maddahi -physiological basis of myocardial perfusion spect

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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.

2

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

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


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 ( )


Myo

ca

0 1 2 3 4 5

1

4

ake


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 ( )


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


0 45 30 45

minutes

Stress

60 3 hrs

Total time: 5 hrs

5

Protocol for Tc-99m Labeled Perfusion ImagingSame Day Rest-Stress


Tc-99m

6.3 mCi

Stress

Tc-99m

34.3 mCi


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


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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Normal wall motion Artifact

H / ki ti S I h iHypo/akinetic Scar Ischemia



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



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

14

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




LAD LCX


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

18

Stress-Rest AC

Stress

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)


• 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)


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Image Quality (N=86)(% rated excellent or good)


95.3

69.8

98.8

84.9

P<0.01 P<0.01


Certainty of Interpretation (N=86) (% definitely normal or abnormal)


90.7

75.6

P<0.01


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ROC Analysis for CAD Diagnosis


PET: 0.82+0.05SPECT: 0.70+0.06

P<0.05 PET vs. SPECT


Conclusion

In this Phase 2 clinical trial, flurpiridaz F 18


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


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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

maddahi -physiological basis of myocardial perfusion spect

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