Annals of Nuclear Cardiology Vol. 7

No. 1

57‒62

REVIEW ARTICLE

Functional Assessment of Coronary Artery Disease by
Myocardial Flow Reserve Versus Pressure-wire Based
Assessment: A Systematic Review
1)

1)

2)

Osamu Manabe, MD, PhD , Tadao Aikawa, MD, PhD , Masanao Naya, MD, PhD ,3)
1)
Shiro Miura, MD, MSc and Noriko Oyama-Manabe, MD, PhD
Received: July 5, 2021/Accepted: August 2, 2021
© The Japanese Society of Nuclear Cardiology 2021
Abstract
Positron emission tomography (PET) permits the noninvasive quantification of myocardial blood flow (MBF).
Myocardial flow reserve (MFR), calculated by dividing stress MBF by rest MBF is a reliable index for thefunctional information of coronary artery disease. A pressure-derived physiological index, such as fractional flow
reserve (FFR) is also an important measurement. Both MFR and FFR values are used to evaluate coronary
physiology; however, but they are not interchangeable because each test has certain discrepancies.
In this systematic review, we provide an overview of coronary physiology with PET compared to pressurederived physiological indices.
Keywords: Coronary artery disease, Fractional flow reserve, Instantaneous wave-free ratio, Myocardial blood
flow, Myocardial flow reserve, Positron emission tomography
Ann Nucl Cardiol 2021; 7 (1): 57‒62

ssessment of the physiologic significance of stenosis andA morphological stenosis is highlighted for the evaluation

lesion severity in patients with CAD. Recently, restingof coronary artery disease (CAD). There are several types ofratio (iFR), has been used as alternative to FFR.

pressure-derived index, such as the instantaneous wave-freecardiovascular tests that lead to large variations in the choiceThis article summarizes the physiologic basis for PET MPI

of diagnostic modalities. Among them, myocardial perfusioncompared to pressure-wire-based assessment, including FFR,

imaging (MPI) using positron emission tomography (PET)

which is one of the most established measures for identifying

permits both qualitative and quantitative assessments ofphysiologically significant coronary stenoses.

patients with CAD. PET has a significantly higher diagnostic
accuracy than single-photon emission computed tomography

PET

because of its higher spatial resolution (1). Dynamic or list-

MPI has played an important role in the diagnosis andmode data collection has been used to quantify myocardialmanagement of patients with known or possible CAD. PET isblood flow (MBF) in recent practical PET MPI studies (2).

one of the most established noninvasive techniques for the

PET quantification allows assessment of the severity ofassessment of blood flow to the myocardium. PET MPI

physiological stenosis.

provides clear evidence for the diagnosis and risk assessment

Ischemic heart disease is caused by oxygen deficiency dueof CAD (1). Dynamic first-pass perfusion PET imaging allows

to an imbalance between demand and supply. The concept of

noninvasive quantification of MBF. Estimation of myocardial

physiological stenosis is essential for CAD assessment.

flow reserve (MFR), which is the ratio of stress/rest MBF,

Coronary revascularization guided by fractional flow reserve

provides several advantages to assess CAD and microvascular(FFR) is the current standard for the functional assessment of

dysfunction in addition to the conventional visual assessment.

doi: 10.17996/anc.21-00144
1) Department of Radiology, Jichi Medical University Saitama Medical
Center, Saitama, Japan
2) Department of Cardiovascular Medicine, Hokkaido University
Graduate School of Medicine, Sapporo, Japan

3) Department of Cardiology, Hokkaido Ohno Memorial Hospital,
Sapporo, Japan

― 58 ―

Manabe et al.
Functional Assessment of Coronary Artery Disease

Ann Nucl Cardiol 2021；7（1）：57‒62

To compare the diagnostic performance of pressure-derived
physiological indices, relative flow reserve (RFR) is sometimes evaluated as the ratio of stress MBF in target myocardial
segments to that of reference myocardial segments (3).
Pressure-wire based assessment of physiological ischemia
FFR is a guide-wire-based procedure to measure bloodpressure differences across coronary artery stenosis, which canbe performed during cardiac catheterization to assess theindication for percutaneous coronary intervention (PCI). FFR
is defined as the ratio of maximal flow achievable in the
stenotic coronary artery relative to the maximal blood flow if
the same coronary artery had no stenosis (4). Even if thedegree of stenosis is similar, the state of ischemia measured by
FFR differs depending on the lesion length, the existence ofcollateral flow, and the shape of the stenotic lesion (5, 6).

