2008 Nuclear Cardiology

Board Exam Preparation Course

September 10-11, 2008
John B. Hynes Convention Center
Boston, MA

Day 1 –
Wednesday, September 10

For Educational Purposes Only. Not To Be Distributed.

 2008 Nuclear Cardiology Board Exam Preparation Course
Wednesday, September 10
John B. Hynes Convention Center
Boston, MA

Table of Contents

General Information ………………………………………………………………………… 1

Color Syllabus, Exam Answer Key, CME Certificate ………………………………...……. 2

Program Schedule …………………………………………………………………………... 3

Program Faculty …………………………………………………………………………….. 5

Faculty Disclosures …………………………………………………………………………. 6

CBNC Exam Content Outline ………………………………………………………………. 7

References…………………………………………................................................................. 8

Basic Physics Principles for Nuclear Cardiology …………………………………………... 10

Basic Instrumentation Principals for Nuclear Cardiology ………………………………….. 37

Production of Radioactive Materials and Radiopharmaceutical Properties ………………… 64

The Basics of Radiopharmaceuticals and Imaging Protocols ………………………………. 86

Stress Testing and Image Interpretation ………………………………..…………………… 114

Diagnosis & Risk Stratification (part 1)………….……………………………………….…. 138

Diagnosis & Risk Stratification (part 2)……………………………………………………... 163

Diagnosis & Risk Stratification (part 3)……………………………………………………... 193

 General Information
Purpose
The purpose of the Nuclear Cardiology Board Exam Preparation Course is to prepare
cardiologists and radiologists for board examinations in nuclear cardiology.

This program is designed for practitioners who are performing nuclear imaging studies and
preparing for certification in nuclear cardiology.

The primary objectives of this Nuclear Cardiology Board Exam Preparation Course are to
enable participants to:

• Appraise knowledge of physics and instrumentation associated with nuclear imaging;

• Explain image acquisition and processing, including artifacts;
• Describe risk stratification;
• Discuss the use of nuclear imaging in assessment of viability;
• Interpret perfusion images, including PET and ventricular function imaging;
• Utilize perfusion imaging in the assessment, diagnosis and response to therapy in CAD
patients and special populations.

Accreditation
The American Society of Nuclear Cardiology is accredited by the Accreditation Council for
Continuing Medical Education to provide continuing medical education for physicians.

CME Credit
The American Society of Nuclear Cardiology designates this educational activity for a maximum
of 16.75 AMA PRA Category 1 CreditsTM. Physicians should only claim credit commensurate
with the extent of their participation in the activity.

Disclaimers:

There is no relationship between the ASNC Nuclear Cardiology Board Exam Preparation Course and any testing or
certification boards. The faculty on this program is in no way affiliated with any testing or certification boards, nor
do they have any specific knowledge of the questions on any exams. The program is intended to serve as an exam
preparation tool; it does not offer extensive training or certification in the field, nor does it offer a guarantee that
participants will pass an exam.

The course content presented in this program is the property of the program faculty and the American Society of
Nuclear Cardiology. Audio recording of the lectures is acceptable; however, filming of the lectures or copying of the
syllabus is strictly prohibited.

There will not be a charge for any certificates requested by September 16, 2009. Any requests after that date will be
assessed a $10.00 service charge for each request.

1
Color Syllabus & Exam Answer Key Online
A full color syllabus and Exam Answer Key are available for viewing online and can be
located at the website below. This is a secure site requiring your log-in and password.
For both members & non-members, you will be receiving an email with your log-in and
password.

http://faculty.asnc.org/syllabus.aspx

Online Meeting Evaluation & CME Certificate

Retrieval
An evaluation form can be found in your syllabus. Please fill out as you attend the course.
This copy is for your records to assist in completing the online form found on the ASNC
website. Beginning, Tuesday, September 16, 2008, attendees of the September 10-11,
2008 Nuclear Cardiology Board Exam Preparation Course can complete the course
evaluation, view and print their CME certificates online by following these simple steps:

1. Visit www.asnc.org/cmeonline and select Nuclear Cardiology Board Exam

Preparation Course. For both members & non-members, your log-in is the
number located on your name badge. Your password is your last name.

2. Complete the course evaluation and click “Submit”

3. Print your certificate

Reporting of CME credit or attendance hours is done on an honor system and hour-for-
hour basis. Please note that physicians should only claim credit commensurate with the
extent of their participation in the activity.

2
 PROGRAM SCHEDULE
DAY 1

7:00 a.m. Registration/Continental Breakfast

8:00 a.m. Welcome/Opening Remarks

Donna M. Polk, MD, MPH

8:10 a.m. Basic Physics Principles for Nuclear Cardiology

E. Lindsey Tauxe, CNMT, MEd

9:05 a.m. Basic Instrumentation Principles for Nuclear Cardiology

Michael K. O’Connor, PhD

10:00 a.m. Break

10:15 a.m. Production of Radioactive Materials and Radiopharmaceutical Properties

Nicki L. Hilliard, PharmD, MHSA, BCNP, FAPhA

11:00 a.m. The Basics of Radiopharmaceuticals and Imaging Protocols

Gary V. Heller, MD, PhD

11:55 a.m. Lunch

12:45 p.m. Exam Questions

Donna M. Polk, MD, MPH and E. Lindsey Tauxe, CNMT, MEd

1:15 p.m. Question and Answer Session

Donna M. Polk, MD, MPH and E. Lindsey Tauxe, CNMT, MEd

1:30 p.m. Stress Testing and Image Interpretation

Robert C. Hendel, MD

2:10 p.m. Break

2:25 p.m. Diagnosis and Risk Stratification (Part I)

Robert C. Hendel, MD

3:05 p.m. Diagnosis and Risk Stratification (Part II)

Gary V. Heller, MD, PhD

3:35 p.m. Diagnosis and Risk Stratification (Part III)

Donna M. Polk, MD, MPH

4:05 p.m. Exam Questions

Gary V. Heller, MD, PhD, Robert C. Hendel, MD, Donna M. Polk, MD, MPH

4:35 p.m. Question and Answer Session

Gary V. Heller, MD, PhD, Robert C. Hendel, MD, Donna M. Polk, MD, MPH

3
4:50 p.m. Break

5:05 p.m. Case Review with Experts

Moderator: Donna M. Polk, MD, MPH
Presenters: E. Gordon DePuey, III, MD, Gary V. Heller, MD, PhD, Robert C.
Hendel, MD

6:30 p.m. Adjourn

DAY 2

7:30 a.m. Continental Breakfast

8:00 a.m. Applied Instrumentation Characteristics in Nuclear Cardiology Imaging

Michael K. O’Connor, PhD

9:05 a.m. Technical Aspects of Acquisition, Processing and Artifacts

E. Lindsey Tauxe, CNMT, MEd

10:00 a.m. Break

10:15 a.m. Artifact Recognition

E. Gordon DePuey, III, MD

11:15 a.m. The Basics of Radiation Safety

Robert A. Pagnanelli, CNMT, RT(N)(R), NCT and Sharmila Dorbala, MD

12:20 p.m. Lunch

1:05 p.m. Radionuclide Ventricular Function Imaging

Robert A. Pagnanelli, CNMT, RT(N)(R), NCT and E. Gordon DePuey, III, MD

2:20 p.m. Assessment of Myocardial Viability, Including PET

Vasken Dilsizian, MD

3:15 p.m. Break

3: 30 p.m. Exam Questions

Sharmila Dorbala, MD and Donna M. Polk, MD, MPH

4:30 p.m. Question and Answer Session

Sharmila Dorbala, MD and Donna M. Polk, MD, MPH

4:45 p.m. Closing Remarks and Course Evaluation

Donna M. Polk, MD, MPH

5:00 p.m. Adjournment

4
 FACULTY
Donna M. Polk, MD, MPH, Program Chair Nicki L. Hilliard, PharmD, MHSA, BCNP, FAPhA
Director of Preventive Cardiology Professor of Nuclear Pharmacy
Director of Women's Heart Program University of Arkansas for Medical Sciences
Hartford Hospital College of Pharmacy
University of Connecticut School of Medicine Little Rock, AR
Hartford, CT
Michael K. O’Connor, PhD
E. Gordon DePuey, III, MD Professor of Radiologic Physics
Director of Nuclear Medicine Mayo Clinic
St. Luke’s Roosevelt Hospital Section of Nuclear Medicine
Professor of Radiology Rochester, MN
Columbia University College of Physicians and
Surgeons Robert A. Pagnanelli, BSRT(R)(N), CNMT, NCT
New York, NY Chief Technologist, Nuclear Cardiology
Duke University Medical Center
Vasken Dilsizian, MD Hillsborough, NC
Professor of Medicine and Diagnostic Radiology
Chief, Division of Nuclear Medicine E. Lindsey Tauxe, CNMT, MEd
Director, Cardiovascular Nuclear Medicine and Director, Cardiology Informatics
PET Imaging Division of Cardiovascular Disease
University of Maryland Medical Center University of Alabama at Birmingham
Department of Diagnostic Radiology and Nuclear Birmingham, AL
Medicine
Baltimore, MD

Sharmila Dorbala, MD
Director of Nuclear Cardiology
Cardiology and Internal Medicine
Brigham and Women’s Hospital
Department of Radiology
Boston, MA

Gary V. Heller, MD, PhD

Associate Director, Cardiology
Director, Nuclear Cardiology
Director, Cardiovascular Fellowship Program
Professor of Medicine and Nuclear Medicine
University of Connecticut School of Medicine
Hartford, CT

Robert C. Hendel, MD, FASNC

Clinical Cardiologist
Midwest Heart Specialists
Fox River Grove, IL

5
As an Accreditation Council for Continuing Medical Education (ACCME) accredited continuing medical
education (CME) provider, ASNC must insure balance, independence, objectivity, and scientific rigor in all of
its continuing medical education activities. In order to achieve these goals, we require everyone who is in a
position to control the content of an educational activity to disclose to us all relevant financial relationships
with any commercial interest. These relationships are those in which the individual benefits by receiving a
salary, royalty, intellectual property rights, consulting fee, honoraria, ownership interest (e.g. stocks, stock
options or other ownership interest, excluding diversified mutual funds), or other financial benefit. Financial
benefits are usually associated with roles such as employment, management position, independent contractor
(including contracted research), consulting, speaking and teaching, membership on advisory committees or
review panels, board membership, and other activities from which remuneration is received or expected. We
also consider relationships of the person involved in the CME activity to include financial relationships of a
spouse or partner. With respect to personal financial relationships, ‘contracted research’ includes research
funding where the institution receives the grant and manages the funds and the person is the principal or named
investigator on the grant. Relevant financial relationships are financial relationships with commercial interests
in the 12-month period preceding the time that the individual is being asked to assume a role controlling
content of the CME activity. In addition, should it be determined that a conflict of interest exists as a result of a
financial relationship a planner or a speaker may have, it will be resolved prior to the activity.

In response to questionnaires submitted to ASNC from planners and speakers for this CME activity, the
following individuals have stated that they have no relevant financial relationships with any commercial
interest that produces health care goods or services, including computer software/hardware, related to the
content of the educational presentation in which they are involved:

Donna M. Polk, MD, MPH

Nicki L. Hiliard, PharmD, MHSA, BCNP, FAPhA

Relevant financial relationships with commercial interests have been stated by the following individuals:

Gordon DePuey, MD: Grant Support – GE Healthcare; Speakers Bureau - Molecular Imaging
Pharmaceuticals, UltraSPECT, Ltd., BMS Medical Imaging; Advisory Board – BMS Medical Imaging, GE
Healthcare, Adenosine Therapeutics; Honoraria – BMS Medical Imaging, GE Healthcare

Vasken Dilsizian, MD: Grant Support – GE Healthcare, Astellas, Philips; Speakers Bureau – GE Healthcare,
Astellas, Covidien; Stock Ownership – GE Healthcare

Sharmila Dorbala, MD: Speakers Bureau – Bracco Diagnostics

Gary Heller, MD: Grant Support – Philips Medical Systems, GE Healthcare, Bracco Diagnostics; Speakers
Bureau – BMS Medical Imaging, Philips Medical Systems, GE Healthcare, Bracco Diagnostics; Advisory
Board – King Pharmaceuticals, Bracco Diagnostics

Robert Hendel, MD: Grant Support – GE Healthcare; Advisory Board – Astellas

Michael K. O’Connor, PhD, Advisory Board – GE Healthcare

Robert Pagnanelli, BSRT (R)(N), CNMT: Speakers Bureau – GE Healthcare, Astellas; Advisory Board – GE
Healthcare

Lindsey Tauxe, CNMT, MEd: Honoraria – Corscan, Inc.

6
 CBNC Board Examination Outline F. Valvular disease, cardiomyopathy, hypertension,
CHF, myocarditis
Following is a detailed outline of the nine major G. Endothelial dysfunction
content areas of the examination, with an indication H. Coronary artery disease
(in parentheses) of the approximate percentage of I. Medical therapy, percutaneous coronary
the examination devoted to each area: intervention, and coronary bypass surgery
J. Indications for the use of alternative diagnostic
techniques (Echo, MRI, coronary calcification, CT
I. PHYSICS AND INSTRUMENTATION (10%) angiography)
(5% in Recertification Examination) K. Bayes' theorem, pre- and post-test likelihood,
A. Basic physics as applied to clinical imaging (e.g., sensitivity, specificity, and referral bias
isotope decay, decay modes, generators, high L. Statistical analyses (e.g., kappa value, Bland-
energy imaging) Altman, ROC curves, Kaplan-Meier)
B. Gamma cameras, collimation, and equipment M. Cost-effectiveness of diagnostic tests and principles
quality control procedures of outcome studies
C. Interactions of radiation with matter
D. Attenuation correction, including transmission and VI. RISK STRATIFICATION (10%)
CT methods A. Coronary artery disease
B. Unstable angina
II. RADIOPHARMACEUTICALS (8%) C. Acute myocardial infarction
A. Radiotracer kinetics and characteristics (e.g., D. Acute chest pain
thallium-201 and technetium-99m) E. Candidates for noncardiac surgery
B. PET agents F. Diabetes
C. Red blood cell tagging G. Chronic renal disease
H. Women
III. RADIATION SAFETY (10%) I. Post revascularization: percutaneous
(15% in Recertification Examination) coronaryintervention and CABG
A. Radiopharmaceutical receiving, handling, J. Evaluation of medical therapy
monitoring, and containment
B. Handling radiopharmaceutical spills and waste VII. MYOCARDIAL PERFUSION IMAGING
C. Storage and calibration of radiopharmaceuticals INTERPRETATION (22%)
D. Dosimetry and MIRD A. Interpretation of perfusion images with technetium-
E. Radiation exposure and ALARA 99m-labeled tracers and thallium-201
F. Governmental regulations B. Interpretation of images with rubidium-82 and N-13-
ammonia
IV. NUCLEAR CARDIOLOGY DIAGNOSTIC TESTS C. Relationship of perfusion abnormalities to clinical,
AND PROCEDURES/PROTOCOLS (15%) hemodynamic, ECG and exercise parameters
A. Image acquisition (e.g., first pass and equilibrium D. Relationship of perfusion abnormalities to coronary
RNA, gating, SPECT) anatomy
B. Image processing (e.g., filtering, reorientation, E. Combined function-perfusion imaging
reconstruction, motion correction)
C. Standard conventions as to how images are VIII. VENTRICULAR FUNCTION IMAGING (10%)
displayed A. Rest and stress first-pass radionuclide
D. Exercise and pharmacologic stress protocols ventriculography
E. Pharmacologic stress agents B. Rest and rest/stress equilibrium radionuclide
F. Artifacts and causes of false-positive and false- ventriculography (planar and SPECT), including
negative results volume measurements and systolic and diastolic
G. Quality control of image processing function
H. Quality assurance of interpretation C. ECG-gated SPECT myocardial perfusion imaging
I. Quantitative aids to interpretation D. Effect of arrhythmia on ECG gating
E. Implications of ventricular function testing for clinical
V. GENERAL CARDIOLOGY AS IT RELATES TO management
IMAGE INTERPRETATION (10%)
A. Coronary anatomy and pathophysiology IX. MYOCARDIAL VIABILITY (5%)
B. Unique characteristics of patient subgroups (e.g., A. Thallium-201 imaging
patients with diabetes, elderly patients, male vs. B. Technetium-99m imaging
female patients) C. FDG imaging
C. Coronary angiography D. Outcome data related to myocardial viability
D. Stress physiology and testing; ECG and clinical E. Relationship to other imaging methods (e.g., echo,
parameters with rest and stress MRI)
E. Measurements of left ventricle systolic and diastolic
function
7
 References

The following is a list of references and guidelines that may be helpful in reviewing for the
examination. This listing is intended for use as a study aid only. This list was not intended to
imply endorsement of these specific references, nor are the test questions taken from these
sources.

Guidelines

ACCF/ASNC Appropriateness Criteria for Single-Photon Emission Computed Tomography

Myocardial Perfusion Imaging (SPECT MPI) J Am Coll Cardiol 2005:46:1587-1605. Errata
2005:2148-50.

American Society of Nuclear Cardiology. Imaging Guidelines for Nuclear Cardiology

Procedures. Ed: DePuey, EG. Revised June 2006.

Cerqueira, MD, Weissman, NG, Dilsizian V, et al. Standardized Myocardial Segmentation and
Nomenclature for Tomographic Imaging of the Heart. A statement for healthcare professionals
from the cardiac imaging committee of the council on clinical cardiology of the American Heart
Association. J Nucl Cardiol 2002; 9: 240-5.

Nuclear Cardiology

Bax JJ (ed). Nuclear Cardiology Knowledge Self-Assessment Program. American Society of

Nuclear Cardiology, Bethesda, MD, rev. 2005.

DePuey EG, Berman DS, Garcia, EV (eds). Cardiac SPECT Imaging. 2nd edition, Lippincott
Williams & Wilkins 2001.

Dilsizian V and Narula J, (eds). Atlas of Nuclear Cardiology, 2nd edition, Braunwald E (series
ed), Current Medicine, Inc., Philadelphia, 2006.

Germano G, Berman DS. Clinical Gated Cardiac SPECT. Futura Publishing, Armonk, NY, 1999.

