Dynamic cardiac PET imaging: Technological improvements advancing future cardiac health
Dynamic cardiac PET imaging: Technological improvements advancing future cardiac health
Grant T. Gullberg 0 1
Uttam M. Shrestha 0 1
Youngho Seo 0
0 Reprint requests: Grant T. Gullberg, PhD, Department of Radiology and Biomedical Imaging, University of California , 185 Berry St., Ste 350, San Francisco, CA 94143-0946 , USA
1 Department of Radiology and Biomedical Imaging, University of California , San Francisco, CA , USA
While PET, in conjunction with CT,1 has been an
important tool in the management of oncology patients,
accounting for 86% of PET scans by 2016,2 PET with
attenuation and motion correction has significant
potential for future cardiac applications, especially with
the ability of PET to perform dynamic imaging to
measure myocardial perfusion—myocardial blood flow
(MBF) and coronary flow reserve (CFR), integrity of
neural transmitters of the autonomic nervous system,
and connecting cardiac efficiency with metabolism of
myocardial substrates. Its potential is found with its
excellent resolution and sensitivity, the ability to use
tracers with a short half-life allowing higher doses, and
possibly in the future the ability to use 18F perfusion
agents that would eliminate the need of an onsite
cyclotron. During dynamic imaging (a dynamic scan
should be performed for every procedure), the high
counts during the blood input phase can paralyze the
camera electronics. Therefore, improved time-of-flight
(TOF) electronics able to accept these high counts rates
and quality control measures to determine the maximum
allowable injected dose (as presented in this issue of the
Journal by van Dijk and colleagues) for dynamic cardiac
PET studies need to be implemented. However, there is
a caveat: restricting the injected dose to meet the count
rate capabilities during the input phase penalizes the
ability to obtain high counts during the later phase of the
dynamic study when the camera electronics are less
likely to be paralyzed. Using constant infusion
techniques can reduce high peak counts during the input
phase, but this reduces the ability to accurately measure
the frequency response of the transfer of blood to tissue
compartments. Other approaches in the future such as
using a library of input functions or blind estimation
may alleviate the limitations of injecting a restricted
dose for dynamic cardiac PET studies. Nevertheless, one
needs to follow caution and consider the fact that the
overall radiation burden to the U.S. population doubled
from the early 1980s to 2006, and the contribution of
nuclear cardiology procedures to ionizing radiation
burden increased 10-fold.3 Thus new and improved
hardware, software, and radiotracer developments play
an important part in the performance of the PET system
for dynamic cardiac applications to provide expected
clinical benefit that outweighs the risks of the procedure.
In the paper by van Dijk and colleagues a simple
method, originally proposed by Renaud et al.,4 was used
to determine the maximum activity of 82Rb allowed for
estimating MBF using the new Philips digital PET
camera with time-of-flight capability. The method is
similar to that of an earlier method used by our group at
UCSF for determining the maximum activity of 18F
tracers allowed for performing kinetic analysis via
image derived blood input measurements from the heart
using the Siemens Biograph 16 PET/CT.5 Basically, the
method injects high levels of radioactivity into a
phantom such as a cardiac insert of an anthropomorphic torso
phantom (Data Spectrum Corp) that saturates the
system. With time, the activity decays decreasing the dead
time or paralysis in the system allowing the counts to
increase (see illustration in Figure 1). When the count
rate increases to a level where the bias between the true
activity and the measured activity is less than some level
of accuracy, such as 1%, that determines the activity—
modified for patient size and weight—that one can inject
to obtain accurate kinetic parameters for the estimation
of myocardial blood flow (MBF).
In the work of van Dijk and colleagues, data were
acquired on three LYSO TOF PET systems: Two analog
systems—Ingenuity TF (Philips Healthcare)6 and
Discovery 690 (GE Healthcare)7—were compared with the
new digital PET prototype camera from Philips
Healthcare.8 Data from these three systems were
reconstructed into 40 dynamic images, each of 15s,
using vendor iterative expectation maximization
reconstruction software with corrections for attenuation,
scatter, randoms, detector efficiency, dead time, and
decay. The phantom results showed that the three
scanners were limited to a maximum injection of 312
MBq (8.43 mCi) for the Philips Ingenuity TF, 650 MBq
(17.57 mCi) for the GE Discovery 690, and 654 MBq
(17.67 mCi) for the Philips digital PET prototype to
insure that the reconstructed images would not deviate
more than 1% from the true activity in a dynamic
cardiac study. It is interesting that the analog GE D690
system with a timing resolution (TR) of 544.3
picoseconds (ps) compared well with the Philips digital PET
prototype (TR = 307 ps) and much better than the
Ingenuity TF (TR = 502 ps). For a clinical study a
physician needs to know how these results translate for a
particular patient whose body habitus can change
dramatically. This is discussed in the paper of van Dijk and
colleagues by anticipating patient-injected doses using
conversion results in the literature for other PET
systems. However, they emphasize that these studies still
need to be performed for the Philips digital PET system.
