Incremental Diagnostic Value of Regional Myocardial Blood Flow Quantification Over Relative Perfusion Imaging With Generator-Produced Rubidium-82 PET

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1 Circulation Journal Official Journal of the Japanese Circulation Society Incremental Diagnostic Value of Regional Myocardial Blood Flow Quantification Over Relative Perfusion Imaging With Generator-Produced Rubidium- PET Keiichiro Yoshinaga, MD, PhD; Chietsugu Katoh, MD, PhD; Osamu Manabe, MD, PhD; Ran Klein, PhD; Masanao Naya, MD, PhD; Mamoru Sakakibara, MD, PhD; Shiro Yamada, MD; Robert A. dekemp, PhD; Hiroyuki Tsutsui, MD, PhD; Nagara Tamaki, MD, PhD Background: Myocardial blood flow (MBF) can be measured with positron emission tomography (PET) and its quantification should provide diagnostic information beyond that obtained through standard visual analysis. However, this possibility has not been fully studied with PET and generator-produced rubidium- ( Rb). We evaluated regional MBF in segments with and without ischemia using Rb PET in patients with coronary artery disease (CAD). Methods and Results: Rest and stress Rb PET and coronary angiography were performed for 12 patients with CAD. Based on angiography and relative Rb perfusion images, segments were classified into 4 groups (Group A: myocardial ischemia with >70% diameter stenosis; Group B: no ischemia with stenosis; Group C: no ischemia without stenosis; Group D: ischemia without stenosis). Rest MBF was similar among the 4 groups. Groups A and B showed reduced hyperemic MBF compared with Group C ( vs. Group C) [Group A (n=16) 1.28±0.58 ml min 1 g 1 ; Group B (n=11) 1.72±0.64 ml min 1 g 1 ; Group C (n=9) 2.60±1.09 ml min 1 g 1 ; Group D (n=2) 2.33 ml min 1 g 1 ]. Coronary flow reserves were inversely correlated with percent diameter stenosis (r= 0.76, P<0.0001). Conclusions: Segments with ischemia and coronary stenosis had reduced hyperemic MBF. Segments with coronary stenosis without ischemia also had reduced hyperemic MBF compared with non-stenotic segments. MBF quantification using Rb PET may provide additional diagnostic information. Key Words: Blood flow; Coronary artery disease; Myocardial perfusion imaging; Positron emission tomography; Rubidium- Detecting myocardial ischemia is important for risk stratification and decision making with regard to coronary revascularization in patients with coronary artery disease (CAD). 1,2 Regional myocardial ischemia is among the indications for revascularization and its detection is therefore important to patient care. Single-photon emission tomography (SPECT) myocardial perfusion imaging (MPI) has played an important role in the detection of myocardial ischemia and has an established role in risk stratification of patients with CAD. 3 7 In SPECT MPI, the diagnosis of regional myocardial ischemia is based on reduced tracer uptake relative to that in other segments that are assumed to be normally perfused. 8 This approach is therefore sometimes considered to underestimate disease severity, especially in patients with multivessel CAD. Positron emission tomography (PET) is a state-of-the-art nuclear cardiology imaging modality, with better diagnostic accuracy than SPECT MPI because it uses attenuation correction However, even with hybrid PET/computed tomography (CT), the accuracy of a diagnosis of coronary vessel-based CAD is still relatively low with relative perfusion imaging, because it uses the same approach as SPECT MPI. 12 Sampson et al reported that patient-based sensitivity and specificity were 93% and 83%, respectively, but on the other hand, the exact agreement between results obtained using rubidium- ( Rb) and the anatomic extent of CAD (as reported with coronary angiography [CAG]) was relatively low at 64%. 12 This limitation is related primarily to the interpretation of relative perfusion imaging, whether with SPECT or with PET. PET is a noninvasive method of quantifying regional myo- Received May 17, 2011; revised manuscript received July 10, 2011; accepted July 19, 2011; released online August 27, 2011 Time for primary review: 19 days Department of Photobiology (K.Y.), Health Sciences (C.K.), Nuclear Medicine (O.M., R.K., N.T.), Cardiovascular Medicine (M.N., M.S., S.Y., H.T.), Hokkaido University Graduate School of Medicine, Sapporo, Japan; and National Cardiac PET Centre, Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario (R.K., R.A.deK.), Canada Mailing address: Keiichiro Yoshinaga, MD, PhD, FACC, Associate Professor, Department of Photobiology, Division of Molecular and Cellular Imaging, Hokkaido University Graduate School of Medicine, Kita 15 Nishi 7, Kita-ku, Sapporo , Japan. kyoshi@ med.hokudai.ac.jp ISSN doi: /circj.CJ All rights are reserved to the Japanese Circulation Society. For permissions, please cj@j-circ.or.jp