Figure 1 Schematic of macro- and microcirculation.
Although the boundary of each compartment is difficult to define
anatomically, the coronary arterial system is composed of macroand microcirculation. Macrocirculation is a proximal compartment
represented by epicardial coronary arteries (A). The distal smaller
compartment is microcirculation, which is represented by arterioles
and capillaries (B).

Multiple clinical studies have shown that FFR values of lessthan 0. 75 to 0. 80 have high specificity for identifying

and pressure-derived physiological indices are summarized inischemia, and 0.80 is the best-endorsed cutoff for deferral of

Table 1. The index obtained from PET and pressure-wire-

PCI for functionally nonsignificant stenoses (7, 8). FFR-

based assessments tends to have a modest, not very highguided revascularization has been the gold standard forcorrelation. What are the reasons for the discrepancy between

assessing the functional significance of epicardial coronary

these physiological indices?

stenosis.

MFR is well known to be influenced not only by stenosis of

Recently, the instantaneous wave-free ratio (iFR) has been

the epicardial artery, but also by coronary microvascular

introduced as a promising alternative to FFR (4). iFR is

dysfunction due to risk factors, such as diabetes, dyslipidemia,

performed using a pressure-sensitive catheter that is passed

hypertension, renal dysfunction, obesity, and smoking (13,distal to the coronary stenosis to measure the pressure drop in14). Therefore, the MFR reflects the condition of the entire

a specific period called a wave-free period, but iFR iscoronary arterial circulation without distinction between

measured under resting conditions without the need for a

macro- and microcirculation. However, the results derived

hyperemic-inducing drug. Recent studies indicate that an iFR-

from pressure-wire-based assessments are lesion-based para-guided strategy is non-inferior to an FFR-guided strategy formeters, which do not represent information on the size of thecoronary revascularization in patients with CAD (9, 10).

perfused area exposed to ischemia due to stenosis, and it isthought that they do not reflect the microcirculatory condition

Epicardial artery and microcirculation(15). A recent study showed that FFR is slightly increased

The concept of physiological stenosis can be easily

during the presentation of microcirculation dysfunction (16).

understood by distinguishing between the epicardial arteries

Therefore, the correlation between pressure-wire-based(macrocirculation) and microcirculation. Both are blood

parameters and PET-derived MFR and stress MBF wasvessels that supply oxygen and nutrients to cardiac myocytes

moderate. In the case of one- or two-vessel disease, it is worth(Figure 1). The epicardial arteries running on the surface ofpointing out that PET-derived RFR has been shown to have athe myocardium, which is typically more than 500 µm in

higher correlation with FFR and iFR than MFR and stressdiameter, depicted on coronary angiography, hold less thanMBF (Table 1) (Figure 3).

10% of the total myocardial blood volume (11). The remaining
is assumed by microcirculation, which is difficult to reveal

The role of physiological measurements of CAD

using conventional imaging techniques (12). Coronary

The Clinical Outcomes Utilizing Revascularization andmicrovascular networks play an important role in coronary

Aggressive Drug Evaluation (COURAGE) trial showed that

vascular resistance in the myocardium. Both arteries consist-

PCI did not reduce coronary events compared to optimal

ing of macro- and microcirculation have the possibility of

medical therapy (OMT) in patients with stable CAD, bringing

narrowing by atherosclerosis with plaque (Figure 2) (13). The

into question the effectiveness of revascularization (30). In

loss of coronary autoregulation is also one of the causes ofrecent years, the ORBITA (percutaneous coronary interven-microcirculation dysfunction.

tion in stable angina) study has reported that PCI does not

Systematic reviews comparing PET-derived flow indicesimprove exercise time compared to placebo procedures inAnn Nucl Cardiol 2021；7（1）：57‒62

Manabe et al.
Functional Assessment of Coronary Artery Disease― 59 ―

Figure 2 Shema of a combination of macro- and microcirculation.
Schema of normal (A), focal stenosis of an epicardial artery (B), microvascular disease (C), andboth macro- and microvascular diseases (D) are displayed. Focal and diffuse epicardial coronary
disease and coronary microvascular dysfunction have the potential to exist simultaneously. The
expansion of focal and diffuse diseases reflect the MFR and FFR values.

