Journal of Cardiology 79 (2022) 247–256

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Journal of Cardiology
journal homepage: www.elsevier.com/locate/jjcc

Original article

Prognostic value of modiﬁed coronary ﬂow capacity by 13 N-ammonia
myocardial perfusion positron emission tomography in patients
without obstructive coronary arteries
Shiro Miura (MD) a,∗, Masanao Naya (MD, PhD) b, Hiraku Kumamaru (MD) c,
Akira Ando (CNMT) d, Chihoko Miyazaki (MD, PhD) e, Takehiro Yamashita (MD, PhD) aa

Department of Cardiology, Hokkaido Ohno Memorial Hospital, Sapporo, Japan
Department of Cardiovascular Medicine, Hokkaido University, Graduate School of Medicine, Sapporo, Japanc
Department of Healthcare Quality Assessment, Graduate School of Medicine, The University of Tokyo, Tokyo, Japand
Division of Diagnostic Radiology Imaging, Hokkaido Ohno Memorial Hospital, Sapporo, Japane
Department of Radiology, Hokkaido Ohno Memorial Hospital, Sapporo, Japanba r t i c l e

i n f oArticle history:
Received 22 March 2021
Revised 14 August 2021
Accepted 24 August 2021
Available online 15 September 2021
Keywords:
Coronary ﬂow capacity
Coronary artery disease
Positron emission tomography
Coronary microcirculationa b s t r a c t
Background: Vasodilator capacity of coronary circulation is an important diagnostic and prognostic tool inpatients with coronary artery disease (CAD). We aimed to clarify the incidence of coronary microvascular
dysfunction (CMD), deﬁned as impaired modiﬁed coronary ﬂow capacity (mCFC) proposed by Johnson
and Gould and measured by 13 N-ammonia myocardial perfusion positron emission tomography (PET), in
patients without obstructive CAD and to evaluate the risk of future cardiovascular events.
Methods: This retrospective study recruited 407 consecutive CAD-suspected patients who underwent
both pharmacological stress/rest 13 N-ammonia PET and coronary angiography. Of the 407 patients, 137
patients (median age, 70 years; 63 women) were eligible and followed up (median, 19.8 months). Endpoints were deﬁned as cardiovascular death or major adverse cardiovascular events (MACEs), such as
cardiovascular death, nonfatal myocardial infarction, unplanned hospitalization for any cardiac reasons,and unplanned coronary revascularization. The impaired mCFC group included patients with mildly toseverely reduced regional CFC in, at least, one vascular territory (n=34), while the remaining patients(n=103) were categorized as having preserved mCFC.
Results: Overall, cardiovascular death and MACEs occurred in ﬁve (4%) patients. The Kaplan–Meier curve
showed a signiﬁcant reduction in event-free survival for cardiovascular death (p=0.004) and MACEs(p<0.0 0 01) in the impaired mCFC group, compared to the preserved mCFC group. Impaired mCFC was
independently associated with the incidence of both cardiovascular death and MACEs after propensityscore adjustments [hazard ratio (HR), 10.7; 95% conﬁdence interval (CI), 1.0–106.0; p=0.04 and HR, 9.5;
95% CI, 2.5–36.2; p<0.001, respectively].
Conclusions: In CAD-suspected patients without obstructive coronary arteries, impaired mCFC was observed in approximately 25% and was associated with a higher risk of cardiovascular death and MACEs.
The mCFC concept can help identify patients who would beneﬁt from speciﬁc therapies or lifestyle modiﬁcations to prevent future MACEs and can clarify potential mechanisms of CMD.
© 2021 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Introduction
Patients with evident ischemia and no obstructive epicardialcoronary artery disease (CAD), named INOCA, are increasingly being recognized [1]; they are frequently referred for coronary angiography (CAG) or coronary computed tomography (CT) angiog∗
Corresponding author at: Department of Cardiology, Hokkaido Ohno Memorial
Hospital, 2-1-16-1 Miyanosawa, Nishi-ku, Sapporo 063-0052, Japan.
E-mail address: s.miura@ohno-kinen.or.jp (S. Miura).

raphy (CCTA). One proposed mechanism contributing to INOCA iscoronary microvascular dysfunction (CMD), which can occur not
only in the absence of obstructive CAD but also in myocardial diseases, obstructive CAD, or during iatrogenic procedures [2]. Cardiac positron emission tomography (PET) has been the gold standard for quantitative myocardial perfusion to deﬁne physiological
CMD severity [3], which is commonly related to the detrimental
effects of cardiovascular risk factors on the arterial wall, vascularsmooth muscle cell layer hypersensitivity, or both [4]. In diagnosing CMD, coronary ﬂow reserve [CFR; calculated as the ratio of

https://doi.org/10.1016/j.jjcc.2021.09.001
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Journal of Cardiology 79 (2022) 247–256

