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Part V
Multidisciplinary Topics
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© Springer International Publishing 2016
M.J. Budoff, J.S. Shinbane (eds.), Cardiac CT Imaging: Diagnosis of Cardiovascular Disease,
DOI 10.1007/978-3-319-28219-0_20
Value Based Imaging for Coronary
Artery Disease: Implications for Nuclear
Cardiology and Cardiac CT
Daniel S. Berman , Alan Rozanski , Piotr Slomka ,
Rine Nakanishi , Damini Dey , John D. Friedman ,
Sean W. Hayes , Louise E. J. Thomson , Reza Arsanjani ,
Rory Hachamovitch , James K. Min , Leslee J. Shaw ,
and Guido Germano
Abstract
Technology in cardiac computed tomography (CT) and nuclear cardiology is constantly
improving. In single photon emission CT (SPECT), new cameras, reconstruction methods,
and protocols have dramatically reduced radiation doses to patients. In positron emission
tomography (PET), application of quantitative measurements of myocardial perfusion
reserve is improving assessment of prognosis. PET/CT is routinely performed in conjunction with coronary artery calcium (CAC) scanning in many centers, extending the ability of
myocardial perfusion imaging (MPI) studies to impact patient management. In cardiac CT,
marked improvements in equipment and reconstruction software have also dramatically
reduced the patient radiation associated with cardiac testing, and have reduced the frequency of non-diagnostic studies. New methods for combining anatomic and functional
assessment with CT—CT perfusion and FFR CT measurements—are beginning to be used
clinically. With the expanding capabilities of each technology, their opportunities to provide
value increases. Given the changing reimbursement paradigm from a volume-based to a
value-based system, the applications of each technology that will survive are those that
improve relationship between outcomes and costs. With respect to coronary artery disease
(CAD), a growing body of evidence exists regarding the value of specifi c tests in the various
clinical settings in which CAD is considered. For prevention, data is strong in that CAC
scanning can provide value by improving outcomes. In the patient with acute chest pain,
CCTA appears to be able to shorten time in the hospital and reduce costs. In patients with
D. S. Berman , MD (*) • P. Slomka , PhD • D. Dey , PhD
J. D. Friedman , MD • S. W. Hayes , MD • L. E. J. Thomson , MBChB
R. Arsanjani , MD • G. Germano , PhD
Departments of Imaging and Medicine ,
Cedars-Sinai Medical Center and the Cedars-Sinai Heart Institute ,
Los Angeles , CA , USA
e-mail: bermand@cshs.org
A. Rozanski , MD
Division of Cardiology , Mt. Sinai Saint Luke’s
and Roosevelt Hospitals , New York , NY , USA
R. Nakanishi , MD, PhD
Department of Medicine , Los Angeles Biomedical Research
Institute at Harbor-UCLA , Torrance , CA , USA
2 0
R. Hachamovitch , MD
Department of Nuclear Medicine , Cleveland Clinic,
Heart and Vascular Institute , Cleveland , OH , USA
J. K. Min , MD, FACC
Department of Radiology , Dalio Institute of Cardiovascular Imaging,
Weill Cornell Medical College and the NewYork Presbyterian
Hospital , New York , NY , USA
L. J. Shaw , PhD
Department of Medicine , Emory Clinical Cardiovascular
Research Institute, Emory University School of Medicine ,
Atlanta , GA , USA
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350
suspected stable ischemic heart disease and an intermediate pre-test likelihood of CAD, the
use of CCTA appears to be valuable. In patients who have known CAD or in whom a
nondiagnostic CCTA is likely, improvement in outcomes based on CCTA is less likely and
testing for ischemia may be preferred. In patients with a very high likelihood of CAD or
known CAD, registry data suggests that ischemia testing, such as that provided by SPECTor PET-MPI studies, may improve outcomes by improving selection of patients for revascularization. The ISCHEMIA trial will test whether a strategy basing decisions for
revascularization on noninvasive assessment of ischemia improves outcomes. Test selection
is highly dependent on accurate pretest risk assessment. An updated method for assessment
of pre-test risk has developed which may lead to improved utilization of cardiac imaging
procedures. In all of the applications of noninvasive imaging, value can only be achieved if
the appropriate patients are selected for testing and if the test result changes management,
such that outcomes can be improved or costs reduced.