Heller GV, Hendel, RC. Nuclear Cardiology: Practical Applications. McGraw-Hill, New York,
NY, 2003.

Iskandrian AS and Verani MS (eds). Nuclear Cardiac Imaging: Principles and Applications. 3rd
edition edition, Oxford University Press, New York, NY 2002.

Wackers, FJTh, Bruni, W, Zaret, BL. Nuclear cardiology, the basics: how to set up and maintain
a laboratory. Humana Press, Inc., Totowa, NJ, 2004.

Zaret BL and Beller GA (eds). Nuclear Cardiology: State of the Art and Future Directions. 3rd
edition, Mosby, St. Louis, MO, 2005.

8
Nuclear Medicine/Nuclear Cardiology

Botvinick EH (ed) Cardiology Combo Topics 1-6. Society of Nuclear Medicine. 2003. (Topics
7-8 in press).

Early PJ and Sodee, DB (eds). Principles and Practice of Nuclear Medicine. 2nd edition, Mosby,
St. Louis, MO 1994. [NOTE: This reference is recommended, especially for cardiologists, for
reviewing "physics" and "technical aspects" of nuclear medicine.]

English, RJ: SPECT: A Primer, 3rd ed. Society of Nuclear Medicine, 1996.

General Cardiology

Braunwald, E (ed): Heart Disease: Textbook of Cardiovascular Medicine, 7th edition, Saunders,
Philadelphia, PA, 2005.

Stress Testing

Ellestad MH. Stress Testing: Principles and Practice, 5th ed. Oxford University Press, New
York, 2003.

Radiation Physics

Chandra R, Nuclear Medicine Physics: The Basics, 6th ed. Lippincott Williams & Wilkin. 2004.

Cherry SR, Sorensen JA, Phelps MC. Physics in Nuclear Medicine, 3rd ed. Saunders. 2003.

9
Ph i P
Physics Principles
i i l forf
Nuclear Cardiology

E. LINDSEY TAUXE MEd

DIVISION OF CARDIOVASCULAR DISEASE
UNIVERSITY OF ALABAMA AT BIRMINGHAM

Atomic and Nuclear Emissions

Î Atomic and Nuclear Transitions

Î Atomic Structure / Emissions
Î Nuclear Structure / Emissions
Î R di
Radioactive
ti Decay
D
Î Interactions with Matter

10
Atomic and Nuclear
Components
Bohr Model of the Atom

Nucleus (Protons & Neutrons)

Orbiting Electrons

Electron shells or energy

levels (K,
(K L,
L M shown)

Outer Electron shell (N)

is unoccupied

Atomic Energy Level Diagram

Free
Electron
N
M
L Binding
Energy
(eV or keV)

K
Ground state

11
Atomic Shells
Principal # Electrons Shell
Quantum # n (2 n2) Name

1 2 K
2 8 L
3 18 M
4 32 N
5 50 O
6 72 P
Maximum # of electrons / shell = 2n2
where n = shell #

Basic Atomic and Nuclear

Physics
Atoms
• Atomic Emissions
– Characteristic x-rays K-shell
vacancy
occur when an inner
shell electron is
ejected, and it’s
vacancy is filled by
another
h electron
l

Characteristic
x-ray

12
Basic Atomic and Nuclear
Physics
Atoms
• Atomic Emissions
– Auger Effect is an K L
alternative to
Characteristic X-rays
• occurs when the
energy produced
from filling vacancy K L
is transferred to
another electron
• called an Auger
Electron Auger Effect

Auger Electron

Atomic and Nuclear Emissions

Î Atomic and Nuclear Transitions

Î Atomic Structure / Emissions
Î Nuclear Structure / Emissions
Î R di
Radioactive
ti Decay
D
Î Interactions with Matter

13
Nuclear Structure
a Nucleus composed of protons + neutrons

a Atomic Number (Z) = # of protons (determines

element)

a Atomic Mass (A) = # of protons and neutrons

a Neutron Number (N) = A - Z

A 131
a Element ‘X’ represented as I , e.g.
Z N I
53 78

Nuclear Families - Definition

a Isotopes - nuclides composed of the same number of
protons (125I, 131I, 127I)
53 53 53
a Isotones - nuclides with the same number of neutrons
(131I, 132Xe, 133Cs)
53 54 55
a Isobars - nuclides with the same atomic mass A
(131I, 131Xe, 131Cs)
53 54 55
a Isomers - nuclides in different excited / metastable
states (99mTc, 99mTc)

14
Basic Atomic and Nuclear Physics
Nucleus

• Characteristics of
Stable Nuclei
– Light Elements
•N=Z
– Heavy Elements
• N = 1.5Z

Line of Stability

Nuclear Energy Level Diagram

0.8
0.722
0 667
0.667
0.6 0.637
Relative
0.404
Energy 0.4 0.364
(MeV) 0.341
0.2
0.164
0.080 ((metastable))
0.0
Ground State

Note: At the nuclear level, energy levels are typically

in the order of MeV rather than eV or keV

15
Basic Atomic and Nuclear Physics
Nucleus

• Nuclear Forces
– Nucleons are Subject to Coulombic forces
and Exchange Forces
– When These Forces are Equal the Nuclide
is Called Stable or Ground State
– When
Wh these
th Forces
F are nott Balanced,
B l d then
th
• Exited State - very unstable and transient
» 10-12sec
• Metastable State - unstable but longer lived
also called Isomeric States

Nuclear Emissions

a D
Decay by β-emission
b β i i with ith t γ-emission
ith / without i i (β -, γ)

a Isomeric Transition (IT) or Internal Conversion (IC)

a Electron Capture and γ emission (EC, γ )

a Positron decay and γ emission (β +, γ)

aDecay by α emission or nuclear fission

16
Decay Schemes for Nuclear
Emissions
Parent A
ZX

β+, EC, γ IT, IC β− , γ

A A Daughter A
Daughter Z-1 Y Daughter ZX Z+1 W

Increasing Atomic Number, Z

Decay by β- Emission
Î Neutron converted into
P t + El
Proton Electron
t + Antineutrino
A ti t i + Energy
E
Î Proton remains in nucleus - converting 14C to 14N
Î Electron and antineutrino ejected from nucleus
Î Transition energy = 0.156 MeV
Î This energy of 0.156 MeV shared between
electron and antineutrino

_
n Æ p + e (β-) + ν + energy

17
Decay by β- Emission

14
6C

β−

14
Increasing Atomic Number, Z 7N

Basic Atomic and Nuclear Physics

Radioactive Decay

• (β−,γ) Decay
–If the
β-
β− results in an unstable
daughter, the daughter will likely
decay y by g a γγ- ray
y emitting y

γ
• ZAX → A Y*
Z+1 → Z+1
AY

18
Decay by β− and γ-ray Emission

ν γ
_

β-

_
n Æ p + e (β-) + ν + γ + energy

Basic Atomic and Nuclear Physics

Radioactive Decay
99Mo
M → 99Tc
T

19
Decay by Isomeric Transition

Decay of metastable (isomeric) state to

ground state with emission of γ-ray

Decay by Isomeric Transition

99mTc 0.140 MeV

99Tc
0 MeV

Decay scheme for 99mTc

20
Decay by Internal Conversion

Internal Conversion
Transition energy transferred
to an orbiting electron (usually
K-shell)

Conversion electron emitted

with energy equal to γ-ray
energy minus binding energy
of K-shell.
Ee = Eγ - EK

Basic Atomic and Nuclear Physics

Radioactive Decay

• Isomeric Transition (IT) and Internal

Conversion (IC)
– if daughter is long lived a metastable state
occurs called Isomeric Transition
• gamma ray emission occurs
– if nulceus transfers energy to an electron,
then Internal Conversion occurs
• conversion electron is emitted

21
Basic Atomic and Nuclear Physics
Radioactive Decay

• Electron Capture
–orbital electron captured by nucleus,
combines with proton to form a
neutron
• p+ + e- → n + ν + energy
• zAX → Z-1AY

Decay by Electron
Electron Capture

Characteristic x-ray

e + p Æ n + ν + energy (EC)
e + p Æ n + ν + γ + energy (EC,γ)

22
Decay by Electron
Electron Capture
γ-ray emission

125
53 I

EC

0.035 MeV

γ
0 MeV
125
52 Te Decreasing Atomic Number, Z

Decay by Positron(β+)Emission

β+

p Æ n + e (β+) + ν + energy

23
Annihilation Reaction
Positron (β+) and an Electron (β-)

Positron collides with an

electron. Both are converted
to energy (E=mc2), resulting
in the emission of 2 gamma
rays, each of energy 511 keV
and emitted in opposing
directions (~180o)

Decay by Positron(β+)Emission

18
9F

Eβmax = 0.633
0 633
MeV

18
8O
Decreasing Atomic Number, Z

24
Decay by α-emission

In alpha-particle emission
emission, 2 protons and 2 neutrons
are ejected from the nucleus

A
ZX ⇒ A-4Z-4Y + α

226
88Ra ⇒ 22286Rn + 22He

Only occurs in elements with high atomic mass

Atomic and Nuclear Emissions

Î Basic Definitions
Î Atomic and Nuclear Transitions
Î Atomic Structure / Emissions
Î Nuclear Structure / Emissions
Î R di
Radioactive
ti Decay
D
Î Interactions with Matter

25
Radioactive Decay
Definition

A process b
by which
hi h an unstable
t bl nucleus
l ttransforms
f
into a more stable one by emitting particles and / or
photons and releasing energy.

Terminology

Parent nucleus = the unstable nucleus

Daughter nucleus = the more stable product
Transition energy Q = energy released

Radioactive Decay
Physical Half-
Half-Life

1 .0
Decayy curve with
0 .9
T = 4 hours
0 .8

0 .7

0 .6
Activity

0 .5

0 .4

0 .3
3

0 .2

0 .1

0 .0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
T im e - H o u r s

26
The Decay Constant
Decay Constant (λ)

Fraction of the atoms undergoing radioactive decay

per unit time (during a time period that is so short,
only a small fraction decay during that interval)

p of N radioactive atoms,, the average

For a sample g
decay rate dN/dt is given by

dN/dt = -λN

Radioactive Decay
Law of Decay

Decay is an exponential function of time

Nt = No e (- λt)

where Nt = number of atoms at time t

and No = number of atoms at time 0
λ = decay constant

27
Radioactive Decay
Definitions

Half-life: Sometimes called Physical Half-life.

Time required for activity to decay to 50% of
its initial value.

Radioactive Decay
The Physical Half-Life (T1/2 or T) is the time required for the
number of atoms to decrease byy half. The relationship p
between the Decay Constant λ, and Half-Life T
is given below

At t = T, Activity = 0.5 x Initial Activity

i.e. N / N0 = 0.5, or
0.5 = e- λ T
∴ loge(0.5) = -λT , or
-0.693 = - λT
∴ λ = 0.693 / T
or T = 0.693 / λ

28
Radioactive Decay
Definitions
Biological Half-life: Unrelated to radioactive decay. Refers
to time required for 50% of a biochemical to be eliminated
from the body. Can be described by λbiol, similar to
radioactive decay.

Effective Half-life: Disappearance with time of a radioactive

biochemical in the body both by radioactive decay and
biological
g elimination.
λeffective = λbiological + λphysical
or
1/Teffective = 1/Tbiological + 1/Tphysical

Physical Half-
Half-Life (T1/2)
Decay Constant (λ) NC Radionuclides

Radionuclide T1/2 λ

Tc-99m 6 hr 0.1151 hr-1

Mo-99 2.79 d 0.248 d-1
Tl-201 3.08 d 0.225 d-1

29
Units of Radioactivity
Definitions

3 7 x 1010 disintegrations / sec

Curie (Ci) 1 Ci = 3.7
1 mCi = 3.7 x 107 disintegrations / sec

Becquerel (Bq) 1 Bq = 1 disintegration / sec

= 2.7 x 10-11 Ci

Conversion Factors
1 mCi = 37 megaBecquerels (MBq)
1 MBq = 27 μCi

Charged Particles in Matter

• α and β particles
loose energy through
Collisions
• Energy loss along the
path of travel is LET
– Linear Energy Transfer
– ↑ α for ↓ β
– Interactions with
charge fields…not
mechanical
• Excitation
• Ionization
• Bremsstrahlung

30
 Charged Particles in Matter
• Excitation occurs when the incident particle
i t
interacts
t with
ith an outer
t shell
h ll electron
l t
– Energy carried off by molecular vibrations,
infrared, visible or UV radiation
• Ionization occurs when an outer shell electron
is ejected
– Secondary electron (δ (δ ray) may cause
ionizations
• Bremsstrahlung occurs when the particle
penetrates the electron cloud

Photon Interactions with Matter

• 100% Energy • <100% Energy • High Energy

Conversion Conversion – > 1.022 MeV
– EM to Kinetic – Energy Degraded
Energy Photon
• Spatially Discrete • Altered Pathway

31
Photon Interactions with Matter

Photon Interactions with Matter

32
Photon Interactions with Matter

Photon Interactions with Matter

Pair Production

33
Photon Interactions with Matter
Multiple Interactions

Photon Interactions with Matter

Secondary Radiations

34
Photon Interactions with Matter
Probability Distribution

Photon Interactions with Matter

Attenuation
• Attenuation depends on
the thickness and Z of the
absorber
– Greater thickness
leads to greater
absorption
– Energy and Z
relationship
p is more
complicated
• Linear attenuation
(μl)…cm-1
coefficient (μ
– The thickness required
to attenuate 50% is
called HVT
I (x) = I (0) e -μμx

35
Physics Principles for
Nuclear Cardiology
Summary
• Relationship of atomic structure to
– Mode of decay
– Emissions
• Understand and explain radioactive
decay
• Interactions
I t ti off photons
h t with
ith matter
tt
– Tissue
– Image quality

36
Basic Instrumentation
P i i l ffor N
Principles Nuclear
l
Cardiology

Michael K
K. O’Connor
O Connor, Ph
Ph.D.
D

Radiation Detectors
Gas-filled Detectors
• Ionization chambers
• Proportional
P ti l counters
t
• Geiger-Mueller counters

Scintillation Detectors
•Inorganic scintillators (NaI)
•Organic liquid scintillators

Semiconductor Detectors
• Ge(Li) and Si(Li) detectors
• CZT detector

37
 Gas--Filled Detectors
Gas

+ (Anode)

- - Current
β-Particle - + + - Amplifier
+
+ - -
+
- + -
+ +

- (Cathode)

Gas--Filled Radiation Detectors

Gas

x rays /γ-rays
• Low detection efficiency for x-rays rays
Why ?

• Can be used for the detection of α, β-particles,

neutrons and x-rays and gamma rays.
How sensitive ?

• Depending on applied voltage, the response

may be energy dependent
More energy = more ionization

38
Effect of Voltage on Detector Performance

Continuous
Discharge
Z
Zone
ulse Height

Recombination
Zone

GM
Counter
Pu

Proportional
P ti l
Ion Counter
Chamber

Voltage

Gas--Filled Radiation Detectors

Gas
• Ion Chamber
Used for dose calibrators,
calibrators pocket dosimeters

• Proportional Counter
Output proportional to absorbed energy
Used to detect neutrons and low energy x-rays

• Geiger-Mueller Counter
Output independent of absorbed energy
Used for survey meters
10 times more sensitive than ion chamber

39
 Radiation Detectors

Gas-filled Detectors
• Ionization chambers
• Proportional counters
• Geiger-Mueller counters

Scintillation Detectors
•Inorganic scintillators (NaI)
•Organic
O i liliquid
id scintillators
i till t

Semiconductor Detectors
• Ge(Li) and Si(Li) detectors
• CZT detector

Solid Scintillation Materials

• Sodium Iodide doped with Thallium (NaI)
used extensively in Nuclear Medicine

• Bismuth Germanium Oxide (BGO)

widely used in PET systems

• Barium Fluoride (BaF2) / Cesium Fluoride (CsF2)

used in PET systems

• Lutetium (Yttrium) Orthosilicate (LSO / LYSO)

used in time-of-flight and newer PET systems

• Plastic
inexpensive bulk scintillator

40
Properties : Solid Scintillators

Property NaI(Tl) CsF BGO BaF2 LSO Plastic

Density (g/cm3) 3.7 4.6 7.1 4.9 7.4 1.0

Photon Yield / keV 40 2.5 4.8 2.0 30 1.5

Scintillation Decay 230 2.5 300 0.8 40 2

ti
time ((nsec))

Hydroscopic Yes Very No Very No No

little

Scintillation Detector
Basic Components
• Scintillating Material, e.g. NaI

• Light detector - photomultiplier tube (PM tube)

High voltage supply
p
Pre-amplifier
• Voltage Discriminator (Pulse-height analyzer)
• Display device, e.g. multi-channel analyzer

41
 Sodium Iodide (Tl)
Advantages Disadvantages
Relatively dense Very fragile - easily
(3.7 g/cm3) - good fractured by mechanical
absorber of γ-rays or thermal stress
Efficient scintillator - NaI (Tl) is hydroscopic -
30 pphotons / kev of hence hermetic sealing
incident radiation is required
Light output proportional Large crystals difficult to
to amount of radiation grow and very expensive
absorbed

Scintillation Detector - PM Tube

Optical window
(Borosilicate glass) Dynode Anode Output signal

'Light' photon

Photo-
electron

Photocathode Vacuum Glass envelope

(Caesium antim ony or
rhubidium caesium )

42
 Scintillation Detector - PM Tube

Dynode Pre Amplifier

Pre-Amplifier
Array
Optically clear window
with Photocathode
directly behind it

Voltage (Energy) Discriminator

• BASIC PRINCIPLES OF PULSE HEIGHT ANALYSYS

– Requires a proportional detector…

Pre -
NaI PMT Amp AMP PHA +

HV

Examination of voltage amplitude to determine energy

43
 Pulse--Height Analysis
Pulse

• What are the various peaks

and valleys in the energy spectrum ?
Counts ( % )

• What parts of the spectrum contain

useful information ?

• Where should we place the energy

window ?

Energy ( keV ) • Why are the peaks so broad ?