2 YOSHINAGA K et al. cardial blood flow (MBF). 13,14 Hajjiri et al reported that MBF quantification had better diagnostic accuracy than did relative perfusion uptake using 13 N-ammonia PET. 15 We demonstrated that regional MBF quantification had an additional diagnostic value over 99m Tc tetrofosmin SPECT MPI using 15 O-water PET. 16 In most previous studies, MBF measurements using PET have been performed using either 15 O-water or 13 N-ammonia, which requires immediate access to an on-site cyclotron. 13,14 This requirement is a major limitation of PET MBF quantification and makes it difficult to evaluate myocardial ischemia or risk in larger populations. Rb is a PET perfusion tracer produced from a strontium- ( Sr)/ Rb generator. 17 In North America, Rb is widely used in PET centers without immediate access to a cyclotron for the diagnosis of CAD. 11,14 Recently, some centers in Japan and Europe have started using Rb. 17,18 However, there are still limited data reported on MBF quantification using Rb Parkash et al, using a net retention model for MBF quantification and examining perfusion in the left ventricle (LV) as a whole, suggested that the results were more severe than those determined using a standard uptake approach to evaluate regional MBF. 24 However, they used the net retention model for MBF quantification, which is an approach that has higher statistical noise and is considered to be less accurate than a compartmental model. Moreover, they evaluated only global LV MBF and did not evaluate regional MBF. To our knowledge, no data evaluating the additional value of regional MBF quantification over relative perfusion imaging using Rb PET have been published. The purpose of the current study was to evaluate the additional diagnostic value of regional MBF quantification over that of relative perfusion imaging in segments with and without ischemia using Rb PET in patients with known or suspected CAD. Methods Study Population Patients with known or suspected CAD, whose condition was stable and who did not undergo coronary revascularization or have a myocardial infarction within 4 weeks prior to the study (n=12) were followed prospectively between August 2007 and September Exclusion criteria were previous myocardial infarction and severe obstructive lung disease. This study was approved by the Hokkaido University Graduate School of Medicine Human Research Ethics Board. Written informed consent was given by all subjects. Study Protocol The study population underwent CAG and Rb PET imaging within 8 weeks (mean interval 11.5±13.4 days, range 1 49 days). All subjects were in a stable clinical condition between the Rb PET and angiographic procedures. PET Acquisition Protocol Patients were instructed to fast for >6 h and to abstain from caffeine-containing products for >24 h before the PET studies. 16,25,26 Participants were positioned with the heart centered in the field of view of a whole-body PET scanner (ECAT HR+, Siemens/CTI Knoxville, TN, USA). All emission and transmission scans were performed in the 2-D acquisition mode. Immediately following the 5-min transmission scan, 1,480 MBq of Rb (Bracco Diagnosis, Princeton, NJ, USA or DRAXIMAGE, Kirkland, QC, Canada) was administered intravenously over 1 min. 18,27 A 10-min, 17-frame dynamic acquisition was initiated (12 10 s, 2 30 s, 1 60 s, s, s). 18,21,27,28 Then, 10 min later, we repeated the same sequence of dynamic acquisition during adenosine triphosphate (ATP) induced hyperemia. ATP (160 μg kg 1 min 1 ) was infused intravenously for 9 min, and image acquisition was started 3 min after the start of the ATP infusion. 