Optimizing quantitative myocardial perfusion by positron emission tomography for guiding CAD management
Optimizing quantitative myocardial perfusion by positron emission tomography for guiding CAD management
K. Lance Gould 0
0 Center for Preventing and Reversing Atherosclerosis; and is the 510(k) applicant for CFR Quant (K113754) and HeartSee (K143664), software packages for cardiac positron emission tomography image processing and analysis, including absolute flow quantification. Reprint requests: K. Lance Gould, MD, Weatherhead PET Center for Preventing and Reversing Atherosclerosis, McGovern Medical School, University of Texas Health Science Center at Houston , 6431 Fannin St., Room MSB 4.256, Houston, TX, 77030, J Nucl Cardiol 1071-3581/ $34.00 Copyright 2016 American Society of Nuclear Cardiology , USA
1 Weatherhead PET Center for Preventing and Reversing Atherosclerosis, McGovern Medical School, University of Texas Health Science Center at Houston , Houston, TX , USA
THE CONCLUSIONS The authors conclude that patients undergoing adenosine stress showed a decrease in measured respiratory rate from initial to later scan phase measurements (12.4 ± 5.7 vs 5.6 ± 4.7 per minute, p 0.001) and had a lower frequency of successful respiratory gating compared to dipyridamole (47% vs 71%, p = 0.12). As a result of the varying respiratory pattern with adenosine, the adenosine imaging quality was inferior to dipyridamole, although dipyridamole respiratory gating still remained unsatisfactory in 29% of dipyridamole cases. If respiratory gating is considered for use in cardiac PET, the authors recommend dipyridamole stress due to its more uniform respiration pattern than adenosine with resulting higher frequency of successful respiratory gating that, however, still remains unsatisfactory in 29% of dipyridamole cases.
WHAT DOES THE REPORT TELL US?
In the current issue, Lassen et al.1 studied the effect of
respiratory gating on myocardial stress perfusion imaging
using positron emission tomography with Rb-82 in 48
patients randomized to adenosine or dipyridamole stress.
The dipyridamole group consisted of non-smoking
women without a family history of cardiovascular disease
and with a mean age of 64 years. The adenosine group
consisted primarily of men (86%) at a mean age of
57 years of whom 39% were current smokers and 48%
had a family history of cardiovascular disease.
The time-based respiratory gating method divides the
respiratory signal into 8 time-equal bins determined by
either the inspiratory or the expiratory peak. The
timebased binning is based on the assumption of a steady,
nonchanging respiratory rate and depth throughout the PET
acquisition often characterizing resting conditions, but
not during stress image acquisition since pharmacologic
stress agents differentially alter the respiratory pattern.
This carefully done study is practically important as
an essentially ‘‘negative’’ by showing definitively that
respiratory gating of PET perfusion images is not useful,
and may be worse than no respiratory gating due to
physiologic varying respiratory rates particularly during
adenosine stress but also to a significant extent with
dipyridamole stress. Thus, the most important
observation is physiology, the variable respiratory patterns after
adenosine with 53% failed respiratory gating and 29%
failure for dipyridamole. These observations preclude
useful respiratory gating for PET myocardial perfusion
for physiologic reasons unrelated to any systematic PET
data that are not reported.
IS WHAT IS MISSING IMPORTANT?
In addition to the systematic physiologic data, the single figure of PET images with successful respiratory
gating shows a substantial difference between the
septal and lateral walls not present on images with no
respiratory gating. This regional discordance of relative
myocardial uptake of Rb-82 on one example raises the
question of whether even ‘‘successful’’ respiratory
gating causes artifacts as reported for misregistration of
emission and CT transmission data for attenuation
correction. While the physiologic observations on
respiratory variation during vasodilator stress are
definitive, its negative finding might be even stonger
by quantifying the differences in relative myocardial
uptake, in absolute myocardial perfusion or CFR with
and without respiratory gating since the study was done
with PET imaging. On the other hand, the physiologic
observation is so definitive that quantitative PET data
might be superfluous.
While not likely to change the conclusion, the
patient selection for adenosine versus dipyridamole
stress is a curious bias at odds with the meticulous,
objective methodology and data on respiratory
variability. No explanation is provided for using dipyridamole
in women and primarily adenosine in men. This striking
difference is not likely random but appears to reflect
some guidelines or practice pattern for the author’s PET
protocols that are not reported. However, again the
definitive physiologic data make this odd selection of
subjects of little import.