Energy Spectrum Components

• Photopeak
p
• Compton Edge
• Backscatter Peak
• Iodine Escape Peak
• Lead x-ray Peaks
• Coincidence summing peak

44
Energy Spectrum Components
Photopeak
γ-ray undergoes photoelectric absorption in crystal

Compton Edge
Maximum energy deposited in crystal after a single
Compton event (49 keV for Tc-99m)

Backscatter Peak
Energy of scattered γ-ray after 180o scattering
(91 keV for Tc-99m)

Energy Spectrum Components

BP PP = Photopeak
PP C1 C2 BP = Backscatter Peak
CE
CE = Compton Edge
Pb IE
C1 = 1st Order Compton
C2 = 2nd Order
O d Compton
C t
NaI
NaI Detector
Detector
Pb = Lead X-ray
Lead IE = Iodine Escape Peak

45
Energy Spectrum Components
1400
Photopeak+Compton
1200 Compton 1st order
Compton 2nd order
Activity (counts)

1000
Compton 3rd order
800 Compton 4th order

600
A

400

200

0
50 60 70 80 90 100 110 120 130 140 150 160
Energy (keV)

Energy Resolution
NaI Detectors
Energy resolution is dependent on
amount of energy deposited in crystal

Low Energy = Low light signal = uncertainty !

Statistical uncertainty results in loss of resolution

At 140 keV, modern gamma camera has an

Energy resolution = 9-11%

46
 Energy Resolution of NaI

Energy Resolution Gamma Energy

20 Camera Resolution
Measured FWHM 99m
Vintage Tc Tl 201
Calculated : FWHM
15 1987 12.1% 19.2%
FWHM (%)

2000 8.7% 15.9%

10

5
0 100 200 300
Energy (keV)

NaI Crystal Efficiency vs. Thickness

100
140 keV
Modern gamma
ection efficiency

80
camera
360 keV
% photopeak

60

40
dete

20

0
0 1 2
NaI(TI) crystal thickness, inches

47
 Scintillation Detectors
Summary

• Voltage pulse ∝ energy deposited in crystal

• Measure voltage = measure energy
• Low voltage gives error in energy measurement
Hence energy resolution ~ 1/√E

• Scatter in source ⇒range of detected energies

• Energy
gy window selects events / energies
g we want

• γ-ray detection efficiency depends on thickness

of NaI crystal and energy of γ-ray.

Radiation Detectors
Gas-filled Detectors
• Ionization chambers
• Proportional counters
• Geiger-Mueller counters

Scintillation Detectors
•Inorganic scintillators (NaI)
•Organic
O i liliquid
id scintillators
i till t

Semiconductor Detectors
• Ge(Li) and Si(Li) detectors
• CZT detector

48
 Semiconductor Detectors

• Direct conversion of γγ-rays

y to small electrical current

• Germanium and Silicon were the most commonly

used semiconductor materials.

• Newer materials used for gamma cameras include

Cadmium Zinc Telluride

• Ge and Si exhibit leakage current - common

to cool Si detectors to -30oC and Ge to -200oC

• CZT can be operated at room temperature

CZT Detector (Cadmium Zinc Telluride)

Dense material =
6 gm/cm3

Energy resolution
(< 5%)

Can be operated
at room temp CZT Detector consisting of individual
modules of CZT each mounted on an
Expensive – Application Specific Integrated
currently limited to Circuit (ASIC)
small FOV detectors
No PMTs required !

49
 Energy Resolution
Comparison of CZT and Sodium iodide

1.1
1
0.9
NaI (10%)
CZT (4.5%)
malized Counts

0.8
0.7
0.6
0.5
0.4
Norm

0.3
0.2
0.1
0
0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300

Energy (keV)

Semiconductor Detectors

• High detection efficiency for x-, γ-rays

• Very high energy resolution (~ 2-4%)

• Fast response time

• Expensive – currently limited to small

imaging systems (breast / cardiac)

50
 Radiation Detectors
Comparison
Detector Intrinsic Dead Energy
Efficiency
Effi i Ti
Time Discrimination
Di i i ti
Ion Chamber Very Low --- None

Proportional Very Low ~msec Moderate

Counter
GM Counter Moderate ~msec None

Scintillation High ~ μsec Moderate

Detector
Semiconductor Moderate < 1 μsec Very Good
Detector

Gamma Camera
Schematic View
TOP VIEW

PMTs

Light
g Pipe
p
SIDE VIEW
NaI Crystal
Lead
Collimator

51
 Gamma Camera

Scintillating
Lead crystal Light
colimator detectors

Compute
x and y
location
of
gamma
ray

Patient Gamma camera Computer Digital

with collimator image

γ-Camera Collimation

Th collimator
The lli t strongly
t l affects
ff t

Î Field of View
Î Spatial Resolution
Î Sensitivity

52
 γ-Camera Collimation
Collimator designed to limit (by attenuation), the detection
of γ-rays to those rays travelling in certain directions.

Collimator composed of a dense material (e.g. lead)

Collimator parameters determined by length and width of

holes and by thickness of septa

γ-Ray
Source

Collimator NaI

Collimation: Resolution vs. Sensitivity

Resolution vs. Sensitivity
Ci

600 High
g sens
Sensitiviity, counts/min/uC

480

360
LEAP
240

High resol
120
Ultra-high resol
0
4.0 5.6 7.2 8.8 10.4 12.0
Collimator resolution (at 10 cm in air)

53
 Summary: Collimation

C lli t P
Collimator Parameter
t R
Resolution
l ti S
Sensitivity
iti it

Ï Hole Diameter Decrease Increase

Ï Hole Length Increase Decrease
Ï Septal Thickness Ï / No change Decrease
Ï Source-Collimator Decrease Ï / No change / Ð
Distance

Collimator Resolution

Very Important !!!

For all types of collimation, resolution

d
degrades
d as th
the object
bj t iis moved
d
away from the collimator face

54
 γ-Camera: System Resolution
System resolution (Rs) is a function of both
Collimator resolution (Rc) & Intrinsic resolution (Ri)

Rs2 = Rc2 + Ri2

Typical values :
Rc = 8 mm
Ri = 3 mm
Rs = 8.5
8 5 mm

Hence the collimator is the major determinant of

resolution in clinical studies

Gamma Camera
NaI Crystal and PMT’s

Optical coupling
PMT PMT PMT
(e.g., grease)

Light Pipe
(Optical window
NaI (TI)
made of
glass/plastic) crystal

Magnesium or Aluminum
aluminum oxide casing

55
 Gamma Camera
Detector Components

Pre-amps Light Pipe &

PMT’s NaI Crystal

Aluminum
cover sheet

Positioning Pulse

Positioning arithmetic refers to

the electronic scheme used to
determine the location of the light
pulse
l emitted h a γ-ray is
itt d when i
absorbed in the NaI crystal

56
PMT Light Distribution from γ-Ray

9 9 3 1

82 78 11 3 1 NaI Crystal

82 424 74 6 1 1

9 78 74 9 2 1 0

9 11 6 2 1 1
Number indicates
relative number
3 3 1 1 1 of light photons
1 1 1 0
detected by each
PMT
Light Distribution

γ-Ray Localization (1
(1--dimension)
NaI Crystal Voltage
Source output Cathode ray tube
+ PMT's

Digitize voltage
T
ADC and calculate
offset from
v center

In a conventional gamma camera, this scheme enables

localization of events to with 3-4 mm

57
 Gamma Camera
• Gamma camera is an analog device !
• Inherently non-uniform !
• Inherently non-linear!

• All gamma cameras incorporate a variety

of correction factors to enable acceptable
clinical use
– Energy correction
– Linearity correction
– Uniformity correction

Gamma Camera

Energy
gy
window

Photopeak
alignment

Raw com bined Aligned

energy peaks energy peaks

58
 Energy Correction
Effect on Energy Resolution

Energy
correction

Improved Energy Resolution

⇒ Better separation of Photopeaks

Energy Correction
Effect on Image Uniformity

Energy
correction

Flood image without Flood image with

energy correction energy correction

59
 PMT Non
Non--Linearities
Output
p Signal
g
A PMT h has a non-linear
li response tto
light across the face of the tube.

There is increased sensitivity to

light at the edge of the tube
compared to the center
PMT
Consequently, events near the
edge of the PMT are mis-positioned
towards the center of the tube

Input light

Linearity Correction

Measured True Hole

Hole Pattern Pattern

• Compute
C t the
th X and
d Y differences
diff between
b t the
th true
t
and measured locations of the holes in the phantom

• Store these differences in a linearity correction map

• Correct all detected events “on-the-fly” using the

correction map to relocate events to their true position

60
 Linearity Correction
Effect on Image Uniformity

Linearity
correction

Flood image Flood image

uncorrected corrected

Uniformity Correction
Matrix Multiplication
A typical scheme for uniformity correction using
matrix multiplication is described below

Î Acquire a high count flood image

Î Measure the average counts per pixel (Pavg)
Î For each pixel compute a correction factor = Pavg / P
Î Store corrections as a uniformityy correction map
p
Î Correct clinical studies by multiplying each pixel in
the clinical image by its corresponding pixel in the
correction map.

61
 Uniformity Correction

Uniformity
correction

Uncorrected Corrected
Uniformity correction is generally used after application of both
energy and linearity correction. It is not designed to correct for
major non-uniformities in the field of view.

Correction Maps
Effect on Image Uniformity
The following gives an indication of the effects of each type
of correction on the intrinsic uniformity of the gamma camera

Correction Uniformity
None 20%-30%
Energy 20%-30%
20% 30%
Energy+Linearity 5%-10%
Energy+Linearity+Uniformity 2%-5%

62
 Gamma Camera
The 4 Critical parameters

The following gamma camera parameters dictate image

quality in clinical studies
Energy Resolution ~10%
Spatial Resolution - Intrinsic 3-4 mm
Spatial Resolution – Collimator 4-10
4 10 mm
Collimator Sensitivity 100-400 cps

63
 Nicki L. Hilliard, PharmD, BCNP
University of Arkansas for Medical Sciences
Littl Rock,
Little R k AR

Methods of Isotope Production

Cyclotron

Linear Accelerator **

Nuclear Reactor

Generator

64
 Radionuclide Production
Cyclotron Reactor Generator
• Thallium-201 • Mo-99 • Tc-99m
• F-18 FDG • Rb-81
• N-13 Ammonia
• O-15 Water
• I-123 MIBG

Isotopes for Cardiac Imaging

Cyclotron

65
Nuclear Reactors

Fission of U-235

Neutron
Bombardment

By-products of U-235
Mo-99 & +I-131

66
Radionuclide Generators

Daughter
• Longer T 1/2 • Not Isotopes
• Short lived • Different
properties

Chemical
Ch i l
Parent
Separation

Mo-99 Sr-82

Tc-99m Rb-82
Commercially Available

67
Tc-99m Generator
€ Developed in 60’s
60 s “Dry”
Dry
€ Currently 2 manu.

“Wet”

Physical Properties of Mo-99

T1/2 • 67 hours

• Beta
Decay • Gamma

Energy • 740 & 780 keV

68
99Mo - 99mTc Decay

99Mo
β−
T1/2 = 67 h
99mTc

T1/2 = 6 h

99Mo - 99mTc Decay

99Mo 86%

99mTc
14% γ
99Tc

69
Generator Production

235U (n
(n,f)
f) 99Mo + others
radiochemistry

MoO4 2- Mo7O246- Mo8O284-

NaCl

Al2 O3

Na 99mTcO4-

Generator
Generator Al
Mo
Column

Al
Elution
Tc Na
•99Mo adsorbed onto
alumina column having
two ionic charges

• 99Mo decays
y into 99mTc

•99mTcO4- form
(pertechnetate) has one
ionic charge

Ion Exchange Column

70
Eluting a Dry
Column Generator

€ Need evac vial and saline

charge
€ Decide how much saline to
elute with (2 ml min)
€ Place saline vial on generator
first
€ Place evac vial on generator
€ Watch to see if saline “bubbles”
€ Leave on generator few
minutes

71
Eluting a
Wet Column
Generator

€ Decide the size of

the evac vial to use
€ Place shielded evac
vial on generator
€ Saline fills to size of
vacuum.

Generator Kinetics
ACTIVITY

TIME

72
 Generator Eluate Q.C.
Moly Breakthrough Test
<0.15 uCi Mo / mCi of TcO4-

Alumina Test
<10 ug
g / ml

Hydrolyzed Reduced (TcO2)

<5% (seen as liver uptake)

Moly Shield

73
Lead Shield Method

Dose
Calibrator

Lead
Shield

Tc
Mo

What happens to the

Moly assay with time?

€ Mo-99 = 67 hr T1/2
€ Tc-99m = 6 hr T1/2
amt Mo-99
amt Tc-99m
 Ratio increases with
time.

74
Alumina Test
€ Use Alumina Test Kit
(pH like paper)
€ USP limit is 10 ug/ml
€ Al+3 may cause an
“Aluminum
u u cocolloid”
od
€ RE uptake (liver)

Na99mTcO4
99mTcO * H20 ((colloid))
95% 2

Solvent front Origin

75
Transient Equilibrium

ACTIVITY

TIME
Example: Mo / Tc Generator

Secular Equilibrium
ACTIVITY

TIME
Example: Sr / Rb Generator

76
Radiopharmaceutical
Parameters to Monitor

€ Radionuclide purity
€ Radiochemical purity
€ Chemical purity
€ Physical purity
€ Biological
Bi l i l purity
it

Pertechnetate + Reducing Agent + Ligand

99m
TcO4- sestamibi
Sn2+

Kit

Desired Product Tc-99m sestamibi

99m
Impurities: T O4-
TcO
TcO2 * H20 (colloid)
Intermediate step products

77
 Salivary Glands
Thyroid
Stomach

Free Pertechnetate

Agents Currently FDA approved for cardiac

imaging
€ Tl201 thallous chloride
€ Tc99m-sestamibi
€ Tc99m-tetrofosmin
€ Rb82 rubidium chloride
€ F18 fluordeoxyglucose
€ Not on market
○ Tc99m-teboroxime

78
 Tc
Tc--99m Tc
Tc--99m
Property Tl
Tl--201 Sestamibi Tetrofosmin
Half--life
Half 73 hr 6 hr 6hr
Photon
Energy 68
68--80 keV (94%) 140 keV (88%) 140 keV (88%)
A
Availability
il bilit C l t
Cyclotron G
Generator-
Generator
t -local
l l G
Generator-
Generator
t -local
l l
+1 Cation
Chemistry Hydrophilic +1 Cation Lipophilic +1 Cation Lipophilic
Uptake Active Na/K ATPase Passive Diffusion Passive Diffusion
% Inj Dose ~4% ~ 1.2% ~ 1.0%
2-4mCi (74
(74-- 10
10--30mCi (370
(370-- 10
10--30mCi (370
(370--
Ad A ti it
Adm.Activity 148MB
148MBq)) 1110MBq)
1110MB ) 1110MBq)
1110MB )

Fixed mitochondria Fixed cytosol

Distribution Redistributes associated associated
First-pass
First-
Study No Yes Yes

Thallium-201

€ Analog of Potassium (K+)

K+
K+ K+
Tl+ Active
Tl+
K+ Tl+ Transport
K+ Process
Tl
Tl+ K+
Tl+

Accumulates in viable myocardium

79
Tc-99m Sestamibi
€ Cationic complex (not K+ analog)
€ Isonitrile compound
€ accumulates in viable myocardial tissue
€ cleared through hepatobiliary system
€ 1.2% of dose taken up by heart

Tetrofosmin Chemistry
€ {Tc(V)[O2(Tetrofosmin)2]}+1
€ Phosphines alone will reduce Tc(VII)
slowly @ room temp ((50% % @ 6 hr @
0.05 mg/ml)
€ Stannous ion speeds up the reduction
€ Gluconate exchange ligand prevents
hydrolysis, takes 15 minutes to
exchange
€ High tetrofosmin concentration and
high activity concentration leads to
radiolytic reduction to Tc (IV),(III) & (I)
complexes

80
Tc-99mTetrofosmin

Add TcO4- + Keep

Incubate for
venting concentration
15 min
needle for O2 low

PET Radiopharmaceuticals

€ Perfusion Agents € Metabolic Agents

y Rubidium-82 y F-18
y N-13 Ammonia Fluorodeoxyglucose
y O-15 Water

81
 Property Rubidium
Rubidium--82 N-13 Ammonia O-15 Water

Half--life
Half 75 sec 10 min 2 min
Photon
E
Energy 511 kkeV
V 511 kkeV
V 511 kkeV
V
Sr-82
Sr-
Availability Generator Cyclotron
Cyclotron--local Cyclotron
Cyclotron--on site
Rubidium Uncharged Water inj.or Carbon
Chemistry cation lipophilic Dioxide inhale
Active Na/K
p
Uptake ATPase Trapped
pp as N N--
Mechanism Pump 13 glutamine Freely diffusible
Administered
Activity 50
50--60mCi 10
10--20mCi 30mCi
Kidney= Bladder= Heart=
Critical Organ 1.92rad/60mCi 0.6rad/20mCi 0.24rad/30mCi

Rubidium-82 (CardioGen-82®)

Generator
G t P Produced
d d
• Sr-82: 25 day T ½
• Rb-82: 75 sec T ½

Secular Equilibrium

Imaging 90 sec post

infusion

82
N-13 Ammonia (perfusion)
Properties Imaging

Lipophillic
10 min T ½ Trapped as N-
13 glutamine

10-20 mCi
Beta + Critical organ:
Bladder

Imaging 5 min
post inj / Stress
511 keV
with 30 min
wait

O-15 Water (perfusion)

€ High background in
cardiac chambers
and lungs.
€ Subtraction of blood
pool with O-15
Carbon Monoxide
inhaled
€ Net myocardial
perfusion
€ Imaging immediately

83
F-18 FDG (metabolism)
Cyclotron Produced

• 110 min T ½

Distribution similar to glucose

• Independent of blood flow

10 mCi after 50 g glucose

loading
• Diabetic patients may be require extra time

Specific Activity
Radioactivity per unit
amountt off substance
b t
(grams or moles)

Based on disintegrations
per min (dpm)

Higher specific activity

gives higher count rate

84
 Breast Feeding

Tc
Tc--99m labeled DMSA, MDP, Interruption of 4 hours
HDP, DISIDA, SC, MIBI,
MIBI, and
Gluceptate,, & In-
Gluceptate In-111 WBC
Tc
Tc--99m labeled MAA, PYP, Interruption of 12 hours
DTPA, and RBCs
DTPA
99mTcO -, I-
4 I-123, Interruption of 24 hours

201,, Ga-
T1--201
T1 Ga-67, II--131 Breastfeeding
Contraindicated

85
 Nuclear Cardiology Board Review Course
Boston MA 10 September 2008

Radiopharmaceutical Protocols
Gary V Heller, MD PhD
Hartford Hospital/University of Connecticut
Hartford CT

Tracers, Protocols
• Tracers,
Tracers PET and SPECT
• Protocols, SPECT
• Protocols, PET

86
 Background
• Tracers reflect changes in blood flow due to
their high myocardial extraction
• Myocardial extraction is maintained
throughout the range of blood flow
p
• Most important characteristics:
• extraction fraction
• linearity with blood flow

Desirable Features of Tracers

ƒ High myocardial extraction rate
ƒ Linear relationship between myocardial uptake and
blood flow
ƒ Low extra-cardiac uptake
ƒ Myocardial redistribution (one injection, Tl-201)
ƒ Easy labeling
ƒ Stability of the labeled compound

87
Clinical Imaging: Current Tracers
• In clinical imaging, flow tracers are not completely
extracted
• Extraction by myocardium depends on the
myocardial flow and tracer kinetics
• Amount of tracer uptake by myocardium after
injection is the product of extraction fraction and
myocardial blood flow
• Tracers with higher first pass extraction will track
blood flows over a wider range (importance:
pharmacologic stress)

Tracer Extraction: Current

Tracers
• All myocardial perfusions imaging agents
show linear relationship between myocardial
blood flow and tracer uptake during resting
conditions

• With increasing blood flow during stress: all

demonstrate “plateau effect”

88
Blood Flow and Tracer Uptake
The ideal perfusion tracer
would track myocardial blood
flow across the entire range of
physiological flows.

