Original article
Characteristics of anginal patients with high resting myocardial blood flow measured with N-13 ammonia PET/CT Sang-Geon Choa, Ju Han Kimb, Jae Young Chob, Hyeon Sik Kimc, Seong Young Kwonc and Hee-Seung Bomc Objectives We hypothesized that anginal patients with low coronary flow reserve (CFR) could have variable clinical features according to resting myocardial blood flow (MBF). Therefore, we analyzed the clinical and imaging characteristics according to resting MBF in anginal patients. Methods We enrolled 70 patients who underwent N-13 ammonia PET–computed tomography (CT) for evaluation of angina. Resting and stress MBF values were obtained and resting MBF was corrected with rate–pressure product to exclude the effect of heart rate and blood pressure on resting MBF. Clinical and imaging characteristics were compared on the basis of MBF and CFR. Results Among patients with CFR less than 2.0, those with high resting MBF (≥1.0 ml/min/g) had significantly fewer number of smokers, were younger, had lower Agatston calcium scores, and had less coronary stenosis compared with those with low resting MBF (< 1.0 ml/min/g). In contrast, there was no significant difference in clinical or imaging findings according to resting MBF when compared among all patients or within those with CFR greater than or equal to 2.0. The subgroup analysis of patients with CFR less than 2.0 revealed lower Agatston calcium score and less coronary stenosis in patients with high resting MBF regardless of stress MBF.
Introduction Myocardial perfusion PET provides high temporal resolution and attenuation correction, and recent advancements in PET technology have brought the assessment of myocardial tracer kinetics into the daily management of coronary arterial disease (CAD) [1]. Clinical reporting of myocardial perfusion PET imaging includes quantitative myocardial blood flow (MBF) and coronary flow reserve (CFR) in addition to traditional relative perfusion and functional parameters of left ventricular contraction [2]. CFR is the ratio of stress MBF to resting MBF, which is an absolute assessment of vasodilatory function of a given arterial distribution [3]. It proved to be a valid, noninvasive marker of the hemodynamic significance of coronary artery stenosis [4,5] and its decrease is an indication of microvascular disease associated with higher rate of adverse cardiovascular events [6,7]. Decreased CFR results mainly from impaired coronary endothelial function, which can diminish the extent of MBF increase during vasodilatory stress. However, by its 0143-3636 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Conclusion High resting MBF is associated with a lower rate of smoking, younger age, less coronary calcium burden, and less coronary stenosis compared with low resting MBF in anginal patients with low CFR. Moreover, in these patients, favorable angiographic features were mainly associated with high resting MBF, irrespective of stress MBF. Therefore, resting MBF should be reviewed to validate the clinical significance of low CFR measured by N-13 ammonia PET/CT especially in anginal patients showing low CFR. Nucl Med Commun 36:619–624 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Nuclear Medicine Communications 2015, 36:619–624 Keywords: age, coronary calcium, coronary flow reserve, coronary stenosis, N-13 ammonia positron emission tomography, resting myocardial blood flow, smoking Departments of aNuclear Medicine, bCardiology, Chonnam National University Hospital, Gwangju and cDepartment of Nuclear Medicine, Chonnam National University Hwasun Hospital, Jeonnam, Korea Correspondence to Hee-Seung Bom, MD, PhD, Department of Nuclear Medicine, Chonnam National University Hwasun Hospital, 322 Seoyang-ro Hwasun-eup, Hwasun-gun, Jeonnam 519-763, Korea Tel: + 82 61 379 7270; fax: + 82 61 379 7281; e-mail: [email protected] Received 29 May 2014 Revised 18 October 2014 Accepted 22 January 2015
definition, decreased CFR can also result from high resting MBF despite preserved stress MBF. In a recent review paper [8], the flow data of two patients with nearly identically reduced stress MBF but different resting MBF were depicted, and markedly different perfusion maps were created showing an ischemic range of CFR in one patient and a nonischemic CFR in the other. Such variability of resting MBF can be confusing for defining the future risk or for selecting treatment strategies merely based on CFR. Higher resting MBF was observed in patients with several cardiovascular risk factors [9–14]. In contrast, resting MBF was correlated with the serum level of HDL in a previous report [15], and a significantly lower resting MBF was observed in patients with coronary atherosclerosis as compared with those without in a recent study [16]. The clinical implication of resting MBF varies among those reports, and thus the clinical interpretation of resting MBF is challenging. We hypothesized that patients with low CFR but high resting MBF possess different characteristics, compared DOI: 10.1097/MNM.0000000000000293
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620 Nuclear Medicine Communications 2015, Vol 36 No 6
with those with low CFR and low resting MBF. Therefore, we investigated the characteristics of anginal patients according to their MBF and CFR.
Methods Patients
Seventy consecutive patients who underwent N-13 ammonia PET/computed tomography (CT) for evaluation of anginal chest pain were enrolled. Exclusion criteria included previous or newly diagnosed myocardial infarction, history of heart failure, known myocardial disease such as cardiomyopathy, valvular heart disease, acute or chronic renal failure, and bronchial asthma. Clinical and imaging characteristics of the enrolled patients are listed in Table 1. This study was approved by the Chonnam National University Hospital Institutional Review Board.
Table 1
Patient characteristics (n = 70)
Sex Male Female Age (years) BMI (kg/m2) Personal history Smoking Diabetes Hypertension Anemia Previous coronary arterial disease ACE inhibitor or angiotensin receptor blocker β-Blocker Calcium channel blocker Statin Antiplatelets Nitrate Laboratory findings WBC count/mm3 Serum creatinine (mg/dl) Total cholesterol (mg/dl) LDL (mg/dl) HDL (mg/dl) Apo A1 (mg/dl) Apo B (mg/dl) Apo B/A1 ratio Lipoprotein (a) (mg/dl) Homocysteine (μmol/l) CT coronary angiography Agatston calcium score Significant stenosis (≥50%) Hemodynamics at rest Resting SBP (mmHg) Resting HR/min RPP (mmHg/min) N-13 ammonia PET results SSS SRS SDS Resting MBF (ml/min/g) Stress MBF (ml/min/g) CFR
43 (61) 27 (39) 63.1 ± 9.7 25.8 ± 3.8 24 (34) 19 (27) 34 (49) 12 (17) 9 (13) 14 (20) 14 (20) 12 (17) 18 (26) 29 (41) 17 (24) 6620.9 ± 1902.0 1.0 ± 1.4 162.0 ± 45.7 97.2 ± 37.6 41.2 ± 10.8 118.9 ± 19.3 79.1 ± 28.6 0.68 ± 0.25 22.1 ± 21.3 10.0 ± 4.9 403.2 ± 563.5 30 (43) 126.8 ± 16.9 71.1 ± 12.3 9044.8 ± 2145.0 7.8 ± 4.9 3.7 ± 4.0 4.0 ± 4.6 1.13 ± 0.31 2.21 ± 0.73 2.05 ± 0.78
Data are mean ± SD, or n followed by percentage in parentheses. ACE, angiotensin-converting enzyme; Apo, apolipoprotein; CFR, coronary flow reserve; CT, computed tomography; HR, heart rate; MBF, myocardial blood flow; RPP, rate–pressure product; SBP, systolic blood pressure; SDS, summed difference score; SRS, summed rest score; SSS, summed stress score; WBC, white blood cell.