Keywords
SPECT-MPI • PET-MPI • Myocardial perfusion imaging • Single photon emission computed
tomography • Positron emission tomography • Cardiac CT • Coronary CT angiography •
Coronary artery calcium scanning
Introduction
The rapid evolution of new medical technologies and therapies and the increasing numbers of patients being studied
or treated based on these developments are leading to an
unsustainable increase in health care costs. In the United
States, through legislation such as the Affordable Care
Act, a transition from a volume-based health care reimbursement to a value-based reimbursement. Over the past
few decades, there has been a rise in the use of imaging
that parallels that of the overall rise in healthcare costs.
While efforts such as implementation of Appropriate Use
Criteria have slowed the rise in these expenses, a continued increase in overall imaging costs is still occurring. It is
virtually inevitable that value-based medical care reimbursement will be increasingly the norm and will apply to
most of the use of medical imaging.
What is value in imaging? Inherently, as with any commodity, value is a function of quality and cost (Fig. 20.1 ).
In cardiology, quality ultimately implies improvement in
patient outcomes. In the patient with coronary artery disease (CAD), these outcomes might reduce cardiac events
such as death or myocardial infarction or improvement in
quality of life. Other measures of quality include accuracy
of diagnosis, effi ciency of service for the patient, and
reduction of any harm that might be associated with the
care such as radiation, or complications from unnecessary
invasive diagnostic or therapeutic procedures. Value is
inversely related to costs, which are not only the costs of
the imaging studies themselves, but all of the costs related
to the study, including cost increases due to downstream
testing and therapies and cost decreases due to more effi cient care from reduced unnecessary downstream testing
and therapies. In the future, whether the payer is the government, insurance companies, or the patients themselves,
it is likely that only those approaches that provide value
will be purchased. In imaging, this implies an increasing
penetrance of value-based imaging, with growth in testing
in areas of proven value and reduction of testing in areas in
which value has not been shown.
In this chapter, we review the technologic developments
in the nuclear cardiology and cardiac CT in light of advances
that are likely to improve value and then to explore the potential “value proposition” of these modalities in the various
clinical settings of suspected or known CAD in which they
are applied.
Fig. 20.1 Value-based imaging: concepts
D.S. Berman et al.
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Technologic Developments
Nuclear Cardiology
In the last several years, there have been several advances in
the technology of nuclear cardiology including single photon
emission computed tomography (SPECT) and positron emission tomography (PET) for myocardial perfusion imaging
(MPI). One of the primary areas of advantage of nuclear cardiology methods is the degree to which automated, objective
quantitative analysis is available and implemented in practice.
These methods are becoming increasingly automatic. They
reduce the dependence on local expertise in interpretation,
leading to increased reliability of the measurements across
laboratories. Importantly, automated assessment has a dramatic effect on reproducibility of measurements, which is
highly important in serial assessment. While the reproducibility of subjective visual assessment is poor, very high
reproducibility of quantitative measurements has been shown
by documented in multiple patient populations [ 1 – 3 ].
Recently, advanced automated quantitation has been shown
to improve accuracy of diagnosis of CAD compared to expert
visual interpretations [ 4 ]. Further, the introduction of machine
learning, in which the computer is provided all of the variables available to the clinician, SPECT MPI has been shown
to provide greater accuracy for CAD detection than either
expert visual or quantitative perfusion defect assessment [ 4 ]
(Fig. 20.2 ; Courtesy Ref. [ 4 ]). It is likely that quantitative
analysis with machine learning will become routine in nuclear
cardiology laboratories.
Specifi cally pertinent to SPECT, recent camera and
computer developments have been introduced that improve
image quality [ 5 ]. The introduction of CZT detector cameras
has resulted in increased counting effi ciency (sensitivity),
which can be employed to reduce time of procedures or
administered radiation doses, while at the same time
improving resolution [ 6 ]. With these cameras, the ability to
perform SPECT MPI with as little as 3 mCi of Tc-99m has
been reported, with an associated radiation dose of approximately 1 mSv to the patient [ 7 , 8 ]. One of these cameras has
been shown to be accurate for detection of CAD even in the
morbidly obese patient (Fig. 20.3 ; Courtesy Ref. [ 9 ]),
allowing cardiac imaging of patients up to 500 lb—perhaps
unachievable with any other modality at this time [ 9 ]. New
approaches to reconstruction of raw data have also become
available for use with standard sodium-iodide detector
Anger cameras, which allow for shorter imaging time or
reduced radiation dose [ 10 , 11 ]. Protocols have also
changed, with stress fi rst sequences, as were used in the initial SPECT imaging applications with Tl-201, becoming
more common. With these, stress only studies become
possible. To accomplish this, either attenuation correction
imaging or two view (prone supine or upright/supine) is
important to reduce the effects of soft tissue attenuation,
particularly important when a rest and stress examination
cannot be compared [ 12 , 13 ]. Numerous publications have
documented that a normal stress only study is associated
with excellent patent prognosis, which is equal to that associated with rest/stress studies (Fig. 20.4 ; Courtesy Ref. [ 14 ])
[ 14 , 15 ]. In 2015 at Cedars-Sinai, stress only studies, with a
radiation dose to the patients of <2 mSv, was performed in
nearly 40 % of cases.
