Medical Policy

This document addresses the use of absolute quantitation of myocardial blood flow (AQMBF), an imaging technique that can be used during various modalities of cardiac imaging including positron emission tomography (PET), cardiac magnetic resonance imaging (CMR), single photon emission computed tomography (SPECT) scan imaging.

Notes:

• This document does not address cardiac imaging services without quantitation. For criteria related to cardiac imaging, refer to applicable documents used by the plan.
• For more information on related topics, please see the following:
  • CG-MED-57 Cardiac Stress Testing with Electrocardiogram
  • MED.00134 Non-invasive Heart Failure and Arrhythmia Management and Monitoring Systems
  • RAD.00068 Myocardial Strain Imaging

Investigational and Not Medically Necessary:

The use of absolute quantitation of myocardial blood flow testing is considered investigational not medically necessary for all indications.

Coronary Artery Disease (CAD)

In a 2022 systematic review and meta-analysis, Kelshiker and associates quantified the association between reduced coronary flow and major adverse cardiovascular events (MACE) and all-cause mortality. A total of 79 studies (n=59740) which incorporated quantitative techniques to evaluate coronary blood flow (invasive and noninvasive) as a prognostic factor for all-cause mortality and/or MACE were reviewed. The meta-analysis included multiple indices of coronary flow measurement including coronary flow reserve (CFR), coronary flow velocity reserve, myocardial blood flow reserve (MBFR), myocardial flow reserve and quantitative myocardial perfusion reserve. Measurements were obtained via echocardiology, PET, CMR or invasively. Hazard ratios (HR) were analyzed for both mortality and MACE. There was significantly increased all-cause mortality and MACE in the presence of abnormal CFR (HR: 3.78, 95% confidence interval [CI], 2.39–5.97; I₂ = 88% and HR: 3.42, 95% CI, 2.92–3.99; I² = 73%; respectively). The findings were consistent among individuals with established cardiovascular pathologies and individuals at risk for vascular disease. Overall heterogeneity was high; the meta-analysis included a heterogeneous population with different disease states and measurement modalities. The meta-analysis was comprised of only observational studies with a high risk of bias. The authors suggest that the findings support that the use of coronary flow assessment could be expanded to individuals with a variety of pathologies. The authors theorize that aggressive risk-factor modification in individuals with abnormal CFR may result in improved clinical outcomes, however they admit that “it has not been proven that improvement in coronary flow is one of the mechanisms by which medical interventions offer benefit to patients”. The meta-analysis does not show that treatment plans would be changed based on the results of quantified myocardial flow results and result in improved clinical outcomes.

The relationship between MBFR obtained via PET imaging and a potential survival benefit following revascularization was examined in 12594 consecutive individuals with suspected or known CAD who underwent myocardial perfusion imaging (MPI). Both all-cause and cardiac mortality were examined. Individuals were followed for a median 3.2 years following imaging. After 3.2 years, approximately 7.1% (n=897) of the individuals underwent early revascularization and 13.5% (n=1699) of the individuals died. An analysis of MBFR and all-cause mortality showed that individuals with an MBFR of less than 1.8 who received early revascularization experienced a survival benefit compared to those who received medical therapy. After adjusting for individual and test characteristics, for every .01 unit decrease in MBFR, there was an associated 9% greater hazard of all-cause death (HR 1.09; 95% CI: 1.08–1.10; p < 0.001). The authors examined the three-way interaction between MBFR, extent of cardiac ischemia and the treatment strategy. The analysis showed that the extent of cardiac ischemia was no longer a prognostic factor when MBFR was placed in the regression model. This finding conflicted with the results of other studies (Giannopoulos, 2020). This observational study did not account for differences in medical therapies in those who did not undergo revascularization, which may have influenced outcomes. The authors recommended that “prospective confirmation of an MBFR based revascularization strategy” is needed.

Juárez-Orozco and colleagues (2018) performed a systematic review to evaluate the prognostic value of quantitative myocardial perfusion imaging with PET using MFR and stress myocardial blood flow (sMBF) indicator for MACE in individuals with suspected or known CAD. A total of eight studies (n=6804) were included. MFR was found to be a significant, independent predictor for MACE in all the included studies with HRs from 1.19 to 2.93. There is insufficient evidence to establish the prognostic value of MFR for cardiac death and all-cause mortality. The heterogeneity in predictor operationalization and study performance shows the need for further standardization.