N-13 ammonia PET Image acquisition
The patients fasted for at least 4 h, and they abstained from methylxanthine derivatives including caffeine for at least 24 h before the N-13 ammonia PET/CT acquisition. Vasodilator medications such as nitrate, β-blocker, or calcium channel blocker were also stopped 24 h before PET acquisition. All patients underwent an appropriate history taking, and their informed consent was obtained. Patients’ resting heart rate (HR) and systolic blood pressure were measured just before N-13 ammonia PET/CT acquisition, and the rate–pressure product (RPP) was calculated by multiplying HR with systolic blood pressure. An intravenous line was placed in the patient’s radial vein, followed by a low-dose CT scan (120 kV, 30 mA) for attenuation correction. The injection was done within 15 s as a bolus. Dynamic image acquisition commenced right after the injection had started and lasted for 6 min. Then, 13 min of ECG-gated static image acquisition followed. An additional intravenous line was placed in the other radial vein after 60 min rest, and 0.14 mg/kg/min of adenosine was infused intravenously for 6 min for vasodilator stress. N-13 ammonia was injected 3 min after the infusion had started. Stress imaging was performed with the same dose and protocol as rest imaging. Image acquisition was performed with a dedicated PET scanner with BGO crystal and an eight-slice CT scanner (Discovery ST; GE Healthcare, Cleveland, Ohio, USA), and image reconstruction was performed using ordered subset expectation maximization with two of iterations. Myocardial blood flow and coronary flow reserve
The resting and stress dynamic imaging data were extracted for MBF analysis. Using PMOD software (PMOD Technologies, Zurich, Switzerland), the myocardium was reoriented into short-axis images. Thereafter, a volume of interest covering the myocardium of the left ventricle was defined. A two-tissue compartment model that assumes the metabolic trapping of N-13 ammonia as an irreversible step was used for calculation of global MBF using the formula previously described by Choi et al. [17]. Resting MBF was corrected with RPP for each patient as follows: (resting MBF/RPP) × 10 000 [18]. CFR was calculated by dividing stress MBF with corrected resting MBF. CT coronary angiography
Image acquisition was performed with a two-phase, contrast-enhanced, ECG-gated, multidetector CT scanner (Sensation Cardiac 64; Siemens Medical Solutions, Erlangen, Germany). Acquisition conditions included 0.75 mm section thickness, 0.33 s gantry rotation time, 800 mAs at 120 kVp of tube current, and pitch 0.2. Serial CT scanning in the axial plane was performed from the level of the left ventricular apex after a bolus injection of 60 ml nonionic contrast medium (Ultravist 370; Bayer Schering Pharma, Berlin, Germany), followed by a bolus
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High resting myocardial blood flow Cho et al. 621
injection of 60 ml saline at the injection speed of 4 ml/s. The axial images were reconstructed at multiple phases that covered the cardiac cycle in increments of 10% of the RR interval between 5 and 95%. Multiphase reconstruction was performed by using short-axis slices from the base to the apex of the heart with the use of the commercially available software Argus (Siemens Medical Solutions). Coronary calcium was quantified using the Agatston calcium score (ACS) using 130 Hounsfield units as the cutoff, and the total calcium score was used for analysis. Two experienced, blinded cardiac imaging specialists reviewed the CT coronary angiography (CTCA) images for the presence of significant (≥50%) stenosis.
Statistical analyses
Clinical and imaging characteristics of the patients were compared between patients with high (≥1.0 ml/min/g) and those with low (< 1.0 ml/min/g) resting MBF among those with CFR less than 2.0 and CFR greater than or equal to 2.0, respectively, as well as among all patients. Subgroup analyses were also performed in patients with CFR less than 2.0 to exclude the confounding effects of stress MBF on the resting MBF-based analyses. Classification of subgroups was based on binary cutoffs of CFR 2.0, stress MBF 2.0 ml/min/g, and resting MBF 1.0 ml/min/g, and the distribution of patients is listed in Table 2. Because CFR lower than 2.0 and low resting MBF and stress MBF greater than or equal to 2.0 ml/ min/g cannot occur simultaneously, the analyses were performed only in those with CFR lower than 2.0 and high resting MBF and stress MBF of 2.0 ml/min/g or higher (group A, n = 16), CFR lower than 2.0 and high resting MBF and stress MBF lower than 2.0 ml/min/g (group B, n = 13), and CFR lower than 2.0 and low resting MBF and stress MBF lower than 2.0 ml/min/g (group C, n = 7). The Student t-test and the Mann–Whitney U-test were used for comparison of continuous variables, whereas the χ2-test and Fisher’s exact test were used for binary variables. Continuous values are given as mean ± SD, and statistical significance was defined as a P-value less than 0.05. Number of patients according to coronary flow reserve and myocardial blood flow
Table 2
≥ 1.0 Stress MBF (ml/min/g) ≥ 2.0 16 < 2.0 13
CFR ≥ 2.0 (n = 34)
< 1.0
≥ 1.0
< 1.0
0 7
17 0
12 5
CFR, coronary flow reserve; MBF, myocardial blood flow.
