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Jamshid Maddahi, MD, FACC, FASNCJamshid Maddahi, MD, FACC, FASNC
Physiological Basis of Myocardial Perfusion SPECT and PET
Physiological Basis of Myocardial Perfusion SPECT and PET
Professor of Molecular and Medical Pharmacology
(Nuclear Medicine) and Medicine (Cardiology)
David Geffen School of Medicine at UCLA
Professor of Molecular and Medical Pharmacology
(Nuclear Medicine) and Medicine (Cardiology)
David Geffen School of Medicine at UCLA
Director, Biomedical Imaging InstituteDirector, Biomedical Imaging Institute
Relation of Degree of Stenosis to Coronary Blood Flow
5
Flow = pressure/resistance
ow Hyperemia
R t
Myocardial Perfusion Imaging
1
2
3
4
Mea
n f
low
rel
ativ
e to
init
ial f
l RestRest
no stenosis
Rest70% stenosis
Stress70% stenosis
Stressno stenosis
Blo
od
flo
w
Stress
0
0 20 40 60 80 100
M
% Stenosis (diameter)
At Rest
Gould KL, et al. Am J Cardiol. 1974;33:87-94.
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201Thallium 99mTc-teboroxime 99mTc-sestamibi
+RCN EtO
CNREtO
99mTc-tetrofosmin
CNR
MetallicElement
N N
TcN
N
NO
O
N
OB
Tc+
RCN CNR
CNR
CH3
CH3 CH3CR =
P
P
Cl CH3
3 3
CH3
O
EtO EtO
C18H40O4P2
Factors Determining Regional Myocardial Uptake of Radioactivity
Regional myocardial blood flowX
Extraction fraction
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3
ake
Relationship Between Tracer Uptake and Myocardial Blood Flow
Teboroxime4
5ar
dia
l Tra
cer
Up
ta
Tl-201
Tc-99m Sestamibi
Tc-99m Tetrofosmin
Teboroxime
2
3
4
Myocardial Blood Flow (ml/min/g)
Myo
ca
0 1 2 3 4 5
1
ake
Relationship Between Tracer Uptake and Myocardial Blood Flow
4
5
Defect intensity= 2.3/2.9 = 0.79 (21% below normal)
ard
ial T
race
r U
pta
Tl-201
Tc-99m Sestamibi2
3
4 ( )
Myocardial Blood Flow (ml/min/g)
Myo
ca
0 1 2 3 4 5
1
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4
ake
Relationship Between Tracer Uptake and Myocardial Blood Flow
4
5
Defect intensity= 1.5/1.7 = 0.88 (12% below normal)
ard
ial T
race
r U
pta
Tl-201
Tc-99m Sestamibi2
3
4 ( )
Myocardial Blood Flow (ml/min/g)
Myo
ca
0 1 2 3 4 5
1
Protocol for Tc-99m Labeled Perfusion ImagingSame Day Rest-Stress
Rest image Stress image
Tc-99m
8 mCi
Stress
Tc-99m
24 mCi
Rest image Stress image
0 45 30 45
minutes
Stress
60 3 hrs
Total time: 5 hrs
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Protocol for Tc-99m Labeled Perfusion ImagingSame Day Rest-Stress
Rest image Stress image
Tc-99m
6.3 mCi
Stress
Tc-99m
34.3 mCi
Rest image Stress image
0 45 30 45
minutes
Stress
60 1/2 hr
Total time: 2.5 hrs
Protocol for Tc-99m Labeled Perfusion ImagingSame Day Stress-Rest
Stress image Rest image
Tc-99m
6.3 mCi
Stress
Tc-99m
34.3 mCi
Stress image Rest image
30 45 60
minutes
Stress
45 1/2 hr
Total time: 2.5 hrs
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Methods to Diagnose/Reduce/EliminateSoft Tissue Attenuation
Gated acquisition to assess regional wall motion
Prone imaging
Upright imaging
Attenuation correction
Attenuation correction
Identification of Attenuation artifact byGated Imaging to Assess Regional Wall Motion
Nonreversible defect Reversible defect
Normal wall motion Artifact
H / ki ti SHypo/akinetic Scar
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Identification of Attenuation artifact byGated Imaging to Assess Regional Wall Motion
Nonreversible defect Reversible defect
Normal wall motion Artifact
H / ki ti S I h iHypo/akinetic Scar Ischemia