18,29 During the ATP stress, symptoms, heart rate, blood pressure, and the ECG were continuously monitored. Image Processing Dynamic image data were reconstructed using filtered backprojection reconstruction with a 12-mm Hann filter with randoms, scatter, attenuation and decay corrections. Each image consisted of 63 transaxial slices, each having voxels with dimensions mm. A myocardial uptake image was generated by summing the last 4 6 min of the image sequence. A blood volume image was created by summing the first 2 min of the image sequence. The images were reoriented and segmented semi-automatically to generate LV blood and myocardial time activity curves (TACs). Standard Relative Perfusion Image Interpretation Two experienced observers blinded to all clinical data reviewed each rest and pharmacological stress myocardial perfusion image. A consensus was reached in cases where there were differences in observations. Regional relative myocardial perfusion was assessed using the 17-segment model. The semiquantitative scoring system of defect severity used a 5-point scale (0 = normal to 4 = absent uptake) as recommended by American Society of Nuclear Cardiology (ASNC). 30 Summed difference scores 2 were considered to indicate the presence of myocardial ischemia. 28,30 Regional perfusion abnormalities were assigned to a coronary arterial territory based on ASNC imaging guidelines. 30 Quantification of MBF Regional MBF quantification was performed using a software program developed in-house. 18 This software semi-automatically defines regions of interest (ROIs) for the LV cavity blood pool and the LV myocardium. 31 The LV wall is divided into 16 segments 32 and grouped into 3 coronary artery territories. 16 The program then performs segmental MBF quantification using a 1-tissue-compartment tracer kinetic model 21,31 as follows. The segmental ROIs were applied to the dynamic image sequence to generate LV blood and myocardium TACs, LV(t) and R(t), respectively. The myocardium was modeled as a partial volume mixture of arterial blood, Ca(t), and tissue, Ct(t), activity concentrations as in Equation 1 where PTF denotes perfusable tissue fraction. Va is the arterial blood volume, and ρis the density of tissue (1.04 g/ml). R(t) = PTF ρ Ct(t) + Va Ca(t) (1) The change in myocardial activity concentration was modeled using the 1-tissue-compartment model in Equation 2, where K1 (ml min 1 g 1 ) is the uptake rate from blood into the tissue and k2 (/min) is the washout rate from myocardial tissue into the blood Ca(t) (Bq/ml). dct(t)/dt = K1 Ca(t) k2 Ct(t) (2) The LV blood activity concentration was modeled as a partial volume mixture of β=85% arterial blood and (1-β=15%) tissue, as shown in Equation 3. LV(t) =β Ca(t) + (1-β) ρ Ct(t) (3) Equations 1 3 were used to estimate the parameters K1, k2, PTF, Va with a non-linear least-squares analysis. Conversion

3 MBF on Rb PET from K1 to MBF was estimated with the modified Renkin- Crone model 18,21 as shown in Equation 4. K1 = MBF[1-0.86exp( 0.543/MBF)] (4) The baseline MBF is closely related to the rate pressure product (RPP). Thus, rest MBF results were corrected for the RPP as rest MBF (normal mean RPP/individual RPP). 16,18 The normal mean RPP at rest in our institution was 8, RPP-corrected coronary flow reserve (CFR) was calculated as the ratio of MBF during hyperemia to RPP-corrected rest MBF. 16,18 CAG All patients underwent CAG using a standard technique. Two experienced investigators blinded to the clinical and Rb PET data analyzed the CAG data. The angiographic criterion used to define the significant coronary stenosis was defined as >70% decrease in diameter for the 3 major coronary arteries or their major branches using quantitative coronary analysis (QCA). 12 Segmentation Classifications Using QCA data and relative Rb relative perfusion images, the LV segments were classified into 4 groups (Group A: myocardial ischemia with >70% diameter stenosis; Group B: no ischemia with stenosis; Group C: no ischemia without stenosis; Group D: ischemia without stenosis). Table 1. Baseline Demographics Known or suspected CAD (n=12) Age (years) 70.8±10.2 Male 6 (50%) BMI (kg/m 2 ) 22.9±5.3 Known CAD 9 (75%) Coronary anatomy 0-vessel disease 1 (8.3%) 1-vessel disease 1 (8.3%) 2-vessel disease 5 (41.7%) 3-vessel disease 5 (41.7%) Cardiac risk factors Diabetes mellitus 5 (41.7%) Hypertension 10 (83.3%) Dyslipidemia 8 (66.7%) Cigarette smoking 2 (16.7%) Data are mean ± SD or number (%) of patients. CAD, coronary artery disease; BMI, body mass index. Statistical Analysis Continuous variables are presented as means and standard deviations. Categorical variables are presented as frequencies with percentages. The Rb PET-derived parameters (MBF and CFR) were compared among the 4 groups using repeated-measures analysis of variance (ANOVA), with the Scheffé F test applied when ANOVA results were statistically significant. The correlations between coronary arterial stenosis