Added value of machine learning combining supine and prone
SPECT-MPI and clinical data
Entire population: (N = 1181)
Entire population: (N = 1181)
ML: Quantitative + Clinical
ML: Quantitative + Clinical
Expert 1: MPS + Clinical
Expert 2: MPS + Clinical
ML: Quantitative Only
TPD
ML – Machine Learning
ML – Machine Learning
MPS – Myocardial Perfusion SPECT
TPD – Total Perfusion Deficit
Area
Area
0.94 ± 0.01**
0.94 ± 0.01*
0.89 ± 0.01
0.85 ± 0.01
0.90 ± 0.01*
0.88 ± 0.01
*Better than TPD (p<0.001)
**Better than TPD and ML Quantitative (p<0.0001)
*Better than Expert 1 and Expert 2 (p < 0.0001)
1.0
0.9
0.8
0.7
Sensitivity
0.6
0.5
0.4
0.3
0.2
0.1
0.0
1.0
0.9
0.8
0.7
Sensitivity
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0.0 0.2 0.4 0.6 0.8
1 - Specificity
1.0
0.0 0.2 0.4 0.6 0.8
1 - Specificity
1.0
a
b
Fig. 20.2 ROC curves comparing the machine learning ( ML) algo-
rithm of quantitative + clinical data ( red ): ( a ): vs ML of quantitative
SPECT-MPI data alone ( blue ) and total perfusion defi cit alone ( green ).
( b ): vs expert visual analysis of supine and prone SPECT-MPI (MPS)
including clinical data by expert 1 ( blue ) and expert 2 ( green ) for the
detection of obstructive coronary artery disease (Reprinted from
Arsanjani et al. [ 4 ] with permission from Springer)
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Fig. 20.3 Case example of high SPECT-MPI image quality obtained with a CZT camera using moving detectors in a 48 year old male with body
mass index (BMI) 60. U upright; S supine; TPD total perfusion defi cit (Reprinted from Nakazato et al. [ 9 ] with permission from Springer)
Prognosis of normal stress-only
vs standard stress/rest SPECT-MPI
1.0
0.9
0.8
0.7
% Survival
0.6
0.5
Log-rank p = 0.02 (unadjusted)
p = 0.89 (adjusted)
Number at risk
Stress-only
Stress-Only
Stress+rest
Stress + Rest
8034 6996 4981 3243 1196
732
Years
2107452574138820
02468
Fig. 20.4 Kaplan-Meier survival curves according to SPECT-MPI
protocol for patients undergoing stress-only (red; n = 8034) or
stress + rest (blue; n = 8820) imaging (Reprinted from Chang et al.
[ 14 ] with permission from Elsevier)
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Important advances have also been made in PET. For
PET-MPI, perhaps the most important of these has been the
incorporation of absolute quantitative myocardial perfusion
measurement. Referred to as myocardial perfusion reserve
(MFR) or coronary fl ow reserve (CFR)—or absolute peak
stress perfusion measurements—these assessments have
now become available through the major software vendors
and excellent correlation between the methods has been
shown [ 16 , 17 ]. These methods, using the widely available
tracer Rb-82, have also validated by comparison with N-13
ammonia PET [ 17 ]. The prognostic value of these absolute
fl ow measurements has been documented in a large number
of clinical studies. Importantly, the added prognostic value
of these measurements when combined with standard relative perfusion PET-MPI assessments has been shown [ 18 ,
19 ]. For any degree of relative perfusion defect abnormality,
mortality has been shown to increase according to the degree
of abnormality of MFR (Fig. 20.5 ; Courtesy Ref. [ 18 ]).
These absolute fl ow measurements provide added value in
many respects, including the ability to recognize when there
has been inadequate vasodilation stimulus due to caffeine
intake by the patient—seen as no increase in fl ow between
rest and stress. These measurements provide an overall
assessment of myocardial perfusion, which is related not
only to the presence of signifi cant epicardial stenosis or stenoses, but also the status of the microvasculature. This capability provides information that is complementary to the
assessment of fractional fl ow reserve (FFR), allowing the
identifi cation of diffuse epicardial disease and microvascular
dysfunction, which have their own prognostic and therapeutic implications beyond those associated with assessment of
an individual coronary lesion [ 20 , 21 ].