Wang and colleagues (2023) assessed the diagnostic efficacy of dynamic SPECT scan compared to conventional SPECT scan in evaluating obstructive CAD. Individuals with suspected or known CAD who were scheduled for a conventional SPECT were included (n=154) and 462 vessels. Each participant underwent both a dynamic and conventional SPECT scan followed by invasive coronary angiography. The dynamic SPECT scan measured both MBF and myocardial flow reserve (MFR). A quantitative assessment using coronary angiography was used as the reference standard for CAD. A 50% or greater reduction in luminal diameter was defined as angiographic obstructive disease. A total of 49.4% (76/154) individuals were categorized with obstructive CAD with 24.2% (112/462) vessels reported as significantly stenotic according to the reference standard. The stress MBF and MFR were more sensitive than MPI, but less specific (78.6%, 75.9%, 31.3% and 54.9%, 67.7% and 91.4%, respectively). The positive predictive value (PPV) for MBF, MFR and MPI respectively were 35.8%, 42.9% and 53.8%. The negative predictive value (NPV) for MBF, MFR and MPI respectively were 88.9%, 89.8% and 80.6%. The study did not include follow-up and did not address clinical outcomes in the tested population.

Observational studies have evaluated the diagnostic and prognostic value of quantitative coronary blood flow measurements in various populations with variable findings (Assante, 2021; Gould, 2021; Harjulahti, 2021; van Diemen, 2021). While quantitative coronary flow measurements may be a promising technique for further evaluating those with known or suspected CAD, there are a number of unknown variables, which require further evaluation. There is a lack of standardized thresholds regarding normal and abnormal findings and conflicting evidence regarding the relationship of comorbidities (for example, age, diabetes status or ischemic burden) and normal or reduced coronary blood flow findings. Further studies are needed to provide clear diagnostic standards by addressing the heterogeneity of the data and to directly measure whether treatment decisions based on quantitative coronary flow measurements will lead to better outcomes for affected individuals.

Monitoring Post Heart Transplant

Feher and associates (2020) evaluated the use of serial CFR assessments as a prognostic indicator of long-term outcomes (> 5 years) in individuals with a history of heart transplantation. A total of 89 individuals who were post-orthotopic heart transplant were included in the study. A dynamic rest-stress PET myocardial perfusion imaging test was performed at the individuals’ annual transplant evaluations. The individuals were followed for the primary outcomes (all-cause mortality) and secondary outcomes (MI and any revascularization). The median follow-up time was 8.6 years. There were a total of 40 deaths, 4 MIs and 14 revascularizations during the follow-up. Individuals with a CFR ≥ 1.5 had an increased risk for death or cardiovascular adverse events (HR: of 2.77; 95% CI, 1.34 to 5.74 and HR: 2.51; 95% CI, 1.23 to 5.10), respectively. This was the first study which evaluated long-term outcomes based on CFR results.

Emerging evidence appears to show CFR may be an independent risk factor and mortality in individuals post heart transplantation. These trials consist of single center, nonrandomized, observational or retrospective studies (Chih, 2018; Clerkin, 2022; Nelson, 2022; Shrestha, 2021; Wiefels, 2022). Additional prospective well-designed studies are needed to validate the predictive value of CFR, standardize cut-off values and to evaluate whether results can direct management resulting in improved clinical outcomes.

Other

Representatives from several cardiology societies published an appropriate use document regarding PET myocardial perfusion imaging (Schindler, 2020). The document reports on the role that MPI has in detecting hemodynamically significant obstructive CAD and cardiovascular risk stratification.  The report states that “noninvasive evaluation and quantification of global and regional myocardial blood flow (MBF)” provides a more comprehensive assessment of ischemic burden. The document does not evaluate the evidence regarding whether quantification measures provide an additional incremental benefit and improves clinical outcomes over standard MPI.