OTHER OBSERVATIONS ON METHODOLOGY OF
Other methodology variations needing mention are
the vasodilator stress protocols. Adenosine is infused
for 6 min but with imaging starting at 2.5 min rather
than the 3 min that is the official protocol
recommended by the ASNC/ACC/AHA procedure
guidelines.2 This earlier 30 s start of imaging may be due to
the time required for infusion of Rb-82. However, the
methods statement is that Imaging was started at
2.5 min, thereby implying that the Rb-82 infusion
would have been started at 2 min in order to image
myocardial uptake at 2.5 min, a detail that is not made
clear. This timing might alter the conclusions, if the
last 3 min of a 6 min adenosine infusion during the
standard time of radionuclide uptake had less
respiratory variation than the first 3 min.
In a parallel variation, the dipyridamole protocol
used the standard dose of 0.56 mg/k, but was given as a
‘‘slow bolus’’ with imaging at 6 min in contrast to the
standard infusion over 4 min with imaging at 8 min.2
However, these small details are not likely to change the
CLINICAL MYOCARDIAL PERFUSION PET FOR
GUIDING MANAGEMENT AND PROCEDURES IN CAD
The authors definitively address a specific, highly
focused question on the usefulness of cardiac PET—
respiratory gating. While accepting that focus as good
scientific design for getting a definitive answer in this
paper, that highly specific focus leaves open the broader
issue of optimal PET methodology for quantifying stress
flow and Coronary Flow Reserve as definitive guides to
managing coronary artery disease (CAD).
Physiologic severity of coronary artery stenosis by
invasive pressure-derived Fractional Flow Reserve
(FFR) is the current ‘‘gold standard’’ for guiding
PCI.3,4 However, FFR is only a relative flow reserve
measurement that was originally validated by
comparison to absolute stress perfusion and Coronary Flow
Reserve by PET.5 Accordingly, in the spirit of this
meticulous, focused, critical study on respiratory-gated
cardiac PET, this editorial provides a perspective on six
broad principles for optimal technical quantitative PET
perfusion imaging as the technical basis for optimally
guiding management and procedures in CAD.
The first common error in myocardial perfusion PET
is emission–attenuation misregistration due to cardiac and
respiratory motion that cause significant quantified
artifactual perfusion defects in 20% or more of PET-CT
scans.6–9 In addition to respiratory variation, cardiac
motion includes systolic–diastolic wall thickening that
alters partial volume loss and translation of the heart
recoiling downward and medially toward the
mediastinum during systole.6–9 Consequently, ECG-gated
systolic images have significantly higher activity recovery
than diastolic images, thereby allowing better partial
volume correction for PET10 and a greater than 50%
reduction of false positives on SPECT scans.11
ECGgated perfusion images also provide accurate measures of
ejection fraction. However, routinely checking and
correcting attenuation–emission co-registration on every
PET scan is not routinely done in many PET facilities.
ARTERIAL ACTIVITY INPUT FUNCTION FOR
Second, the selection of the ROI for arterial input to
determine absolute perfusion in cc/min/gm and
Coronary Flow Reserve is perhaps the most critical and most
neglected of all the technical elements of quantitative
myocardial perfusion12,13 for several reasons. No one
fixed ROI is optimal for all patients. Arterial input ROIs
located on late myocardial images back projected onto
early first-pass images are commonly not in the left
atrium during significant portions of the heart cycle due
to heart and respiratory motion. Spillover activity from
adjacent subclavian veins and pulmonary artery
branches frequently contaminates ROIs back projected
from late myocardial images due to imprecise location
over the left atrium.