An important further study is to evaluate the effects of
these results on the accuracy and precision of the
estimated nonlinear kinetic parameters, which depend
significantly upon the data statistics and the algorithmic
methods used. These measurements have important
implications for using PET to measure MBF and for
other applications requiring dynamic imaging to
measure coronary flow reserve, pre- and post-synaptic
neuronal transmission rates, cardiac metabolic rates, and
cardiac efficiency. Rubidium-82 has a relatively short
half-life of 76s and high activities are therefore required
to obtain sufficient image quality; whereas 18F-agents
would expect to provide overall better accuracy and
precision because the longer half-life of 110 minutes
allows for better statistics during the wash-out phase of
the kinetic analysis.
PET has made substantial hardware improvements
advancing TOF capability over the last 40 years making
significant impact upon image quality.9 The idea to use
TOF information was originally proposed early on in the
development of PET, and the first TOF PET systems
were industrialized in the 1980s.10 A good review of
these early developments11 revealed several hardware
deficiencies at that time. For one, dead time due to event
pileup was a very significant problem limiting TOF
systems to operate only in 2D mode, but the new
technology has allowed modern PET systems to operate
TOF in 3D mode. Major hardware advancements
include new detector materials, such as Lutetium
(Yttrium) Oxyorthosilicate (LSO and LYSO), providing
excellent stopping power for 511 keV photons with high
photon yield at fast rise times; more compact SiPM12
compared to PMTs, with faster photon amplification,
capable of being inserted into a MRI scanner;
accessibility of application-specific integrated circuits (ASICs)
allowing more dense and complex electronics; and faster
computing hardware to process data. TOF imaging
thought not possible in the early scanners developed in
the 80s is now possible and has significant advantages.
The accuracy of photon detection, the uniformity across
the detector, and the TOF resolution have been
improved by eliminating photomultipliers and Anger
logic and using SiPMs with 1:1 coupling. Additional
improvements come from improving crystal depth of
interaction, energy resolution, and timing estimation in
PET detectors with deconvolution and maximum
likelihood pulse shape discrimination.13 It may be possible
that in the future PET systems will have coincidence
timing resolutions of 10 ps providing a resolution of 5
mm without requiring any reconstruction; however, in
order to reach the 10 ps range radically new approaches
must be developed for scintillator light generation, light
transport, and light conversion.14 One step in this
direction is to have fully digital PET detectors without
photon conversion to visible light15 such as in cadmium
zinc telluride detectors presently being used in some
SPECT systems. Another promising development is
using a library of known waveforms to train deep
convolutional neural networks (CNNs) to estimate PET
time-of-flight from the leading edge of a coincident
waveform. Berg and Cherry have shown that this
improves coincidence timing by as much as 23%.16 In
the future, CNNs could be used to improve sampling
rate, resolution, partial volume, and noise in the
waveform due to electronic and statistical noise.
The development of PET reconstruction algorithms
has also had an important impact on the ability to
process cardiac PET data and to accurately model the
physical effects of the imaging detection process.17,18
Advanced algorithms have significantly improved image
quality with corrections for physical effects of
attenuation, detector efficiency, detector geometric response,
scatter, randoms, prompt gammas, dead time, and
changes in TOF resolution as a function of measured
detector count rate.19 Acquisition of list-mode data
temporally marks every event according to TOF position
in the acquired data. Anatomical positions of heart tissue
during the cardiac and respiratory cycle can be sorted by
these timing marks for which TOF list-mode iterative
maximum likelihood algorithms with correction for
motion can accurately reconstruct the position of events,
significantly improving cardiac image quality. With the
aim of reducing dose, adaptive statistical iterative
reconstruction algorithms can also be used to reconstruct
CT scans of low dose for attenuation correction.20
Furthermore, the addition of TOF capability presents some
very interesting mathematical subtleties from which one
can infer attenuation21 without requiring a CT scan, and
can also record motion.22 With the advancement in deep
learning it is conceivable that, in the future, CNN might
be used to prescribe count levels during a brief time of
high counts and thus maintain accurate high counts
during the other time of the scan when the count level
does not saturate the camera. Thus, both advanced
hardware and algorithms that accurately model physical
effects of the image detection process are key for the
estimation of accurate parametric images23 of
physiological processes that provide clinical parameters of
MBF, CFR, synaptic neuronal uptake and wash-out, and
metabolic rates from dynamic data.