A 2021 guideline from the AHA/ACC/ASE /CHEST/SAEM/SCCT/SCMR on the evaluation and diagnosis of chest pain contains several recommendations specific to MBFR:

• For patients with obstructive CAD who have stable chest pain symptoms undergoing stress PET MPI or stress CMR, the addition of MBFR is useful to improve diagnosis accuracy and enhance risk stratification. [Class (strength) of Recommendation (COR): 2a; Level of Evidence (LOE): B-NR].
• For patients with persistent stable chest pain and nonobstructive CAD, stress PET MPI with MBFR is reasonable to diagnose microvascular dysfunction and enhance risk stratification [COR: 2a; LOE: B-NR].
• For patients with persistent stable chest pain and nonobstructive CAD, stress CMR with the addition of MBFR measurement is reasonable to improve diagnosis of coronary myocardial dysfunction and for estimating risk of MACE. [COR: 2a; LOE: B-NR].

COR Class 2a (Moderate) Benefit >> Risk
LOE B-NR (Nonrandomized)

• Moderate-quality evidence from 1 or more well-designed, well-executed nonrandomized studies, observational studies, or registry studies
• Meta-analysis of such studies

These recommendations do not address whether the additional clinical information results in a change in treatment plans and improves clinical outcomes.

In 2018, the Society of Nuclear Medicine & Molecular Imaging (SNMMI) and the American Society of Nuclear Cardiology (ASNC) published a joint position paper regarding the use of clinical quantification of myocardial blood flow using PET for the diagnosis, prognostic, assessment, and treatment guidance of CAD. The paper includes, but is not limited to, the following key points:

• Use of stress MBF and MFR for diagnosis is complex, as diabetes, hypertension, age, smoking, and other risk factors may decrease stress MBF and MFR without focal epicardial stenosis.
• Patients with preserved stress MBF and MFR are unlikely to have high-risk epicardial CAD.
• Severe reductions in global MFR (< 1.5) are associated with a substantially increased risk of adverse outcomes and merit careful clinical consideration.
• A preserved global MFR of more than 2.0 has an excellent negative predictive value for high-risk CAD (i.e., left main and 3-vessel disease).
• Preserved stress MBF of more than 2 mL/min/g and MFR of more than 2 reliably exclude the presence of high-risk angiographic disease (negative predictive value > 95%) and are reasonable to report when used in clinical interpretation.
• A severely decreased global MFR (< 1.5 mL/min/g) should be reported as a high-risk feature for adverse cardiac events but is not always due to multivessel obstructive disease. The likelihood of multivessel obstructive disease may be refined by examination of the electrocardiogram, regional perfusion, coronary calcification, and cardiac volumes and function.
• Regional decreases in stress MBF (< 1.5 mL/min/g) and MFR (< 1.5) in a vascular territory may indicate regional flow-limiting disease.
• PET MFR/invasive CFR and invasive [fractional flow reserve] FFR are related but are not interchangeable measures, with discordance in 30%–40% of lesions.
• MFR and invasive CFR measure the combined hemodynamic effects of epicardial stenosis, diffuse disease, and microvascular dysfunction. FFR measures the combined hemodynamic effects of focal and diffuse atherosclerosis. Microvascular dysfunction increases coronary resistance and blunts the pressure gradient across a stenosis and may sometimes lead to falsely negative FFR readings of flow-limiting lesions. The latter may explain some of the discrepancies between FFR and MFR/CFR.

The SNMMI/ASNC paper addresses when and how to report MBF and MFR values in the context of PET MPI studies to improve the accuracy of when angiographic CAD is detected. While there are some broad MBF and MFR thresholds within which the risk of CAD and/or an increased risk of cardiovascular events is increased or decreased, there are no physiologic standard thresholds of hyperemic MBF or MFR that can be used to accurately predict obstructive stenosis on coronary angiography. This lack of specific data is based on an evidence based collected from heterogeneous sources with a mix of participants, using different endpoints and differing methodologies. The thresholds may also vary due to different laboratories using different software. Quantitative perfusion measurements are associated with a large amount of variability between tests. Individuals with no health problems and no risk factors (n=100) and individuals with CAD or known risk factors underwent serial quantitative imaging taken minutes apart. The test-retest precision, as measured by the coefficient of variance (COV) for serial stress ml/min/g minutes apart was ± 10%. When testing was separated by days or weeks, the COV was ± 20% (Gould and Bui, 2021).  

