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