hyperemic to rest absolute myocardial blood ﬂow (MBF)] reﬂects
the most straightforward assessment of coronary vasodilator capacity [5]. Nonetheless, CFR depends on both resting and vasodilated coronary hemodynamics, and physiological changes in these
conditions may inadvertently affect the CFR result [6]. To overcome
such CFR limitations, the coronary ﬂow capacity (CFC) concept was
introduced by integrating CFR with the maximal ﬂow during coronary vasodilation into a comprehensive framework [7, 8]. Recently,
CFC was reported to be associated with the size-dependent highest mortality risk that is meaningfully decreased with revascularization, which was not proven for global CFR [9]. However, because these novel parameters (CFR and CFC) provide a quantitative
assessment of the integrated effects of epicardial coronary stenosis, diffuse atherosclerosis, and CMD [10], it might not be straightforward to estimate CMD severity and clarify clinical outcomes,
apart from epicardial coronary stenosis, even in patients without
obstructive coronary arteries. Thus, we created a modiﬁed CFC(mCFC) category by integrating the regional CFC category withineach coronary territory into the entire CFC category for each patient.
This study aimed to assess the predictive value of mCFC andﬂow-based diagnosis for ischemic heart disease based on coronary
artery territories utilizing 13 N-ammonia PET in patients without
obstructive coronary arteries and to characterize the predictors of
impaired mCFC to assess microvascular dysfunction.

dynamic frames were reconstructed. CT was used for attenuation
correction. Patients were instructed to completely fast for >6 hand refrain from consuming caffeinated beverages and foods forat least 12 h before the examination. The pharmacological stressscan was performed during adenosine triphosphate (ATP)-induced
hyperemia for 5 min, at a rate of 160 μg•kg−1 •min−1 [11, 12]. The
rest scan was performed with 3 MBq/kg of 13 N-ammonia for 30 s
after 1 h. After a 3-min ATP infusion, 13 N-ammonia was injected
at a dose of 3 MBq/kg for 30 s, and the mentioned protocol was
followed. Heart rate and blood pressure were recorded during therest test and every minute during and after ATP infusion, with continuous electrocardiogram monitoring.
PET images were quantitatively analyzed using a commercially available dedicated software package (Syngo MBF®, Siemens
Healthcare, Erlangen, Germany). Quantitative analysis was semiautomated using a two-compartment model [13]. The mean MBF
values (mL/g/min) were measured for the three regions of the left
anterior descending, left circumﬂex, and right coronary arteries using the 17-segment standard American Heart Association model at
rest and during stress. Mean CFR was calculated as the ratio ofstress MBF (stress scan) to rest MBF (rest scan) in each region andglobally. Originally, Gould et al. advocated that each color-coded
pixel is spatially mapped back onto its LV location with percentage of left ventricle calculated for each range of combined CFR andstress perfusion pixel values listed in the CFC color histogram bar[14]. Here, we added a more practical concept of coronary territory onto the original CFC to create a new classiﬁcation, mCFC, foreach patient using scatter plot CFR and stress MBF (Fig. 2). A color
ﬂow map of the left ventricle indicated coronary ﬂow in a patientutilizing the CFR and stress MBF for each coronary territory. This
allowed for classiﬁcation into the following six unique categories:
normal ﬂow, minimal reduced ﬂow, mildly reduced ﬂow, moderately reduced ﬂow, deﬁnite ischemia, and myocardial steal. Preserved mCFC was deﬁned as “normal” or “minimally reduced” ﬂow
in every coronary territory within the left ventricle with a colorbased interpretation of the ﬂow capacity. Thus, patients with impaired mCFC had “mildly reduced” or less coronary ﬂow in at least
one coronary territory.

Materials and methods
Study population
We evaluated 458 consecutive patients who underwent PET
myocardial perfusion imaging for the evaluation of suspected CAD
based on clinical indications between January 2017 and April 2020
at Hokkaido Ohno Memorial Hospital (Fig. 1). Among them, 407
underwent coronary assessments with CCTA, invasive CAG, or both,within 60 days of PET examination, and 164 patients showed noﬁndings of obstructive CAD in each coronary artery (<50% coronary diameter stenosis or fractional ﬂow reserve >0.80). We further excluded patients with left ventricular (LV) ejection fractions<40% (n=15), known myocardial infarction (n=5), cardiomyopathy (n=3), moderate or severe valvular disease (n=3), or congenital heart disease (n=1), ﬁnally resulting in 137 participants. Fig. 2
displays the comprehensive data from a single patient, including CCTA, relative uptake maps, absolute ﬂow, and CFR maps foreach coronary territory, and color ﬂow map as a sample. mCFC
was deﬁned as “impaired” (n=34), if regional CFC was mildlyreduced or worse in any coronary territory among three major
coronary-supplied territories, based on a scatter plot CFR versus
stress MBF [7]. The remaining patients (n=103) were included in
the “preserved” mCFC group. Patients’ medical histories, past or
current medication use, and selected laboratory values were ascertained during PET imaging. The Institutional Review Boards (IRB) of
Hokkaido Ohno Memorial Hospital approved this study (IRBs number: 2019-7), and all patients provided written informed consent
before CAG, CCTA, and PET examination; however, the requirement
for consent was waived for this study due to its retrospective nature. This study complied with all IRB requirements based on the
Declaration of Helsinki and ethical principles in the Belmont Report.