The SNMMI/ASNC paper considers that that there is incremental prognostic value in the use of PET to measure stress MBF and MFR in individuals with known or suspected CAD. These findings are based on mainly retrospective or single institution observational studies (Di Carli, 2011; Farhad, 2013; Herzog, 2009; Murthy, 2011; Murthy, 2014; Slart, 2011; Tio, 2009; Ziadi, 2011). There is a question of the clinical significance of this finding. There is no randomized data which supports the use of any stress imaging modality to guide treatment such as revascularization or medical therapy. The authors at SNMMI/ASNC conclude:

Quantification of MBF and MFR represents a substantial advance for diagnostic and prognostic evaluation of suspected or established CAD. These methods are at the cusp of translation to clinical practice. However, further efforts are necessary to standardize measures across laboratories, radiotracers, equipment, and software. Most critically, data are needed supporting improved clinical outcomes when treatment selection is based on these measures.

The 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease (CCD) includes a recommendation for MBFR as a diagnostic modality:

In patients with CCD undergoing stress PET MPI or stress [cardiac magnetic resonance] CMR imaging, the addition of myocardial blood flow reserve (MBFR) can be useful to improve diagnostic accuracy and enhance risk stratification. [COR: 2a; LOE: B-NR].

The guideline supports the recommendation by noting:

Reduced MBFR reflects abnormalities of flow within the epicardial coronary arteries, microvasculature, or both, and independently predicts risk of major CAD events. Measurement of MBFR can be effectively accomplished using PET or CMR. Normal MBFR may be helpful in excluding high-risk anatomy, although global reduced levels (< 2) may provide a better estimate of disease extent and severity. Nonobstructive CAD with reduced MBFR is more frequently observed in women.

The 2016 ASNC/SNMMI procedure standard on PET imaging lists five indications in which AQMBF appears to be helpful. The authors note that MBF values should be considered with clinical characteristics and other imaging findings when used to diagnose or direct management. The 2016 guideline includes values which vary from those listed in the 2018 guideline (MFR > 2.3 indicates favorable prognosis in the 2016 version compared to > 2.0 in the 2018 version). The shift in prognostic cut-off value supports the summary statement in the 2018 practice guideline that further validation and standardization are needed.

Summary

Diagnostic and prognostic MBF and MFR measurements may be affected by methodologic, technical, biological, and pathophysiological factors. Critical methodologic factors include the choice of the radiotracer and pharmacologic stress agent. PET camera system technology, tracer kinetic model, and imaging-analysis software may all affect quantification of MBF. Normal flow values will also depend on biological factors such as age, sex, genetic variations and hormonal cycles. The biological and methodological variables which may affect MBF values present a challenge for determining a single universal threshold to define normal and abnormal MBF values (Schindler, 2023).

There are a number of values associated with the AQMBF and the meaning of these values alone or relation to each other and cardiac risk factors in not yet known. Giannopoulos (2020) commented on the Patel study (2020) and noted the following about global MBFR and current cardiac therapy goals:

Current concepts rely on the role of ischaemia testing to identify coronary territories jeopardized by impaired myocardial perfusion and address these territories by targeted revascularization procedures. Global MBFR, however, represents a more abstract and more universal coronary risk marker integrating diffuse vs. regional myocardial perfusion and macro- vs. micro vascular blood flow. Thus, it may seem surprising that MBFR turns out to be a better guide for selecting treatment strategies than ischaemia testing.

Nonobstructive CAD may represent a whole new population of individuals with suspected ischemic heart disease. There is a lack of recommendations regarding treatment of this group. Gulati and colleague (2022) note:

Given that most of the current guideline directed medical therapies have only been examined in those with obstructive CAD, what remains missing is a therapeutic agent that might target abnormal CFR and potentially decrease future risk of MACE in patients with nonobstructive CAD or those with pure microvascular dysfunction with normal coronary anatomy.