The available perfusion tracers

"roll off" at higher levels of flow.

The different tracers begin to

reach a plateau at different
levels of myocardial blood flow.

Tracer Extraction
• Plateau effect differs between tracers
• Flow tracer closest to linearity will most accurately
reflect differences between stress and rest conditions
• Flow tracers with the least linearity might not exhibit
differences between rest and stress conditions
• Tc
Tc-99m
99m labeled teboroxime has the highest
percentage of extraction in the myocardium

89
 Tracer Uptake

From Bateman, et al. ACC 51st Annual Scientific Session,

March 17-20, 2002, Atlanta, Georgia, USA

Tracer Clearance
• Clearance of each agent also varied
• Thallium clearance slow but begins within 10
minutes (must begin imaging early)
• Sestamibi and tetrofosmin retained for
several hours
• Teboroxime clearance is most rapid
– imaging must commence immediately after
injection

90
 Individual Tracers: Thallium-201
• Used in MPI since 1977
• Redistribution allows single injection stress
and rest imaging
• Excellent first pass extraction
– (81% at normal flow)
– 4% of injected dose localizing in myocardium
• Linear relationship of Tl-201 activity to
3ml/min/gm

Thallium-201
Suboptimal features of Tl-201:
Tl 201:
• Low photon energy spectrum (60-80 KeV)
– suboptimal image quality
– Problem in obese patients
• Lengthy
g y half-life
– increased radiation exposure (20-25 mSv)
– decreasing the dose leads to lower photon flux
and the need for longer imaging times

91
 1 Activity
Thallium -201

Tc-99m Teboroxime
• Tc-99m hydrophylic
y p y and LARGE molecule
• Highly lipophilic cation
• Highest myocardial extraction of all Tc-99m radiotracers
• Uptake is linear of a wide range of coronary blood flow rates
(closest to O-15)
• Initial uptake in myocardium very high
• Little activity in the liver

92
 Tc-99m Teboroxime
• Rapid myocardial washout and rapid increase
in hepatic activity
• Clinical Implications:
ƒ Begin acquiring data very soon after injection
ƒ Inconsistencies between projections
ƒ Late acquisition
ƒ Poor myocardium to liver ratio, imaging artifacts

Teboroxime Uptake

From Bateman, et al. ACC 51st Annual Scientific Session,

March 17-20, 2002, Atlanta, Georgia, USA

93
 Technetium-99m sestamibi
• Has favorable characteristics for MPI
• Labeled with Tc-99m, stable in kit form
• Using gated SPECT, both perfusion and
function evaluation can be obtained
• Stability of tracer allows repeat acquisitions
– (camera malfunction, patient movement)

• Long retention requires two injections

Technetium-99m sestamibi
Drawbacks of Tc-99m sestamibi:
• Extraction non-linear at higher flow rates
• First pass extraction fraction only 60%
• Lack of redistribution
– 2 separate injections required to document ischemia
• Labeling
gpprocedure requires
q q
quality
y control p
processes
• Excretion through the hepatobiliary system
– intense activity in small bowel, sub diaphragmatic artifacts

94
 Technetium-99m sestamibi

Technetium-99m tetrofosmin
• Technetium-99m 11,2-bis(bis[2-
2-bis(bis[2-
ethoxyethyl]phosphino)ethane
• Lipophilic, cationic complex
• Rapidly cleared from the blood pool after
j
intravenous injection
• Slow myocardial clearance
• No clinically significant delayed redistribution

95
 Technetium-99m tetrofosmin:
Drawbacks
• First-pass myocardial extraction 54%
• Myocardial plateau at 1.7 x normal flow
• May underestimate blood flow 1.5 to 2.0
ml/min per gm
• Potentially decreased sensitivity of vaso
vaso-
dilator MPI compared to Tl-201 imaging

Technetium-99m tetrofosmin

96
 PET Perfusion Tracers
• [13 N] ammonia: extraction fraction > 90%
• Rubidium-82:
– lower extraction fraction, reaches plateau more rapidly at
hyperemic range of flow
– very short half-life
– Exercise studies difficult in PET scanner
– Attenuation correction requires close alignment of
transmission and emission data
– Most PET studies use pharmacological rather than exercise
stress

Myocardial Perfusion PET Tracers

AGENT 1/2-LIFE DOSE MEAN POSITRON PRODUCTION

RANGE

O-15 2.0 min 60–100 1.1 mm Cyclotron

Water mCi
N-13
N 13 9 8 min 7–20 mCi
9.8 0 7 mm
0.7 Cyclotron
Ammonia
Rb-82 75 sec 20–60 2.4 mm Generator
mCi

97
 Myocardial Perfusion PET Tracers
O-15 Water
• Requires on-site cyclotron
• Most closely meets criteria for an ideal flow tracer
• Extraction fraction approaches unity and does not decline
with higher flows
• Remains in blood pool – poor quality images with low
target to background ratios
• Not suitable for clinical imaging, not FDA approved, not
payable by Medicare
• Used mostly for measuring myocardial blood flow in
research studies

Myocardial Perfusion PET Tracers

N-13 Ammonia

• Requires nearby (on-site) cyclotron

• Half-life 10 minutes
• Excellent myocardial uptake & retention
• Bolus (10–20 mCi)
• Applicable to exercise or pharmacologic stress
• Established flow quantification ability
• FDA approved
appro ed and Medicare reimb
reimbursed
rsed
• ½-life long for through-put efficiencies
• In some patients, increased lung retention; frequent excess
liver & bowel uptake
• Lower counts in lateral wall in some normal patients

98
 Myocardial Perfusion PET
Tracers: Rubidium-82
• Half-life 75 seconds
• Strontium-82
Strontium 82 generator q28 days
• Radionuclide always available (facilitates add-ons)
• Can re-image in minutes if technical problems (should
almost never have a poor quality study)
• Tl-201 – like kinetics: high extraction at high flows
(enhances detection of mod-severity CAD)
• FDA approved and Medicare reimbursed
• Short half-life (technically challenging; pharm stress only;
less useful for very obese)
• Flow quantitation not as well validated

Comparison of Common Perfusion

Agents
Characteristic 201
0 Tl 99mTc
99 99mTc
99 Sestamibi Rubidium-82
Tetrofosmin

Cell uptake Active Passive Passive Active

Clearance Moderate Slow Slow Decay

Extraction fract. 0.85 0.54 0.55-0.65 Higher than 65%
Redistribute Yes partial Minimal No
Measure of blood
G d
Good Ad
Adequate
t Ad
Adequate
t G d
Good
flow
Poor-
Gated images Excellent Excellent Excellent
Adequate
Photon energy 70 KeV 140 keV 140 KeV 511 KeV
Half-life 73 hours 6 hours 6 hours 75 seconds
Clearance Renal Hepatic Hepatic Renal

99
 Stress Protocols
• SPECT protocols
protocols, thallium/technetium
• PET protocols

Radiopharmaceutical Protocols

ƒ One day dual isotope

ƒ Two-day technetium
ƒ One day single isotope
ƒ Rest-stress
ƒ Stress-rest
ƒ Stress-only imaging with ECG-gated SPECT
and validated attenuation correction
ƒ One day stress-delay thallium

100
Dual Isotope Imaging
ƒ Advantages:
ƒ Fast protocol
ƒ Thallium for viability
ƒ Prognostic data available
ƒ Disadvantages
ƒ More difficult to evaluate transient LV cavity
dilation
ƒ Evaluation of fixed vs partially reversible
defects for attenuation artifact or CAD
ƒ If viability issue, wait at least 4 hours for
imaging

Same Day Protocol: Single Isotope

ƒ Advantages:
ƒ Good
G d validation
lid ti off viability
i bilit ffor T
Tc-99m,
99 comparable
bl tto
Rest-Redist Tl-201(Udelson, Kaufman)
ƒ “Fast Track” Protocol reduces start to finish
ƒ Interpretation of images easier (same isotope for stress,
rest)
ƒ Determination of transient LV cavity dilation easier
ƒ Validated attenuation correction

101
 Same Day Protocol: Single Isotope
ƒ Disadvantages:
ƒ One iimage off llesser quality
O lit
ƒ Rest –stress necessitates both images
ƒ Stress-rest: poor quality stress images
ƒ Missed ischemia?

One Day Protocol: Single Isotope

0 min 45 60min
45-60min 60 90min
60-90min 75 135min
75-135min

rest rest perform stress

injection acquisition stress acquisition

• Rest injection 10 -15 mCi Stress acquisition:

Exercise: 15 min
• Stress injection 30 - 45 mCi Pharmacologic: 45min
• Stress Gated Combined: 15 min

102
Two Day Protocol: Technetium
ƒ Advantages:
ƒ High quality stress and rest images
ƒ Gating for both stress and rest
ƒ Option: stress first, if normal, no rest
ƒ Stress only imaging with attenuation correction
ƒ Disadvantages:
ƒ Requires two separate days for patients
ƒ Increases decision process for physicians
ƒ Camera availability

Impact of Cardiac Drugs, B-Blockers:

Exercise/Pharmacologic Stress
ƒ Cardiac drug effects:
• Exercise: beta blockers, nitrates, statins,
calcium channel blockers
• Dobutamine stress: beta blockers
• Vasodilator stress: similar impact?

103
 Why PET?
ƒ Availabilityy of PET cameras: oncology
gy
ƒ Availability of radiopharmaceutical Rb-82
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)

Options for Cardiac PET

ƒ Myocardial perfusion imaging for diagnosis,
risk stratification, CAD
ƒ Vasodilator stress
ƒ Dobutamine stress
ƒ Exercise (recent JACC articles from Toronto)
ƒ Agents available: Rb-82, N-13 Ammonia,
O 15 water
O-15 water, on the horizon: F
F-18
18 perfusion
ƒ Myocardial viability: FDG/perfusion agent
ƒ Cardiac Sarcoid identification

104
 Advantages of PET Perfusion

• Image quality
• Diagnostic accuracy
• Risk stratification
• Rapid procedure
• Added information: blood flow, calcium,
Coronary CT

Comparison of Myocardial
Perfusion PET and SPECT
Several potential advantages of PET MPI compared to
SPECT-
• Higher spatial resolution

• Greater counting efficiencies

• Robust attenuation correction

Bateman et al. JNC 2006; 13(1): 24-33

105
 Image quality scores for PET and SPECT
perfusion and ECG-gated scans

Bateman et al. JNC 2006; 13(1): 24-33

Comparison of degrees of Interpretive Certainty

of SPECT and PET studies

Bateman et al. JNC 2006; 13(1): 24-33

106
 PET Accuracy for CAD Detection

# Pts Sensitivity Specificity

Marwick (1992) 74 90% 100%

Grover-McKay (1992) 31 100% 73%
Stewart (1991) 81 83% 86%
Go (1990) 202 93% 78%
Demer (1989) 193 83% 95%
Tamaki (1988) 51 98% 100%
Gould (1986) 31 95% 100%

TOTAL 663 89% 86%

Diagnostic Accuracy: Tc-99m

SPECT vs Rb-82 PET

100
*
90
* *
80
70 * * *
60
PET
50
SPECT
40
30
20
* 0 05
*p<0.05
10
0
Sens Spec Accuracy Sens Spec Accuracy

Overall CAD Individual Artery

Bateman et al Circ 2004;76:S611

107
 DIAGNOSTIC ACCURACY DIAGNOSTIC ACCURACY
BY GENDER BY BMI
100 *P=0.05 *P=0.0 100 *P=0.0 *P=0.02
1 5
80 88 80 87
84 85
% %
60 69 % 67 60 70
67
%
% % %
%
40 40

20 20

0 0
Men Women BMI<30 BMI>30
100 MVD SENSITIVITY
*P=0.03
80
SPECT 60 71
%
PET 40 48
%
20

0
MVD Bateman, JNC 13: 24 – 33, 2006

Quantitation of TID in Relation to Dipyridamole-

Stress Rb-82 Myocardial Perfusion PET
1.3
1.24

+/-0.23
Average 1.2 1.16
Quantitative
Score 1.11
+/-0.13
1.1
+/-0.15

1.0
0-4 5-8 >8

Summed Difference Score

123 total patients Bateman, AHA 2005

108
 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
• Significance with accuracy, high grade
stenosis, MVD

Left Ventricular Ejection Fraction Reserve is

Inversely Related to the Magnitude of Jeopardized
Myocardium
P < 0.001

15 P = 0.07
Left ventricular ejection fraction

10

P = 0.05
5.3
4.4
reserve (%)

5
3.6

-0.2
0
n = 353 n = 24 n = 104 n = 28

-5

-10 Normal Scar Mild-mod Severe

reversibility reversibility

82Rb PET scan results

Dorbala et al, J Nucl Med 2007;48:349

109
 Prognostic Value of Rb-82 Myocardial
Perfusion PET Using Dipyridamole
153 consecutive pts followed for 3.0 +/- 0.9 yrs

50

40

30
Cumulative
Death & MI
(%) 20 27%
17%
10 4%
0
0
Normal Mild Mod Severe
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

110
 PET/CT Protocol: Hartford
Hospital
Rb--82
Rb Rb--82
Rb
50
50--60 mCi 50
50--60 mCi
Dipyridamole
0.56 mg/kg

gated gated
scout CT
CT--trans rest scout
scoutCT
CT--trans stress

70
70--90 sec 70
70--90 sec

Approx 1 min Approx 7 min Approx 6 min Approx 1 min Approx 7 min

Elapsed time: 30 Minutes

111
SPECT/PET May Underestimate
Disease Burden: Stable CAD

Calcium score: 890

Courtesy: Brigham and

Women’s Hospital

112
 Shaw et al. Radiology. 2003:228:826-833.

Tracers, Protocols
• Tracers,
Tracers PET and SPECT
• Protocols, SPECT
• Protocols, PET

113
 ASNC BOARD REVIEW

STRESS TESTING AND

IMAGE INTERPRETATION

Robert C. Hendel, MD, FACC, FAHA, FASNC

Midwest Heart Specialists

Winfield, Illinois

INFLUENCE OF MEDICATIONS ON SPECT

MYOCARDIAL PERFUSION IMAGING

EXERCISE, DOBUTAMINE
• Beta Blockers
–Prevent maximal HR response
–Underestimation of ischemia

ADENOSINE/DIPYRIDAMOLE
• Nitrates, calcium channel antagonists, beta blockers
–Reduction of diagnostic sensitivity
–Underestimation of ischemia
• Caffeine/methylxanthines
–Reduction of hyperemia
–Reduction of ischemia detection (?)

114
 MEDICATION USE AND
RADIONUCLIDE IMAGING

• If for diagnosis of CAD, DISCONTINUE CARDIOACTIVE

MEDICATIONS (nitrates, beta blockers, calcium channel
blockers, caffeine/methyxanthines, dipyridamole)

• If for assessment of therapy/prognosis, CONTINUE ALL

MEDICATIONS

• Decisions regarding use of medications must be

individualized and discussed with referring physician, if
possible.