The existing PET or SPECT myocardial perfusion tracers
are not ideal. One problem of the existing myocardial perfusion tracers is that their uptake in the myocardium is not linear with respect to fl ow at high fl ow rates. A new
radiopharmaceutical currently in clinical trials overcomes
this and other limitations of the currently used tracers.
Flurpiridaz F-18 is linearly extracted across the range of
fl ow, providing greater contrast within a perfusion defect
compared to a normal zone than is achieved with Tc-99m
sestamibi [ 22 – 24 ] (Fig. 20.6 ; Courtesy Ref. [ 24 ]). This is
also likely to be true with respect to Rb-82, which has shown
a similar plateauing of uptake with respect to fl ow as the
SPECT agents. F-18 provides superior resolution compared
to Rb-82, and due to its 110 min half-life can be used with
exercise. It also lends itself to stress only application and
does not require an on-site cyclotron [ 23 ] or expensive gen-
erator. It has the potential, depending on pricing, to become
the PET-MPI agent of choice.
Increasingly, PET-MPI and SPECT-MPI are combining
functional and anatomic assessment of patients with suspected CAD. PET-MPI is currently almost exclusively performed with PET/CT scanners [ 10 ]. SPECT/CT scanners are
also growing in their use. The use of these hybrid scanners
provides the capability to routinely measure and report the
Fig. 20.5 Unadjusted
annualized cardiac mortality by
tertiles of CFR and categories of
stress PET-MPI perfusion defect
( PD ). CD cardiac mortality. 9
(Reprinted from Murthy et al.
[ 18 ] with permission from
Wolters Kluwer Health, Inc)
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coronary artery calcium (CAC) score on patients undergoing
MPI. This addition of the CAC score has several major
advantages. From the standpoint of interpretation, the presence of CAC and its extent provide additional powerful
information which can improve the accuracy of interpretation of MPI when borderline perfusion defects are noted:
when the CAC score is 0, the interpreter is able to be confi dent in considering an “equivocal” perfusion scan as “probably normal”, while when the CAC is high, the equivocal
scan can be considered to be “probably abnormal” (Fig. 20.7 ).
Perhaps most importantly, combining CAC with PET- or
SPECT-MPI assessments overcomes one of the major limita-
tions of MPI in detection of epicardial CAD: its reliance on
the presence of a hemodynamically signifi cant lesion. Over a
decade ago, it was recognized that high CAC scores are common in patients with normal SPECT-MPI [ 25 ]. By adding
CAC assessment, the combined MPI/CAC study allows both
the assessment of the coronary atherosclerotic burden as well
as the fl ow limiting disease [ 26 – 28 ].
Finally, molecular imaging is an area of particular strength
for nuclear cardiology, taking advantage of the ability of
minute amounts of tracer to be employed, such that the
administered tracer has no effect on the physiologic effect of
the molecule. Virtually any biologically active molecule can
Fig. 20.6 Case example of Flurpiridaz F 18 PET ( top two rows ) vs
Tc-99m rest SPECT ( bottom two rows ). The patients was an 87 year old
woman with shortness of breath 3 months after stenting the left anterior
descending coronary artery. An anterior wall stress perfusion defect is
seen on both types of scans but is shows greater contrast on the
Flurpiridaz F 18 images. Coronary angiography subsequently demonstrated subtotal in-stent stenosis. ADENO adenosine; VLA vertical long
axis; HLA horizontal long axis; MIBI sestamibi (Reprinted with permis-
sion from Berman et al. [ 24 ] with permission from Elsevier)
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355
be labelled with a PET radioisotope, providing the opportunity for PET molecular imaging (and for some molecules
SPECT imaging) to provide unique insights into pathophysiologic processes. From a practical perspective of broad
application in medicine, it must be realized that each tracer
developed would need to go through a long and costly development to reach standard clinical use. However, there are
two tracers that are approved by the FDA and widely available that can be applied to the assessment of the patient with
atherosclerosis. F-18 FDG is widely used for assessment of
cancer. It has also been used for over 30 years for the assessment of myocardial viability. Multiple studies have shown
that F-18 FDG can also be used for imaging of arterial
infl ammation, with well-developed application in carotid
imaging [ 29 ]. While not yet a routine clinical tool, FDG
carotid assessment is already playing an important role in
assessing novel therapies [ 30 , 31 ]. F-18 FDG can also be
effective in imaging of infection, including infected cardiac
devices and intravenous lines.