Results Myocardial blood flow and coronary flow reserve
Overall, the mean resting MBF, stress MBF, and CFR were 1.28 ± 0.26 ml/min/g, 2.31 ± 0.69 ml/min/g, and 1.84 ± 0.62, respectively, in patients with high resting MBF, and 0.83 ± 0.13 ml/min/g, 2.02 ± 0.76 ml/min/g, and 2.45 ± 0.90 in those with low resting MBF. CFR was significantly lower in patients with high resting MBF (P = 0.001), despite similar stress MBF (P = 0.111). In patients with CFR lower than 2.0, CFR values were similar between patients with high and those with low resting MBF (1.47 ± 0.36 vs. 1.36 ± 0.35; P = 0.270), although stress MBF was significantly higher in those with high resting MBF (2.02 ± 0.62 vs. 1.10 ± 0.36 ml/min/g; P = 0.001). In patients with CFR greater than or equal to 2.0, CFR was significantly lower in those with high resting MBF (2.47 ± 0.43 vs. 2.90 ± 0.61; P = 0.013), although their stress MBF was significantly higher (2.81 ± 0.51 vs. 2.40 ± 0.51 ml/min/g; P = 0.005), as shown in Table 3. Clinical characteristics and CT coronary angiographic findings Patients with CFR < 2.0
Patients with high resting MBF were significantly younger (62.6 ± 10.6 vs. 72.1 ± 5.4 years; P = 0.018), had fewer smokers (17 vs. 71%; P = 0.010), and had lower ACS (355.4 ± 532.6 vs. 1205.7 ± 795.7; P = 0.006) and less coronary stenosis (41 vs. 100%; P = 0.006) compared with those with low resting MBF (Table 3). On subgroup analysis, groups A and B did not show any significant difference in clinical or CTCA features between each other. However, they both showed significantly lower ACS (275.5 ± 343.2, 453.8 ± 704.1, and 1205.7 ± 795.7 for groups A, B, and C, respectively) and had lower frequency of significant stenosis (38, 46, and 100%) compared with group C (Fig. 1). Patients with CFR ≥ 2.0
There was no significant difference in clinical characteristics or CTCA findings according to resting MBF, except RPP and HR, which were corrected in the calculation of resting MBF (Table 3).
Discussion
Resting MBF (ml/min/g) CFR < 2.0 (n = 36)
Statistical calculation was performed using SPSS, version 21.0 for Windows (SPSS Inc., Chicago, Illinois, USA).
The present study was conducted to clarify the meaning of high resting MBF in patients with anginal chest pain. As expected, high resting MBF led to lower CFR despite similar or even higher stress MBF. However, it was associated with favorable features including younger age, fewer smokers, lower ACS, and less coronary stenosis as compared with lower resting MBF when analyzed in
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622 Nuclear Medicine Communications 2015, Vol 36 No 6
Table 3
Comparison of clinical and imaging characteristics by resting myocardial blood flow within different coronary flow reserves Resting MBF (ml/min/g) CFR < 2.0 (n = 36)
Females Age (years) BMI (kg/m2) Smoking Diabetes Hypertension Previous coronary arterial disease Anemia ACE inhibitor or angiotensin receptor blocker β-Blocker Calcium channel blocker Statin Antiplatelets Nitrate WBC count/mm3 Serum creatinine (mg/dl) Total cholesterol (mg/dl) LDL (mg/dl) HDL (mg/dl) ApoA1 (mg/dl) ApoB (mg/dl) Apo B/A1 ratio Lipoprotein (a) (mg/dl) Homocysteine (μmol/l) CT coronary angiography Agatston calcium score Significant stenosis (≥50%) Resting SBP (mmHg) Resting HR/min RPP (mmHg/min) SSS SRS SDS
CFR ≥ 2.0 (n = 34)
≥ 1.0 (n = 29)
< 1.0 (n = 7)
P-value
≥ 1.0 (n = 17)
< 1.0 (n = 17)
P-value
14 (48) 62.6 ± 10.6 25.9 ± 3.8 5 (17) 9 (31) 20 (69) 6 (21) 5 (17) 8 (28) 6 (21) 8 (28) 9 (31) 14 (48) 11 (38) 6882.8 ± 1847.2 0.8 ± 0.2 171.0 ± 53.6 106.7 ± 46.3 41.6 ± 10.2 119.2 ± 17.2 85.5 ± 34.1 0.73 ± 0.32 19.1 ± 9.7 11.6 ± 6.5
1 (14) 72.1 ± 5.4 26.1 ± 4.0 5 (71) 2 (29) 3 (43) 2 (29) 2 (29) 2 (29) 1 (14) 0 (0) 1 (14) 2 (29) 2 (29) 6228.6 ± 3724.1 1.0 ± 0.2 155.7 ± 49.8 98.4 ± 37.4 36.6 ± 12.7 107.8 ± 18.2 79.4 ± 25.0 0.73 ± 0.16 30.8 ± 32.0 10.4 ± 2.4
0.111 0.018* 1.000 0.010* 0.641 0.196 0.497 0.415 0.645 0.585 0.142 0.355 0.306 0.501 0.165 0.146 0.505 0.901 0.163 0.408 0.944 0.760 0.900 1.000
7 (41) 63.1 ± 9.5 26.1 ± 4.2 8 (47) 5 (29) 5(29) 0 (0) 2 (12) 2 (12) 3 (18) 2 (12) 2 (12) 4 (24) 2 (12) 6435.3 ± 1410.2 0.7 ± 0.2 157.6 ± 41.5 88.1 ± 28.4 43.5 ± 13.4 122.7 ± 25.6 73.1 ± 26.5 0.60 ± 0.17 25.7 ± 34.2 8.0 ± 1.3
5 (29) 60.4 ± 8.2 24.9 ± 3.8 6 (35) 3 (18) 6 (35) 1 (6) 3 (18) 2 (12) 4 (24) 2 (12) 6 (35) 9 (53) 2 (12) 6500.0 ± 1368.3 1.5 ± 2.8 153.9 ± 33.9 90.7 ± 28.6 40.2 ± 7.7 119.3 ± 15.5 72.2 ± 17.0 0.62 ± 0.17 19.1 ± 12.1 9.3 ± 4.1
0.360 0.394 0.252 0.364 0.344 0.500 0.500 0.500 0.699 0.500 0.699 0.112 0.079 0.699 0.769 0.146 0.919 0.838 0.496 0.899 0.820 0.860 0.980 0.595
355.4 ± 532.6 12 (41) 120.1 ± 13.1 66.4 ± 12.2 7982.9 ± 1764.8 8.8 ± 5.0 4.2 ± 4.3 4.6 ± 4.5
1205.7 ± 795.7 7 (100) 137.3 ± 13.6 72.6 ± 15.8 9824.4 ± 1476.9 8.7 ± 5.0 5.1 ± 5.0 3.6 ± 3.5
0.006* 0.006* 0.002* 0.366 0.005* 0.907 0.131 0.102
235.7 ± 298.2 6 (35) 124.8 ± 11.2 71.2 ± 11.5 8934.2 ± 1934.1 6.2 ± 4.3 2.6 ± 2.2 3.6 ± 4.9
321.8 ± 473.2 5 (29) 136.1 ± 22.8 78.2 ± 8.5 10645.7 ± 2188.0 7.2 ± 5.2 2.8 ± 3.6 4.4 ± 4.8
0.838 0.500 0.067 0.038* 0.018* 0.658 0.708 0.339
Data are mean ± SD, or n followed by percentage in parentheses. ACE, angiotensin-converting enzyme; Apo, apolipoprotein; CFR, coronary flow reserve; CT, computed tomography; HR, heart rate; MBF, myocardial blood flow; RPP, rate–pressure product; SBP, systolic blood pressure; SDS, summed difference score; SRS, summed rest score; SSS, summed stress score; WBC, white blood cell. *P < 0.05.
