Reporting myocardial flow reserve with PET. Ready or not, here it is! But walk before you fly!
Reporting myocardial flow reserve with PET. Ready or not, here it is! But walk before you fly!
Daniel Juneau 0 2
Robert A. deKemp 0 1
Rob S. B. Beanlands 0
0 Reprint requests: Rob S. B. Beanlands, MD, Division of Cardiology, Department of Medicine, National Cardiac PET Centre, University of Ottawa Heart Institute , 40 Ruskin Street, Ottawa, ON K1Y 4W7 , Canada
1 Division of Cardiology, Department of Medicine, National Cardiac PET Centre, University of Ottawa Heart Institute , Ottawa, ON , Canada
2 Nuclear Medicine, Centre Hospitalier de l'Universite ́ de Montre ́al (CHUM) , Montreal , Canada
Relative perfusion images have been the mainstay
of myocardial perfusion imaging (MPI) for more than 30
years. While positron emission tomography (PET)
tracers for cardiac imaging have been available for more
than 4 decades, cardiac PET was mostly a research tool
until the last decade, when the expansion of PET
oncological imaging saw a significant improvement in
the clinical availability of this technology. Advances in
acquisition technology have also enabled the
simultaneous measurement of relative perfusion and absolute
flow. Amongst its many advantages over single-photon
emission computed tomography (SPECT) MPI, PET
permits routine, accurate, and reproducible non-invasive
measurement of myocardial blood flow (MBF), in
absolute units (mL/min/g of myocardium), which can be
measured at rest and peak stress, and from which
myocardial flow reserve (MFR; the ratio of stress MBF
divided by rest MBF) can be calculated. Both stress
MBF and MFR have since demonstrated their diagnostic
and prognostic capacity in multiple settings and
populations. They have become firmly established as reliable
clinical research tools. In this issue of the Journal of
Nuclear Cardiology, the question of whether or not these
tools and metrics are ready for prime-time use as an
integral part of clinical reporting is debated. Opposing
views are presented, with M. Di Carli1 defending the
‘‘pro’’ position and H. Schelbert2 defending the ‘‘con’’
Di Carli presents 2 main arguments for the added
value of MBF and MFR in routine clinical reporting: an
increased accuracy for the detection of obstructive
coronary artery disease (CAD) and better prognostic
information for risk stratification. Increased accuracy is
achieved mainly because absolute quantification helps
overcome two of the most important shortcomings of
conventional relative MPI; it increases the ability to
detect multivessel disease, which can sometimes present
with a so-called ‘‘balanced ischemia’’ pattern3,4, and it
enables the detection of non-obstructive atherosclerosis
(epicardial lesions of less than 50%), which cannot be
assessed using relative MPI alone, but still carries an
increased risk of cardiac events.5-7 Regarding the
prognostic value of MBF and MFR, Di Carli presents the
available evidence, which clearly demonstrates that
MFR and stress MBF are both powerful prognostic
tools, with incremental and independent information
from relative MPI findings.6,7 He does acknowledge the
limitations, including the lack of a true absolute ‘‘one
size fits all’’ cut-off value for normalcy, for either stress
MBF or MFR, and the existence of clinical conditions
which can limit the accuracy or usefulness of these
Arguing the ‘‘con’’ position, Schelbert first raises
the issue of the appropriateness criteria. He, rightfully,
points out that there is a dearth of data regarding the
ability of MBF and MFR to influence clinical decision
making, and whether cardiac risk re-classification using
these metrics has a significant impact on pretest
diagnostic and therapeutic decisions. Schelbert points out the
complexity of the many autoregulatory forces and
factors which impact the vasodilatator capacity and
response. He discusses how this complexity likely plays
a part in the variability of MBF measurements, and the
variability of MFR in ‘‘normal’’ individuals. He also
raises concerns over the importance of reviewing the
technical aspects of flow measurement, and the
possibility of drug-related antagonistic effects such as
caffeine. He suggests that further work will be required
to better harmonize and define what constitutes a normal
or an abnormal flow response. He then concludes by
saying that while MBF and MFR measurements can
significantly contribute to the diagnosis and
management of CAD, further data are required before they can
be fully incorporated in the reporting of PET MPI.