Identification of Attenuation artifact byGated Imaging to Assess Regional Wall Motion
Nonreversible defect Reversible defect
Normal wall motion Artifact Shifting artifact or ischemia
H / ki ti S I h iHypo/akinetic Scar Ischemia
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Methods to Diagnose/Reduce/EliminateSoft Tissue Attenuation
Gated acquisition to assess regional wall motion
Prone imaging
Upright imaging
Attenuation correction
Attenuation correction
Supine vs. prone imaging
Supine
ProneProne
Supine
Prone
Prone
Supine
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Semi-recumbent imaging
Stress
Rest
Stress
Stress
Rest
Rest
Rest
Stress
Upright imaging
Stress
Rest
Stress
Stress
Rest
Rest
Rest
Stress
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SPECT Based Transmission Imaging
Scanning Line Source Scanning Point Source
Line Source/Fan Beam Line Source Array
Gd-153 Ba-133
J. Cullom, Ph.D., MAHI
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SPECT-CT Imaging (No Attenuation Correction)
SPECT-CT Imaging (After Attenuation Correction)
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X-ACT Attenuation Correction System
Fluorescence X-rays
Fanbeam
Solid-State DetectorsOperating In High Counting Rate M d (>5 106
X-RayLine
Source Generator
collimators
Maddahi J, et al ICNC 2009
Mode (>5 x 106 cps per 20 cm x 15 cm detector area)
P015 no AC
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P015 after AC
P026 no AC
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P026 after AC
Confidence of interpretation
Multi-Center Validation of AC for Upright SPECT MPI
Maddahi et al, JNC Submitted
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Overall Detection of CAD
Multi-Center Validation of AC for Upright SPECT MPI
Maddahi et al, JNC Submitted
Multi-Center Validation of AC for Upright SPECT MPI
LAD LCX
Maddahi et al, JNC Submitted
RCA
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Possibility of Short Protocol withSame-Day Stress-Rest Imaging
Stress Rest
Definite normal No
Possible defect Yes
Definite defect Yes
Possibility of Short Protocol withSame-Day Stress-Rest Imaging
Stress Stress + AC RestStress Stress AC Rest
Definite normal No
Normal No
Defect YesPossible defect
Normal No
Defect YesDefinite defect
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Stress
AC
Stress
AC
AC
AC
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Stress-Rest AC
Stress
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19
Stress
AC
AC
AC
AC
Stress-Rest AC
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Rest-Stress Protocols
Rapid Imaging
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Benefits of Rapid SPECT Imaging
• Patient conveniencePatient convenience
• Decreased patient motion and associated artifact
• Increased patient throughput
• Decrease radiation dose to patientsDecrease radiation dose to patients
• Potential for dynamic imaging and absolute quantitation of myocardial blood flow
2-Minute Gated Acquisition with D-SPECT
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nSPEED Rest-Stress Upright Imaging(5.3 and 2.9 min, Dual Head)
Blinded Visual Assessment of Image QualitynSPEED vs. Standard (n=448)
nSPEED = Standard
nSPEED better than Standard
19 2%
1.3%
nSPEED worse than Standard
Stress Images Rest Images
19 4%
2%
19.2%79.5%
19.4%78.6%
Maddahi et al, JNC 2009; 16(3): 351-7
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y = 1.005x