Fig. 1
(a) Agatston calcium score
(b)
∗
2500
∗
∗ 1205.7 ± 795.7
2000 NS
1500
∗
NS 100% 75%
453.8 ± 704.1
50%
1000 275.5 ± 343.2
25%
500
0%
0 A
B Groups
C
A
B
C
Groups Stenosis (−)
Stenosis (+)
Subgroup analysis within patients with low coronary flow reserve. In patients with CFR < 2.0, the Agatston calcium score was significantly lower (a) and coronary stenosis was less frequently found (b) in those with high resting MBF. However, within those with high resting MBF, no significant difference was found according to stress MBF. *P < 0.05; CFR, coronary flow reserve; MBF, myocardial blood flow; NS, not significant.
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High resting myocardial blood flow Cho et al. 623
patients with CFR less than 2.0. Even after excluding the confounding effect of stress MBF on resting MBF-based analyses, favorable CTCA findings still remained significantly associated with high resting MBF. However, the association was not evident when analyzed in all patients or only in those with CFR of at least 2.0. In young asymptomatic individuals, the normal range of noninvasive CFR is greater than 4.0 [19,20], whereas 2.0 is generally accepted as the threshold for myocardial ischemia [21]. A decrease in CFR reflects impaired coronary vasomotion to increase MBF during stress, which is thought to precede atherosclerosis [22,23]. Quantification of MBF and CFR by myocardial perfusion PET makes it possible to assess the hemodynamic changes associated with coronary endothelial dysfunction in a noninvasive manner. However, resting MBF, the denominator component of CFR, also varies with different clinical conditions or cardiovascular risk factors and thus a low CFR does not necessarily mean a reduction in stress MBF [24]. Some previous reports described several pathologic conditions associated with higher resting MBF, including chronic kidney disease (CKD) or hemodialysis state [9–12], metabolic syndrome [13], and familial hyperlipidemia [14]. Fukushima et al. [9] recruited 36 patients with CKD and 44 controls who were matched with age, sex, and hemodynamics and found that resting MBF was significantly higher in those with CKD (1.2 ± 0.6 vs. 0.8 ± 0.2 ml/min/g, P = 0.001). Resting MBF was still higher in CKD patients after correction for cardiac work, and it showed significant inverse correlation with estimated glomerular filtration rate (r = − 0.44). Di Carli et al. [13] reported that resting MBF showed a stepwise increase with increasing features of metabolic syndrome, whereas adenosine-induced stress MBF remained similar, and consequently stepwise reduction of CFR. Although the differences in resting MBF and CFR were not significant after correction of cardiac work with RPP, their observation that RPP was significantly higher in those with syndrome features indicates the possibility of upregulated cardiac workload by early coronary atherosclerosis. In addition, reduction of resting MBF after short-term cardiovascular conditioning along with a lowfat diet [25] and low-dose angiotensin-converting enzyme inhibitor medication [26] indicates a pathologic aspect of increased resting MBF, which should be corrected. In contrast, Duvernoy et al. [15] reported in a study with 15 postmenopausal women and 15 men with one or more risk factors that female sex and higher HDL were the predictive factors for higher resting MBF. Liga et al. [16] recruited 167 patients with anginal chest pain and low-tointermediate pretest probability, and analyzed predictors of resting MBF less than 0.60 ml/min/g, which was the median value in that population. They found that more female than male patients, patients with less coronary
atherosclerosis, and those with less coronary stenosis were observed among patients with resting MBF greater than or equal to 0.60 ml/min/g. Consistent with the latter studies showing a positive aspect of high resting MBF, this study also showed that more favorable cardiovascular risk factors including younger age, lower smoking rate, lower ACS, and less coronary stenosis were observed in patients with high resting MBF. Interestingly, clinical and angiographic characteristics were significantly different between patients with high and those with low resting MBF only when compared within those with CFR less than 2.0, but not in those with preserved CFR. Once CFR was preserved, there was no clinical significance of resting MBF in terms of clinical and angiographic characteristics, and thus reviewing resting MBF was not considered necessary. In addition, revealing the clinical implication of resting MBF in this study was possible by a further subgroup evaluation of the effect of stress MBF to overcome the interaction among resting, stress MBF, and CFR. Hence, even though a single study cannot fully explain the role of resting MBF in the evaluation of angina, the results of the present study suggest that the meaning of resting MBF should be differentially interpreted according to CFR, which has not been analyzed in previous reports. Heterogeneous implications of high resting MBF result not only from the difference in patient selection or analytical methods but also from lack of integrating MBF and CFR. More detailed evaluation integrating resting, stress MBF, and CFR should be performed in future studies, although there is no currently available guide for physiological integration of noninvasive MBF and CFR [8]. Coronary calcium burden is associated with increased cardiovascular risk [27,28] and proved to be independently predictive of all-cause mortality in a large cohort study [27]. In a previous report by Curillova and colleagues coronary calcium burden was mainly associated with stress MBF and CFR. Stress MBF was significantly different among different groups of discrete calcium score ranges, whereas resting MBF was not. They emphasized the modest, but statistically significant, inverse correlation between coronary artery calcium and CFR, although the additional explanatory role was relatively small [29]. It differs from our results in that the differences in CTCA findings were mainly associated with resting MBF. However, they enrolled only patients without definite ischemia (SSS >1), and thus advanced coronary atherosclerosis or overt CAD was probably not included, whereas we did not exclude patients with definite ischemia or obstructive CAD. Therefore, our study population might have had relatively more advanced atherosclerosis for which resting MBF can be more clinically meaningful compared with stress MBF or CFR as shown in Fig. 1.
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624 Nuclear Medicine Communications 2015, Vol 36 No 6
There are several limitations in this study. The analysis was performed in a retrospective manner and the number of patients is relatively small. Further, we did not follow up the patients for a sufficient amount of time to evaluate their prognosis. The prognostic implication of high resting MBF cannot be concluded in this study, although it is conceivable to some extent.
Conclusion When CFR was reduced to less than 2.0 in anginal patients, high resting MBF was found to be associated with favorable clinical and angiographic characteristics, including younger age, lower rate of smoking, lower ACS, and less coronary stenosis, as compared with those with low resting MBF. In particular, the favorable angiographic features were still evident in patients with high resting MBF, regardless of stress MBF. Therefore, resting MBF should be reviewed in anginal patients showing low CFR, which may not indicate diminished stress MBF but high resting MBF associated with more favorable clinical and angiographic features.
Acknowledgements
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This study was supported by a grant (A070001) from the Korea National Enterprise for Clinical Trials. 20
Conflicts of interest
There are no conflicts of interest.