One of the problems of CAD that is not routinely
addressed by any of the standard imaging methods is that
they do not assess the activity of disease. It is widely recognized that coronary infl ammation plays a pivotal role in the
development of plaque rupture—the process that triggers
most myocardial infarctions [ 32 ]. Severe coronary stenoses
can be completely stable, with only fi brous or calcifi ed
plaque, and have minimal likelihood of causing a coronary
thrombosis. On the other hand large infl amed plaques may
not cause a coronary stenosis, but could be at high risk of
rupture [ 33 ] (Fig. 20.8 ). Imaging of coronary plaque infl am-
mation with PET has the potential to assess the activity of
CAD. Recently, exciting development has been reported
with the use of the simple salt-F-18 sodium fl uoride—for
identifi cation of high risk coronary artery plaque [ 34 , 35 ].
This agent was used over 40 years ago as a bone scanning
tracer. It tracks the active deposition of calcium. In a series of
reports, Dweck, Joshi, and Newby have reported that F-18
fl uoride can localize in coronary plaque. In an important
study of F-18 fl uoride imaging in 80 patients, these investigators studied 40 patients with acute ischemic syndromes
(ACS) and 40 with stable angina [ 35 ]. The found that 93 %
of the patients with ACS had F-18 fl uoride uptake in the area
Fig. 20.7 Case example of combined SPECT-MPI and coronary artery
calcium scanning ( CAC ). The patient was a 57 year old male. The
SPECT-MPI study was considered probably abnormal based on the per-
fusion study alone. The fi nding that the CAC score was 1463 (97
th
percentile) resulted in increased observer certainty in interpreting the study
as abnormal
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found to be the culprit plaque on invasive coronary angiography (ICA) (Fig. 20.9 ; Courtesy Ref. [ 27 ]). In the patients
with stable angina, 45 % had F-18 fl uoride uptake, in each
corresponding to a lesion with adverse plaque characteristics
on IVUS. The current paradigm for guiding revascularization of patients with stable ischemic heart disease (SIHD) is
to revascularize based on the presence of hemodynamically
signifi cant stenosis. It is possible that if CAD can be characterized by the degree of infl ammation associated with it, that
patients with stenoses but inactive disease might be safely
guided toward conservative management rather than toward
revascularization.
Cardiac CT
Cardiac CT has been employed for 20 years for CAC measurements—performed with minimal radiation, in a single
breath, and no contrast. As discussed below, this is a powerful tool for prevention in CAD. Coronary CT angiography
(CCTA) is a younger method—with its use being accepted
only in 64 detector row scanners or more, scanners that were
introduced in 2005. This method provides exquisite images
of the coronary arteries. Beyond allowing assessment of
coronary stenosis, not possible with non- contrast CT, CCTA
allows assessment of noncalcifi ed plaque. Motoyama et al.
demonstrated that certain adverse characteristics of coronary
plaques were associated with increased ACS events [ 36 ]
(Fig. 20.10 ). Subsequently, considering positive remodeling
and low attenuation plaque (associated with lipid content and
the size of the necrotic core), these authors demonstrated in
a series of over 1000 patients without obstructive CAD that
patients with the number of adverse plaque features as associated with the frequency of ACS events [ 37 ]. Shmilovich
et al. demonstrated that adverse plaque characteristics added
to % stenosis in prediction of myocardial ischemia [ 38 ]
(Fig. 20.11 Shmilovich). Subsequently, Nakazato et al. dem-
onstrated that the aggregate plaque volume on CCTA added
to diameter stenosis in prediction of reduced FFR in intermediate coronary lesions [ 39 ]. More recently, Park et al. dem-
onstrated that positive remodeling on CCTA was associated
with ischemia-causing lesions across the degrees of coronary
artery stenosis [ 40 ]. These adverse plaques characteristics
can be appreciated visually, but their manual measurement is
time consuming and tedious, and not likely to become commonly performed. Importantly, automated software
approaches to assessment of coronary plaque have been
developed allowing assessing of a wide variety of plaque
Fig. 20.8 Left : Cross-section of a stable atheroma associated with high grade coronary stenosis. Right : Cross-section of an fatal infl amed, lipid
rich plaque which had ruptured, associated with a mild coronary stenosis (Reprinted from Moreno et al. [ 33 ] with permission from Elsevier)
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