R2 = 0 957100
Measurement of LVEF (%) from Gated Stress SPECT nSPEED vs. Standard
R = 0.957
40
60
80nS
PE
ED
0
20
0 20 40 60 80 100Standard
Maddahi et al, JNC 2009; 16(3): 351-7
Dedicated PET Hybrid PET/CT
PET CT
Germanium rod sources for AC
Minimal radiation exposure
Relatively inexpensive
CT used for transmission mapMore radiation Expensive (but anatomic data & CTA)
Rotating rod
Adapted from E Garcia, Emory Univ
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PET Myocardial Perfusion Tracers
Tracer Ext. Fraction T1/2 Production
O-15 Water 100% 2.09 min Cyclotron
N-13 Ammonia 85% 9.96 min Cyclotron
Rubidium-82 65% 76 sec Generator
Advantages of PET vs. SPECT
• Fast protocolsast p otoco s
• Improved image quality in obese patients
• Improved specificity (less attenuation artifacts)
• Improved sensitivity for detection of CAD– Better tracers with higher extraction fraction – Higher system resolution– Imaging at peak stress
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PET Perfusion Imaging ProtocolN-13 Ammonia
TxRest
Perfusion Adenosine
N-13 ammonia30 mCi
N-13 ammonia30 mCi
Stress PerfusionPerfusion de os e
0 5 20 30 41
minutes
36 56
Perfusion
Total time: <1 hr
Rapid PET Rb-82 ECG-Gated Rest/Peak
Stress Acquisition Protocol
Rb 827-Minute
Adenosine
3.53.5
Tx
Rb-8240 mCi Rb-82
40 mCi
Adenosine Stress
10 s
Scan
Emission Scan, (150 secs), 3D with gating, starting 2.5 mins after
Rb-82
Emission Scan, (150 secs), 3D with gating, starting 2.5 mins after
Rb-82
Bateman t, Mid America Heart InstituteTotal time: <20 mins
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Stress 82 Rb
Rest 82 Rb
LMLM
Rest
LVEF = 58%LVEDV = 177 mlLVESV = 74 ml
Stress
LVEF = 39%LVEDV = 182 mlLVESV = 112 ml
Dorbala S et al. J Nucl Med. 2007;48:349.
Left Ventricular Ejection Fraction Reserve Improves Identification of Multivessel CAD
MPI AloneMPI Alone MPI + EF ReserveMPI + EF Reserve
2-vessel pattern
1-vessel pattern
No defect
3-vessel left main pattern
72
56 43
17
44 50
20%
40%
60%
80%
100%
67
33
17
11
0
6
56
79
20%
40%
60%
80%
100%
Angiographic extent of CAD
defect
1-vessel CAD N=23
2-vessel CAD N=13
Left main/3-
vessel CAD N=17
110
70%
Left main/3-vessel CAD
N=17
1-vessel CAD N=23
2-vessel CAD N=13
110 0
21
0%
Dorbala S et al. J Nucl Med. 2007;48:349.
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O
BMS747158 (Flurpiridaz): Chemical Structure
Mitochondrial Complex 1 (MC-1) Inhibitor
N
N
Cl
O
O18F
N
N
O
Cl
O
O18F
Mitochondrial Complex 1 (MC-1) Inhibitor
18F
2-tert-Butyl-4-chloro-5-[4-(2- (18F)fluoro-ethoxymethyl)-benzyloxy]-2H-pyridazin-3-one
F
Characteristics of the Ideal PET Perfusion Tracer
•• FF--18 label18 label–– Available as unit dose from a regional cyclotronAvailable as unit dose from a regional cyclotron
– Ideal PET resolution (positron range)
– Possibility of rest-exercise imaging
•• High extraction fractionHigh extraction fractiongg–– Better perfusion defect detectionBetter perfusion defect detection
–– Reliable absolute quantitationReliable absolute quantitation
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Sequential Whole Body Images of 18F flurpiridaz
19 1495638
21 3 45 6 7221 3 45 6 7
30 min10 min 50 min 120 min 150 min 210 min 270 min
Time after injection Normalized to maximum
30 min10 min 50 min 120 min 150 min 210 min 270 min
Maddahi J, et al. J Nucl Med 2011; 52:1490-8
• No tracer related adverse events were noted.