WHEN FEASIBLE,
EXERCISE TESTING IS PREFERRED
The Rationale

• Exercise
E i duration
d ti (ti
(time or METS)
• Symptoms
• Arrhythmia/conduction disorders
• Reason for termination
• Heart rate response
• Blood pressure response
• ECG changes

115
 PHARMACOLOGIC STRESS TESTING
Indications and Applications

• Inability to exercise
–CNS
–Orthopedic
• Limited capacity for exercise
–Poor conditioning/motivation
–PVD
–COPD
–Medication
• Contraindications
C t i di ti tto exercise
i
–AAA
–Aortic stenosis
• Left bundle branch block/pacermaker

MYOCARDIAL PERFUSION IMAGING

IN THE UNITED STATES
9,000,000

8,000,000

7,000,000
Number of Procedures

6,000,000

5,000,000

4,000,000

3,000,000
, ,

2,000,000

1,000,000

0
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
PHARM STRESS 28% 44%
Pharmacologic Exercise TOTAL
Source: AMR Data

116
 PHARMACOLOGIC STRESS TESTING
IN THE UNITED STATES
80
Adenoscan
70 Dipyridamole

60 Dobutamine
Market Share (%)

50

40

30
M

20

10

0
95

96

97

98

99

00

01

02

03

04

05

06

07
19

19

19

19

19

20

20

20

20

20

20

20

20
Source: AMR Data

PHARMCOLOGIC STRESS
MYOCARDIAL PERFUSION IMAGING

Dobutamine
8%

Adenosine
Dipyridamole
py 52%
40%

Source: AMR

117
 PRACTICE SURVEY
Percent of Patients Who Receive Exercise Stress Tests,
Pharmacologic Stress Tests Alone or Both

Other 1%
Exercise Testing
Alone
42%
Combo Pharma
Stress Test/Low
Level Exercise,
15%

Pharmacological
Stress Testing Alone
42%

ASNC 2007 SQ. 5 (n=106)

STRESS TESTING
Characteristics of Technique

EXER DOBUT DIPYRID ADENO

Ę CBF 2-3X 2-3X 3-4X 3-5X
Ischem ia ? Yes Yes No No
Onset, min 3-5 2-4 4-6 1-2
Offset, min 2-5 4-6 10-30 0.5-1
AV Block No No Sl ncrease Increase
SA/AV cond Increase Sl increase Sl decrease Decrease
Ectopy Yes Yes Rare Rare
Ę CBF =changein coronary bloodflow; min =minutes;
SA/AVcond= sinoatrial and atrioventricular nodeconduction

118
 CONTRAINDICATIONS TO
PHARMACOLOGIC STRESS TESTING

• DIPYRIDAMOLE, ADENOSINE
• GENERAL –Use of dipyridamole (for adenosine)
–Hypotension –Severe (active) asthma or COPD
–ACS w/i 24 hours –Allergy to aminophylline
–Decompensated heart failure –2nd or 3rd AV block
–Caffeine, other methyxanthine w/i12 hrs
–Critical AS
–Severe LM stenosis • DOBUTAMINE
–Severe LV outflow obstruction –Hypertension
yp
–Hypersensitivity to agent –Uncontrolled atrial fibrillation/flutter
–Serious VEA
–Large aortic aneursym
–Beta-blockers w/i 24 hrs

DOBUTAMINE STRESS TESTING

Radiopharmaceutical
mcg/kg/min

5 10 20 30 40 50 SPECT
0 3 6 9 12 15 18 21 30 45 60 75
minutes minutes

Atropine
0.5-1.0 mg

119
HEMODYNAMIC EFFECTS OF DOBUTAMINE

100 100

80 80
Systolic BP
BP (mm Hg)

HR (bpm)
60 60

40 40
Heart rate

20 20
Diastolic BP
0 0

B 5 10 20 30 40
Dobutamine dose (μg/kg/min)

DIPYRIDAMOLE STRESS TESTING

Radiopharmaceutical

DIPYRIDAMOLE SPECT
0 1 2 3 4 5 6 7 30 45 60 75
minutes minutes

Aminophylline
0.56 mg/kg 50-125 mg IVP

120
 ADENOSINE STRESS TESTING

Radiopharmaceutical

ADENOSINE SPECT
0 1 2 3 4 5 6 7 30 45 60 75
minutes minutes

140 mcg/kg/min

ADENOSINE STRESS TESTING

Abbreviated Protocol

Radiopharmaceutical

ADENOSINE SPECT
0 1 2 3 4 30 45 60 75
minutes minutes
140 mcg/kg/min

121
HEMODYNAMIC EFFECTS OF ADENOSINE
150 120
†
140 * 110
Systolic BP
130 100
†
BP (mm Hg)

120 * 90
HR (bpm)

§
110 Heart rate
‡ 80
100 70
90 60
†
80 50
*
Diastolic BP
70 40

B 50 75 100 140
Adenosine dose (μg/kg/min)
†B-140 (P=0.0003); *100-140 (P=0.0001); ‡B-75 (P<0.05); §75-100 (P=0.0001).
Verani MS et al. Circulation. 1990;82:80-87.

122
CORONARY FLOW IN PATIENT
WITH CAD AT REST

Resultant Image
Uniform

R r
Flow maintained due to coronary autoregulation

CORONARY FLOW IN PATIENT

WITH CAD AFTER VASODILATOR

Resultant Image
Heterogeneous

r r
Flow disparity due to augmented flow in
normal bed and attenuated response in stenosed bed

123
 SAFETY OF DIPYRIDAMOLE TESTING
IN 73,806 PATIENTS

EVENT FREQUENCY
Death 0.95/10,000
NFMI 1.76 /10,000
VT/VF 0.81 /10,000
TIA 1.22 /10,000
Bronchospasm 1.22 /10,000

Lette et al, 1995

J Nucl Cardiol 2:3

PHARMACOLOGIC STRESS TESTING

WITH VASODILATORS

GENERAL PROPERTIES DIFFERENCES

• Excellent safety with stable pts • Dipyridamole
• Avoid w/ bronchospasm, AV block –Indirect action
–Prolonged action
• May be combined with exercise
• Adenosine
• Well-proved
p diagnostic
g and
–Direct receptor agonism
prognostic utility
–Rapid onset/offset
–Avoid if pt receiving dipyridamole

124
 ADENOSINE STRESS TESTING
With and Without Adjunctive Exercise

Radiopharmaceutical
p
6 MINUTE
ADENOSINE ADENOSINE
(STANDARD) 0 1 2 3 4 5 6 7 8
minutes

Radiopharmaceutical

4 MINUTE ADENOSINE
ADENOSINE EXERCISE
+ EXERCISE
0 1 2 3 4 5 6 7 8
minutes

HEPATIC ACTIVITY WITH ADENOSINE

MYOCARDIAL PERFUSION IMAGING
Impact Of Adjunctive Exercise

6 minute adenosine 4 minute adenosine + exercise

Elliott et al., 2000
JNC; 7; 584

125
REDUCTION OF SYMPTOMS WITH
ADJUNCTIVE EXERCISE
Symptom Severity Score

45
40
35 p < 0.0001
30
25
20
15 •
10
5
•
0
Adenosine Only Adenosine+Exercise

Elliott et al., 2000

J Nucl Cardiol; 7; 584

PHARMACOLOGIC STRESS TESTING

Adjunctive Exercise

• Can be performed in most patients

• Minimal logistic issues
• Similar diagnostic information
• Improved image contrast
(myocardium:background ratios)
• Less hepatic interference
• Markedly reduced side effects
–Symptoms
–Conduction disturbances

126
 PHARMACOLOGIC STRESS TESTING
Side Effects
ADENOSINE1 DIPYRIDAMOLE2 DOBUTAMINE3
n=92 56
n=9,2 n=476 n=10 76
n=1,0
Chest Pa in 35% 20% 39%
Flushing 37% 43% <1%
Dyspnea 35% 3% 6%
Dizziness 9% 12% 4%
GI di scomfort 15% 6% 1%
Heada che 14% 12% 7%
A h th mia
Arrhyth i 3% 5% 45%
AV Block 8% 0% 0%
STĘ 6% 8% 20-31%
ANY 81% 47% 50-75%
STĘ = ST se gment changes on ECG; ANY = any side effect

1Cerquiera, JACC 1994; 23: 384 2Ranhosky, Circ 1990; 81: 1205 3Elhendy, JNM 1998; 39: 1662

THE NEED FOR NEW METHODS OF

PHARMACOLOGIC STRESS TESTING

• Frequently
q ypperformed p
procedure ((≈3M/yr)
y)

• Serious adverse effects

–AV block (up to 8%)
–Bronchospasm (<1%)

• “Bothersome” side effects

–Total (50-80%)
–Chest pain (20-40%)
–Flushing (40%)

• Continuous infusion required

127
 ADENOSINE RECEPTORS
Agonists and Antagonists
A2A agonists
g
Coronary Vasodilatation
A2A Peripheral vasodilation (?)
ZM241385
Anti-inflammatory

CPX ↓ A-V conduction

adenosine Negative chronotropy
A1 Chest pain
Preconditioning
enhances
A2B Peripheral vasodilation
Bronchiolar constriction
dipyridamole
A3 Mast Cell Degranulation,
Preconditioning (?)
Modified from R. Barrett

PHARMACOLOGIC STRESS AGENTS

A2A Receptor Agonists

• Equivalent diagnostic information

CGS 21680 (prototype)
CGS-21680 ( t t )
He et al (Baylor) • Less hypotension, more significant
tachycardia
Binodenoson
(King Pharmaceuticals) • No significant effects of conduction

Regadenoson • Reduced side effects (usually)

(Astellas Pharma) • Improved tolerability
Apadenoson • Bolus administration for some agents
(PGxHealth/Clinical Data Inc.)
• Potential expanded use in patients with
bronchospastic disease

128
STRESS TESTING WITH MYOCARDIAL
PERFUSION IMAGING
Conclusions

• Exercise preferred in most situtations (except LBBB)

• New methods for ECG analysis now available
• Pharmacologic methods provide excellent alternative
• Adenosine/dipyridamole preferred
• Dobutamine when bronchospasm/COPD present
• Diagnostic and prognostic value for all methods
• New selective receptor agonist now available

INTERPRETATION OF SPECT
MYOCARDIAL PERFUSION IMAGES
Stepwise Approach
• Interpret all images on workstation
• Review rotating projection images
• Carefully align and normalize slices
• Review SPECT images
• Review gated data
• F
Form initial
i i i l conclusion
l i
• Review clinical, stress test, and
angiographic information
• Reach final conclusion

129
 INTERPRETATION OF SPECT
MYOCARDIAL PERFUSION IMAGES
Projection Image Review

• Patient motion
• Lung uptake
• Count density QuickTime™ and a
Microsoft Video 1 decompressor
are needed to see this picture.
• Sources of attenuation
• Extracardiac activity
• Cardiac chamber size

QuickTime™ and a
Cinepak decompressor
are needed to see this picture
picture.

130
 INTERPRETATION OF SPECT
MYOCARDIAL PERFUSION IMAGES
SPECT Images

• Confirm orientation
• Align slices
• Normalize intensity
• Cavity size
• Evaluate relative perfusion
• Confirm defect in multiple projections
• Review quantitative data
• Define severity and extent and
identify high risk or MVD distribution

Gray scale,
linear

Heller and
Hendel,
Nuclear
Cardiology
Practical
Applications,
2004.

131
 Hot body
(thermal),
exponential

Heller and
Hendel,
Nuclear
Cardiology
Practical
Applications,
2004.

Warm metal,
linear.

Heller and
Hendel,
Nuclear
Cardiology
Practical
Applications,
2004.

132
 Warm metal,
exponential.

Heller and
Hendel,
Nuclear
Cardiology
Practical
Applications,
2004.

COMPARATIVE ASSESSMENT OF
PERFUSION DEFECT SIZE

Small Moderate Large

Vessels ≤1 1-2 2-3

Summed Score 4-8 9-13 >13

Polar p
plot,, % <10%
0 10-20%
0 0 >20%
0

Modified from Wackers IN:

Clinical Nuclear Cardiology
Zaret and Beller, 2005

133
 SPECT MPI
Quantitation

• Methods
–Semiquantitative
–Circumferential • Adjunctive tool, not primary “reader”
–Polar
–3D surface map • Confirmatory, “confidence-builder”
• Provides degree of abnormalcy
• Multiple tools available
–QPS/QGS
QPS/QGS • Reduced
R d d iinter-,
t i t
intra-reader
d variability
i bilit
–Emory Toolbox
–4D-M SPECT • Useful for serial imaging
–WLCQ
–Others

134
SEMIQUANTITATIVE SCORING
17 Segment Model

Cerqueira et al, 2002

Circulation 105: 539-42.

135
 ARTIFACT RECOGNITION AND REDUCTION

• Patient motion
–Prevention is best
–Repeat acquisition, if severe
–Motion correction software

• Soft tissue attenuation

–Supine/prone imaging
–Attenuation correction

INTERPRETATION OF SPECT
MYOCARDIAL PERFUSION IMAGES
Gated SPECT Images

•M
Myocardial
di l thickening
hi k i
(brightening)

• Wall motion
–Regional
–Global
QuickTime™ and a
Cinepak decompressor
are needed to see this picture.

• LVEF

• Ischemic vs.
non-ischemic

136
 INTERPRETATION OF SPECT
MYOCARDIAL PERFUSION IMAGES
Stepwise Approach
• Interpret all images on workstation
• Review rotating projection images
• Carefully align and normalize slices
• Review SPECT images
• Review gated data
• F
Form initial
i i i l conclusion
l i
• Review clinical, stress test, and
angiographic information
• Reach final conclusion

137
 ASNC BOARD REVIEW

DIAGNOSIS AND RISK

STRATIFICATION (Part 1)

Robert C. Hendel, M.D., F.A.S.N.C.

Midwest Heart Specialists

Winfield, Illinois

DIAGNOSTIC VALUE OF EXERCISE SPECT

MYOCARDIAL PERFUSION IMAGING
Impact of Tracer/Protocol

100
95 93 95
90 91 91 90 91
80
77 75
72 71
60 Tl-201
MIBI
TETRO
40 Dual

20

0
SENS SPEC NORM

138
 DIAGNOSTIC VALUE OF EXERCISE SPECT
MYOCARDIAL PERFUSION IMAGING

100 91
87 89

80 73 75

60
Percent

Sensitivity
Specificity
40

20

0
Exercise Pharmacologic Normalcy
Stress
n=33 studies n=17 studies n=12 studies

Adapted from Klocke FJ, et al. Available at: http:// www.acc.org/clinical/guidelines/radio/index.pdf

ADENOSINE THALLIUM IMAGING

FOR DETECTION OF CAD

100
97
91
75 83

Sensitivity,
% 50

25

0
1 VD 2 VD 3 VD
Disease Extent
Mahmarian, 1994

139
 IMPACT OF EXERCISE INTENSITY

100

80
85% MPHR
* 70% MPHR
60
*
40
* p<0.001

20

0
MPI ECG Angina

Heller et al Am J Cardiol 1991;68:569

IMPACT OF CAFFEINE ON
ADENOSINE SPECT IMAGING

50

40

30 With Caffeine
No Caffeine

20

10

0
SSS SDS Defect Size

Zoghbi et al JACC 2006;47:2296

140
SEQUENTIAL DIPYRIDAMOLE SPECT MPI FOLLOWING
INSTITUTION OF ANTI-ISCHEMIC THERAPY
Detection of Disease

SPECT2-1 p=NS
100 p= 004
p=.004 p=.000003
000003
SPECT-2 100%
93% p=.00004 92%
80
79%
73%
60 64% 62%

40
50%

20
LAD LCX RCA Overall
(N=14) (N=14) (N=11) (N=39)
0
Sharir et al J Am Coll Cardiol 1998;31:1540

IMPACT OF BETA BLOCKER (Metoprolol)

ON DIPYRIDAMOLE SPECT IMAGING

100%
p <.05 versus placebo
80%

60% Placebo
Low dose
High dose
40%

20%

0%
Sensitivity Ischemia (+)
Taillefer et al
JACC 2003;42:1475

141
 SPECT Imaging

Placebo

Low-dose
Metoprolol

High-dose
Metoprolol

D.R.
Taillefer et al JACC 2003;42:1475

MEDICATION USE AND

RADIONUCLIDE IMAGING

• If for diagnosis of CAD

CAD, DISCONTINUE CARDIOACTIVE
MEDICATIONS (nitrates, beta blockers, calcium channel
blockers, caffeine/methyxanthines, dipyridamole)

• If for assessment of therapy/prognosis, CONTINUE ALL

MEDICATIONS

• Decisions regarding use of medications must be

individualized and discussed with referring physician, if
possible.

142
 LEFT BUNDLE BRANCH BLOCK
A Diagnostic Dilemma

• “False”
False defects usually in septum,
anterior walls 100
–Asymmetric contraction, compression 82
–Apical involvement unusual 80
–Reversible, with heart rate changes

Specificity, %
60

• Artifacts common 42
40
–Exercise (14-50%)
–Dobutamine
Dobutamine (84-100%)
(84 100%) 20

• Use vasodilator stress without exercise 0

Exercise Adenosine

• Ventricular pacing similar

O’Keefe, 1995

GATED SPECT
Normal Left Ventricular Systolic Function

SHORT AXIS

QuickTime™ and a
Cinepak decompressor
are needed to see this picture.

LONG AXES

143
 COMPARATIVE DIAGNOSTIC VALUE
OF MPI IN WOMEN (n=115)
p = 0.0004
p = 0.02
100 p = 0.01

80 84
92
82
60 67
59
40
20
0
Tl-201 MIBI Gated SPECT
Taillefer, 1997
Sensitivity Specificity JACC 29: 69

IMPROVED DIAGNOSTIC
INTERPRETATION WITH GATED SPECT

• <10% Likelihood of 100 Low Likelihood Patients

CAD (n=137)
Perfusion
80
• “Normal” improved
74% 93% Perfusion
60 +Function
(p<0.0001)

40
• “Abnormal” improved
78% 92% (p=0.09) 20

0
Smanio, 1997 NL ± NL ± ABN ABN
JACC 168: 1687

144
 PRONE SPECT IMAGING
100
83 86
80
• Usually done as adjunct to 65
supine imaging 60

40
• Combined supine/prone Slomka, 2007
superior for diagnosis 20 JNC 14: 4
–Improved ROC areas 0
–Allows for similar diagnostic Supine Prone Combined
value in obese patients as non- 60
obese

Equivocal Interpretation, %
–Documented value for women
40
Supine
Sup/Prone
• Preserved prognostic utility Atten Corr
All
with prone imaging 20

Malkerneker, 2007
0 JNC 14: 314
Men Women

UNCORRECTED

145
 CORRECTED

DIAGNOSTIC VALUE OF
ATTENUATION CORRECTION
SENSITIVITY SPECIFICITY NORMALCY
AUTHOR n SYSTEM NC
N.C. AC
A.C. NC
N.C. AC
A.C. NC
N.C. AC
A.C.

Ficaro 119 U Mich. 78% 84% 48% 82% 88% 98%

Hendel 200 ADAC 76% 78% 44% 50% 86% 96%

Links* 112 SMV 84% 88% 69% 92% 69% 92%

Shotwell 118 Picker 82% 86% N.A. N.A. 74% 88%

Gallowitsch 49 Elscint 89% 94% 69% 84% NA

N.A. NA
N.A.

Lenzo 171 Siemens 93% 93% 84% 88% 78% 85%

Links 66 GE 85% 93% N.A. N.A. 54% 77%

TOTAL 834 81% 87% 64% 81% 80% 90%

*Includes motion correction and depth-dependent blur correction.

†Includes scatter correction.