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Characteristics of anginal patients with high resting myocardial blood flow measured with N-13 ammonia PET/CT Sang-Geon Choa, Ju Han Kimb, Jae Young Chob, Hyeon Sik Kimc, Seong Young Kwonc and Hee-Seung Bomc Objectives We hypothesized that anginal patients with low coronary flow reserve (CFR) could have variable clinical features according to resting myocardial blood flow (MBF). Therefore, we analyzed the clinical and imaging characteristics according to resting MBF in anginal patients. Methods We enrolled 70 patients who underwent N-13 ammonia PET–computed tomography (CT) for evaluation of angina. Resting and stress MBF values were obtained and resting MBF was corrected with rate–pressure product to exclude the effect of heart rate and blood pressure on resting MBF. Clinical and imaging characteristics were compared on the basis of MBF and CFR. Results Among patients with CFR less than 2.0, those with high resting MBF (≥1.0 ml/min/g) had significantly fewer number of smokers, were younger, had lower Agatston calcium scores, and had less coronary stenosis compared with those with low resting MBF (< 1.0 ml/min/g). In contrast, there was no significant difference in clinical or imaging findings according to resting MBF when compared among all patients or within those with CFR greater than or equal to 2.0. The subgroup analysis of patients with CFR less than 2.0 revealed lower Agatston calcium score and less coronary stenosis in patients with high resting MBF regardless of stress MBF.
Introduction Myocardial perfusion PET provides high temporal resolution and attenuation correction, and recent advancements in PET technology have brought the assessment of myocardial tracer kinetics into the daily management of coronary arterial disease (CAD) [1]. Clinical reporting of myocardial perfusion PET imaging includes quantitative myocardial blood flow (MBF) and coronary flow reserve (CFR) in addition to traditional relative perfusion and functional parameters of left ventricular contraction [2]. CFR is the ratio of stress MBF to resting MBF, which is an absolute assessment of vasodilatory function of a given arterial distribution [3]. It proved to be a valid, noninvasive marker of the hemodynamic significance of coronary artery stenosis [4,5] and its decrease is an indication of microvascular disease associated with higher rate of adverse cardiovascular events [6,7]. Decreased CFR results mainly from impaired coronary endothelial function, which can diminish the extent of MBF increase during vasodilatory stress. However, by its 0143-3636 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Conclusion High resting MBF is associated with a lower rate of smoking, younger age, less coronary calcium burden, and less coronary stenosis compared with low resting MBF in anginal patients with low CFR. Moreover, in these patients, favorable angiographic features were mainly associated with high resting MBF, irrespective of stress MBF. Therefore, resting MBF should be reviewed to validate the clinical significance of low CFR measured by N-13 ammonia PET/CT especially in anginal patients showing low CFR. Nucl Med Commun 36:619–624 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Nuclear Medicine Communications 2015, 36:619–624 Keywords: age, coronary calcium, coronary flow reserve, coronary stenosis, N-13 ammonia positron emission tomography, resting myocardial blood flow, smoking Departments of aNuclear Medicine, bCardiology, Chonnam National University Hospital, Gwangju and cDepartment of Nuclear Medicine, Chonnam National University Hwasun Hospital, Jeonnam, Korea Correspondence to Hee-Seung Bom, MD, PhD, Department of Nuclear Medicine, Chonnam National University Hwasun Hospital, 322 Seoyang-ro Hwasun-eup, Hwasun-gun, Jeonnam 519-763, Korea Tel: + 82 61 379 7270; fax: + 82 61 379 7281; e-mail: [email protected] Received 29 May 2014 Revised 18 October 2014 Accepted 22 January 2015
definition, decreased CFR can also result from high resting MBF despite preserved stress MBF. In a recent review paper [8], the flow data of two patients with nearly identically reduced stress MBF but different resting MBF were depicted, and markedly different perfusion maps were created showing an ischemic range of CFR in one patient and a nonischemic CFR in the other. Such variability of resting MBF can be confusing for defining the future risk or for selecting treatment strategies merely based on CFR. Higher resting MBF was observed in patients with several cardiovascular risk factors [9–14]. In contrast, resting MBF was correlated with the serum level of HDL in a previous report [15], and a significantly lower resting MBF was observed in patients with coronary atherosclerosis as compared with those without in a recent study [16]. The clinical implication of resting MBF varies among those reports, and thus the clinical interpretation of resting MBF is challenging. We hypothesized that patients with low CFR but high resting MBF possess different characteristics, compared DOI: 10.1097/MNM.0000000000000293
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620 Nuclear Medicine Communications 2015, Vol 36 No 6
with those with low CFR and low resting MBF. Therefore, we investigated the characteristics of anginal patients according to their MBF and CFR.
Methods Patients
Seventy consecutive patients who underwent N-13 ammonia PET/computed tomography (CT) for evaluation of anginal chest pain were enrolled. Exclusion criteria included previous or newly diagnosed myocardial infarction, history of heart failure, known myocardial disease such as cardiomyopathy, valvular heart disease, acute or chronic renal failure, and bronchial asthma. Clinical and imaging characteristics of the enrolled patients are listed in Table 1. This study was approved by the Chonnam National University Hospital Institutional Review Board.
Table 1
Patient characteristics (n = 70)
Sex Male Female Age (years) BMI (kg/m2) Personal history Smoking Diabetes Hypertension Anemia Previous coronary arterial disease ACE inhibitor or angiotensin receptor blocker β-Blocker Calcium channel blocker Statin Antiplatelets Nitrate Laboratory findings WBC count/mm3 Serum creatinine (mg/dl) Total cholesterol (mg/dl) LDL (mg/dl) HDL (mg/dl) Apo A1 (mg/dl) Apo B (mg/dl) Apo B/A1 ratio Lipoprotein (a) (mg/dl) Homocysteine (μmol/l) CT coronary angiography Agatston calcium score Significant stenosis (≥50%) Hemodynamics at rest Resting SBP (mmHg) Resting HR/min RPP (mmHg/min) N-13 ammonia PET results SSS SRS SDS Resting MBF (ml/min/g) Stress MBF (ml/min/g) CFR
43 (61) 27 (39) 63.1 ± 9.7 25.8 ± 3.8 24 (34) 19 (27) 34 (49) 12 (17) 9 (13) 14 (20) 14 (20) 12 (17) 18 (26) 29 (41) 17 (24) 6620.9 ± 1902.0 1.0 ± 1.4 162.0 ± 45.7 97.2 ± 37.6 41.2 ± 10.8 118.9 ± 19.3 79.1 ± 28.6 0.68 ± 0.25 22.1 ± 21.3 10.0 ± 4.9 403.2 ± 563.5 30 (43) 126.8 ± 16.9 71.1 ± 12.3 9044.8 ± 2145.0 7.8 ± 4.9 3.7 ± 4.0 4.0 ± 4.6 1.13 ± 0.31 2.21 ± 0.73 2.05 ± 0.78
Data are mean ± SD, or n followed by percentage in parentheses. ACE, angiotensin-converting enzyme; Apo, apolipoprotein; CFR, coronary flow reserve; CT, computed tomography; HR, heart rate; MBF, myocardial blood flow; RPP, rate–pressure product; SBP, systolic blood pressure; SDS, summed difference score; SRS, summed rest score; SSS, summed stress score; WBC, white blood cell.