Table 1 Relationship between PET-derived flow indices and pressure-derived physiologic indices in patients with CAD
PET-derived indices
Study

N

PET tracer

Stress MBF(mL/g/min)

MFR (CFR)

Pressure-derived indices

Correlation

RFR

FFR

iFR

MFR (CFR)
vs. FFRRFR vs.
FFR

Dai N, et al. (17)109

13N-ammonia−

2.3±0.7

0.83±0.11

0.83±0.11

0.92±0.12−

0.786
Spearman’s ρ

Bendix K, et al. (18)25

15O-water

2.49±0.67(Diseased vessels)
2.89±0.65(Refer ence vessels)

2.55±0.60(Diseased vessels)
3.02±0.59(Reference vessels)−

0.68±0.18(Diseased vessels)
0.90±0.08(Refer ence vessels)

−

0.493
Pearson’s r−Everaars H, et al. (19)40

15O-water

2.55±0.9

3.0±0.9−

0.93 (0.84‒0.97)

−

−

−

0.61±0.17(61 of 90 vascularterritories)−

0.56
Pearson’s r

0.76
Pearson’s r

Driessen RS, et al. (20)53

15O-water

1.57±0.59

2.02±0.69

0.65±0.18(48 of 90 vascularterritories)

Chih S, et al. (21)40
(only hearttransplantpatients)

82Rb

1.95±0.75

2.38±0.82

−

−

−

−

0.28
Pearson’s r

Kawaguchi N, et al. (22)63

13N-ammonia

Diseased vessels;
1.67±0.54
Reference vessels;
2.19±0.52

Diseased vessels;
1.85±0.69
Reference vessels;
2.38±0.69

−

−

−

0.32
Spearman’s ρ−

Lee JM, et al. (23)Hwang D, et al. (24)115

13N-ammonia

1.80±0.43

2.13±0.58

0.77±0.09

0.81 (0.73‒0.85)

0.92 (0.87‒0.94)

0.400
Spearman’s ρ

0.6830Spearman’s ρ

Lee JM, et al. (25)56

13N-ammonia

High iFR vessels;
1.94±0.45
Low iFR vessels;
1.60±0.33

High iFR vessels;
2.27±0.50
Low iFR vessels;
1.76±0.33‒

High iFR vessels;
0.77 (0.76‒0.78)
Low iFR vessels;
0.68 (0.61‒0.73)

High iFR
vessels;
0.92 (0.91‒0.94)
Low iFR vessels;
0.81 (0.71‒0.87)−−

Lee JM, et al. (26)130

13N-ammonia

2.08±0.55

2.25±0.66

0.85±0.11

0.84±0.11;
0.85 (0.78‒0.93)−

0.38
Pearson’s r

0.78
Pearson’s r

Valenta I, et al. (27)29

13N-ammonia

Diseased vessels;
1.44 (1.23‒1.72)
Reference vessels;
1.60 (1.37‒1.82)

Diseased vessels;
1.97 (1.71‒2.36)
Reference vessels;
2.23 (1.76‒2.37)

−

−

−

0.50
Pearson’s r−Peelukhana SV, et al. (28)813N-ammonia

1.85±0.22

2.44±0.11−

0.79±0.03−

0.08
Spearman’s ρ−

De Bruyne B, et al. (29)22

15O-water−−

0.60±0.26

0.61±0.17

−

−

0.87
Pearson’s r

Values are presented as the mean±standard deviation or median (interquartile range).
CAD: coronary artery disease, CFR: coronary flow reserve, FFR: fractional flow reserve, iFR: instantaneous wave-free ratio, MBF: myocardial blood flow, MFR: myocardial flow reserve, PET: positron emission
tomography, RFR: relative flow reserve.