• Dosimetry was within the clinically acceptable range, using up to 14 mCi combined rest-stress dose.
Conclusions of Phase 1 Flurpiridaz F 18 Study
• Stress imaging was feasible with both treadmill exercise and pharmacologic vasodilation.
• Myocardium was clearly visualized for several hours after rest and stress injection with good myocardial to b k d tibackground ratio.
• Five minute gated acquisition - starting 2 minutes after injection - yielded high quality images.
Maddahi J, et al. JACC 2009; 53:A297
Maddahi J, et al. J Nucl Med 2011; 52:1490-8
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Objectives
• To assess clinical safety
BMS747158-201Flurpiridaz F 18 Injection Phase 2 Study
To assess clinical safety
• To compare flurpiridaz F 18 PET and Tc-99m labeled SPECT MPI with respect to:– Image quality
Certainty of interpretation– Certainty of interpretation– Detection of CAD
Maddahi J. et al. Eur Heart J 2011; 13:A45
• 21 US centers
Study Population (N = 143)
BMS747158-201Flurpiridaz F 18 Injection Phase 2 Study
• 107 males and 36 females
• Age range: 29-88 yrs (mean = 62.4 yrs)
• 108 White, 3 Asian, 16 African American, 16 Others
Height (cm): 134 191 (mean 171 1)• Height (cm): 134-191 (mean = 171.1)
• Weight (kg): 49-132 (mean = 82.9)
• BMI: 17.4 – 41.9 (mean = 28.3)
Maddahi J. et al. Eur Heart J 2011; 13:A45
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Image Quality (N=86)(% rated excellent or good)
BMS747158-201Flurpiridaz F 18 Injection Phase 2 Study
95.3
69.8
98.8
84.9
P<0.01 P<0.01
Maddahi J. et al. Eur Heart J 2011; 13:A45
Certainty of Interpretation (N=86) (% definitely normal or abnormal)
BMS747158-201Flurpiridaz F 18 Injection Phase 2 Study
90.7
75.6
P<0.01
Maddahi J. et al. Eur Heart J 2011; 13:A45
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ROC Analysis for CAD Diagnosis
BMS747158-201Flurpiridaz F 18 Injection Phase 2 Study
PET: 0.82+0.05SPECT: 0.70+0.06
P<0.05 PET vs. SPECT
Maddahi J. et al. Eur Heart J 2011; 13:A45
Conclusion
In this Phase 2 clinical trial, flurpiridaz F 18
BMS747158-201Flurpiridaz F 18 Injection Phase 2 Study
injection:
• Had a favorable safety profile and was well tolerated.
• Was an improvement compared to Tc-99m SPECT MPI with respect to:
– Rest and stress image quality
– Certainty of image interpretation
– Sensitivity for detection of CAD
Maddahi J. et al. Eur Heart J 2011; 13:A45
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Quantitation of Myocardial Blood FlowQuantitation of Myocardial Blood Flow
AbsoluteAbsolute == ml/min/gml/min/g
Flow ReserveFlow Reserve == Peak hyperemic/resting flowPeak hyperemic/resting flow
RelativeRelative == Normalized to bestNormalized to best
RelativeRelative == Normalized to best Normalized to best perfused regionperfused region
Stress
Rest
Stress
Rest
Stress
Rest
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Coronary Flow ReserveTime Activity Curves
1.46
1.67
1.67Ti (S )Time (Sec)
Advantages of PET vs. SPECTAbsolute Quantitation of Blood Flow
• Better identification of MVD
• Assessment of microvascular disease
• Evaluation of endothelial dysfunction and
response to Rxresponse to Rx
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Absolute Quantitation of Myocardial Blood Flow with 18F Flurpiridaz PET
2.36
1.18
3.73
1.58
*
0.660.76
Maddahi J, Huang SC, et al, ASNC 2011 * p<0.002 vs. Normal