146
 RISK STRATIFICATION

LOW-RISK Avoid additional testing

PATIENTS
Lower risk and cost

Alter management
HIGH-RISK
PATIENTS
Consider revascularization

RISK STRATIFICATION
RISK OF CARDIAC DEATH OR MI:

Low
<1% per year

Intermediate
1-3% per year

High
~3%-5% per year

Source: Adapted from Gibbons et al. J Am Coll Cardiol 1999;33:2092-2197.

147
 RATIONALE FOR PROGNOSTIC
ASSESSMENT WITH MYOCARDIAL
PERFUSION IMAGING

• Identification of ischemia and assessment

of physiologic importance
• Determination of location, extent and
severity of perfusion abnormalities
• Association with “hard”, “soft” events
IIschemia:
h i ACS,
ACS need d ffor revascularization
l i i
Function: death, heart failure
• Prediction of functional recovery
• Impact on medical decision-making

QuickTime™ and a
Cinepak decompressor
are needed
d d tto see thi
this picture.
i t

148
 PROGNOSTIC VALUE OF SPECT IMAGING
7
5.9
6
Annual Event Rate, %

5
4
3
2
1 0.6

0
Normal Abnormal*
n= 39,173 69,655
Shaw and *Moderate- severe
Iskandrian
JNC 2004; 11: 171

CARDIAC EVENT-FREE SURVIVAL WITH

NORMAL Tc-99m TETROFOSMIN SPECT

1.00 Exercise
Cumulative Event-Free Survival

.98
.96
(n=3,438)
.94
.92
Adenosine
.90 (n=3,742)
.88
.86 Dobutamine
.84
.82
(n=625)
.80
.78
.76
.74
.72 χ2=54, p<0.0001
.70
0 1
0.5 1.0 1.5

Follow-up (Years)

n= 7,377 6,472 4,210 2,238

149
 RISK ADJUSTED SURVIVAL
WITH NORMAL SPECT MPI
Impact of Radiopharmaceutical
1.00
201Tl (n=3,257)
99mTc Tetrofosmin (n=4,728)
0.98
Cumulative survival

99mTc Sestamibi (n=2,423)

0.96

0.94
p > 0.2

0.92

0.90
0 6 12 18 24 30 36
Follow-up (months)
Shaw et al, 2003
JNM 44: 134

Meta Analysis Results: Cardiac Event Rates

24 Studies (9930 / 4988 pts) Exercise MPI

Pharmacologic MPI
Annualized Event Rates

12 * * p < 0.001
]

9.98
10
8
6 4.5
4 *
]

1.78
2 0.64
0
Normal Abnormal
Scan Result
Navare et al, J Nuc Card 2004:11;543

150
 ECG CHANGES WITH PHARMACOLOGIC
STRESS TESTING AND RELATIONSHIP TO
MPI RESULTS

• n=3,231
ST ²'s Abnormal MP
72%
7% • Overall, 2% of patients had
ischemic ST ∆’s and normal
No ECG ²'s SPECT images
93%
• Confirmed with use of either
py
adenosine or dipyridamole =
0.9% incidence
(Klodas et al JNC 2003; 10: 4)
Norma
MPI
29%
Abbott et al, 2003
JNC 10:9

ADENOSINE-INDUCED ECG CHANGES

WITH NORMAL SPECT IMAGES
Impact on Outcome

• Follow-up=29±12 mo

Death NFMI Revasc

• Event-free survival
(NFMI/cardiac death ECG (-) 1.0% 0.5% 2.5%
–No ECG∆’s: 1.5%
–ECG
ECG ∆∆’s:
s: 10.6%
10 6% ECG (+) 3 0%
3.0% 7 6%
7.6% 13 6%
13.6%
p<0.0007

Abbott et al, 2003

JNC 10:9

151
 NORMAL MPI: ALWAYS A LOW RISK?
Impact Of Abnormal Stress Test
Variable On Outcome

AUTHOR,
U O , VARIABLE LOW
O RISK
S HIGH
G RISK
S
yr
Hachamovich, DTS 0.3% 2.3%
1996
Hachamovich, Angina/CAD 0.5% 2.5%
1998
Calnon, Dob ECG (+) 1.5% 7.8%
2001
Abbott, Ad ECG (+) 0.6% 4.4%
2002
Klodas, Ad ECG (+) 1.0%* 4.0%
2002

* Assumed based on historical control

INCREMENTAL VALUE OF SPECT IMAGING

FOR THE PREDICTION OF NFMI OR DEATH
(n = 316; F/U = 28 months)

40

30
obal Chi-Square

20
Glo

10

0
Gender (A) A +Exer (B)B + Cath (C)B + SPECTC + SPECT

Iskandrian, et al, 1993

JACC 22: 665

152
 HIERARCHICAL, INCREMENTAL
PROGNOSTIC DATA FOR PREDICTION
OF MAJOR CARDIAC EVENTS

3
35
p<0.01
30
p=0.02
25
p<0.05
20
15
p<0.01
10
5
0
sex (A) A+age B+clinical C+EST D+SPECTD+#defect
(B) (C) (D) (E)
Vanzetto, 1999
Circulation 100: 1521

PROGNOSTIC VALUE OF VASODILATOR

MYOCARDIAL PERFUSION IMAGING
IN PATIENTS WITH LBBB

100
(119) (63)
80
p < 0.0001

60
(35)
(16)
40

20 Low risk
High risk
0
0 1 Year 2 3

Wagdy HM, et al. Circulation. 1998;97:1563-1570.

153
 DEATH OR NON-FATAL MYOCARDIAL INFARCTION
BASED ON DUKE TREADMILL SCORES
AND SPECT IMAGING RESULTS

12
Normal
c Event Rate, Percent

10 Mild
Severe
8

4
Cardiac

0 n= 762 113 51 834 185 168 28 22 40

Low Intermediate High
n=2200
Duke Treadmill Score

Hachamovitch R, et al. Circulation

Circulation.. 1996;93:905-
1996;93:905-914.

MYOCARDIAL PERFUSION IMAGING

Prognostic Indicators
• Defect presence
• Extensive and/or severe defect
• Multivessel distribution
• Defect reversibility
• Post-infarct ischemia
• Transient
T i LV dil
dilation
i (TID)
• Left ventricular dilation (EDV<70 ml; EDV <120 ml)
• Abnormal lung activity
• Left ventricular dysfuction (LVEF<45%)

154
PROGNOSTIC VALUE OF DEFECT EXTENT
1.00
N
Normal
l
0.98
Cumulative Survival

0.96 1-2 Segments

0.94

0.92
3-5 Segments

0 90
0.90

0.88
0 5 10 15 20 25 30 35 40 45 50 55

Follow-up (Months)

Machecourt J, et al. J Am Coll Cardiol. 1994;23:1096-1106.

1-YEAR RATE OF EVENT-FREE SURVIVAL

BY POST-STRESS GATED LVEF AND SUMMED
DIFFERENCE SCORE IN PATIENTS UNDERGOING
PHARMACOLOGIC Tc-99m SPECT IMAGING
al
1-Year Death or MI-Free Surviva

0.987
1 0.976
0.98
0.949
0.96
0.97 0.962
0.94
0.92
0.9 0.915 EF >45%

0.88 EF <45%
0.86
Low Mild Mod-Severe

n= 1,934 115 39
115 78 34

p < 0.0001

155
 HIERARCHICAL, INCREMENTAL
PROGNOSTIC DATA FOR PREDICTION
OF MAJOR CARDIAC EVENTS

3
35
p<0.01
30
p=0.02
25
p<0.05
20
15
p<0.01
10
5
0
sex (A) A+age B+clinical C+EST D+SPECTD+#defect
(B) (C) (D) (E)
Vanzetto, 1999
Circulation 100: 1521

CARDIAC EVENTS BASED ON

SPECT IMAGING RESULTS (n=5,183)

5
Death 4.2
4 MI
2.9 2.9
3 2.7
2.3
2
0.8
1 0.5
0.3

0
Normal Mild Abn Mod Abn Sev Abn
Hachamovitch R, et al. Circulation
Circulation.. 1998;97:535-
1998;97:535-543.

156
 PROGNOSTIC VALUE OF
ELECTROCARDIOGRAPHICALLY-
GATED SPECT PERFUSION IMAGING
Left ventricular function is a ((the)) key
y
determinant for long-term survival

• Patient subgroups
–General
–Post-MI
• Gated SPECT
• LV assessmentt
–Contrast ventriculography
–Echocardiography
–Radionuclide
ventriculography

CARDIAC DEATH STRATIFIED BY PERFUSION

ABNORMALITY AND EJECTION FRACTION

10 92
9.2
9
c Death Rate (%/year)

8
7
6 5.7
EF>45%
5
EF<45%
4
3
Cardiac

2
1 0.9
1 0.4
0
0
Normal Mild-Mod Severely
abnormal abnormal

Sharir T, Circulation. 1999;100:1035-1042

157
 CARDIAC DEATH STRATIFIED BY
EJECTION FRACTION AND ESV

9
7.9
8
c Death Rate (%/year)

7
6
5 ESV <70 ml
4 ESV >70 ml

3 2.6
Cardiac

2 1.7

1 0.5
0
EF>45% EF<45%

Sharir T, Circulation. 1999;100:1035-1042

MYOCARDIAL PERFUSION IMAGING

IN THE COMMUNITY

EF ≥40% EF <40%
1.00 1.00
Event--Free

Event--Free

.96 .96
mulative Event

mulative Event
Survival

Survival

.92 .92
0-1 0-1
.88 2-3 .88 2-3
4 4
.84
84 .84
84
Cum

Cum

.80 .80
0.0 0.5 1.0 1.5 2.0 0.0 0.5 1.0 1.5 2.0
Follow-
Follow-Up (Years) Follow-
Follow-Up (Years)

n=1612
Thomas G, et al. J Am Coll Cardiol.
Cardiol. 2004;43:213-
2004;43:213-223.

158
 HEART:LUNG RATIO
Marker Of LV Dysfunction, Increased Risk

TRANSIENT LEFT VENTRICULAR

CAVITY DILATION (TID)

• Mechanism • Severe,, extensive CAD

–True cavity enlargement –Usually with significant ischemic
defect
• Implies post-stress stunning
–Variable anatomy
–“Apparent” dilation
• Left main
• Subendocardial ischemia
• Proximal LAD
–Automated measurement • MVD

• Visual and/or quantitative • Microvascular disease

–Dual isotope: 1.22 –May be without perfusion defect
–Single isotope: 1.05 –Etiology
–Adenosine: 1.36 (?) • HTN
• DCM

159
 TRANSIENT ISCHEMIC DILATION OF LV
Identification of Severe and Extensive CAD

Validation set
n=77
Dual Isotope
SPECT

Mazzanti et al, 1996

JACC 27: 1612

PROGNOSTIC VALUE OF LV CAVITY

DILATION DURING DIPYRIDAMOLE
Tc-99m SESTAMIBI SPECT IMAGING
• Cavity dilation
–Transient:
T i 14%
–Persistent: 14%

• Events related to type of Death or MI

cavity enlargement
–Transient: MI
–Persistent: death, CHF

• Relative risk of hard event

–Transient: 6.7 (2.4-19.6)
All events
–Persistent: 4.0 (1.7-9.4)

McCellan et al
AJC 1997; 79: 600

160
 TID WITH NORMAL SPECT

• 1,560
1 560 pt with normal SPECT
–436 vasodilator 3.5 p=0.010
3.2
–1,124 exercise
3.0
• Overall event rate low 2.5
–CD/MI: 0.4%/yr p=0.014
–All events: 1.2%/yr 2.0 1.8
Controls (<1.21)
TID (1.21-1.79)
1.5
• TID predictive of total events 1.0
–Independent and incremental 10
1.0 0.7
–DM, known CAD stronger
predictors
0.5
–Especially concerning with DM, 0.0
elderly, angina
Exercise Vasodilator
–Severe disease only when TID
present
Abidov et al, 1003
JACC 42: 1818

TID: CORRELATIONS AND

CONTROVERSIES

• DM, elderly, known CAD, chest pain and LVH are

additive prognostic variables with TID

• TID may correlate with ischemic stunning

• Controversyy still exists regarding

g gpprognostic
g
implications of TID without perfusion defects
–More frequent with vasodilator stress
–Low specificity-only 13% had severe/extensive disease

161
 POST-STRESS (ISCHEMIC)
MYOCARDIAL STUNNING
• May persist for up to 24 hours, but usually resolves
within 30
30-60
60 minutes
–Timing of image acquisition may be critical (also Tl/Tc)
• Variable thresholds
–Exercise: >5 %
–Vasodilator >6%, >12%
• Increasingly recognized
–May occur with vasodilator stress, but less common
th after
than ft exercise
i
–Occurs in up to 1/3 of patients with severe ischemia
• Diagnostic value
Johnson, 1997 –Low sensitivity but high specificity (>90%)
Emmett, 2002 –Correlation with extent of reversible defects
Druz, 2004
–Negative correlation with TID, due to increased ESV
Hung, 2006

CONCLUSIONS
SPECT MYOCARDIAL PERFUSION IMAGING

• Excellent diagnostic accuracy

–With
With all tracers and stress modalities
–Caution with use of anti-anginal Rx, caffeine (vasodilators)
–Additive value of supine/prone imagine,attenuation correction
and gated SPECT

• Excellent prognostic value

–The power of a normal study
–Increased risk of pharmacologic stress
–Incremental value of SPECT
–Added value of LV function

• High risk markers

–Added value of LV function
–Lung activity
–TID

162
 Nuclear Cardiology Board Review Course
Boston MA 10 September 2008

Di
Diagnosis
i and
d Ri
Risk
k St
Stratification
tifi ti
Part II
Gary V Heller, MD PhD
Hartford Hospital/University of Connecticut
Hartford CT

Topics to be Covered: Part II

ƒ Pre-op Assessment
ƒ ED assessment
ƒ Post revascularization: CABG and PCI
ƒ Asymptomatic patient

163
Pre-Operative Evaluation

Considerations for Perioperative

Cardiac Evaluation
‹ Urgency of the surgery
‹ Type of surgical procedure
‹ Cardiac risk of the patient

164
High Non-cardiac Surgical Risk
ƒ Emergent major operation, especially elderly
ƒ Major vascular surgery
ƒ Peripheral vascular surgery
ƒ Prolonged surgical procedures

Intermediate Non-cardiac
Surgical Risk
ƒ Intra-peritoneal and intra-thoracic surgery
ƒ Carotid endarterectomy
ƒ Head and neck
ƒ Orthopedic
ƒ Prostate

165
Low Non-cardiac Surgical Risk
ƒ Endoscopic procedures
ƒ Superficial surgery
ƒ Cataract surgery
ƒ Breast surgery

Major Clinical Predictors of Increased

Risk
ƒ Unstable coronary syndromes
ƒ Acute MI
ƒ Unstable angina
ƒ Decompensated heart failure
ƒ Clinically important arrhythmias
ƒ Severe valvular disease

166
Intermediate Clinical Predictors of
Increased Risk
ƒ Mild angina pectoris
ƒ Prior MI
ƒ Compensated CHF
ƒ Diabetes mellitus
ƒ Renal insufficiency

Minor Clinical Predictors of

Increased Risk
ƒ Advanced age
ƒ Abnormal resting ECG
ƒ Non-sinus rhythm (eg, atrial fibrillation)
ƒ Low functional capacity (one flight stairs)
ƒ History, stroke
ƒ Hypertension uncontrolled
Hypertension,

167
Pre-Operative Cardiac Risk
ƒ Low Risk:
ƒ Low-risk patient Î low likelihood of peri-
operative cardiac complications
ƒ Able to undergo surgery without further
pre-operative testing or treatment

Gerson, M. Clinics in Chest Medicine; 14:263, 1993.

Pre-Operative Cardiac Risk

ƒ High Risk:
ƒ High-risk patient Î high likelihood of peri-
operative cardiac complications
ƒ Patients usually have known heart disease
ƒ Treatment required to remove / reduce cardiac
risk prior to elective surgery
ƒ Cardiac catheterization
ƒ Beta-blockade (3-4 days)

Gerson, M. Clinics in Chest Medicine; 14:263, 1993.

168
Pre-Operative Cardiac Risk
ƒ Intermediate Risk:
ƒ Intermediate-risk patient Îrisk stratification
ƒ Many patients have this medium level of risk for
peri-operative cardiac complications
ƒ Further testing required to determine course of
treatment prior to surgery

Gerson, M. Clinics in Chest Medicine; 14:263, 1993.

Meta-Analysis of Pre-op
Procedures
‹ Dipyridamole Thallium (1985-1994)
– 1994 patients
– 10 studies
‹ Dobutamine Echo (1991-1994)
– 445 patients
– 5 studies
t di

‹ Shaw LJ et al., JACC 1996;27:787-98

169
Low Risk Patients
ƒ 1% event rate regardless of imaging
ƒ No benefit to risk stratification

Shaw LJ et al.,, JACC 1996;27:787-98

;

Intermediate and High Risk

Patients
‹ Thallium
– Normal 1%
– Fixed 7%
– Reversible 9%

– Cardiac Death or MI
– O.R.
OR 3 3.9
9 (2
(2.5-5.6)
5 5 6)

Shaw LJ et al., JACC 1996;27:787-98

170
Intermediate and High Risk Patients:
Size of Defect
ƒ Reversible Defects
ƒ 1 or more 14.4%
ƒ 2 or more 29.6%
p=0.0001

Shaw LJ et al., JACC 1996;27:787-98

1996;27:787 98

Conclusion: Low risk patients do not benefit

from pre-op evaluations, intermediate risk
patients do

Stepwise Approach to Evaluation

‹ Ifurgent, proceed
‹ Coronary revascularization <5yrs and
stable, proceed
‹ Recent coronary evaluation and stable,
proceed
‹ Major clinical predictors: evaluation
‹ Intermediate risk patient: assess
functional capacity and surgical risk

171
What can we take from these
studies?
ƒ Old data – Planar thallium for most of
th lit
the literature
t
ƒ Modern surgeries are better, medication
are better
ƒ Intermediate risk group can be split into
high and low risk.
ƒ Determining pre-test risk
ƒ Determining incremental risk from imaging

Evaluation of CABG Patients

ƒ The role of MPI in the assessment of

patients prior to CABG is well established.
ƒ Its role in the evaluation of patients
following CABG is less well defined.

