET RadiotracersPET Radiotracers
*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 valueNo artifact 19(17%) 49(44%) 0.0001
Minor artifact 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
Major GI uptake 2(2%) 1(1%) 0.32
Bateman et al. JNC 2006; 13(1): 24-33
Pharmacologic Stress Myocardial Perfusion Imaging
SPECT Rb-82 PET
Normal73%
Abnormal25%
2% Non-Diagnostic
Myocardial Perfusion PET in Patients with a Non-Diagnostic SPECT
64% were womenMean BMI 32Mean age 62 yrs
233 consecutive pts with a non-
diagnostic SPECT followed by MP PET <90
days
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
SPECT
PET
DIAGNOSTIC ACCURACY BY GENDER DIAGNOSTIC ACCURACY BY BMI
69%84%
*P = 0.55
67%88%
*P = 0.009
70%87%
67%85%
*P = 0.05 *P = 0.02
MVD SENSITIVITY
48%
71%*P = 0.03
Bateman TM et al. J Nucl Cardiol. 2006; 13:24-33.
Diagnostic Accuracy: PET vs SPECT
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
(%)
0 4%
17%27%
SSS <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 ProtocolsPET Protocols
e-
β+
γ 511 keV
γ 511 keV E = mc2
180 °
Positron Emission and Annihilation Positron Emission and Annihilation EventsEvents
Positron range
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 ScanTransmission 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: RubidiumPrescan Delay: Rubidium--8282
• Radiotracer half-life: 76 seconds
• Prescan delay– 70-120 sec (Rb-82)
– 4-7 min (N-13 ammonia)• Total acquisition time: 7
minutes
Vom Dahl J, et al. Circulation. 1996;93:238-245.
Images
Rubidium-82Short half-life (75 seconds)Requires on-site generatorLine from generator to patientAcquisition of data must be very fast (2-3 minutes)Because of rapid acquisition, pharmacologic stress only (for present)Because of rapid acquisition, data during hyperemia
More wall motion abnormalitiesTrue LV cavity dilation
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
Time(minutes) 0 45 60
RadiopharmaceuticalInjection
(rest)
Rest Imaging
120 135
Radiopharmaceutical
Injection
(peak exercise/pharm stress)
Stress Imaging
90
Elapsed Time: 2 ½-4 hoursImaging time: 30 minutes
Radiation exposure: 10-25 mSv
PETPET--CT Protocol, 2012CT Protocol, 2012
CTCT--transmissiontransmission
RbRb--82822020--60 mCi60 mCi
7070--90 sec90 sec
GatedGatedrestrest
PharmacologicPharmacologicstress*stress*
7070--90 sec90 sec
RbRb--82822020--60 mCi60 mCi
GatedGatedstressstress
Approx 1 minApprox 1 min Approx 7 minApprox 7 min Approx 6 minApprox 6 min Approx 7 minApprox 7 min
Elapsed Time: 25 Minutes
*Dipyridamole, regadenoson, or dobutamine.Dipyridamole, regadenoson, or dobutamine.
CTCT--transmission: transmission: (optional)(optional)
Approx 1 minApprox 1 min
Radiation Exposure: 2-5 mSv
Unique Aspects, New Developments, in PET Perfusion: 2012
Transient ischemic cavity dilation, reversible wall motion abnormalities
Quantitation of regional blood flow:Reality, 2012: Rubidium-82, N13 Ammonia
Culprit lesion, eliminate false negative
New at risk population
New Perfusion agents, F-18two in FDA Phase 2, 3
Ischemic memory agent, neuronal imaging agent in development
Radiation exposure
Novel Information From PETNovel Information From PET
Transient Cavity Dilation in Rest/Dipyridamole Transient Cavity Dilation in Rest/Dipyridamole Stress RbStress Rb--82 PET Myocardial Perfusion*82 PET Myocardial Perfusion*
32%32%39%39%
%
123 Catheterized patients
Bateman TM. American Heart Association Scientific Sessions; 2005.
*Imaging during stress with PET
TID = transient ischemic dilatation.Padala A, et al. American College of Cardiology Annual Scientific Session; Orlando, FL; March 29-31, 2009. Presentation 0908-7.