While evidence has shown that MBF quantitation is able to detect CAD and flow-related abnormalities, there is a paucity of studies which show that the additional information over visually inspected assessment results in improved clinical outcomes. There is also no evidence that determining MBF quantitation has been used as a screening tool in individuals with CAD to guide further treatment, such as medical intervention or cardiac catheterization (Shrestha, 2017). The current body of evidence does appear to show an association between abnormal MFR and increased risk of adverse cardiovascular outcomes. There is a lack of prospective studies which show how quantitative coronary flow measurements results would change management or improve clinical outcomes (Bom, 2020; Indorkar, 2019; Taqueti, 2015). Further studies are needed to better evaluate how to use MBF and MFR results to standardize normal and abnormal clinical values and to incorporate these results into treatment plans and improve clinical outcomes.

A 2023 consensus statement by a quantitative cardiovascular imaging study group (Mézquita, 2023) notes the clinical need for imaging in suspected or known CAD:

The appropriate assessment of the severity of coronary artery stenosis and the extent of atherosclerotic burden is paramount for the selection of the most effective preventative measures and for guiding clinical decision-making in patients with known or suspected CAD…Ideally, imaging would help to stratify patients who benefit from optimal medical treatment (OMT) and risk factor modification alone or from additional revascularization by either percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery.

While invasive imaging was the reference standard in the past, studies have shown no significant difference between invasive imaging and noninvasive CT imaging (Mézquita, 2023). MPI studies are standard noninvasive evaluation methods to diagnose, evaluate and monitor CAD. MPI can be accomplished using multiple modalities, including stress echocardiography, PET, CMR, SPECT scan and coronary CT angiography. Qualitative or semiqualitative evaluation using visual assessment of areas of abnormal perfusion is the most used approach. The inability of these methods to delineate the extent and severity of disease has been cited as a limitation of this technology. The use of quantitation techniques was developed to provide “an objective and reproducible estimate of myocardial ischemia and risk prediction” (Waller, 2014). Quantitation can be completed by PET, SPECT and CMR. PET scanning has the advantage of accurate depth-independent attenuation correction, which allows for AQMBF (Ziadi, 2017). Quantitative MBF is thought to have the potential to become a standard biomarker which can be used to stratify individuals with one or more vessel obstructive CAD (Papanastasiou, 2016).

MBF quantitation can be accomplished during SPECT scanning using dynamic SPECT scans. This new modality uses either cadmium-zinc-telluride (CZT) detectors with parallel-hole collimation or rapid-rotating gantry NaI (T1) SPECT (Wang, 2023). CZT-SPECT scan allows for simultaneous capturing of data of the radiotracer through left ventricle and myocardium (D’Anntonio, 2023).

Blood flow and flow reserve can be measured invasively or noninvasively. Invasive coronary angiography was considered the gold standard in CAD diagnosis. However, the procedure is associated with radiation and contrast injections (Panjer, 2022).  Unlike invasive techniques which directly measure coronary blood flow, noninvasive methods indirectly measure epicardial coronary artery blood flow volume via blood flow in myocardial tissue. Noninvasive MBF can be calculated at rest or under pharmacologically induced stress.

There are a number of measures which can be calculated using AQMBF. Global MBFR is commonly used, and has been reported as having a strong association with adverse outcomes (Patel, 2020). The cause and implications of a low global MBFR is unclear. Patel (2020) notes:

Low global MBFR values may be due to multi vessel coronary disease that should be revascularized with CABG or multivessel PCI in patients with higher comorbidity burden. In contrast, low global MBFR may be secondary to a single obstructive lesion with other comorbidities that lead to low global flows such as diabetes, obesity, and old age.

The leading cause of death post heart transplant is cardiac allograft vasculopathy (CAV). CAV causes impaired blood flow in the epicardial coronary arteries and the microvasculature. At 5 years post-transplant, approximately 30-45% of post-transplant cases have some degree of CAV. This increases to 50-65% at 10 years post-transplant (Clerkin, 2022). CAV is one of the leading causes of death following transplant. Coronary angiography is the standard surveillance tool used to monitor for CAV. Intravascular ultrasound is considered to have superior diagnostic accuracy over coronary angiography. These techniques come with risks inherent with invasive procedures and are unable to assess distal vessels and microvasculature (Nelson, 2022).