OutcomesPatient follow-up was performed using a questionnaire administered by telephone to all patients or their general practitioners or
cardiologists, and additional information was gathered from medical charts. The median follow-up period was 19.8 months [interquartile range (IQR): 14.1–31.2] after the PET scan, until the endof June 2020. Endpoints were deﬁned as cardiovascular death or
major adverse cardiovascular events (MACEs), such as cardiovascular death, nonfatal myocardial infarction, unplanned hospitalization
for any cardiac reasons, and coronary revascularization, including
percutaneous coronary intervention (PCI) or coronary artery bypass
grafting [15]. Of note, cardiovascular deaths included deaths resulting from myocardial infarction, sudden cardiac death, or death due
to heart failure (HF), stroke, cardiovascular hemorrhage, or othercardiovascular causes.
Statistical analysis
Baseline characteristics were reported as counts with percentages for categorical variables and medians with IQRs for continuous variables. We used the Fisher’s exact test and Wilcoxon
rank-sum test to assess differences in categorical and continuous baseline characteristics between the preserved and impaired
mCFC patients. Survival curves for the primary MACE endpoint andoverall survival in both groups were compared. Cox proportionalhazards models were used to examine the association between

PET acquisition protocol imaging analysis
All patients underwent single-day stress/rest 13 N-ammonia PET
with a PET/CT scanner (Biograph mCT Flow 64-4R PET/CT system; Siemens Healthcare, Germany). Dynamic PET at rest and during pharmacologic stress was performed in the 3D list mode, and248

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S. Miura, M. Naya, H. Kumamaru et al.

Fig. 1.

Journal of Cardiology 79 (2022) 247–256

Patient ﬂow chart. CAD, coronary artery disease; PET, positron emission tomography; mCFC, modiﬁed coronary ﬂow capacity.

1.88) vs. 2.63 mL/g/min (IQR, 2.24–2.92); p<0.001, respectively],while global rest MBF was similar in both groups (p=0.72). The
preserved mCFC group showed a normal ﬂow in 55% of the patients and minimally reduced ﬂow in 45%. In the impaired mCFC
group, a mildly reduced ﬂow was the most common, occurringin 76% of the patients. Disagreement on the mCFC classiﬁcation
among the three coronary territories was observed in 82% of theimpaired mCFC group and only 20% in the preserved mCFC group(p<0.001) (Table 2 and Online Fig. 1). The comparison of stress
MBF, rest MBF, and CFR by coronary territories between the twogroups is shown in Fig. 3, highlighting that rest MBF was uniformly
similar between them across all coronary territories. A signiﬁcantdifference in stress MBF and CFR was observed between the twogroups throughout the three coronary territories.

mCFC and outcome events, with and without controlling for age
and sex. Additionally, propensity scores (PS) were estimated forall patients using the following 6 established risk factors basedon previous studies [16, 17]: age, sex, diabetes (treatment withglucose-lowering medications or previous diagnosis of diabetes),
hypertension (treatment with antihypertensive drugs or hypertension history), chronic kidney disease (CKD) [deﬁned as an estimated glomerular ﬁltration rate (eGFR) <60 ml/min/1.73 m2 ], andoverweight (body mass index >25 kg/m2 ). We grouped the patients into ﬁve based on the quintiles of PS values and estimatedthe adjusted hazard ratios (HRs) using Cox regression models forboth cardiovascular death and MACEs by including the PS quintiles as a linear term. A p-value<0.05 was considered signiﬁcant.
All statistical analyses were performed using the R statistical software version 3.3.2 (R Foundation for Statistical Computing, Vienna,
Austria).

Impact of impaired mCFC on clinical outcome
Results

During the median follow-up period of 19.8 months with a
99% follow-up rate (135/137) until the end of June 2020, when all
were administratively censored, cardiovascular death occurred inﬁve (4%) patients, including sudden death in three and HF-related
death in two (Table 3). There were unplanned hospitalizations due
to cardiac reasons in 11 (8%) patients, speciﬁcally HF in 6, and ischemic heart events needing urgent admission but not requiring
any coronary revascularizations in 6 patients. One patient developed both HF and an ischemic heart event at different times. Contrarily, nonfatal myocardial infarctions never occurred, and coronary revascularization was performed with PCI in one patient fromthe preserved mCFC group. Overall, the incidence of unplanned
hospitalizations signiﬁcantly differed between the preserved andimpaired mCFC groups (2% and 26%, p<0.001, respectively).

The clinical characteristics and imaging parameters of the 137
patients are summarized in Tables 1 and 2. The median age was 70
years (IQR, 61–75); 46% were women, and 12% were asymptomatic.
The patients with impaired mCFC had a higher rate of hypertension and diabetes mellitus at baseline and underwent more CAG
examinations than those with preserved mCFC. The proportion of
women did not differ between the two groups. Regarding imaging
parameters, the impaired mCFC group had lower LV ejection fraction (rest and stress) and higher summed stress and rest score values. Global CFR and stress MBF were signiﬁcantly lower in the impaired mCFC group than in the preserved mCFC group [1.81 (IQR,
1.52–2.21) vs. 2.81 (IQR, 2.43–3.32); p<0.001; and 1.66 (IQR, 1.37–
249

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Journal of Cardiology 79 (2022) 247–256