172
Pre-surgical Prediction of Improvement
in LV Function after CABG: TI-201
P=.02
P=.002 P=NS
0.60
0.55 •

0.50 •
•
0.45
Ejection Fraction

•• „
0.40 • •
• •• •
0.35 • •
• • ••
0.30 •• „ •• • „
„ •• •
0.25 •• •
•• •
E

•• •
0.20 •
•
0.15 p=NS •

0.10
Pre--Op
Pre 8 Weeks Pre--Op
Pre 8 Weeks
Patients with >7 Viable Patients with ≤7 Viable
Segments (n=10) Segments (n=11)

Ragosta M, et al. Circulation. 1993;87:1630-1641

Myocardial Perfusion Imaging Predicts

Long-Term Outcome After CABG
100 More Viability
Less Viability
90
Event-free

70
% Event-

P=.025

50

30
0 12 24 36 48 60
Time (Months)

Pagley PR, et al. J Am Coll Cardiol. 1996;27:299A

173
 INCREMENTAL VALUE OF SPECT
FOLLOWING CABG IN PTS WITH ANGINA

16
p<0.01
Global Chi Square
12

p=n.s.
8

0
Clinical [A] A + Exercise [B] B + Cath [C] C + MPI

Nallamothu et al AJC 1997 80 1517-1521

SURVIVAL AFTER CABG: MYOCARDIAL

PERFUSION IMAGING
nual Cardiac Death Ratte, %

3.1
3 CABG <5 years
CABG >5 years
2.1
2

1
1 0.7 0.7
Ann

0
0
Normal Mildly Abnormal Moderately/Severely
Abnormal
SSS 0-3 4-8 >8
N 134 158 161 211 333 547
Zellweger MJ, et al. J Am Coll Cardiol. 2001;37:144-152.

174
 The Post-CABG Patient:
Risk Stratification
Symptomatic patients All patients
<5 years post CABG >5 years post CABG
CD 11.4%
4% Nuclear stress testing CD 22.1%
1%
CD 1.9%

No perfusion defect Perfusion defect

CD 0.5% CD 2.3%

EF≥45% EF<45%
CD 1.4% CD 5.4%

SDS≥2 SDS<2
No/Mild ischemia Mod/Severe ischemia
CD 0.6% CD 2%

+
+ Viability
Medical Coronary angiography
management
–

Zellweger MJ, et al. J Am Coll Cardiol. 2001;37:144-152.

APPROPRIATENESS CRITERIA FOR SPECT MPI

Post-Revascularization ( CABG)

Evaluation of chest pain A

Asymptomatic, < 5 y s/p CABG U
Asymptomatic, ≥ 5 y s/p CABG A
Asymptomatic, asymptomatic before PCI, U
< 2 y s/p PCI
Asymptomatic, symptoms before PCI, < 2 I
y s/p PCI
Asymptomatic, ≥ 2 y s/p PCI U
Brindis et al, 2005 JACC 46: 1587-605

175
 SPECT AFTER PCI

ƒ Chest pain is poor indicator of ischemia

after PCI; SPECT is good predictor of
ischemia
ƒ Routine testing after PCI NOT
recommended
ƒ False (+) results early after PCI , early
experience
ƒ Little role for SPECT < 3 mo after PCI

SYMPTOMS VS. SPECT FOR

DETECTION OF RESTENOSIS

90
80
70
60
50 Chest Pain
40 SPECT
30
20
10
0
Sens Spec Acc

Giedd, Bergmann, 2004 JACC 43: 328.

176
 VALUE OF SPECT MPI IN RISK
STRATIFICATION AFTER PCI
196 Subjects
12-18 mo p
post-PCI
Exercise MIBI

Symptomatic No Symptoms
n=70 n=126

Ischemia No Ischemia No Ischemia Ischemia

n=20 n=50 n=102 n=24
Events: 40% Events: 4% Events: 6% Events: 33%

Extent and Severity Related to Outcome

SDS: HR=1.6 (95% CI=1.3-1.9)
Event: SDS=3.2 ± 3.0
No Event: SDS=0.7 ± 1.0 Acampa, 2003 AJC
91: 259

ACC/AHA/ASNC PRACTICE GUIDELINES 2003

Following Revascularization

‹ Exercise or pharmacologic stress

SPECT at 3-5 years after PCI or CABG
in selected high risk asymptomatic
p
patients
Class IIa, Level of evidence B

Klocke et al, 2003

www.asnc.org

177
APPROPRIATENESS CRITERIA FOR SPECT MPI
Post-Revascularization (PCI or CABG)

Evaluation of chest pain A

Asymptomatic, < 5 y s/p CABG U
Asymptomatic, ≥ 5 y s/p CABG A
Asymptomatic, asymptomatic before PCI, U
< 2 y s/p PCI
Asymptomatic, symptoms before PCI, < 2 I
y s/p PCI
Asymptomatic, ≥ 2 y s/p PCI U
Brindis et al, 2005 JACC 46: 1587-605

Acute Rest SPECT Imaging

ƒ Ability to give a definitive answer
ƒ Value of a negative study
ƒ Value of an abnormal study
ƒ Limitations

178
 What is the Significance
of a Normal Image?
ƒ Negative predictive value of multiple studies
(2000 patients): 99-100%
(2000+ 99 100% (Acute MI, <1%)
1%)
ƒ In short term, no cardiac deaths in patients
with normal studies
ƒ Current triage practice: 5-8% of ED
discharged patients sustain AMI, with
mortality of 6%
ƒ Caution: injection >4 hours after resolution of
symptoms
ƒ Conclusion: If study is normal, discharge
patient

Rest MPI in Patients with Acute Chest Pain Syndrome

Study Year N TracerSens Sp NPV NL ABNL

D/ Rev D/MI Rev

Wackers 1976 200 Tl-201 100% 100% 100% Clinical

Wackers 1979 203 Tl-201
Tl 201 100% 72% 100% 0% --- 100% --- Clinical
Maseri 1976 6 Tl-201 100% 100% 100% Clinical
Bilodeau 1991 45 Tc-Mi 96% 79% 94% Cath
Varetto 1993 64 Tc-Mi 100% 92% 100% 0% 0% 43% 17% Cath
Hilton et al. 1994 102 Tc-Mi 94% 83% 99% 0% 1% † 71% Clinical
Varetto 1994 27 Tc-Mi 100% 93% 99% Cath
Hilton et al.
al 1996 150 Tc Mi 100% 78% 99%
Tc-Mi 0% .01%
01% 53% 34% Clinical
Kontos 1997 532 Tc-Mi 93% 71% 99% 0.6% 3% 15% 27% Clinical
Tatem et al. 1997 438 Tc-Mi 100% 78% 100% 0% 3% 7% 32% Clinical
Heller et al. 1996 357 Tc-Te 90% 60% 99% 0.9% 12% 16% Clinical

Duncan and Heller ACC Current Journal Review N/D 1999:52

179
 Risk Stratification With Acute MPI:
Prediction of Early Cardiac Events (< 72 hours)

35 32
Normall ((n=338)
N 338)
30 Abnormal (n=100)
Percent Events

25
20
15
10 7
5 2
0
0
MI Any Event
RR = 50 RR = 15
Tatum JL, et al. Ann Emerg Med. 1997;29:116-125.

Acute Rest SPECT Imaging

ƒ Ability to give a definitive answer
ƒ Value of a negative study
ƒ Value of an abnormal study
ƒ Limitations

180
 What is the Accuracy of Acute
Imaging for Acute MI?
ƒ Sensitivity: 90-100% in numerous studies
(t t l patients:
(total ti t 2000+)
ƒ Specificity in the same studies: 60-70%
ƒ Positive studies also associated with unstable angina,
CAD

ƒ Number of MI/abnormal study :25-30%

ƒ Current admission practices: Acute MI in 6%
ƒ Conclusion: data suggests high accuracy for
acute MI

Rest MPI in Patients with Acute Chest Pain Syndrome

Study Yea N Tracer Sens. Spec NPV NL ABNL

D/MI Rev D/MI Rev

Wackers 1976 200 Tl-201 100% 100% 100% Clinical

Wackers 1979 203 Tl-201 100% 72% 100% 0% --- 100% --- Clinical
Maseri et al. 1976 6 Tl-201 100% 100% 100% Clinical
Bilodeau 1991 45 Tc-Mi 96% 79% 94% Cath
Varetto et al 1993 64 Tc-Mi 100% 92% 100% 0% 0% 43% 17% Cath
Hilton et al. 1994 102 Tc-Mi 94% 83% 99% 0% 1% † 71% Clinical
Varetto et al. 1994 27 Tc-Mi 100% 93% 99% Cath
Hilton et al. 1996 150 Tc
Tc-Mi
Mi 100% 78% 99% 0% .01%
01% 53% 34% Clinical
Kontos 1997 532 Tc-Mi 93% 71% 99% 0.6% 3% 15% 27% Clinical
Tatem et al. 1997 438 Tc-Mi 100% 78% 100% 0% 3% 7% 32% Clinical
Heller et al. 1996 357 Tc-Te 90% 60% 99% 0.9% 12% 16% Clinical

Duncan and Heller ACC Current Journal Review 1999:52

181
 Chest Pain in the ED
Incremental Prognostic Value of
Rest MPI
20
18 RF = risk factors for CAD P < 0.001
CP = chest pain 17.9
16
obal chi-square

14
12 P = 0.05
10
P = 0.02
8
6 78
7.8
Glo

4 5.5
2
0
0
Age, Gender (A) A + >/=3 RF (B) B + ECG, CP (C) C + SPECT

N=358 Patients Heller GV, et al. J Am Coll Cardiol. 1998;31:1011-1017

Sensitivity of Perfusion Imaging and cTnI

for Identifying Cardiac End Points
MPI Initial cTnt Serial 1 Serial 2
97
100 92 90
90 85 82
76
80
70
60 53
50 45
40 30
26
30 22
17 20 15
20 10 10
10
0
MI Revasc CAD M+S

Kontos et al Circ 1999:99;2079

182
 44 year old male presents with intermittent chest pain
for 24 hours, normal ECG, injected during symptoms
ED ES

Short Axis

Vertical Long Axis

Horizontal Long Axis

Impact of Scan Results on Decision

Making: Normal vs Abnormal
60

50

40
Normal
30
Abnormal
20

10

0
home non CCU CCU

Knott et al J Nucl Card 2002:9;257

183
Accuracy of Acute Rest MPI in Patients with
and Without Symptoms at Presentation
Acute MPI ECG

120
96
100 84
79
74 74
80 65

60
35 38
40
20
0
Sens. Spec. Sens. Spec.

With Chest Pain Without Chest Pain

From Bilodeau et al JACC 1991:18;1684

Duration of Perfusion Abnormalities after Resolution

of Symptoms: an Angioplasty Model

Fram et al JACC 2003;41:452

184
 Effectiveness of ED Sestamibi
Imaging in Suspected ACI

T o ta l H o s p ita l A d m is s ioo n s
700 P<0.001
600
500
400 Non-ACI
300 ACI
200
100
0
Usual Care Sestamibi Scan

Udelson et al JAMA 2002;288;2693

Percent Hospitalized by Confirmed

Diagnosis and Diabetes Status
Patients with no ACI (2,144)

Scan No Scan p-value Odds ratios

Non-DM 40.2% 50.0% 0.001 0.68

(n=1875) (0.56, 0.81)
Diabetic 54.2% 62.9% 0.2 0.70
(n=269) (0.43,1.15)
Non-ACI Patients: OR for non-hospitalization, non-DM and DM: p=0.90
Kapatanopoulos et al JNC 2004;11:570

185
AHA/ACC/ASNC Recommendations
for Emergency Department Imaging

Indication Test Class Level of

Evidence
Assessment of Rest MPI I A
myocardial risk in
possible ACS
Diagnosis of CAD in Same day I B
Possible ACS with rest/stress
negative w/u, RMPI MPI
Routine imaging in Rest MPI III C
pts with MI

Outline: Early Detection of CAD

ƒ Early detection
ƒ Asymptomatic (screening)
ƒ Early symptoms (diagnosis)
ƒ Diabetic patients
ƒ Asymptomatic patients
ƒ Diagnosis, symptomatic patients
ƒ Risk stratification

186
 Screening for Coronary Artery
Disease
ƒ Goals of CAD therapy:
ƒ Symptomatic
S t ti relief
li f
ƒ Improve outcomes (Cardiac death, myocardial infarction,
ACS
ƒ Methods for achieving goals:
ƒ Medical therapy alone
ƒ Coronary revascularization alone
ƒ Combined
C bi d medical/revascularization
di l/ l i ti th therapy
ƒ Therefore, screening should impact therapies

Screening for Coronary Artery Disease:

Does it compare to Screening for Cancer?
ƒ Miller and Shaw (JNC 2005;12:158):
ƒ Similar prevalence of Prostate cancer and CAD after 50 (20%
vs. 16%)
ƒ Similar blood screening tools (hs-CRP vs. PSA)
ƒ Both have NI tests (MPI, CT, stress echo vs. digital exam,
Ultrasound)
ƒ Argument can be made for screening!
ƒ Soman and Udelson (JNC 2005; 12:145):
ƒ Screening
g should provide a change
g in outcomes, not
demonstrated in asymptomatic patients (coronary
revascularization)
ƒ Absence of large multicenter data in asymptomatic patients
ƒ Conclusion: await more data

187
 Conclusion: Screening of
Asymptomatic Patients for CAD
‹ Conceptually a compelling argument,
particularly over the age of 50
‹ However, no data are available in a general
population
‹ Conclusions:
– Screening in an asymptomatic population is not
recommended
– Screening in a mildly symptomatic population is
justified in terms of behavioral, interventional
changes in therapy

Outline: Early Detection of CAD

‹Early detection
ƒ Asymptomatic (screening)
ƒ Early symptoms (diagnosis)
‹Diabetic patients
ƒ Diagnosis, symptomatic patients
ƒ Risk stratification
ƒ Asymptomatic patients
‹Ethnic groups, differences?

188
 Incidence of CAD in
Asymptomatic Type-2 Diabetics

12
of Diabetics with CAD

10

4
%o

0
Janand-Dellene Koistinen Naka
Study
Janand-Delenne B, et al. Diabetes Care. 1999;22:1396-1400;
Koistinen MJ. BMJ. 1990;301:92-95;
Naka M, et al. Am Heart J. 1992;123:46-53.

Detection of Ischemia in Asymptomatic

Patients with Diabetes (DIAD)

Asymptomatic Patients with Diabetes

1,000 Eligible Consented Patients

(Clinical Profile, Biomarkers)

Randomization

500 Patients 500 Patients

Aden-SPECT No Testing
Follow-up

Normal Abnormal Wackers et al. Diabetes Care 2004:27; 1954

Follow-up

189
 Detection of Ischemia in Asymptomatic
Patients with Diabetes: Preliminary Results

ƒ 1,124 patients enrolled, 502 randomized to

adenosine Sestamibi
adenosine-Sestamibi
ƒ Percent abnormal: 27%
ƒ Percent ischemia: 18%
ƒ Percent “high risk”: 6%
ƒ Predictors: not risk factors
ƒ Duration of diabetes
ƒ Autonomic dysfunction
ƒ Other studies: peripheral vascular disease, abnormal
ECG
Wackers et al. Diabetes Care 2004:27; 1954

CT C C S

70
3
C
T CA 5
T CA 1 612 H C
LAD 59 C 20 10 24 251

190
F I MPS M S
I CA C
I I 10
25
0 01 19 9
20 I ≥5 I ≥10

15
10 6
8 9
10
5 2
5 1 6 2 4 2 8
2 1
0 4 0 0 0 5
0
CA 0 1 9 10 9 10 39 40 9 10
250 49 207 290 248 15

S B JAC 204

Conceivable Screening Algorithm

Asymptomatic Pts with Type 2 Diabetes

Age > 50 Years

EBCT Calcium Score

> 100 Agatston

(Adenosine) Stress SPECT

191
Risk Stratification Part II
ƒ Pre-op Assessment
ƒ ED assessment
ƒ Post revascularization: CABG and PCI
ƒ Asymptomatic patient

192
 Diagnosis and Risk
Stratification Part III
Donna M Polk, MD, MPH
Hartford Hospital
University of Connecticut
Hartford, CT

Topics to be covered: Part III

• Women
• Diabetics
• Renal Insufficiency
• CHF
• Elderly
• Cost Effectiveness

193
 • Women
• Diabetics
• Renal Insufficiency
• CHF
• Elderly
• Cost Effectiveness

AHA Consensus Statement—Algorithm for Evaluation

of Symptomatic Women Using Cardiac Imaging
Intermediate to high likelihood women with atypical or typical
chest pain symptoms
Good exercise tolerance Diabetes, abnormal 12-L ECG,
+ normal 12-L ECG or questionable exercise capacity
Risk factor
modification ± Exercise or pharmacologic stress imaging
anti-ischaemic Rx Exercise
TM test
Able to Unable to
Low exercise exercise
Int risk
Post-ETT
TM
LK Exercise Pharmacologic
stress stress

Normal or mildly
abnormal with Moderate to severely
Cardiac
normal LV function abnormal or
catheter
depressed EF
ETT=exercise treadmill test; EF=ejection fraction; LV=left ventricle; TM=treadmill.
Mieres. Circulation. 2005;111(5):682-696.

194
 ECG Testing in Women
• Limitations:
– Sensitivity 61%, specificity 70%*
– “false
“f l positives”
iti ”
• Estrogen effect
• Lower prevalence of obstructive disease
• Lower functional capacity
• Symptoms of limited predictive value
• Predictive value enhanced by additional
information such as Duke treadmill score
• High negative predictive value in low
pretest probability of CAD and low-risk
Duke treadmill score
*Kwok, Am J Cardiology1999:83:660-666

Prognostication by Exercise
Capacity

1.3-5.4

5.5-7.0

7.1-8.0
8.1-9.2
9.3-14.6

FOLLOW-UP (years)

Source: Mora et al, JAMA 2003;290:1600-7.