CAD affects approximately 1 in 20 adults in the US older than age 20 and is a leading cause of death. CAD can be categorized as obstructive or nonobstructive. Nonobstructive CAD had been categorized as a non-significant finding. However, recent studies have suggested that the presence of nonobstructive CAD is associated with an increased risk of myocardial infarctions (MIs) and mortality when compared to individuals with no apparent CAD. The ruptured plaques associated with nonobstructive CAD are the genesis for a significant number of MIs (Maddox, 2014).

Absolute Quantitation of Myocardial Blood Flow. Method used to measure the blood flow in the myocardium.

Coronary Flow Reserve (CFR): Ratio between MBF at rest and MBF during pharmacological stress (ml/min/g). Also known as Myocardial Flow Reserve (MFR).

Myocardial Blood Flow (MBF): Quantitative blood flow measure at rest or in stress.

Nonobstructive CAD: The presence of atherosclerotic plaque which in the past, was not expected to be significant (obstruct blood flow or cause anginal symptoms).

Obstructive CAD: The presence of atherosclerotic plaque in the coronary arteries which lead to narrowing of the arteries and decreased blood flow.

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
For the following procedure codes, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Peer Reviewed Publications:

1. Assante R, Mainolfi CG, Zampella E, et al. Relation between myocardial blood flow and cardiac events in diabetic patients with suspected coronary artery disease and normal myocardial perfusion imaging. J Nucl Cardiol. 2021; 28(4):1222-1233.
2. Bom MJ, van Diemen PA, Driessen RS, et al. Prognostic value of [15O]H2O positron emission tomography-derived global and regional myocardial perfusion. Eur Heart J Cardiovasc Imaging. 2020; 21(7):777-786.
3. Chih S, Chong AY, Erthal F, et al. PET Assessment of epicardial intimal disease and microvascular dysfunction in cardiac allograft vasculopathy. J Am Coll Cardiol. 2018; 71(13):1444-1456.
4. Clerkin KJ, Topkara VK, Farr MA, et al. Noninvasive physiologic assessment of cardiac allograft vasculopathy is prognostic for post-transplant events. J Am Coll Cardiol. 2022; 80(17):1617-1628.
5. D'Antonio A, Assante R, Zampella E, et al. Myocardial blood flow evaluation with dynamic cadmium-zinc-telluride single-photon emission computed tomography: Bright and dark sides. Diagn Interv Imaging. 2023; 104(7-8):323-329.
6. Di Carli MF, Murthy VL. Cardiac PET/CT for the evaluation of known or suspected coronary artery disease. Radiographics. 2011; 31(5):1239-1254.
7. Farhad H, Dunet V, Bachelard K, et al. Added prognostic value of myocardial blood flow quantitation in rubidium-82 positron emission tomography imaging. Eur Heart J Cardiovasc Imaging. 2013; 14(12):1203-1210.
8. Feher A, Srivastava A, Quail MA, et al. Serial assessment of coronary flow reserve by rubidium-82 positron emission tomography predicts mortality in heart transplant recipients. JACC Cardiovasc Imaging. 2020; 13(1 Pt 1):109-120.
9. Fukushima K, Javadi MS, Higuchi T, et al. Prediction of short-term cardiovascular events using quantification of global myocardial flow reserve in patients referred for clinical 82Rb PET perfusion imaging. J Nucl Med. 2011; 52(5):726-732.
10. Giannopoulos AA, Gaemperli O. The power of myocardial blood flow reserve in personalizing management of patients with stable coronary artery disease. Is it time to move on from percentage of ischaemia? Eur Heart J. 2020; 41(6):769-771.
11. Gould KL, Bui L, Kitkungvan D, Patel MB. Reliability and reproducibility of absolute myocardial blood flow: does it depend on the PET/CT technology, the vasodilator, and/or the software? Curr Cardiol Rep. 2021; 23(3):12.
12. Gould KL, Kitkungvan D, Johnson NP, et al. Mortality prediction by quantitative PET perfusion expressed as coronary flow capacity with and without revascularization. JACC Cardiovasc Imaging. 2021; 14(5):1020-1034.