Radionuclide myocardial perfusion imaging (MPI)
is the most established cardiovascular imaging technique
with significant clinical benefits including diagnosing
the presence and extent of coronary artery disease
(CAD), estimating functional importance of
hemodynamically significant epicardial disease, and improving
risk stratification of patients.24 MPI PET tracers that are
FDA approved and reimbursable are limited to the
generator produced 82Rb (75 seconds) and cyclotron
produced 13NH3 (9.96 minutes). H215O (122 seconds) is
the ideal perfusion tracer but its fast decay makes it
difficult to handle in routine clinical operations and its
poor contrast is not ideal for lesion detection. 18F-tagged
agents (110 minutes) would be preferred due to
advantages of better positron range than 82Rb and not
requiring a cyclotron on site. The 18F-labeled Flurpiridaz
is currently in clinical trials, is an inhibitor of
mitochondrial complex I (MC-I), has a high first-pass
extraction with slow wash out, has demonstrated an
excellent relationship to flow in animal models, and has
shown good diagnostic accuracy for the detection of
CAD in humans.25 We found in animal studies that
18Ffluorodihydrorotenol (18FDHROL), an analog of
rotenone, which also targets MC-I, provided better contrast
than 13NH3 (Figure 2). We also found that the wash-in
rate constant of 18FDHROL in the hypertensive
spontaneous hypertensive rat (SHR) was higher throughout
its life than the normotensive WKY,26 likely due to
increased oxygen needs of the hypertrophied myocytes
where enlarged muscle fibers increase diffusion
distances making it far less efficient.27
PET is ideal for researching and diagnosing the
autonomic nervous system because of the ability to
image the numerous 11C-tagged pre- and post-synaptic
radiotracers, developed over the last 25 years, capable of
distinguishing subcellular catecholamine dysfunction
from complete denervation of cardiac sympathetic and
parasympathetic innervation.28,29 The FDA has
approved the SPECT tracer 123I-MIBG for evaluation of
those patients with Class II-III congestive heart failure
(CHF) and LVEF\35%.30 MIBG is an analog of the
false neurotransmitter guanethidine taken up by
adrenergic neurons of the cardiac sympathetic nervous
system, similar to norepinephrine and allows a unique
characterization of alterations in cardiac regional
sympathetic nerve function. Using 123I-MIBG and 201Tl with
dynamic pinhole SPECT, we found in our study of the
spontaneous hypertensive rat (SHR) that the abnormal
nervous system activity in hypertrophic cardiomyopathy
appears earlier than perfusion31 and may be indicative of
a failing heart in late stages of heart failure (HF).
Comparable results using the analogous PET agent
11Cmeta-hydroxyephedrine (11C-HED) have been reported,
where PET imaging in HF patients with preserved
ejection fraction (HFpEF) has been able to predict lethal
arrhythmias, sudden cardiac death, response to cardiac
resynchronization therapy, and relate severity of
diastolic dysfunction to impaired cardiac sympathetic
nervous system innervation.28,29 The longer half-life
tracers, such as 18F-LMI1195, has similar tracer kinetics
to 123I-MIBG and would be a preferred PET radiotracer
to image the autonomic nervous system.32 The use of
PET to image the cardiac parasympathetic nervous
system radiotracers is limited; however, 11C-donepezil a
reversible antagonist of acetylcholine, has shown
potential efficacy in initial studies.29
Dynamic PET imaging of glucose metabolism, fatty
acid metabolism, and oxygen utilization provides
information about metabolic shifts related to function,33
making PET an outstanding tool in conjunction with
MRI for measuring cardiac efficiency.34 The three main
metabolic substrates of the heart are carbohydrates, fatty
acids, and ketone bodies with exogenous fatty acids
accounting for 60%-70% of the energy production in the
normal heart.35 In health, the myocardium increases
fatty acid metabolism with an acute reduction in
mechanical function,36 but conversely acute reduction in
myocardial fatty acid metabolism in cardiomyopathy is
also associated with impaired function.37 In the case of
pressure overload, we found in studies using the SHR an
increased reliance on carbohydrate oxidation in an
attempt to maintain contractile function with a decline in
fatty acid and oxygen utilization.26 Additionally, in
PET/MRI studies of the normal Lewis rat, we found that
glucose metabolic rate was inversely proportional to
tissue work38 indicating that a more efficient metabolic
substrate such as fatty acid would more likely be
proportional to increased work. These results are exciting
and provide an impetuous to study cardiac efficiency in
relation to glucose and fatty acid metabolism in health
and disease. Using PET/MRI one can measure
myocardial efficiency on a tissue-by-tissue region of
interest by calculating the ratio of external cardiac
tissue work using MRI to oxygen utilization using PET
measures of 11C-acetate kinetics as a surrogate for
energy input.34 Work (work = force 9 distance) is
obtained by MRI measures of distance (strain) and force
(stress), inferred from the inclusion of intraventricular
pressure measurements in a finite element (FE)
electromechanical cardiac model.
Dynamic cardiac PET will make significant inroads
in the future in the management of patients with cardiac
disease. PET is ideal for performing perfusion,
innervation, and metabolic studies. The combination of using
PET to study metabolism with MRI to study work
allows one to study the efficiency of the heart in disease.
With the progress made over the last 40 years, it is
conceivable that a TOF timing can reach 10 ps. A
detector that does not require light energy conversion
would go a long way to achieving this goal. Algorithm
developments will continue that correct for attenuation
and motion using only TOF information. The reduction
in dose will go hand in hand with the improvement in
PET technology. For dynamic cardiac PET, it is
important to ensure accuracy of the reconstructed data
particularly during the high activity period of the blood
input phase. The dead time correction and the threshold
activity that paralyzes the detector electronics should be
verified and measured by the user, preferably also
provided by the vendor. Finally, every cardiac PET study
should be performed dynamically, even if only a static
result is all that is needed; nothing is lost and much can
be gained by performing the study dynamically.
The authors declare that there is no conflict of interest to
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