Fig. 2. A representative case of a symptomatic 74-year-old woman in the impaired modiﬁed coronary ﬂow capacity (CFC) group. (A) A coronary computed tomography
angiography demonstrating no signiﬁcant epicardial stenosis. (B) Adenosine triphosphate-induced 13 N-ammonia positron emission tomography-derived quantiﬁcation valueof stress myocardial blood ﬂow (MBF) (left), rest MBF (center) and, coronary ﬂow reserve (CFR) (right) in the 17-segment standard American Heart Association model and(C) based on the three major coronary territories. A scatter plot of CFR versus absolute stress MBF originally proposed by Johnson and Gould [7] showed that regional CFC
was plotted based on stress MBF and CFR in the three coronary territories supplied by the major coronary arteries (right coronary artery, left anterior descending coronary
artery, and left circumﬂex coronary artery), and the worst regional CFC was interpreted as the patient’s modiﬁed CFC as illustrated in (D). PET, positron emission tomography;
MBF, myocardial blood ﬂow; CFR, coronary ﬂow reserve; RCA, right coronary artery; LCX, left circumﬂex coronary artery; LAD, left anterior descending coronary artery; CFC,
coronary ﬂow capacity; mCFC, modiﬁed coronary ﬂow capacity.

The Kaplan–Meier survival curves indicated that the impaired
mCFC group had a signiﬁcantly higher rate of cardiovascular death(log-rank p=0.004) and MACEs (log-rank p<0.0 0 01) than the preserved mCFC group (Fig. 4). Event-free survival for cardiovascular death at 24 months in the preserved and impaired mCFC
groups was 99% and 86%, respectively. In the crude assessment
displayed in Table 4, the impaired mCFC group had a signiﬁcantly high hazard ratio of MACEs [HR, 10.7; 95% conﬁdence interval (95% CI), 2.9–39.2; p<0.001] and cardiovascular death (HR,12.1; 95% CI, 1.3–108.0; p=0.02). The sex- and age-adjusted (HR,10.9; 95% CI, 3.0–39.7; p<0.001) and PS-adjusted (HR, 9.5; 95%
CI, 2.5–36.2; p<0.001) models showed signiﬁcant associations between impaired mCFC and MACEs. Similarly, the associations between impaired mCFC and cardiovascular death were signiﬁcant in
the age- and sex-adjusted (HR, 12.4; 95% CI, 1.3–111; p=0.02) andPS-adjusted (HR, 10.7; 95% CI, 1.0–106; p=0.04) analyses.

Discussion
We have demonstrated that in 137 patients without obstructive
coronary arteries undergoing myocardial perfusion PET, 25% had
impaired mCFC and 23% had lower global CFR (<2.0), while 88%
were symptomatic. Patients with impaired mCFC had a higher incidence of hypertension and diabetes at baseline than those withpreserved mCFC. Regarding clinical outcomes, patients with impaired mCFC were associated with a 9.5 times greater risk of
MACEs after PS adjustments than those with preserved mCFC.
Reportedly, CFC integrates the simultaneous regional size severity of the resting MBF, maximal MBF, and CFR by providing speciﬁc
patterns that are more accurate than those of CFR alone for distinguishing the effects of focal CAD, diffuse non-obstructive CAD,
and CMD by accounting for perfusion heterogeneity [18]. CFC canhave some merits in combating potential limitations of CFR. For ex250

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Journal of Cardiology 79 (2022) 247–256

Table 1Baseline Characteristics in Patients with Preserved and Impaired mCFC.
Characteristic
Demographic characteristics
Age, years
Female sex, n (%)
Body mass index, kg/m2
Body mass index >25 kg/m2 , n (%)
Symptomatic status, n (%)
Typical angina or exertional dyspnea
Atypical angina
Asymptomatic
Medical history, n (%)
Hypertension
Dyslipidemia
Diabetes mellitus
Prior percutaneous coronary intervention
Peripheral arterial disease
Prior heart failure
Atrial ﬁbrillation
Hemodialysis
Current smoker
Chronic lung disease
Malignancy
Medications, n (%)
Antiplatelet therapy
Calcium channel blockers
β -blockers
Cholesterol-lowering agents
ACEI/ARB
Nitrates
Diuretic
Oral hypoglycemic agents
InsulinLaboratory values
Hemoglobin, g/dl
eGFR, pg/ml
eGFR<60, n (%)
LDL cholesterol, mg/dl
HbA1c, %Fasting glucose, mg/dl
NT-proBNP, pg/ml
Coronary assessment, n (%)
CCTAInvasive CAG
Deferred by fractional ﬂow reserve

Overall (n=137)

Preserved mCFC (n=103)

Impaired mCFC (n=34)

p-value

70 [61, 75]
63 (46)24.6 [22.4, 27.0]
56 (41)

69 [61, 74]
48 (47)24.5 [22.3, 26.5]
39 (38)73 [61, 76]
15 (44)25.1 [22.8, 29.0]
17 (50)

0.40
0.84
0.24
0.23

80 (58)41 (30)16 (12)59 (57)33 (32)
11 (11)21 (62)8 (23)
5 (15)

0.59

85 (62)73 (53)34 (25)26 (19)7 (5)14 (10)12 (9)5 (4)
30 (22)12 (9)9 (7)

57 (55)52 (51)19 (18)16 (16)
4 (4)
7 (7)
9 (9)
2 (2)
24 (23)
8 (8)
7 (7)