Interestingly, both authors cite many of the same
publications. There is no dispute regarding the data
itself, which clearly supports the diagnostic and
prognostic value of stress MBF and MFR. Rather, the debate
is how the nuclear cardiology community should
proceed at this time with MBF and MFR as a clinical tool.
The contentious areas mostly concern the technical
aspects of MBF and MFR measurement, the definition
of normalcy, and the appropriateness/added value of
these metrics in clinical decision making.
Regarding the technical aspects, several studies
have shown good test–retest repeatability of stress MBF
and MFR measurements (day-to-day coefficient of
variation (CoV) = 20%) and reproducibility among
laboratories (\10% CoV when using similar
methods).8-12 Recently, Kitkungvan et al and Klein et al
demonstrated very good methodological repeatability
(\10% CoV) over short time intervals between
scans.11-13 Studies have also shown, for both
13N-ammonia and 82Rb, the two most commonly used PET
perfusion tracers, that MFR values exhibit an excellent
correlation between different software packages when
the same compartment model is used14-16 although the
coefficients of variation are higher for absolute flow
measurements compared to relative perfusion imaging
because of added biological variability.12
Schelbert also mentions the possibility of falsely
abnormal (impaired) MFR due to antagonistic effect on
the vasodilatator effect from drugs or
caffeine-containing products. While this is indeed a possibility, this is
not an argument against the use of MFR in routine
clinical work, but rather an argument for it. For example,
if a patient who had not undergone caffeine withdrawal
as instructed was to undergo relative MPI, the study
might be falsely interpreted as normal, while the same
patient undergoing MBF and MFR measurement would
likely demonstrate an absence of MBF change between
rest and stress studies. An experienced imager would
recognize that a patient with non-responsiveness to
pharmacological stress does not demonstrate the features
expected with severe multivessel CAD. Global and
regional flows are at or near 1.0, with homogeneous
rather than heterogeneous MFR; uptake similar to rest
and no new defects; little or no hemodynamic changes;
and no high-risk response features (e.g., ECG changes,
stress-induced perfusion defects, wall motion
abnormalities, TID, RV uptake).17,18 In addition to RPP
changes, a splenic ‘‘switch-off’’ response can also be
seen as an indicator of adequate vasodilator stress, i.e.,
reduced tracer uptake in the spleen due to the differential
effects of adenosine on the spleen (seen with
dipyridamole or adenosine but not regadenoson).19 With
relative MPI only, it is not possible to determine
nonresponsiveness which would otherwise contribute to a
false-negative study if disease were missed. When
nonresponsiveness is identified on quantitative PET flow
studies, a repeat test with prolonged caffeine abstinence
(e.g., 72 hours) or with an alternate pharmacologic stress
agent such as dobutamine would be recommended.
The lack of a clearly defined cut-off value for
normalcy can be problematic. In nuclear cardiology, we pride
ourselves in making such definitive distinctions between
normal and abnormal. With the wide range of
physiological flow values and their significant variance,11,12 as
well as effects of age, sex, resting hemodynamics, and risk
factors, for example, a standard normal value becomes
harder to define and may be different for different
populations. However, this may be less important at the
extreme values. As noted by both Schelbert and Di
Carli,1,2 a MFR value of\1.5, either in a single territory or
in multiple territories, has been strongly associated with
obstructive CAD and cardiac events, while a globally
‘‘normal’’ stress MBF and MFR[2.0 suggest an excellent
prognosis even in patients with known CAD.4,6,7 Since a
patient with single-vessel CAD may still have global MFR
[2.0, caution is needed in reporting flow data in these
circumstances. It is important for the imager and the
referring physician to understand that abnormal relative
perfusion may account for a symptomatic obstructive
lesion and still have normal global flow reserve. When
reporting flow data in these circumstances, the imager
should qualify the flow data interpretation and mention
the regional heterogeneity or consider not reporting it to
avoid what may appear to be a conflicting message. There
is a need for standardization of reporting and perhaps the
development of new nomenclature whereby a global flow
reserve value of [2.0 is not defined as ‘‘normal’’ but
Further, it is extremely important that these metrics
not be considered as independent; they are part of a
complete assessment of coronary physiology—the full
PET MPI study which includes everything from the
patient’s pretest probability and risk factors, the stress
ECG, the relative MPI findings (uptake defects, transient
ischemic dilatation), LV function, and the CTAC
calcium findings. Stress MBF and MFR measurements do
not replace or override these findings; they complement
and enhance them.