13. Green R, Cantoni V, Acampa W, et al. Prognostic value of coronary flow reserve in patients with suspected or known coronary artery disease referred to PET myocardial perfusion imaging: A meta-analysis. J Nucl Cardiol. 2021; 28(3):904-918.
14. Gulati M, Parwani P. Myocardial blood flow reserve: The Achilles' heel of CAD prognostication? JACC Cardiovasc Imaging. 2022; 15(9):1645-1647.
15. Harjulahti E, Maaniitty T, Nammas W, et al. Global and segmental absolute stress myocardial blood flow in prediction of cardiac events: [15O] water positron emission tomography study. Eur J Nucl Med Mol Imaging. 2021; 48(5):1434-1444.
16. Herzog BA, Husmann L, Valenta I, et al. Long-term prognostic value of 13N-ammonia myocardial perfusion positron emission tomography added value of coronary flow reserve. J Am Coll Cardiol. 2009; 54(2):150-156.
17. Indorkar R, Kwong RY, Romano S, et al. Global coronary flow reserve measured during stress cardiac magnetic resonance imaging is an independent predictor of adverse cardiovascular events. JACC Cardiovasc Imaging. 2019; 12(8 Pt 2):1686-1695.
18. Juárez-Orozco LE, Tio RA, Alexanderson E, et al. Quantitative myocardial perfusion evaluation with positron emission tomography and the risk of cardiovascular events in patients with coronary artery disease: a systematic review of prognostic studies. Eur Heart J Cardiovasc Imaging. 2018; 19(10):1179-1187.
19. Kelshiker MA, Seligman H, Howard JP, et al; Coronary Flow Outcomes Reviewing Committee. Coronary flow reserve and cardiovascular outcomes: a systematic review and meta-analysis. Eur Heart J. 2022; 43(16):1582-1593.
20. Maddox TM, Stanislawski MA, Grunwald GK, et al. Nonobstructive coronary artery disease and risk of myocardial infarction. JAMA. 2014; 312(17):1754-1763.
21. Mehra MR, Boulet J, Pelletier-Galarneau M. The panvascular interplay in pathophysiology and prognosis of cardiac allograft vasculopathy. J Am Coll Cardiol. 2022; 80(17):1629-1632.
22. Mézquita AJV, Biavati F, Falk V, et al. Clinical quantitative coronary artery stenosis and coronary atherosclerosis imaging: A Consensus Statement from the Quantitative Cardiovascular Imaging Study Group. Nat Rev Cardiol. 2023; 20(10):696-714.
23. Murthy VL, Lee BC, Sitek A, et al. Comparison and prognostic validation of multiple methods of quantification of myocardial blood flow with 82Rb PET. J Nucl Med. 2014; 55(12):1952-1958.
24. Murthy VL, Naya M, Foster CR, et al. Improved cardiac risk assessment with noninvasive measures of coronary flow reserve. Circulation. 2011; 124(20):2215-2224.
25. Nelson LM, Christensen TE, Rossing K, et al. Prognostic value of myocardial flow reserve obtained by 82-rubidium positron emission tomography in long-term follow-up after heart transplantation. J Nucl Cardiol. 2022; 29(5):2555-2567.
26. Panjer M, Dobrolinska M, Wagenaar NRL, Slart RHJA. Diagnostic accuracy of dynamic CZT-SPECT in coronary artery disease. A systematic review and meta-analysis. J Nucl Cardiol. 2022; 29(4):1686-1697.
27. Papanastasiou G, Williams MC, Dweck MR, et al. Quantitative assessment of myocardial blood flow in coronary artery disease by cardiovascular magnetic resonance: Comparison of Fermi and distributed parameter modeling against invasive methods. J Cardiovasc Magn Reson. 2016; 18(1):57.
28. Patel KK, Spertus JA, Chan PS, et al. Myocardial blood flow reserve assessed by positron emission tomography myocardial perfusion imaging identifies patients with a survival benefit from early revascularization. Eur Heart J. 2020; 41(6):759-768.
29. Pelletier-Galarneau M, Dilsizian V. Microvascular angina diagnosed by absolute PET myocardial blood flow quantification. Curr Cardiol Rep. 2020; 22(2):9.
30. Schindler TH, Fearon WF, Pelletier-Galarneau M, et al. Myocardial perfusion PET for the detection and reporting of coronary microvascular dysfunction: A JACC: Cardiovascular Imaging Expert Panel Statement. JACC Cardiovasc Imaging. 2023; 16(4):536-548.