28 (82)21 (62)15 (44)10 (29)3 (9)7 (21)3 (9)3 (9)6 (18)
4 (12)
2 (6)

0.005
0.32
0.005
0.083
0.36
0.04
1.0
0.09
0.63
0.49
1.0

48 (35)48 (35)32 (23)68 (50)57 (42)5 (4)11 (8)
27 (20)2 (2)33 (32)35 (34)21 (20)49 (48)40 (39)3 (3)7 (7)14 (14)0 (0)15 (44)13 (38)11 (32)19 (56)17 (50)2 (6)4 (12)
13 (38)
2 (6)

0.21
0.68
0.16
0.43
0.31
0.59
0.46
0.005
0.06

14 [13, 15]
68 [60, 78]
32 (24)104 [20, 212]
6.0 [5.7, 6.4]
112 [99, 138]
93 [44, 207]

14 [13, 15]
71 [61, 80]
22 (22)106 [20, 185]
5.9 [5.6, 6.2]
111 [96, 128]
88 [51, 159]

13 [11, 15]
64 [58, 74]
10 (29)102 [23, 212]
6.3 [5.9, 6.8]
121 [107, 162]
116 [29, 506]

0.14
0.09
0.48
0.81
0.004
0.01
0.58

95 (69)80 (58)21 (15)76 (74)54 (52)14 (14)19 (56)26 (77)7 (21)

0.05
0.01
0.41

Data are presented as median [interquartile range] or n (%) of patients.
mCFC, modiﬁed coronary ﬂow capacity; ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers; eGFR,
estimated glomerular ﬁltration rate; LDL, low-density lipoprotein; NT-proBNP, N-terminal pro–B-type natriuretic peptide; CCTA, coronary computed tomographic angiography; CAG, coronary angiography.

ample, rest ﬂow may be physiologically elevated in the setting ofanxiety or increased myocardial workload, whereas maximal ﬂow
in such settings will remain adequate when CFR is low without ischemic signs or symptoms. In this case, CFC would indicate normal
ﬂow capacity based on normal maximal ﬂow. Here, we added aunique aspect into the original CFC concept, by examining whether
vascular beds perfused by major coronary artery vessels with averaged stress MBF and CFR in that coronary ﬂow are inevitably affected by atherosclerosis burden within each of the arteries. These
concepts are already gaining increasing popularity by extrapolation to invasive CFC, assessed in terms of Doppler ﬂow velocity,wherein the magnitude is intrinsically corrected for the amount of
perfused myocardial mass in the coronary arterial distribution [8].
Hence, it may be of great importance to explore perfusion-territory
speciﬁc data to evaluate its diagnostic and prognostic values in
CAD-suspected patients undergoing myocardial perfusion PET.
Regarding characteristics of our study population, 243 (60%) of
the 407 patients who underwent both CAG and cardiac PET examinations showed obstructive coronary arteries, and one-fourthof the 137 patients without obstructive coronary arteries showed
impaired mCFC. The unique relationship between symptoms andmCFC highlighted no statistical difference in symptomatic status
between the two groups, and approximately 15% of the impaired
mCFC group was asymptomatic. Patients without obstructive coronary arteries are often told that their pain is noncardiac; therefore,
no further work-up is often planned, resulting in missed opportunities to diagnose and explore treatments for CMD for both symptom management and risk reduction. Concerning cardiovascularrisk factors, baseline hypertension and diabetes had signiﬁcantly
higher incidences in the impaired mCFC group, at 82% and 62%,
respectively. The reduction in PET-derived CFR has been found inpatients with hypertension regardless of the presence of LV hypertrophy, suggesting that intrinsic microvascular abnormalities (vascular remodeling and endothelial dysfunction) might play a moresigniﬁcant role in CMD development [19]. Similarly, impaired CFR
on cardiac PET has been demonstrated in patients with diabetes[20]. Independent of cardiovascular risk factors such as hypertension and diabetes, CKD is proposed as a more signiﬁcant risk factor in impaired renal function, including even minor renal abnormalities, that may promote cardiovascular diseases [21, 22]. Brieﬂy,
endothelial dysfunction is the potential pathophysiological mechanism involved in the association between CMD and CKD [23]. Here,251

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Journal of Cardiology 79 (2022) 247–256

Table 2
Myocardial Perfusion PET Findings in Patients with Preserved and Impaired mCFC.

Hemodynamics conditions during PET
Rest heart rate, bpm
Stress heart rate, bpm
Rest systolic blood pressure, mmHg
Stress systolic blood pressure, mmHg
Rest diastolic blood pressure, mmHg
Stress diastolic blood pressure, mmHg
Rest rate-pressure product, mmHg∗ bpm
Stress rate-pressure product, mmHg∗ bpm
Rest EDV (mL)Rest LVEF, %Stress LVEF, %delta LVEF, %Stress-induced increased LVEF, n (%)
Summed rest score
Summed stress score
Summed difference score
Rest MBF (mL/g/min)Corrected rest MBF, mL/g/min†Stress MBF (mL/g/min)
CFR
CFR <2.0, n (%)
Corrected CFR
Maximum CFR in 17 segments
Minimum CFR in 17 segments
Rest CVR, mm Hg/(ml/min/g) ‡Stress CVR, mm Hg/(ml/min/g) ‡Interpretation of mCFC, n (%)
Normal ﬂow capacity
Minimally reduced
Mildly reduced
Moderately reduced
Deﬁnite ischemia
Myocardial steal
Disagreement in regional CFC among three coronary territories§