Finally, the information required to obtain and
measure MBF and MFR is, in a sense, ‘‘free’’ when
acquired during pharmacologic stress and using PET
instrumentation that is capable of accurate first-pass
imaging.20 MBF quantification does not require any
Flow data should be considered in conjunction with
• History, ECG, calcium, perfusion, LV size and function, RV uptake, TID
Interpreting physicians and PET center teams and their physicians should have
• Significant experience and knowledge of flow quantification, its strengths and limitations
• Thorough understanding of the quality controls and assurance involved
Interpreting physicians should
• Recognize the limitations and cautionary conditions, such as patients with
– Prior coronary artery bypass surgery
– Severe renal dysfunction
– Moderate to severe LV dysfunction
– Large regions of myocardial scar
• Recognize non-responsiveness to pharmacological stress
• Keep the referring physicians in mind and
– Be aware of their knowledge and understanding of the value and limitations of flow measurements
– Understand what question they are asking and how flow measurements can or cannot help
• Remember that they may benefit from direct correspondence in complex cases
additional patient procedure and does not expose the
patient to additional risk or radiation. In the same way,
LV function and wall motion became possible using
ECG-gated SPECT, adding important prognostic
information to the whole report; so too will flow data provide
additional valuable information to PET MPI. This
information, if taken in proper context, enhances
accuracy and prognostic value which should impact
decisions for angiography, and help direct interventional
vs. medical therapy.
As noted by our debaters, there is a paucity of data
on the impact of MFR on clinical decision making,
downstream diagnostic testing, and treatment. Whether
such clinical decisions impact outcome also depends on
the effectiveness of the therapy chosen.21 Ideally,
randomized controlled trials of strategies using PET flow
data versus standard-of-care would provide definitive
answers. However, such trial design is extremely
difficult to implement and, as noted, depends on the
effectiveness of the therapy selected. In the meantime,
reclassifying patients using MFR (as demonstrated by
Murthy et al7) provides high clinical utility in defining
risk, which in itself should direct the clinician to more or
less aggressive interventions and management
strategies. Finally, there are higher risk interventions (PCI and
CABG) for obstructive disease, necessitating an
important decision point where imaging has demonstrated a
crucial role. Indeed, functional measurements of flow,
such as fractional flow reserve (FFR)-directed therapy,
have had impact on outcomes (albeit FFR is an invasive
measurement).22 On the other hand, defining
non-obstructive disease, while useful, currently has no specific
interventional or medical therapy recommendations
associated with it, short of risk factor modification.
Evidence is rapidly emerging on the importance of
microvascular disease in the development and progress
of atherosclerosis including sex differences, heart failure
with preserved ejection fraction, and transplant
vasculopathy.23 As greater understanding of these disease
states emerges, novel therapies may be forthcoming, in
which case flow quantification with non-invasive PET
imaging will be at the focal point of decision making.
Our debaters also note the need for the development
of criteria for quality control, interpretation, and
reporting. There are recent guidelines and position
statements that will help in this regard,18 but there is still
work to be done to enable measurements that are fully
interchangeable between sites. So, are PET flow data
ready or not for clinical use? Ready to walk, yes, but not
to run. The first steps are the most important and need to
occur carefully so PET flow ‘does not stumble.’ Clinical
interpretation needs to be performed under the right
conditions (Table 1). At this time, reporting should be
confined to experienced centers, where the combination
of both experienced and educated imagers and referring
physicians can be achieved. Part of this education is
incumbent to the interpreting physician who will likely
need to keep in mind the degree of familiarity of the
referring physician and adjust the level of details and
guidance in the report accordingly. A simple numerical
cut-off value might well be enough in an experienced
reference center, when dealing with a physician or team
who are accustomed to using these metrics, but more
detailed information/guidance will need to be provided
by the interpreting physician when interacting with a
less experienced team. As more and more physicians
and centers embrace the possibilities afforded by flow
data, our knowledge will continue to grow, and the
capacity for better ‘‘harmonization’’ of reporting and
interpretation will increase. Recent advances in blood
flow quantification using SPECT24-26 may greatly
increase access to flow measurements, which would
further accelerate clinical integration. Currently,
however, there are far less data available on SPECT than
PET quantification, and this technology remains purely a
research tool at this time.