31. Shrestha U, Sciammarella M, Alhassen F, et al. Measurement of absolute myocardial blood flow in humans using dynamic cardiac SPECT and 99mTc-tetrofosmin: Method and validation. J Nucl Cardiol. 2017; 24(1):268-277.
32. Shrestha UM, Sciammarella M, Pampaloni MH, et al. Assessment of late-term progression of cardiac allograft vasculopathy in patients with orthotopic heart transplantation using quantitative cardiac 82Rb PET. Int J Cardiovasc Imaging. 2021; 37(4):1461-1472.
33. Slart RH, Zeebregts CJ, Hillege HL, et al. Myocardial perfusion reserve after a PET-driven revascularization procedure: a strong prognostic factor. J Nucl Med. 2011; 52(6):873-879.
34. Taqueti VR, Hachamovitch R, Murthy VL, et al. 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(1):19-27.
35. Tio RA, Dabeshlim A, Siebelink HM, et al. Comparison between the prognostic value of left ventricular function and myocardial perfusion reserve in patients with ischemic heart disease. J Nucl Med. 2009; 50(2):214-219.
36. van Diemen PA, Wijmenga JT, Driessen RS, et al. Defining the prognostic value of [15O]H2O positron emission tomography-derived myocardial ischaemic burden. Eur Heart J Cardiovasc Imaging. 2021; 22(6):638-646.
37. Wang L, Zheng Y, Zhang J, et al. Diagnostic value of quantitative myocardial blood flow assessment by NaI(Tl) SPECT in detecting significant stenosis: a prospective, multi-center study. J Nucl Cardiol. 2023; 30(2):769-780.
38. Wiefels C, Almufleh A, Yao J, et al. Prognostic utility of longitudinal quantification of PET myocardial blood flow early post heart transplantation. J Nucl Cardiol. 2022; 29(2):712-723.
39. Ziadi MC. Myocardial flow reserve (MFR) with positron emission tomography (PET)/computed tomography (CT): clinical impact in diagnosis and prognosis. Cardiovasc Diagn Ther. 2017; 7(2):206-218.
40. Ziadi MC, Dekemp RA, Williams KA, et al. 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(7):740-748.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Bandettini WP, Kwong RY, Patel AR, Plein S; Society for Cardiovascular Magnetic Resonance. Society for Cardiovascular Magnetic Resonance perspective on the ACC/AHA/ASE/ASNC/ASPC/HFSA/HRS/SCAI/ SCCT/SCMR/STS 2023 multi-modality appropriate use criteria for the detection and risk assessment of chronic coronary disease. J Cardiovasc Magn Reson. 2023; 25(1):59.
2. Bateman TM, Heller GV, Beanlands R, et al. Practical Guide for Interpreting and Reporting Cardiac PET Measurements of Myocardial Blood Flow: An Information Statement from the American Society of Nuclear Cardiology, and the Society of Nuclear Medicine and Molecular Imaging. J Nucl Med. 2021; 62(11):1599-1615.
3. Dilsizian V, Bacharach SL, Beanlands RS, et al. ASNC imaging guidelines/SNMMI procedure standard for positron emission tomography (PET) nuclear cardiology procedures. J Nucl Cardiol. 2016; 23(5):1187-1226.
4. Murthy VL, Bateman TM, Beanlands RS, et al; SNMMI Cardiovascular Council Board of Directors; ASNC Board of Directors. Clinical Quantification of Myocardial Blood Flow Using PET: Joint Position Paper of the SNMMI Cardiovascular Council and the ASNC. J Nucl Med. 2018; 59(2):273-293.
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9. Writing Committee Members; Virani SS, Newby LK, Arnold SV, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/ PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2023; 82(9):833-955.

1. National Heart, Lung, and Blood Institute (NIH). Coronary Heart Disease: Diagnosis. Last updated March 24, 2022. Available at: https://www.nhlbi.nih.gov/health/coronary-heart-disease/diagnosis. Accessed on March 11, 2024.

Coronary Flow Reserve (CFR)
Myocardial Blood Flow Reserve (MBFR)
Myocardial Flow Reserve (MFR)
Myocardial Perfusion Reserve (MPF)

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