Overall (n=137)

Preserved mCFC (n=103)

Impaired mCFC (n=34)

p-value

67 [58, 75]
77 [70, 85]
132 [117, 147]
116 [101, 128]
70 [63, 82]
62 [56, 70]
8400 [7198, 10200]
9116 [7500, 10656]
86 [70, 109]
70 [64, 78]
70 [62, 76]-2 [-4, 1]
39 (29)1 [0, 3]
4 [2, 8]2 [1, 4]0.93 [0.77, 1.10]
1.07 [0.91, 1.27]
2.34 [1.93, 2.76]
2.63 [2.14, 3.18]
31 (23)2.26 [1.83, 2.68]
3.35 [2.70, 4.00]
1.94 [1.65, 2.40]
97 [81, 114]
34 [28, 43]

67 [58, 75]
80 [70, 85]
128 [117, 147]
116 [104, 127]
70 [64, 81]
63 [57, 70]8580 [7198, 10096]
9348 [7628, 10709]
85 [67, 109]
72 [66, 79]
71 [65, 76]-2.00 [-4, 1]
28 (27)
1 [0, 2]
3 [2, 6]
2 [1, 4]0.93 [0.77, 1.10]
1.11 [0.94, 1.27]
2.63 [2.24, 2.92]
2.81 [2.43, 3.32]
6 (6)2.40 [2.06, 2.79]
3.61 [3.08, 4.14]
2.11 [1.82, 2.56]
96 [79, 114]
32 [26, 38]

69 [61, 75]
75 [70, 83]
136 [118, 149]
107 [94, 132]
73 [63, 84]
59 [52, 71]8347 [7238, 11051]
8105 [6965, 10231]
90 [76, 108]64 [55, 75]
62 [55, 72]-2 [-4, 2]
11 (32)
2 [1, 6]
8 [3, 11]
4 [0, 5]0.94 [0.72, 1.10]
0.99 [0.86, 1.20]
1.66 [1.37, 1.88]
1.81 [1.52, 2.21]
25 (74)1.50 [1.26, 2.06]
2.26 [1.88, 3.07]
1.48 [1.20, 1.59]
100 [86, 124]
48 [40, 59]

0.43
0.38
0.48
0.10
0.49
0.20
0.44
0.11
0.38
0.001
0.001
0.87
0.66
0.002
0.003
0.19
0.72
0.10
<0.001<0.001<0.001<0.001<0.001<0.0010.33<0.00157 (42)46 (34)26 (19)
6 (4)
1 (1)
1 (1)
49 (36)57 (55)46 (45)
0 (0)
0 (0)
0 (0)
0 (0)
21 (20)

0 (0)
0 (0)
26 (76)6 (18)1 (3)1 (3)28 (82)<0.001<0.001

Data are presented as median [interquartile range] or n (%) of patients.
PET, positron emission tomography; mCFC, modiﬁed coronary ﬂow capacity; EDV, end-diastolic volume; LVEF, left ventricular ejection fraction; MBF, myocardial
blood ﬂow; CFR, coronary ﬂow reserve; CVR, coronary vascular resistance. †Corrected rest MBF is computed by multiplying by the rest rate-pressure product/10
0 0 0. ‡Stress/rest coronary vascular resistance (CVR) is calculated by dividing stress/rest mean arterial pressure by CFR. §Disagreement in regional CFC is considered if regional CFC among three coronary territories in a single patient are not uniformly allocated to the same CFC category ranging from normal ﬂow tomyocardial steal.
Table 3
Detailed Clinical Outcomes in Patients with Preserved and Impaired mCFC.

All-cause death
Cardiovascular deathHeart failure-related death
Sudden death
MACEs
Nonfatal myocardial infarction
Unplanned hospitalization
Heart failure
Ischemic heart event
Coronary revascularization
Follow-up period, months

Overall (n=137)

Preserved mCFC (n=103)

Impaired mCFC (n=34)

p-value

5 (4)
5 (4)
2 (1)
3 (2)
13 (9)0 (0)
11 (8)
6 (4)
6 (4)
1 (1)
19.8 [14.1 - 31.2]

1 (1)
1 (1)
0 (0)
1 (1)
3 (3)
0 (0)
2 (2)
1 (1)
1 (1)
1 (1)
19.8 [13.9 - 29.3]

4 (12)
4 (12)2 (6)2 (6)10 (29)0 (0)9 (26)
5 (15)
5 (15)0 (0)21.8 [15.1 - 33.8]

0.01
0.01

<0.001NA<0.0011.0
0.38

Data are presented as median [interquartile range] or n (%) of patients.
mCFC, modiﬁed coronary ﬂow capacity; MACEs, major adverse cardiovascular events.
Table 4Crude and Adjusted Effects of Impaired mCFC on Cardiovascular Death and MACEs.
Crude

Cardiovascular death
Impaired mCFC
MACEs
Impaired mCFC

Age- and sex-adjusted

PS-adjusted

HR (95% CI)

p-valueHR (95% CI)

p-valueHR (95% CI)

p-value

12.1 (1.3 - 108)0.02

12.4 (1.3 - 111)

0.02

10.7 (1.0 - 106)0.04

10.7 (2.9 - 39.2)

p<0.001

10.9 (3.0 - 39.7)

p<0.001

9.5 (2.5 - 36.2)

p<0.001

MACEs, major adverse cardiovascular events; mCFC, modiﬁed coronary ﬂow capacity; HR, hazard ratio; CI, conﬁdence interval; PS, propensity score.
HRs were calculated with preserved mCFC used as a reference.