In conclusion, PET MBF and MFR measurements
provide useful data that enhance both accuracy and risk
stratification for PET MPI. Evaluation of flow data and
its reporting in clinical practice should consider the
specific incremental information to assist with clinical
decision making; explain the relevance of any added
information; and recognize cautionary situations
including non-responders and certain clinical scenarios
(Table 1). Keys to successful implementation and
getting the most out of adding flow data to a reporting
strategy include the experience of the imaging team as
well as the knowledge and understanding of referring
physicians. However, research must continue. We need
to understand the full clinical value of flow
quantification; for example, the role and potential treatments of
microvascular disease and, even more importantly, the
role of flow measures in selecting and monitoring
revascularization therapies and indeed the impact of
these therapy decisions on cardiac outcomes. As
demonstrated successfully for FFR measurements of
hemodynamic significance22,27 and FDG PET viability
imaging,28 quantitative measurements will become
essential in clinical reports when they can be used
reliably to make concrete recommendations for effective
treatments which have been shown to improve patient
outcome. So PET MBF/MFR reporting is ready to
‘walk.’ With further research, clinical PET flow
reporting will be able to accelerate its pace to ‘run’ and
who knows, may one day ‘fly’!
DJ. has no disclosures related to this work. R.S.B.B. is or
has been a consultant for and received grant funding from
Lantheus Medical Imaging, GE, and Jubilant DraxImage.
R.A.dK is a consultant for Jubilant DraxImage and receives
technology license revenues from Jubilant DraxImage and
INVIA Medical Imaging Solutions.
1. Di Carli MF. Measurement of MBF by PET is ready for prime time as an integral part of clinical reports in diagnosis and risk assessment of patients with known or suspected CAD-PRO . J Nucl Cardiol . 2017 . https://doi.org/10.1007/s12350-017-1035-4.
2. Schelbert H . Measurement of MBF by PET is ready for prime time as an integral part of clinical reports in diagnosis and risk assessment of patients with known or suspected CAD For prime time not yet-need impact and certainty . J Nucl Cardiol . 2017 . https://doi.org/10.1007/s12350-016-0423-5.
3. Parkash R , deKemp RA , Ruddy TD , Kitsikis A , Hart R , Beauchesne L , Beauschene L , Williams K , Davies RA , Labinaz M , Beanlands RSB . Potential utility of rubidium 82 PET quantification in patients with 3-vessel coronary artery disease . J Nucl Cardiol Off Publ Am Soc Nucl Cardiol . 2004 ; 11 : 440 - 9 .
4. Ziadi MC , Dekemp RA , Williams K , Guo A , Renaud JM , Chow BJW , Klein R , Ruddy TD , Aung M , Garrard L , Beanlands RSB . Does quantification of myocardial flow reserve using rubidium-82 positron emission tomography facilitate detection of multivessel coronary artery disease ? J Nucl Cardiol Off Publ Am Soc Nucl Cardiol . 2012 ; 19 : 670 - 80 .
5. Taqueti VR , Hachamovitch R , Murthy VL , Naya M , Foster CR , Hainer J , Dorbala S , Blankstein R , Di Carli MF. Global coronary flow reserve is associated with adverse cardiovascular events independently of luminal angiographic severity and modifies the effect of early revascularization . Circulation . 2015 ; 131 : 19 - 27 .
6. Ziadi MC , Dekemp RA , Williams KA , Guo A , Chow BJW , Renaud JM , Ruddy TD , Sarveswaran N , Tee RE , Beanlands RSB . Impaired myocardial flow reserve on rubidium-82 positron emission tomography imaging predicts adverse outcomes in patients assessed for myocardial ischemia . J Am Coll Cardiol . 2011 ; 58 : 740 - 8 .