Multiple, short, brief (15 s) first-pass arterial input
images are so noisy with poor count density that ROIs
cannot be optimally directly located over left atrial or
aortic activity uncontaminated by adjacent subclavian
veins or pulmonary artery branches. Locating ROIs over
the LV gives consistently erroneous arterial input values
due to LV translation into and out of the fixed ROI during
the cardiac cycle and due to spillover from myocardial
activity during late arterial activity acquisition.13
Variable suboptimal ROI selection causes great
variability of quantitative perfusion. Therefore, we use
semi-automated software to locate rapidly 5 to 6 ROIs
directly on high-quality 2-min first-pass images in the
ascending and descending aorta, the high, mid, and low
left atrium, and in the pulmonary artery, and right atrium
to bracket the maximum activity that correct ROIs must
remain below. The highest activity of these alternative
ROIs without contamination by readily identified
subclavian or pulmonary artery branches provide the
optimal ROI and arterial input for each individual
patient with resulting reproducible, clinically reliable
measurements of perfusion and CFR.13
MAXIMUM PHARMACOLOGIC STRESS IS
ESSENTIAL FOR GUIDING CAD INTERVENTIONS
Third, maximum stress is essential since submaximal
stress causes erroneous low stress flow misleadingly
suggesting diffuse or focal low stress flow due to diffuse
disease or focal stenosis. Such ‘‘poor stress’’ images are
essentially false positives since repeat PET with maximal
stress shows high coronary flow capacity. Measurable
blood caffeine is the commonest cause in approximately
4000 quantitative PET studies in the Weatherhead PET
Center such that we measure blood caffeine in all patients
and repeat the study if critical for a clinical decision based
on quantitative perfusion. The standard regadenoson
protocol with radionuclide injection at 10 to 20 s after a
10 s infusion causes stress perfusion that is 20% lower
than maximum stress perfusion by the 4-8 min
dipyridamole or the 3-6 min adenosine protocols.14
Regadenoson, therefore, fails to demonstrate true severity
on relative images and erroneously suggests worse
absolute stress flow capacity and more severe disease than seen
with maximum stress.
2D VERSUS 3D PET-CT SCANNERS
Fourth, widespread 2D PET-CT scanner adequately
acquire the first-pass arterial input of 35 to 40 mCi of
Rb-82 for absolute perfusion in cc/min/gm and CFR.
However, all current 3D PET-CT scanners saturate with
this first-pass arterial concentration of RB-82 such that
only 20 to 25 mCI can be given with resulting count
poor images and suboptimal regional stress flow and
CFR in our experience.15,16 Consistent with our
observation, centers using 3D PET-CT scanners usually report
global stress perfusion and CFR, not regional
quantitative perfusion, but the topic remains debated. Likely still
newer generation of 3D scanners not currently on the
market may improve this first-pass capacity for Rb-82,
while maintaining high-quality late myocardial images
adequate for regional quantitative perfusion. On the
other hand, the dose of N-13 ammonia is low enough at
10 to 20 mCi that virtually all current 3D scanners
measure the first-pass arterial input accurately without
saturating the scanner.
MODELS FOR QUANTITATIVE
Fifth, flow models for calculating absolute
myocardial perfusion are specific for each radionuclide and are
well validated for Rb-82, N-13 ammonia, and
oxygen15. The argument that greater extraction fraction by the
myocardium yields the ‘‘best’’ quantitative perfusion is
nonsense because the flow-dependent extraction or
trapping of each of these radionuclides is accounted
for in the flow model. Each of these radionuclides has
been proven to measure myocardial perfusion
accurately, despite their widely different extraction or
myocardial trapping characteristics.
The advantages of the ‘‘simple’’ or ‘‘retention’’
model of Yoshida et al.17 are high-quality 2-min
firstpass images that provide for direct, robust, optimal
individualized arterial ROI and arterial input function
for individual patients compared to
multi-compartmental models16,17 with resulting ‘‘higher sensitivity for
detection and localization of abnormal flow and
myocardial perfusion reserve…without the computational
complexity and sensitivity to noise—of the
CINE CT VERSUS HELICAL CT FOR
Sixth, a single, seconds-long helical CT image for attenuation correction may not match the average attenuation structures altering the emission image acquired over 5 min for Rb-82 due to respiratory and cardiac
motions. Even shifting seconds-long helical image data to
superimpose them may not be satisfactory in some cases
due to the helical CT scan capturing only on moment
within the cardiac and respiratory cycles. However, cine
CT or its equivalent captures the average attenuation
corrections over several respiratory and cardiac cycles,
thereby matching the emission images.7–9
STANDARDS FOR QUANTITATIVE PET TO GUIDE
While many PET centers do not use the technical
protocols outlined here, this editorial honors and reflects
the careful, objective, focused study on respiratory
gating in this issue; the kind of critical self-examination
of one’s own methods for errors; and suboptimal
performance that leads to improvement, proof of
reproducibility, and relevance to documented ischemia by
angina and ST depression during vasodilator stress.18,19
Figure 1 illustrates quantitative PET that defines
physiologic severity of focal and diffuse disease based on
documented ischemic thresholds of severity.20 The
color-coded severity predicts progressive risk of major
adverse coronary events (MACE) including PCI or
coronary bypass surgery with or separately from death
and myocardial infarction.21 Therefore, as exemplified
in the current report by Lassen et al.,1 we owe to our
patients such compulsive attention to technical and
physiologic details for assessing the physiologic severity
of focal and diffuse CAD to guide management and
procedures. For other centers using other protocols, such
reproducibility and ischemia or outcomes-driven
thresholds are essential as the basis for PET quantitative
perfusion and nuclear cardiology to grow into a future
potentially definitive role for managing CAD.