252

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Journal of Cardiology 79 (2022) 247–256

Fig. 3. Adenosine triphosphate-induced 13 N-ammonia positron emission tomography-derived quantiﬁcation measurements by coronary territory. (A) Comparison of stressmyocardial blood ﬂow (MBF), (B) rest MBF, and (C) coronary ﬂow reserve in the three coronary territories supplied by the major coronary arteries (right coronary artery, left
anterior descending coronary artery, and left circumﬂex coronary artery), with global left ventricle between the preserved (n=103) and impaired (n=34) modiﬁed coronary
ﬂow capacity groups. MBF, myocardial blood ﬂow; CFR, coronary ﬂow reserve; RCA, right coronary artery; LCX, left circumﬂex coronary artery; LAD, left anterior descending
coronary artery; mCFC, modiﬁed coronary ﬂow capacity.

a difference in eGFR value was observed between the preserved
mCFC and impaired mCFC groups (eGFR, 71 vs 64 pg/ml; p=0.09),
although it was not signiﬁcant. Interestingly, this ﬁnding may be
explained partially by a previous study that found that mild-tomoderate CKD was not independently associated with a reduction in peak myocardial ﬂow or CFR, although loss of CFR may
accelerate in mild-to-moderate CKD [24]. Overall, we believe thatthese associations among CMD, CKD, and traditional cardiovascularrisk factors could facilitate a deeper understanding of the potential
mechanisms of CMD development, as well as the importance of
CMD management in patients without obstructive CAD.
Importantly, disagreements in regional mCFC among the threecoronary territories were much more frequently observed in the
impaired mCFC group (82%) than in the preserved mCFC group(20%), as illustrated in Online Fig. 1, indicating that coronary ﬂow
had more heterogeneous distribution in the impaired mCFC groupthan in the preserved mCFC group. However, the overall mediansummed difference score on myocardial perfusion imaging (MPI)

was low at 2 (interquartile: 2–4), with no difference between bothgroups. This increases the signiﬁcance of assessing both regionaland global mCFC in addition to absolute indices (stress/rest MBF
and CFR) in patients without obstructive CAD, although the “visual
analysis” might be close to normal in the MPI study.
Technical problems to measure these PET-derived indices need
to be considered. For example, as illustrated in Fig. 2, CFR in the
RCA territory may be often calculated relatively higher than theother two territories due to overﬂow artifact from the adjacent
RV blood pool during the early phase of the scan, or motion artifact that is frequently observed in RCA and LAD territories. However, the imbalance/heterogeneity of coronary ﬂow in patients with
non-obstructive CAD could result mainly from not only hemodynamically signiﬁcant epicardial plaque burden in each coronary
artery but also from imbalanced distribution of CMD. Reportedly,
substantial discordance of classiﬁcation of CMD among coronary
artery territories observed in women with chest pain and nonobstructive CAD was consistent with our ﬁndings that CMD is dis253

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S. Miura, M. Naya, H. Kumamaru et al.

Journal of Cardiology 79 (2022) 247–256

Fig. 4. Kaplan–Meier curves of freedom from cardiovascular death (A) and major adverse cardiovascular events (MACEs) (B) between the patients with impaired and preserved modiﬁed coronary ﬂow capacity. MACEs include cardiovascular death, nonfatal myocardial infarction, unplanned hospitalization for any cardiac reasons, and coronary
revascularization. mCFC, modiﬁed coronary ﬂow capacity; PET, positron emission tomography.

tributed heterogeneously in the myocardium [25]. The patchy distribution of CMD could be explained by transmural heterogeneity, which cannot be assessed with diagnostic imaging. There isalso evidence for transmural heterogeneity due to reduced myogenic response in the subendocardium compared with the subepicardium [26]. This may account for the greater vulnerability of thesubendocardium to ischemic injury. Since myocardial metabolism
is aerobic with high baseline oxygen extraction, there is almost alinear relationship between oxygen demand and coronary blood
ﬂow. The local perfusion of the myocardium is highly heterogeneous, with high and low oxygenated areas, even in a normal heart[23]. Therefore, the heterogeneity is more prominent in patientswith CMD because heterogeneity results from adaptive processesof microcirculation in response to functional demands. These include fast changes in arteriolar diameter due to changes in smoothmuscle tone and slower long-term structural microvascular remodeling with the addition or removal of vessels by angiogenesis or
vascular pruning [27]. With these concepts applied, the disagreement between wire-derived regional CFR and cardiovascular magnetic resonance (CMR) imaging-derived global CFR in stable CAD
patients may be explained by the heterogeneity of coronary ﬂow[28].
Regarding clinical outcomes, the data on the prognostic valueof CMD in patients without obstructive coronary arteries remain
scarce. Impaired CFR or CMD has already been shown to predict
worse outcomes, irrespective of the cut-off used in recent studies [29], where patients with obstructive CAD were not speciﬁcally excluded through CCTA or invasive CAG. In a retrospective
study with 79 non-obstructive CAD patients [30], univariable Cox
regression analysis showed that CFR <2.0 was a signiﬁcant predictor of both mortality and MACEs, which is comparable to ourobservations. Nevertheless, a low sample size that is insuﬃcientfor multivariable analysis and a low complete follow-up rate (56%)
should be noted as limitations. Additionally, the idea of a regional,
rather than global, CFC has been developed recently. Gould et al.
have claimed that a severely reduced CFC in only 0.5% of the myocardium contains predictive information [9]. Another unique aspect of clinical events in this study is the signiﬁcant difference in