7. Murthy VL , Naya M , Foster CR , Hainer J , Gaber M , Di Carli G , Blankstein R , Dorbala S , Sitek A , Pencina MJ , Di Carli MF . Improved cardiac risk assessment with noninvasive measures of coronary flow reserve . Circulation . 2011 ; 124 : 2215 - 24 .
8. Klein R , Renaud JM , Ziadi MC , Thorn SL , Adler A , Beanlands RS , deKemp RA . Intra- and inter-operator repeatability of myocardial blood flow and myocardial flow reserve measurements using rubidium-82 pet and a highly automated analysis program . J Nucl Cardiol Off Publ Am Soc Nucl Cardiol . 2010 ; 17 : 600 - 16 .
9. El Fakhri G , Kardan A , Sitek A , Dorbala S , Abi-Hatem N , Lahoud Y , Fischman A , Coughlan M , Yasuda T , Di Carli MF. Reproducibility and accuracy of quantitative myocardial blood flow assessment with (82 ) Rb PET : Comparison with (13)N-ammonia PET . J Nucl Med Off Publ Soc Nucl Med . 2009 ; 50 : 1062 - 71 .
10. Schindler TH , Zhang X-L , Prior JO , Cadenas J , Dahlbom M , Sayre J , Schelbert HR . Assessment of intra- and interobserver reproducibility of rest and cold pressor test-stimulated myocardial blood flow with (13)N-ammonia and PET . Eur J Nucl Med Mol Imaging . 2007 ; 34 : 1178 - 88 .
11. Kitkungvan D , Johnson NP , Roby AE , Patel MB , Kirkeeide R , Gould KL . Routine clinical quantitative rest stress myocardial perfusion for managing coronary artery disease: Clinical relevance of test-retest variability . JACC Cardiovasc Imaging . 2017 ; 10 : 565 - 77 .
12. Beanlands RSB , Chong A -Y, deKemp RA. Clinical PET flow reserve imaging: Is there precision to treat patients or populations? JACC Cardiovasc Imaging . 2017 ; 10 : 578 - 81 .
13. Klein R , Ocneanu A , Renaud JM , Ziadi MC , Beanlands RSB , deKemp RA . Consistent tracer administration profile improves test-retest repeatability of myocardial blood flow quantification with (82)Rb dynamic PET imaging . J Nucl Cardiol Off Publ Am Soc Nucl Cardiol . 2016 . https://doi.org/10.1007/s12350- 016-0698-6.
14. Nesterov SV , Deshayes E , Sciagra` R, Settimo L , Declerck JM , Pan X-B , Yoshinaga K , Katoh C , Slomka PJ , Germano G , Han C , Aalto V , Alessio AM , Ficaro EP , Lee BC , Nekolla SG , Gwet KL , deKemp RA , Klein R , Dickson J , Case JA , Bateman T , Prior JO , Knuuti JM . Quantification of myocardial blood flow in absolute terms using (82)Rb PET imaging: The RUBY-10 Study. JACC Cardiovasc Imaging . 2014 ; 7 : 1119 - 27 .
15. Slomka PJ , Alexanderson E , Ja´come R , Jime´nez M, Romero E , Meave A , Le Meunier L , Dalhbom M , Berman DS , Germano G , Schelbert H . Comparison of clinical tools for measurements of regional stress and rest myocardial blood flow assessed with 13Nammonia PET/CT . J Nucl Med Off Publ Soc Nucl Med . 2012 ; 53 : 171 - 81 .
16. Dekemp RA , Declerck J , Klein R , Pan X-B , Nakazato R , Tonge C , Arumugam P , Berman DS , Germano G , Beanlands RS , Slomka PJ . Multisoftware reproducibility study of stress and rest myocardial blood flow assessed with 3D dynamic PET/CT and a 1-tissuecompartment model of 82Rb kinetics . J Nucl Med Off Publ Soc Nucl Med . 2013 ; 54 : 571 - 7 .
17. Juneau D , Erthal F , Ohira H , Mc Ardle B , Hessian R , deKemp RA , Beanlands RSB . Clinical PET myocardial perfusion imaging and flow quantification . Cardiol Clin . 2016 ; 34 : 69 - 85 .