― 60 ―Ann Nucl Cardiol 2021；7（1）：57‒62

Manabe et al.
Functional Assessment of Coronary Artery Disease

Figure 3 Representative case of macrovascular disease.
Angiography of the left coronary artery (LAD) (A), perfusion polar map of stress (B) and rest (C), rest
(D), stress myocardial blood flow (MBF) (E), and myocardial blood flow (MFR) (F) by 13N-NH3 PET (E)are shown. A man in his 70s had significant stenosis in the middle of the LAD (yellow arrow) with an FFR
value of 0.48 and an iFR value of 0.50. Ischemia in the mid to distal LAD territory and reduced MFR in the
LAD territory are seen on 13N-NH3 PET.

patients with medically treated angina and severe coronary

on exercise tests without imaging. Ischemia eligibility criteria

stenosis (31).

by nuclear perfusion test are in cases where ischemic changes

Meanwhile, the nuclear substudy of the COURAGE trial

are qualitatively observed in 10% or more of the entire

showed that significant ischemia reduction was observed in

myocardium, and quantitative evaluations, such as MBF andpatients treated with PCI+OMT, and patients who achieved

MFR are not included in the analysis. PET is the most

≥5% ischemia reduction had a lower unadjusted risk for deathvalidated and quantitative approach for evaluating myocardial

or myocardial infarction, particularly if baseline ischemia isischemia and coronary vasomotor function. Furthermore, there

moderate to severe (32). The Fractional Flow Reserve Versus

is growing evidence that PET-based stress MBF and MFR

Angiography for Multivessel Evaluation 2 study showed thatprovide incremental prognostic value over the qualitative

fractional FFR-guided PCI reduced events in patients withassessment of myocardial ischemia (34, 35). Taqueti et al.

stable CAD compared to medical therapy. Therefore,

reported that coronary artery bypass grafting may be morefunctional ischemia diagnosis has become mandatory for

effective for long-term prognosis in patients with significant

medical fee calculations in Japan.

CAD and reduced MFR (36), which may be partly explained

The International Study of Comparative Health Effective-by the significant increase in MFR after complete revascular-

ness with Medical and Invasive Approaches (ISCHEMIA)

ization with coronary artery bypass grafting (37). Appropriate

trial was conducted under the hypothesis that early invasive

criteria for coronary revascularization for stable angina havetreatment strategies reduce coronary events in patients with

been proposed, but based on the results of the ISCHEMIA

moderate or advanced ischemia compared to conservative

study, assessing the physiologic significance of stenosis maytreatment strategies managed with medical treatment (33).

help further subdivided indications.

However, this trial showed that invasive treatment strategies
did not reduce the risk of cardiac events, including

Conclusion

cardiovascular death, myocardial infarction, hospitalization

Both PET and pressure-wire-based assessments, such as

for unstable angina or heart failure, and resuscitation after

FFR, are used to evaluate the physiologic significance of

cardiac arrest. The ISCHEMIA trial included patients with atstenosis, which is indispensable when considering theleast moderate ischemia on imaging tests or severe ischemia

treatment of patients with CAD. PET is a modality that can

Ann Nucl Cardiol 2021；7（1）：57‒62

Manabe et al.
Functional Assessment of Coronary Artery Diseasereflect the entire vascular system, including epicardial andmicrovascular conditions. FFR can detect physiologicalischemia of coronary artery lesions and provide information
directly related to treatment. Each test has a certain degree of6.

discrepancy. Myocardial ischemia associated with a microvascular disease or diffuse coronary atherosclerosis without
significant epicardial stenosis will produce different results

7.

between PET and pressure-wire based indices.
8.

Acknowledgments
None.
Sources of funding
This study was supported by grants from the Japan Society
for the Promotion of Science (JSPS) KAKENHI # 21K07603

9.

(OM).
10.

Conflicts of interest
Dr. Noriko Oyama-Manabe has consulted for Canon
Medical Systems; she also received payment for lectures from

11.

Daiichi-Sankyo, GE Healthcare, Nihon Medi-Physics, Co.,
Ltd., and Canon Medical Systems.

12.

Reprint requests and correspondence:
Noriko Oyama-Manabe MD, PhD
Department of Radiology, Jichi Medical University Saitama
Medical Center, 1-847 Amanuma-Cho, Omiya-Ku, Saitama

13.

330-8503 Japan
E-mail: norikomanabe@jichi.ac.jp

14.

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