MACE rates between the two groups, mainly driven by a higher
incidence of unplanned hospitalizations for cardiac reasons in the
impaired mCFC group. However, a considerable gap in myocardial
infarction or revascularization rates was not found between themat reasonably low rates in a relatively short follow-up period. Conversely, unplanned admissions for documented ischemic signs, including typical chest pain attack, ST changes on an electrocardiogram, or newly developed wall motion asynergy on echocardiogram were among the unique manifestations mimicking epicardial coronary ischemic events, often needing CAG. One study has
shown that impaired CFR was an independent risk factor for HF
development [31], and CFR evaluated by CMR imaging was signiﬁcantly lower in patients with HF and preserved LVEF (HFpEF) thanin hypertensive patients with LV hypertrophy and controls. However, it remains debatable whether the impaired CFR might be apathophysiological factor for HFpEF or be related to the disease
severity.
Study limitations and strengths of our study
First, this study had a relatively small sample size, with few
events, and a relatively short follow-up period, although a highcomplete follow-up rate was achieved. Moreover, we cannot exclude the possibility of recruiting relatively high-risk patients, suchas, potentially, those with signiﬁcant coronary calcium or plaqueburden, or undiagnosed silent subendocardial myocardial infarction because myocardial perfusion PET/CT is often applied in Japan
when other modalities provide inconclusive ﬁndings. This trend
may reﬂect the relatively high event-rate in the study. Second, we
derived the global mCFC based on regional CFC analysis, by using
the lowest regional MBF estimates for the three main coronary vascular territories. We could not discuss fully whether global mCFC
could provide any diagnostic or prognostic advantages comparedto other established parameters, such as global CFC, stress MBF,
or CFR, although the concept of integrating regional ﬂow evaluation into clinical risk assessment is potentially reasonable. Further
studies might be necessary to justify a relevant cut-off for mCFC
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S. Miura, M. Naya, H. Kumamaru et al.

Journal of Cardiology 79 (2022) 247–256

classiﬁcation in justifying CMD diagnosis and its effect on clinicaloutcomes. Third, according to the stress protocol, we conducted
all myocardial perfusion PET examinations with pharmacologicalstress testing, not exercise stress testing, which can be a more
physiologic procedure with the added prognostic value of exercise
capacity and electrocardiographic changes. Nevertheless, perfusion
PET with exercise stress testing, which is not commercially available in Japan, has a low diagnostic value in patients who cannot
achieve an adequate heart rate and blood pressure response due
to a noncardiac physical limitation, particularly in the older population such as our study participants. Finally, we should interpret
mCFC based on coronary territory with caution because myocardial segments are generally assigned to coronary vascular territories, depending on the most frequent vascular distribution pattern.
However, these assumptions may be inaccurate due to individual
variability in coronary anatomy [32].

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Conclusions
In the 137 patients without obstructive coronary arteries, veriﬁed by CCTA or invasive CAG, mCFC integrating regional CFR andregional absolute stress perfusion based on coronary artery territory as a novel quantitative myocardial perfusion measurement
utilizing 13 N-ammonia PET/CT can be an incremental tool for predicting cardiovascular mortality and MACEs highlighting the highprevalence of CMD deﬁned by mCFC at 25%. Our results showedthat mCFC can help cardiologists identify patients who would beneﬁt from speciﬁc therapies or lifestyle modiﬁcations for preventing
future cardiovascular events, and it can help cardiologists understand potential mechanisms of CMD. Future long-term prospective
studies are necessary to achieve better classiﬁcation and to establish potential treatments for patients without obstructive coronary
arteries and CMD.

Funding
This research received no grant from any funding agency in the
public, commercial, or not-for-proﬁt sectors.

Disclosures
Dr Kumamaru has received a consultation fee from Mitsubishi
Tanabe Pharma and a speaker fee from Pﬁzer Japan Inc. He is alsoaﬃliated with the Department of Healthcare Quality Assessment
at the University of Tokyo. The department is a social collaboration supported by the National Clinical Database, Johnson & Johnson K.K., and Nipro Corporation.

Declaration of Competing Interest
The other authors declare no conﬂict of interest.

Acknowledgments
None.

Supplementary materials
Supplementary material associated with this article can befound, in the online version, at doi:10.1016/j.jjcc.2021.09.001.
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2019;26:1844–52.

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256

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