18. Dilsizian V , Bacharach SL , Beanlands RS , Bergmann SR , Delbeke D , Dorbala S , Gropler RJ , Knuuti J , Schelbert HR , Travin MI . ASNC imaging guidelines/SNMMI procedure standard for positron emission tomography (PET) nuclear cardiology procedures . J Nucl Cardiol Off Publ Am Soc Nucl Cardiol . 2016 ; 23 : 1187 - 226 .
19. Bami K , Tewari S , Guirguis F , Garrard L , Guo A , Ruddy TD , Beanlands RS , deKemp RA , Chow BJ , Dwivedi G . Prognostic value of splenic response ratio in rubidium-82 positron emission tomography myocardial perfusion imaging . Circulation . 2016 ; 134 : A17358 - A17358 .
20. Renaud JM , Yip K , Guimond J , Trottier M , Pibarot P , Turcotte E , Maguire C , Lalonde L , Gulenchyn K , Farncombe T , Wisenberg G , Moody J , Lee B , Port SC , Turkington TG , Beanlands RS , deKemp RA . Characterization of 3-dimensional PET systems for accurate quantification of myocardial blood flow . J Nucl Med Off Publ Soc Nucl Med . 2017 ; 58 : 103 - 9 .
21. Mc Ardle B , Shukla T , Nichol G , deKemp RA , Bernick J , Guo A , et al. Long-term follow-up of outcomes with F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction secondary to coronary disease . Circ Cardiovasc Imaging . 2016 ; 9 : e004331 .
22. Tonino PAL , De Bruyne B , Pijls NHJ , Siebert U , Ikeno F , van't Veer M , Klauss V , Manoharan G , Engstrøm T , Oldroyd KG , Ver Lee PN , MacCarthy PA , Fearon WF . Fractional flow reserve versus angiography for guiding percutaneous coronary intervention . N Engl J Med . 2009 ; 360 : 213 - 24 .
23. Taqueti VR , Shaw LJ , Cook NR , Murthy VL , Shah NR , Foster CR , Hainer J , Blankstein R , Dorbala S , Di Carli MF. Excess cardiovascular risk in women relative to men referred for coronary angiography is associated with severely impaired coronary flow reserve, not obstructive disease . Circulation . 2017 ; 135 : 566 - 77 .
24. Wells RG , Marvin B , Poirier M , Renaud JM , deKemp RA , Ruddy TD . Optimization of SPECT measurement of myocardial blood flow with corrections for attenuation, motion, and blood-binding compared to PET . J Nucl Med Off Publ Soc Nucl Med . 2017 . https://doi.org/10.2967/jnumed.117.191049.
25. Klein R , Hung G-U , Wu T-C , Huang W-S , Li D , deKemp RA , Hsu B . Feasibility and operator variability of myocardial blood flow and reserve measurements with 99mTc-sestamibi quantitative dynamic SPECT/CT imaging . J Nucl Cardiol Off Publ Am Soc Nucl Cardiol . 2014 ; 21 : 1075 - 88 .
26. Shrestha U , Sciammarella M , Alhassen F , Yeghiazarians Y , Ellin J , Verdin E , Boyle A , Seo Y , Botvinick EH , Gullberg GT . Measurement of absolute myocardial blood flow in humans using dynamic cardiac SPECT and 99mTc-tetrofosmin: Method and validation . J Nucl Cardiol Off Publ Am Soc Nucl Cardiol . 2017 ; 24 : 268 - 77 .
27. De Bruyne B , Pijls NHJ , Kalesan B , Barbato E , Tonino PAL , Piroth Z , Jagic N , Mo¨ bius-Winkler S , Rioufol G , Witt N , Kala P , MacCarthy P , Engstro¨m T , Oldroyd KG , Mavromatis K , Manoharan G , Verlee P , Frobert O , Curzen N , Johnson JB , Ju¨ni P, Fearon WF . Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease . N Engl J Med . 2012 ; 367 : 991 - 1001 .
28. Abraham A , Nichol G , Williams KA , Guo A , deKemp RA , Garrard L , et al. 18F-FDG PET imaging of myocardial viability in an experienced center with access to 18F-FDG and integration with clinical management teams: The Ottawa-FIVE substudy of the PARR 2 trial . J Nucl Med Off Publ Soc Nucl Med . 2010 ; 51 : 567 - 74 .