N-13 ammonia PET Image acquisition
The patients fasted for at least 4 h, and they abstained from methylxanthine derivatives including caffeine for at least 24 h before the N-13 ammonia PET/CT acquisition. Vasodilator medications such as nitrate, β-blocker, or calcium channel blocker were also stopped 24 h before PET acquisition. All patients underwent an appropriate history taking, and their informed consent was obtained. Patients’ resting heart rate (HR) and systolic blood pressure were measured just before N-13 ammonia PET/CT acquisition, and the rate–pressure product (RPP) was calculated by multiplying HR with systolic blood pressure. An intravenous line was placed in the patient’s radial vein, followed by a low-dose CT scan (120 kV, 30 mA) for attenuation correction. The injection was done within 15 s as a bolus. Dynamic image acquisition commenced right after the injection had started and lasted for 6 min. Then, 13 min of ECG-gated static image acquisition followed. An additional intravenous line was placed in the other radial vein after 60 min rest, and 0.14 mg/kg/min of adenosine was infused intravenously for 6 min for vasodilator stress. N-13 ammonia was injected 3 min after the infusion had started. Stress imaging was performed with the same dose and protocol as rest imaging. Image acquisition was performed with a dedicated PET scanner with BGO crystal and an eight-slice CT scanner (Discovery ST; GE Healthcare, Cleveland, Ohio, USA), and image reconstruction was performed using ordered subset expectation maximization with two of iterations. Myocardial blood flow and coronary flow reserve
The resting and stress dynamic imaging data were extracted for MBF analysis. Using PMOD software (PMOD Technologies, Zurich, Switzerland), the myocardium was reoriented into short-axis images. Thereafter, a volume of interest covering the myocardium of the left ventricle was defined. A two-tissue compartment model that assumes the metabolic trapping of N-13 ammonia as an irreversible step was used for calculation of global MBF using the formula previously described by Choi et al. [17]. Resting MBF was corrected with RPP for each patient as follows: (resting MBF/RPP) × 10 000 [18]. CFR was calculated by dividing stress MBF with corrected resting MBF. CT coronary angiography
Image acquisition was performed with a two-phase, contrast-enhanced, ECG-gated, multidetector CT scanner (Sensation Cardiac 64; Siemens Medical Solutions, Erlangen, Germany). Acquisition conditions included 0.75 mm section thickness, 0.33 s gantry rotation time, 800 mAs at 120 kVp of tube current, and pitch 0.2. Serial CT scanning in the axial plane was performed from the level of the left ventricular apex after a bolus injection of 60 ml nonionic contrast medium (Ultravist 370; Bayer Schering Pharma, Berlin, Germany), followed by a bolus
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High resting myocardial blood flow Cho et al. 621
injection of 60 ml saline at the injection speed of 4 ml/s. The axial images were reconstructed at multiple phases that covered the cardiac cycle in increments of 10% of the RR interval between 5 and 95%. Multiphase reconstruction was performed by using short-axis slices from the base to the apex of the heart with the use of the commercially available software Argus (Siemens Medical Solutions). Coronary calcium was quantified using the Agatston calcium score (ACS) using 130 Hounsfield units as the cutoff, and the total calcium score was used for analysis. Two experienced, blinded cardiac imaging specialists reviewed the CT coronary angiography (CTCA) images for the presence of significant (≥50%) stenosis.
Statistical analyses
Clinical and imaging characteristics of the patients were compared between patients with high (≥1.0 ml/min/g) and those with low (< 1.0 ml/min/g) resting MBF among those with CFR less than 2.0 and CFR greater than or equal to 2.0, respectively, as well as among all patients. Subgroup analyses were also performed in patients with CFR less than 2.0 to exclude the confounding effects of stress MBF on the resting MBF-based analyses. Classification of subgroups was based on binary cutoffs of CFR 2.0, stress MBF 2.0 ml/min/g, and resting MBF 1.0 ml/min/g, and the distribution of patients is listed in Table 2. Because CFR lower than 2.0 and low resting MBF and stress MBF greater than or equal to 2.0 ml/ min/g cannot occur simultaneously, the analyses were performed only in those with CFR lower than 2.0 and high resting MBF and stress MBF of 2.0 ml/min/g or higher (group A, n = 16), CFR lower than 2.0 and high resting MBF and stress MBF lower than 2.0 ml/min/g (group B, n = 13), and CFR lower than 2.0 and low resting MBF and stress MBF lower than 2.0 ml/min/g (group C, n = 7). The Student t-test and the Mann–Whitney U-test were used for comparison of continuous variables, whereas the χ2-test and Fisher’s exact test were used for binary variables. Continuous values are given as mean ± SD, and statistical significance was defined as a P-value less than 0.05. Number of patients according to coronary flow reserve and myocardial blood flow
Table 2
≥ 1.0 Stress MBF (ml/min/g) ≥ 2.0 16 < 2.0 13
CFR ≥ 2.0 (n = 34)
< 1.0
≥ 1.0
< 1.0
0 7
17 0
12 5
CFR, coronary flow reserve; MBF, myocardial blood flow.