Impact of TID in Predicting Outcomes in Patients Impact of TID in Predicting Outcomes in Patients Undergoing RbUndergoing Rb--82 PET Imaging82 PET Imaging
4.1
7.6
10.7
0
2
4
6
8
10
12
No Perfusion Defect, No TID
Perfusion Defect, No TID
Both Perfusion Defect and TID
Annual All‐Cause Mortality
P < 0.01
P < 0.01
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 LVEF Reserve Is Inversely Related to the Magnitude of Jeopardized MyocardiumMagnitude of Jeopardized Myocardium
Dorbala S, et al. J Nucl Med. 2007;48:349-358.
P < 0.001
P = 0.07
P = 0.05
Normal Scar Mild-mod reversibility
Severe reversibility
82Rb PET scan results
Left
vent
ricul
ar e
ject
ion
frac
tion
re
serv
e (%
)
n = 104n = 24n = 353 n = 28
5.34.4 3.6
-0.2
-10
-5
0
5
10
15
P < 0.001
P = 0.07
P = 0.05
Normal Scar Mild-mod reversibility
Severe reversibility
82Rb PET scan results
Left
vent
ricul
ar e
ject
ion
frac
tion
re
serv
e (%
)
n = 104n = 24n = 353 n = 28
5.34.4 3.6
-0.2
-10
-5
0
5
10
15
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
P = 0.003
P < 0.0001
P < 0.0001
5.67.6
2.5
- 6.7
-20
-15
-10
-5
0
5
10
15
1
Left
vent
ricul
ar e
ject
ion
frac
tion
re
serv
e (%
)
Impact of LVEF Reserve in Predicting Impact of LVEF Reserve in Predicting Cardiac EventsCardiac Events
Dorbala S, et al. JACC Cardiovasc Imaging. 2009;2:846-854.
Flow QuantificationFlow Quantification
Why CanWhy Can’’t We Be Certain That This Normal Myocardial t We Be Certain That This Normal Myocardial Perfusion PET Scan Rules Out Extensive CAD?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 MPIFlow Quantification: How It Is Changing MPI2 Themes:2 Themes:
1. Spatially-relative MPI is not as good as we would like
2. There is much more to coronary anatomy than the epicardial coronary arteries
Camici PG, Rimoldi OE. J Nucl Med. 2009;50:1076-1087.
Micro-Circulation Epicardial
Time (sec)
Activ
ity
Right ventricle
Left ventricle
Myocardium
30 SEC
35 SEC
40 SEC
45 SEC
50 SEC
55 SEC
60 SEC
65 SEC
70 SEC
80 SEC
90 100
El Fakhri G, et al. J Nucl Med. 2005;46:1264-1271.
MBF Quantification: PET• Dynamic acquisition
• Kinetic analysis • MBF estimated in mL/g/min
Images Appear Normal Visually Images Appear Normal Visually –– So What So What Does Normal Myocardial Flow Reserve Add?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
Schenker MO, et al. Circulation. 2008;117:1693-1700.
Risk Stratification and Calcium Score and PET MPI
New Perfusion Tracers: PETNew 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
47
Mitochondrial Complex 1 (MCMitochondrial Complex 1 (MC--1) Inhibitor1) Inhibitor
22--terttert--ButylButyl--44--chlorochloro--55--[4[4--(2(2-- ((18F)fluoro18F)fluoro--ethoxymethylethoxymethyl))--benzyloxy]benzyloxy]--2H2H--pyridazinpyridazin--33--oneone
Ver. 18Aug 09
Yu, et al., J Nucl Cardiol. 2007;14(6):789-98
Chemical Structure of Flurpiridaz F 18
48
* p<0.05Flurpiridaz F 18 (n=4)201Tl (n=3)99mTc-sestamibi (n=3)
**
0
1
2
3
0 1 2 3 4 5Coronary perfusion flow (ml/min/g)
Upt
ake
Yu, et al., J Nucl Cardiol. 2007;14(6):789-98
First Pass Uptake in Isolated Rabbit Hearts
Ver. 18Aug 09
Quality Control
Stress
Stress
Stress
Horizontal-Long Axis
Short Axis
Vertical-Long Axis
Rest
Rest
RestF18DC
Horizontal-Long Axis
Short Axis
Vertical-Long Axis
F18DP
Stress
Stress
Stress
Rest
Rest
Rest
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 DosimetryRadiation 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
Radiation DosimetryRadiation Dosimetry
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 Recommendations for Reducing Radiation Exposure in Myocardial Perfusion ImagingExposure in Myocardial Perfusion Imaging
Cerqueira MD, et al. J Nucl Cardiol. 2010;17:709-718.
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.
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
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