195
 Prognostic Value of Functional Capacity in Asymptomatic
(n=8,715) and Symptomatic (n=8,214) Women

2.5
An nual Death Rate (% / ye ar)
2

1.5

0.5

0
8 or 7.1-8.0 5.5-7.0 1.3-5.4 8 or 7.1-8.0 5.5-7.0 1.3-5.4 Pharm
higher higher Stress
Asymptomatic Women Symptomatic Women
Source: Mora et al. JAMA 2003, Gulati Circulation 2003, Marwick Am J Med 1999, Marwick Circulation 2001
Pharm stress = Women referred for Adenosine or Dipyridamole SPECT or Dobutamine stress echocardiography

AHA Consensus Statement—Algorithm for Evaluation

of Symptomatic Women Using Cardiac Imaging
Intermediate to high likelihood women with atypical or typical
chest pain symptoms
Good exercise tolerance Diabetes, abnormal 12-L ECG,
+ normal 12-L ECG or questionable exercise capacity
Risk factor
modification ± Exercise or pharmacologic stress imaging
anti-ischaemic Rx Exercise
TM test
Able to Unable to
Low exercise exercise
Int risk
Post-ETT
TM
LK Exercise Pharmacologic
stress stress

Normal or mildly
abnormal with Moderate to severely
Cardiac
normal LV function abnormal or
catheter
depressed EF
ETT=exercise treadmill test; EF=ejection fraction; LV=left ventricle; TM=treadmill.
Mieres. Circulation. 2005;111(5):682-696.

196
 Comparative Test Statistics on
Diagnostic Accuracy in Women With
Contemporary Techniques

Sensitivity Specificity
ECG 61% 70%
Echo 86% 90%
Nuclear (Tl-201) 78% 64%

Modified from Kwok et al. Am J Cardiol. 1999.

Improved Specificity of Perfusion

Imaging in Women with Tc99m
Sestamibi
Tl-201 Stenosis >70%
Tc99m sestamibi
Tc99m sestamibi + Gated SPECT
100 92.2
84.4
80
67.2
Percent

60

40
P

P=.02 P=.17
20
P=.0004
0
n=43 n=54 n=59
n=115

Taillefer R, et al. J Am Coll Cardiol. 1997;29:69-77.

197
 Comparative Test Statistics on
Diagnostic Accuracy in Women With
Contemporary Techniques

Sensitivity Specificity
ECG 61% 70%
Echo 86% 90%
Nuclear (Tl-201) 78% 64%
aNuclear (Tc) 80% 92%
bPharm Stress 91% 86%

aAdded data from J Am Coll Cardiol. 1997; bAmanullah et al. J Am Coll Cardiol. 1996.

Modified from Kwok et al. Am J Cardiol. 1999.

Incremental Value:
Exercise Tl-201 SPECT in Women

18
16
14
Global X2

12
10
8
6
G

4
2
0
Age Ex-HR Rev-Defect Defect Size Lg Defect Extent

Pancholy et al. JNC. 1995;2:110.

198
 Gender Differences in Risk
Stratification with Exercise MPI
20
18
16 Men
14
Women
12
10
8
6
4
2
0
Normal Mild/Moderate Severe

Hachamovitch et al. JACC. 1995:26;1457.

R S
S SPECT V T
W
N V T I
1 0 0 1 0 0
1 1
2 2
0 9 0 9
3

0 8 0 8 3
S

0 7 0 7
W M
C

3 402 4 50
0 6 0 6
0 0 5 1 1 5 2 2 5 3 0 0 5 1 1 5 2 2 5 3
Y Y
E N D END S G
S M A J M 19 106 172

199
 Synthesis of Evidence: Annual risk of cardiac death or MI
in important patient subsets referred to gated SPECT
imaging including diabetic and non-diabetic women and
men.
12
Cardiaac Death or MI Rate (/Yrr)

10

8
Low Risk
6
High Risk
4

0
Women Men Diabetics Non- Diabetic Diabetic
Diabetics Women Men

Source: Shaw J Nuc Cardiol 2004, Berman et al. JACC 2003;41:1125-33.

Risk Stratification: IV Adenosine Tc-

99m SPECT Imaging: Women

12

10

8
Cardiac Events
6
Cardiac Death
4

0
Normal Mild Moderate Severe

Hachamovitch et al. AJC. 1997;80:426.

200
• Women
• Diabetics
• Renal Insufficiency
• CHF
• Elderly
• Cost Effectiveness

Annual Risk of Cardiac Death or MI:

Influence of Diabetes
12
Low risk
High
g risk
10

0
Diabetics Nondiabetics Diabetic women Diabetic men

Shaw and Iskandrian. J Nucl Cardiol. 2004;11:171.

201
 SPECT MPI in Diabetes:
Sensitivity and Specificity*
100 Diabetics 90 91 90
89
86 86
90 Nondiabetics
80
70
56
Percent

60 50
46
50 43

40
30
20
10
111 142 27 46 96 119 42 69 65 72
0
Sensitivity Specificity Sensitivity Specificity Normalcy
Rate
>50% Stenosis >70% Stenosis

*Kang X, et al. Am Heart J. 1999;137:949-957.

Added Value of Nuclear Imaging for Risk

Stratification in Diabetic Patients

350
Incrremental Chi-square

300
250
200 Clinical Risk
+ Diabetes
150 + Nuclear
100
50
0
Cardiac Death CD or MI

Giri S et al. Circulation. 2002;105:32-40.

202
 Cardiac Events in Diabetics:
Relationship to Stress MPI
10
9
7%
>7%
Cardiac Event Rate 8
7
6
5 3-4%
4
3
2 1-2%
1
0
Normal Mildly Moderately to
Abnormal Severely
Abnormal
Kang X, et al. Am Heart J. 1999;138:1025-1032.

Significance of Normal Stress MPI:

Diabetic vs Non-diabetic Patients
Normal Perfusion
1.00
Non-diabetics

Diabetics
umulative Survival

.95

Log Rank Statistic=18.28,

.90 P=0.0001
Cu

.85

Diabetics
Non-diabetics
.80
0.0 .5 1.0 1.5 2.0 2.5 3.0
Follow-up (Years)
Giri S, et al. Circulation. 2002;105:32-40.

203
 • Women
• Diabetics
• Renal Insufficiency
• CHF
• Elderly
• Cost Effectiveness

Renal Disease in the USA

Most patients with CKD

will die from CVD not from
ESRD ESRD

300,000
Chronic Renal
Insufficiency
8 Million

Subclinical Kidney Disease*

11.2 Million
Coresh J et al. Am J Kidney Dis. 2003 Jan;41(1):1-12

204
 Cardiovascular Disease Mortality
General Population vs ESRD Patients
100
Annual CVD Mortality (%)

10

GP Male
1
GP Female
GP Black
GP White
0.1
Dialysis Male
Dialysis Female

0.01 Dialysis Black

Dialysis White

0.001
25-34 35-44 45-54 55-64 66-74 75-84 >85

Age (years)
GP: General Population Foley RN, et al. Am J Kidney Dis. 1998;32:S112-S119.

RISK ASSESSMENT WITH SPECT MPI IN

CHRONIC RENAL FAILURE
Study n % abnormal Prediction Relative
Risk
Kim, 2004 227 23% Mortality --
Dussol 97 10% MACE --
2004
Hase, 49 47% MACE 49.9
2004
Patel, 174 -- MACE 5.0
2003
Dahan, 60 28% MACE 9.2
1998

205
Prognostic value of adenosine stress MPI in patients
with end-stage renal disease.

Hase, Nephrol. Dial. Transplant.2004 19:1161-1167.

Event free survival after Transplant

Patel. Am J Cardiol. 2003 Jul 15;92(2):146-51..

206
 SPECT and ESRD CVD
Outcomes
• Few MPI studies have been reported in
patients with ESRD

• Abnormal in 22-50% of patients with ESRD

• Perfusion defects (and age, DM) are highly

predictive of outcomes in ESRD
1. Hase, H et al. Nephrol Dial Transplant 2004;19:1161-1167
2. Kim SB et al. American Journal of Nephrology 2004;24:448-452
3. Patel AD et al. Am J Cardiol. 2003;92:146-51

• Women
• Diabetics
• Renal Insufficiency
• CHF
• Elderly
• Cost Effectiveness

207
 Radionuclide Imaging Techniques in
Heart Failure

ƒ Clinical perspective
–Detect CAD as the etiology
–Assess potential role of
revascularization

Prevalence of Ischemia/Hibernation in
Heart Failure Patients
CHRISTMAS Trial baseline data, N = 406 FC1-3 CHF pts

100
79
of CHF patients

80
58
60 54

40
%o

20

0
HM Rev Ischemia HM or Rev Isch

Lancet 2003

208
 Detecting CAD in HF:
Guidelines
• ACC/AHA 2001 HF Guidelines:
– LVD and angina => direct to angiography
– HF, no angina => “..only angiography can reliably
demonstrate or exclude…CAD…” (Cath = Class
IIA, Noninv imaging = IIB)
• ACC/AHA/ASNC 2003 RNI Guidelines:
– Assessment of the co-presence of CAD in HF
without angina = Class IIA

Myocardial Perfusion Imaging

to Detect CAD in Heart Failure
Author Year Technique NPV(%) PPV(%)
Bulkley 1976 Pl-Tl201 100 72
Dunn 1982 Pl-Tl201 100 40
Saltissi 1981 Pl-Tl201 100 65
Eichorn 1988 Pl-Tl201 100 71
Chi k
Chickamorii 1992 Pl
Pl-Tl201
Tl201 100 65
Tauberg 1993 Pl-Tl201 100 61

Shafer, Udelson J Nucl Cardiol 2003

209
 Differentiating Ischemic vs
Non-ischemic Cardiomyopathy
40

30
Summed
Stress 20
Score

10

0
Ischemic Non-ischemic
Danias PG et al, Am J Card 1998

Use of SPECT MPI to Distinguish

Ischemic/Non-ischemic Cardiomyopathy:
Perfusion and Function Combined
100
90
80
70
60
50
40
30
20
10
0
Sensitivity Specificity Accuracy

Danias et al A J Cardiol 2004;94:14

210
 Non-Invasive Testing to
Detect CAD in Heart Failure

M
Myocardial
di l perfusion
f i iimaging
i
– Very high negative predictive value
– If perfusion scan normal or very mildly
abnormal, important CAD very unlikely to
be present => no catheterization indicated
for CAD detection/assessment of
revascularization

Quantitative SPECT Tracer Activity:

Relation to Segmental Viability/
Functional Recovery
100
Tl201
% Viable Segments

80 MIBI

60

40

20

0
80-100% 60-80% 40-60% <40%
Quantitative Tracer Uptake (% of peak)
Udelson JE et al, Circulation 1994

211
 Meta-Iodobenzylguanidine
(mIBG)
• NE (norepinephrine) is synthesized by
normal adrenergic neurons
neurons, stored in
adrenergic granules, and secreted in
response to neuronal stimulus. Some of the
secreted NE is taken up and stored again in
granules - this reuptake occurs via an energy-
p
dependent mechanism and through g ppassive
diffusion.
• Guanethidine is a neuron-blocking agent
(false neurotransmitter) that acts selectively
on sympathetic nerve endings

Meta-Iodobenzylguanidine
(mIBG)
• mIBG is a physiologic analog of
norepinephrine (NE) and the false
neurotransmitter guanethidine.
• mIBG is not metabolized therefore stays
localized in the myocardial sympathetic
nerve endings

212
 ANALYSIS OF MIBG
PLANAR IMAGES
HMR Ratio
ROI’s
O drawn around heart
and mediastinum, counts
per pixel determined for
each, and ratio calculated.

Myocardial Washout
[(Early late counts
[(Early-late
corrected for I-123 decay) x
100] /early counts

Morozumi et al . J Nucl Med 1997;38: 49-52.

Imaging with mIBG

• Heart to mediastinum uptake (H/M ratio)
obtained in early
y and delayed
y images
g
– High ratio indicates localization of tracer in
myocardium and intact autonomic tone
• Myocardial washout is rate of decrease in
myocardial counts over time
– Washout reflects adrenergic activity and tone.
Normal WR is low (<10-20% in 4 hours)
– degree of increase associated with severity of
myocardial neuronal dysfunction/denervation
• Crude assessments due to low count rates

213
123I-mIBGPlanar
Imaging

End stage HF
Control

Survival during 24-mo follow-up more

effectively stratified by
H/M ratio than LVEF

Merlet P J Nucl Med 1999;40:917

214
Response to therapy: ARB/ACE

Kasama J Nuc Med 2003;44:884-890

• Women
• Diabetics
• Renal Insufficiency
• CHF
• Elderly
• Cost Effectiveness

215
 PROGNOSTIC VALUE OF MPI IN THE
ELDERLY: published literature

Author Year Method n Predictor

Iskandrian 1988 Exer Tl 499 Abnormal
Steingart 2002 Exercise 578 (-)
Schinkel 2005 Dob tetro 272 SSS, abnormal
Shaw 1992 Dipyr Tl 348 Abnormal
Hilton 1992 Exer Tl 120 Abnormal
Lima 2004 Sestamibi 328 Abnormal
Valeti 2005 Thallium 247 SSS
De Winter 2005 Tetrofosmin 294 SRS, ESV, EF. TID
Zafir 2005 Thallium 162 LV dilation, ischemia

PROGNOSTIC VALUE OF GATED SPECT

IN THE ELDERLY

• 295 pts, ≥ 75 y.o.a

• Bicycle, dipyridamole
(65%)
• Follow-up=25.9 months

• Predictors of all-cause
morality
–SRS
SRS
–TID
–LVEF
• Cardiac mortality
Annual Mortality
–SRS
> 45%: 5.15%
–ESV 30-45%: 11.1%
<30%: 17.4% De Winter, 2005
JNC 12: 662

216
 PROGNOSTIC VALUE OF STRESS
MPI IN THE VERY ELDERLY

• 162 consecutive pts

– 29% bicycle
– 71% dipyridamole
LV Dilation
O.R. = 6.9
• 83±3 y.o.a
– Range: 80-90 y.o.a.

• Follow-up: 45 months
– NFMI, cardiac death

Ischemia
O.R. = 2.8

Zafir 2005
JNC 12: 671

Conclusion: Elderly patients

ƒ Less prognostic data, but similar outcomes with
younger patients
ƒ Exercise is still preferred if possible
ƒ Combination protocols may be quite useful in
this population (dipyridamole/adenosine with
exercise)

217
• Women
• Diabetics
• Renal Insufficiency
• CHF
• Elderly
• Cost Effectiveness

Cost Effective
• Cost effectiveness is enhanced if a test is
an independent
i d d t predictor
di t off outcomes
t and d
adds prognostic information to the pretest
data

218
 Cost vs Outcome Relationship
Cost-Effectiveness Ratios
“Flat of Curve” Rx
Additional Yield

C A = Dominant (cost saving)

B
B = Attractive (<$50,000/LY)

C = Unattractive
A

A (>$100,000/LY)

Additional Cost
($)

COST-EFFECTIVE RISK STRATIFICATION

Normal ECG

Low Risk (<.15) Int-High Risk (>.15)

0.4% 3.2%

(-) SPECT (+) SPECT (-) ETT (+) ETT

0% 2 7%
2.7% 1 3%
1.3% 3 9%
3.9%

$211,470
(-) SPECT (+) SPECT (-) SPECT (+) SPECT
1.0% 2.5% 1.1% 6.4%

$147,000 $25,134
Hachamovich, 2002
Circulation 105: 823

219
 THE END STUDY
Economic Consequences of
Diagnostic and Prognostic Strategies

• T
Two cohorts
h t off stable
t bl angina
i pectoris
t i patients
ti t
– 5,423 direct angiography
– 5,826 perfusion imaging+selective angio
• Matched pretest risk of CAD
• All outpatients
t ti t w/o/ recentt hospitalization
h it li ti
• Seven hospitals
• Follow up: 2.5±1.5 years
Shaw et al, 1999
JACC 33:661

END Study: Outcome by

Screening Strategy
Revascularization Cardiac Death or MI

35 35 Directt C
Di Cath
th
30 30 MPI/Selective Cath
30
27
25 25
% Events

20 20
16 14 16
15 13 15
10 10 9.0 8.3
5.0 4.7
5 5 2.5 2.1
0 0
Low Int High Low Int High
Clinical Likelihood Clinical Likelihood

Adapted from Shaw LJ, et al. J Am Coll Cardiol. 1999;33:661-669.

220
 END Study: Cost by Screening
Strategy
Direct Catheterization Stress MPI + Selective Cath
$6,000
$4.8 Diagnostic Cost
$4.2 Follow-up Cost
$4,000
*
$2.9 * $2.8
*
$2.4
$2.0
$2,000

$0
Low Int High Low Int High
N = 813 2,928 1,682 826 3,379 1,631

Pretest Clinical Risk Pretest Clinical Risk

(n=5,423) (n=5,826)
*P<.01 vs catheterization.
Adapted from Shaw LJ, et al. J Am Coll Cardiol. 1999;33:661-669.

Cost of Screening with SPECT vs

Catheterization in Women with
Stable Chest Pain
Noninvasive Strategy Invasive Strategy
5 000
5,000
MPI with selective cath Direct cath
*
4,000
$3,687
*
* $2,740 $2,585
3,000 $2,490

2,000 $1,587 $1,693

1 000
1,000

$0
Low Intermediate High
Clinical Risk
*P<.05
Adapted from Shaw LJ, et al. J Nucl Cardiol. 1999;6:559-569.

221
 POTENTIAL COST SAVINGS USING
STRESS NUCLEAR IMAGING VS. DIRECT
CATHETERIZATION
Diagnostic Testing Selective Catheterization
St t
Strategy (I th
(In the S
Setting
tti off
Demonstrable Ischaemia)

Range of Cost Savings

CSMC (N=5,286) 22% to 55%

EMPIRE (N=396) 23% to 34%

END (N=11,249) 30% to 41%

Shaw LJ, Hachamovitch R, Berman DS, et al. J Am Coll Cardiol 1999;33:661-669, Underwood SR,
Godman B, Salyani S, Ogle JR, Ell PJ. Economics of myocardial perfusion imaging in Europe - The
EMPIRE study. Eur Heart J 1999;20:157-166, Hachamovitch R, Berman DS, Shaw LJ, et al. Circulation
1998; 97:535-543

• Women
• Diabetics
• Renal Insufficiency
• CHF
• Elderly
• Cost Effectiveness

222