Results Myocardial blood flow and coronary flow reserve
Overall, the mean resting MBF, stress MBF, and CFR were 1.28 ± 0.26 ml/min/g, 2.31 ± 0.69 ml/min/g, and 1.84 ± 0.62, respectively, in patients with high resting MBF, and 0.83 ± 0.13 ml/min/g, 2.02 ± 0.76 ml/min/g, and 2.45 ± 0.90 in those with low resting MBF. CFR was significantly lower in patients with high resting MBF (P = 0.001), despite similar stress MBF (P = 0.111). In patients with CFR lower than 2.0, CFR values were similar between patients with high and those with low resting MBF (1.47 ± 0.36 vs. 1.36 ± 0.35; P = 0.270), although stress MBF was significantly higher in those with high resting MBF (2.02 ± 0.62 vs. 1.10 ± 0.36 ml/min/g; P = 0.001). In patients with CFR greater than or equal to 2.0, CFR was significantly lower in those with high resting MBF (2.47 ± 0.43 vs. 2.90 ± 0.61; P = 0.013), although their stress MBF was significantly higher (2.81 ± 0.51 vs. 2.40 ± 0.51 ml/min/g; P = 0.005), as shown in Table 3. Clinical characteristics and CT coronary angiographic findings Patients with CFR < 2.0
Patients with high resting MBF were significantly younger (62.6 ± 10.6 vs. 72.1 ± 5.4 years; P = 0.018), had fewer smokers (17 vs. 71%; P = 0.010), and had lower ACS (355.4 ± 532.6 vs. 1205.7 ± 795.7; P = 0.006) and less coronary stenosis (41 vs. 100%; P = 0.006) compared with those with low resting MBF (Table 3). On subgroup analysis, groups A and B did not show any significant difference in clinical or CTCA features between each other. However, they both showed significantly lower ACS (275.5 ± 343.2, 453.8 ± 704.1, and 1205.7 ± 795.7 for groups A, B, and C, respectively) and had lower frequency of significant stenosis (38, 46, and 100%) compared with group C (Fig. 1). Patients with CFR ≥ 2.0
There was no significant difference in clinical characteristics or CTCA findings according to resting MBF, except RPP and HR, which were corrected in the calculation of resting MBF (Table 3).
Discussion
Resting MBF (ml/min/g) CFR < 2.0 (n = 36)
Statistical calculation was performed using SPSS, version 21.0 for Windows (SPSS Inc., Chicago, Illinois, USA).
The present study was conducted to clarify the meaning of high resting MBF in patients with anginal chest pain. As expected, high resting MBF led to lower CFR despite similar or even higher stress MBF. However, it was associated with favorable features including younger age, fewer smokers, lower ACS, and less coronary stenosis as compared with lower resting MBF when analyzed in
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622 Nuclear Medicine Communications 2015, Vol 36 No 6
Table 3
Comparison of clinical and imaging characteristics by resting myocardial blood flow within different coronary flow reserves Resting MBF (ml/min/g) CFR < 2.0 (n = 36)
Females Age (years) BMI (kg/m2) Smoking Diabetes Hypertension Previous coronary arterial disease Anemia ACE inhibitor or angiotensin receptor blocker β-Blocker Calcium channel blocker Statin Antiplatelets Nitrate WBC count/mm3 Serum creatinine (mg/dl) Total cholesterol (mg/dl) LDL (mg/dl) HDL (mg/dl) ApoA1 (mg/dl) ApoB (mg/dl) Apo B/A1 ratio Lipoprotein (a) (mg/dl) Homocysteine (μmol/l) CT coronary angiography Agatston calcium score Significant stenosis (≥50%) Resting SBP (mmHg) Resting HR/min RPP (mmHg/min) SSS SRS SDS
CFR ≥ 2.0 (n = 34)
≥ 1.0 (n = 29)
< 1.0 (n = 7)
P-value
≥ 1.0 (n = 17)
< 1.0 (n = 17)
P-value
14 (48) 62.6 ± 10.6 25.9 ± 3.8 5 (17) 9 (31) 20 (69) 6 (21) 5 (17) 8 (28) 6 (21) 8 (28) 9 (31) 14 (48) 11 (38) 6882.8 ± 1847.2 0.8 ± 0.2 171.0 ± 53.6 106.7 ± 46.3 41.6 ± 10.2 119.2 ± 17.2 85.5 ± 34.1 0.73 ± 0.32 19.1 ± 9.7 11.6 ± 6.5
1 (14) 72.1 ± 5.4 26.1 ± 4.0 5 (71) 2 (29) 3 (43) 2 (29) 2 (29) 2 (29) 1 (14) 0 (0) 1 (14) 2 (29) 2 (29) 6228.6 ± 3724.1 1.0 ± 0.2 155.7 ± 49.8 98.4 ± 37.4 36.6 ± 12.7 107.8 ± 18.2 79.4 ± 25.0 0.73 ± 0.16 30.8 ± 32.0 10.4 ± 2.4
0.111 0.018* 1.000 0.010* 0.641 0.196 0.497 0.415 0.645 0.585 0.142 0.355 0.306 0.501 0.165 0.146 0.505 0.901 0.163 0.408 0.944 0.760 0.900 1.000
7 (41) 63.1 ± 9.5 26.1 ± 4.2 8 (47) 5 (29) 5(29) 0 (0) 2 (12) 2 (12) 3 (18) 2 (12) 2 (12) 4 (24) 2 (12) 6435.3 ± 1410.2 0.7 ± 0.2 157.6 ± 41.5 88.1 ± 28.4 43.5 ± 13.4 122.7 ± 25.6 73.1 ± 26.5 0.60 ± 0.17 25.7 ± 34.2 8.0 ± 1.3
5 (29) 60.4 ± 8.2 24.9 ± 3.8 6 (35) 3 (18) 6 (35) 1 (6) 3 (18) 2 (12) 4 (24) 2 (12) 6 (35) 9 (53) 2 (12) 6500.0 ± 1368.3 1.5 ± 2.8 153.9 ± 33.9 90.7 ± 28.6 40.2 ± 7.7 119.3 ± 15.5 72.2 ± 17.0 0.62 ± 0.17 19.1 ± 12.1 9.3 ± 4.1
0.360 0.394 0.252 0.364 0.344 0.500 0.500 0.500 0.699 0.500 0.699 0.112 0.079 0.699 0.769 0.146 0.919 0.838 0.496 0.899 0.820 0.860 0.980 0.595
355.4 ± 532.6 12 (41) 120.1 ± 13.1 66.4 ± 12.2 7982.9 ± 1764.8 8.8 ± 5.0 4.2 ± 4.3 4.6 ± 4.5
1205.7 ± 795.7 7 (100) 137.3 ± 13.6 72.6 ± 15.8 9824.4 ± 1476.9 8.7 ± 5.0 5.1 ± 5.0 3.6 ± 3.5
0.006* 0.006* 0.002* 0.366 0.005* 0.907 0.131 0.102
235.7 ± 298.2 6 (35) 124.8 ± 11.2 71.2 ± 11.5 8934.2 ± 1934.1 6.2 ± 4.3 2.6 ± 2.2 3.6 ± 4.9
321.8 ± 473.2 5 (29) 136.1 ± 22.8 78.2 ± 8.5 10645.7 ± 2188.0 7.2 ± 5.2 2.8 ± 3.6 4.4 ± 4.8
0.838 0.500 0.067 0.038* 0.018* 0.658 0.708 0.339
Data are mean ± SD, or n followed by percentage in parentheses. ACE, angiotensin-converting enzyme; Apo, apolipoprotein; CFR, coronary flow reserve; CT, computed tomography; HR, heart rate; MBF, myocardial blood flow; RPP, rate–pressure product; SBP, systolic blood pressure; SDS, summed difference score; SRS, summed rest score; SSS, summed stress score; WBC, white blood cell. *P < 0.05.