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2. Handel RC , et al. ACCF/ASNC/ACR/AHA/ASE/SCCT/SCMR/ SNM 2009 appropriate use criteria for cardiac radionuclide imaging: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the American Society of Nuclear Cardiology, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the Society of Cardiovascular Computed Tomography, the Society for Cardiovascular Magnetic Resonance, and the Society of Nuclear Medicine . Circulation . 2009 ; 119 : e561 - 87 .
3. De Bruyne B , Fearon WF , Pijls NH , Barbato E , Tonino P , Piroth Z , Jagic N , Mobius-Winckler S , Rioufol G , Witt N , Kala P , MacCarthy P , Engstro¨m T , Oldroyd K , Mavromatis K , Manoharan G , Verlee P , Frobert O , Curzen N , Johnson JB , Limacher A , Nu¨esch E, Ju¨ni P. FAME 2 trial investigators . Fractional flow reserve-guided PCI for stable coronary artery disease . N Engl J Med . 2014 ; 371 : 1208 - 17 .
4. van Nunen LX , Zimmermann FM , Tonino PA , et al. Fractional flow reserve versus angiography for guidance of PCI in patients with multivessel coronary artery disease (FAME): 5 year follow up of a randomised controlled trial . Lancet . 2015 . doi: 10 .1016/S01406736(15) 000574 .
5. De Bruyne B , Baudhuin T , Melin JA , Pijls NH , Sys SU , Bol A , Paulus WJ , Heyndrickx GR , Wijns W. Coronary flow reserve calculated from pressure measurements in humans. Validation with positron emission tomography . Circulation . 1994 ; 89 : 1013 - 22 .
6. Loghin C , Sdringola S , Gould KL . Common artifacts in PET myocardial perfusion images due to attenuation-emission misregistration: clinical significance, causes and solutions in 1177 patients . J Nucl Med . 2004 ; 45 : 1029 - 39 .
7. Gould KL , Pan T , Loghin C , Johnson N , Guha A , Sdringola S. Frequent diagnostic errors in cardiac PET-CT due to misregistration of ct attenuation and emission PET images: a definitive analysis of causes, consequences and corrections . J Nucl Med . 2007 ; 48 : 1112 - 21 .
8. Gould KL , Pan T , Loghin C , Johnson NP , Sdringola. Reducing radiation dose in rest stress cardiac PET-CT by single post stress cine CT for attenuation correction-quantitative validation . J Nucl Med 2008 ; 49 : 738 - 45 .
9. Johnson NP , Pan T , Gould KL . Shifted helical CT to optimize cardiac PET-CT co-registration: quantitative improvement and limitations . J Mol Imaging . 2010 ; 9 : 256 - 67 .
10. Johnson NP , Gould KL . Partial volume correction incorporating Rb-82 positron range for quantitative myocardial perfusion PET based on systolic-diastolic activity ratios and phantom measurements . J Nucl Cardiol . 2011 ; 18 : 247 - 58 .
11. Kitkungvan D , Vejpongsa P , Korrane KP , Sdrigola SS , Gould KL. Clinical utility of enhanced relative activity recovery on systolic myocardial perfusion SPECT-lessons from PET . J Nucl Med . 2015 ; 56 : 1882 - 8 .
12. Bacharach SL , Carson RE . In hotblood-quantifying the arterial input function . JACC Cardiovasc Imaging . 2013 ; 6 : 569 - 73 .
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21. Taqueti VR , Hachamovitch R , Murthy VL , Naya M , Foster CR , Hainer J , Dorbala S , Blankstein R , Di Carli MF , Global coronary flow reserve associates with adverse cardiovascular events independently of luminal angiographic severity, and modifies. The effect of early revascularization . Circulation . 2015 ; 131 : 19 - 27 .