Fig. 1
(a) Agatston calcium score
(b)
∗
2500
∗
∗ 1205.7 ± 795.7
2000 NS
1500
∗
NS 100% 75%
453.8 ± 704.1
50%
1000 275.5 ± 343.2
25%
500
0%
0 A
B Groups
C
A
B
C
Groups Stenosis (−)
Stenosis (+)
Subgroup analysis within patients with low coronary flow reserve. In patients with CFR < 2.0, the Agatston calcium score was significantly lower (a) and coronary stenosis was less frequently found (b) in those with high resting MBF. However, within those with high resting MBF, no significant difference was found according to stress MBF. *P < 0.05; CFR, coronary flow reserve; MBF, myocardial blood flow; NS, not significant.
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High resting myocardial blood flow Cho et al. 623
patients with CFR less than 2.0. Even after excluding the confounding effect of stress MBF on resting MBF-based analyses, favorable CTCA findings still remained significantly associated with high resting MBF. However, the association was not evident when analyzed in all patients or only in those with CFR of at least 2.0. In young asymptomatic individuals, the normal range of noninvasive CFR is greater than 4.0 [19,20], whereas 2.0 is generally accepted as the threshold for myocardial ischemia [21]. A decrease in CFR reflects impaired coronary vasomotion to increase MBF during stress, which is thought to precede atherosclerosis [22,23]. Quantification of MBF and CFR by myocardial perfusion PET makes it possible to assess the hemodynamic changes associated with coronary endothelial dysfunction in a noninvasive manner. However, resting MBF, the denominator component of CFR, also varies with different clinical conditions or cardiovascular risk factors and thus a low CFR does not necessarily mean a reduction in stress MBF [24]. Some previous reports described several pathologic conditions associated with higher resting MBF, including chronic kidney disease (CKD) or hemodialysis state [9–12], metabolic syndrome [13], and familial hyperlipidemia [14]. Fukushima et al. [9] recruited 36 patients with CKD and 44 controls who were matched with age, sex, and hemodynamics and found that resting MBF was significantly higher in those with CKD (1.2 ± 0.6 vs. 0.8 ± 0.2 ml/min/g, P = 0.001). Resting MBF was still higher in CKD patients after correction for cardiac work, and it showed significant inverse correlation with estimated glomerular filtration rate (r = − 0.44). Di Carli et al. [13] reported that resting MBF showed a stepwise increase with increasing features of metabolic syndrome, whereas adenosine-induced stress MBF remained similar, and consequently stepwise reduction of CFR. Although the differences in resting MBF and CFR were not significant after correction of cardiac work with RPP, their observation that RPP was significantly higher in those with syndrome features indicates the possibility of upregulated cardiac workload by early coronary atherosclerosis. In addition, reduction of resting MBF after short-term cardiovascular conditioning along with a lowfat diet [25] and low-dose angiotensin-converting enzyme inhibitor medication [26] indicates a pathologic aspect of increased resting MBF, which should be corrected. In contrast, Duvernoy et al. [15] reported in a study with 15 postmenopausal women and 15 men with one or more risk factors that female sex and higher HDL were the predictive factors for higher resting MBF. Liga et al. [16] recruited 167 patients with anginal chest pain and low-tointermediate pretest probability, and analyzed predictors of resting MBF less than 0.60 ml/min/g, which was the median value in that population. They found that more female than male patients, patients with less coronary
atherosclerosis, and those with less coronary stenosis were observed among patients with resting MBF greater than or equal to 0.60 ml/min/g. Consistent with the latter studies showing a positive aspect of high resting MBF, this study also showed that more favorable cardiovascular risk factors including younger age, lower smoking rate, lower ACS, and less coronary stenosis were observed in patients with high resting MBF. Interestingly, clinical and angiographic characteristics were significantly different between patients with high and those with low resting MBF only when compared within those with CFR less than 2.0, but not in those with preserved CFR. Once CFR was preserved, there was no clinical significance of resting MBF in terms of clinical and angiographic characteristics, and thus reviewing resting MBF was not considered necessary. In addition, revealing the clinical implication of resting MBF in this study was possible by a further subgroup evaluation of the effect of stress MBF to overcome the interaction among resting, stress MBF, and CFR. Hence, even though a single study cannot fully explain the role of resting MBF in the evaluation of angina, the results of the present study suggest that the meaning of resting MBF should be differentially interpreted according to CFR, which has not been analyzed in previous reports. Heterogeneous implications of high resting MBF result not only from the difference in patient selection or analytical methods but also from lack of integrating MBF and CFR. More detailed evaluation integrating resting, stress MBF, and CFR should be performed in future studies, although there is no currently available guide for physiological integration of noninvasive MBF and CFR [8]. Coronary calcium burden is associated with increased cardiovascular risk [27,28] and proved to be independently predictive of all-cause mortality in a large cohort study [27]. In a previous report by Curillova and colleagues coronary calcium burden was mainly associated with stress MBF and CFR. Stress MBF was significantly different among different groups of discrete calcium score ranges, whereas resting MBF was not. They emphasized the modest, but statistically significant, inverse correlation between coronary artery calcium and CFR, although the additional explanatory role was relatively small [29]. It differs from our results in that the differences in CTCA findings were mainly associated with resting MBF. However, they enrolled only patients without definite ischemia (SSS >1), and thus advanced coronary atherosclerosis or overt CAD was probably not included, whereas we did not exclude patients with definite ischemia or obstructive CAD. Therefore, our study population might have had relatively more advanced atherosclerosis for which resting MBF can be more clinically meaningful compared with stress MBF or CFR as shown in Fig. 1.
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624 Nuclear Medicine Communications 2015, Vol 36 No 6
There are several limitations in this study. The analysis was performed in a retrospective manner and the number of patients is relatively small. Further, we did not follow up the patients for a sufficient amount of time to evaluate their prognosis. The prognostic implication of high resting MBF cannot be concluded in this study, although it is conceivable to some extent.
Conclusion When CFR was reduced to less than 2.0 in anginal patients, high resting MBF was found to be associated with favorable clinical and angiographic characteristics, including younger age, lower rate of smoking, lower ACS, and less coronary stenosis, as compared with those with low resting MBF. In particular, the favorable angiographic features were still evident in patients with high resting MBF, regardless of stress MBF. Therefore, resting MBF should be reviewed in anginal patients showing low CFR, which may not indicate diminished stress MBF but high resting MBF associated with more favorable clinical and angiographic features.
Acknowledgements
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This study was supported by a grant (A070001) from the Korea National Enterprise for Clinical Trials. 20
Conflicts of interest
There are no conflicts of interest.
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