and hyperemic MBF and CFR were assessed using Spearman s linear regression analysis. A P-value<0.05 was considered statistically significant. Statistical calculations were carried out using SAS software (SAS Institute, Inc, Cary, NC, USA). Results Patients Characteristics The 12 consecutive patients (mean age, 70.8±10.2 years, 6 men) underwent Rb PET and CAG (Table 1); 9 patients had known CAD and 3 patients had suspected CAD. The mean time interval between Rb PET and CAG was 11.5±13.4 days (range 1 49 days). In total, 10 of the 12 patients (83%) had multivessel coronary stenosis. Table 2. Hemodynamics at Rest and During ATP Stress Rest ATP P value Heart rate (beats/min) 61.9± ±6.9 <0.001 Systolic BP (mmhg) 127.8± ± Diastolic BP (mmhg) 63.8± ± RPP (beats min 1 mmhg 1 ) 7,935.8±1, ,411.8±1, Data are mean ± SD. ATP, adenosine triphosphate; BP, blood pressure; RPP, rate-pressure product. Table 3. Coronary, SDS, and MBF at Rest and During ATP Stress Group A (n=14) [stenosis and ischemia] Group B (n=10) [stenosis without ischemia] Group C (n=10) [no stenosis without ischemia] Group D (n=2) [no stenosis with ischemia] Coronary stenosis (%) 89.2±8.4 ( ) 81.8±8.0 ( ) 46.1±16.7 ( ) 55.5 (47.0, 64.0) SDS 4.9±1.9 ( ) 0.15±0.34 (0 1.0) 0.15±0.47 (0 1.5) 3.8 (3.5, 4.0) Rest MBF (ml g 1 min 1 ) Hyperemia (ml g 1 min 1 ) CFR P value [Rest vs. Hyperemia] 0.91± ± ± ± ± ±0.71 < ± ± ±0.71 < NA Data are mean ± SD (Groups A, B, and C). Data are mean in Group D. Data range also expressed for coronary stenosis and SDS data. SDS, summed difference score; MBF, myocardial blood flow; ATP, adenosine triphosphate; CFR, coronary flow reserve.

4 YOSHINAGA K et al. Figure 1. Representative images from a 58-year-old man with 3-vessel disease showing stenosis of LAD segments 6 (75%), 7 (75%) and 9 (90%); LCX segment 12 (90%); and RCA segments 3 (75%) and 4 AV (90%). (A) ATP stress and rest Rb showed moderate reversible ischemia in the lateral region and mild reversible ischemia mid to distal anterior. (B) Hyperemic MBF (ml min 1 g 1 ) was 1.91 in the LAD territory, 1.78 in the RCA territory, and 1.26 in the LCX territory. ATP, adenosine triphosphate; CFR, coronary flow reserve; LAD, left anterior descending; LCX, left circumflex; MBF, myocardial blood flow; RCA, right coronary artery. MBF (ml/min/g) 3.5 Group A (n=14) +Ischemia P=ns Rest MBF P=ns Hyperemia Group B (n=10) Group C (n=10) Group D (n=2) Ischemia Figure 2. MBF at rest and during ATP stress. There was no significant difference in rest MBF among the 4 groups. Hyperemic MBF in segments with coronary stenosis was lower than in segments with normal perfusion without coronary stenosis. ATP, adenosine triphosphate; MBF, myocardial blood flow.

5 MBF on Rb PET Hemodynamics During ATP Stress The ATP stress was well tolerated by all participants. Two patients had ischemic changes on ECG and 2 patients had chest pain during ATP stress. ATP stress significantly increased heart rate and tended to increase RPP with the Rb PET studies (Table 2). Rest MBF and MBF During ATP Stress Rest MBF was similar among the 4 groups (Table 3). The MBF of Group A segments (n=14) and Group D segments (n= 2) did not increase during hyperemia as compared with MBF at rest (Figures 1,2; Table 3). In Group B (n=10) and Group C (n=10) segments, there were significant MBF increases during hyperemia as compared with MBF at rest. Group A segments and Group B segments showed reduced hyperemic MBF compared with that for Group C segments () (Figure 2). Groups A and B also showed reduced CFR compared with that for Group C () (Figure 3). There was no significant difference between Group A and Group B segments for either hyperemic MBF or CFR. CFR Group A Ischemia (n=14) P=ns Group B (n=10) Group C (n=10) Group D Ischemia (n=2) Correlations Between Rb Measurements and Coronary Hyperemic MBF (r= 0.76, P<0.0001) and CFR (r= 0.76, P< ) inversely correlated with percent diameter stenosis on quantitative CAG (Figure 4). Discussion Hyperemic MBF and CFR inversely correlated with percent coronary artery diameter stenosis on quantitative CAG. Segments with reversible ischemia and coronary stenosis had reduced hyperemic MBF. Even segments that had significant coronary stenosis, but were negative for ischemia, had reduced hyperemic MBF compared with that for non-stenotic segments. Thus, MBF quantification by Rb PET may provide additional diagnostic information over that obtained through standard visual analysis in patients with CAD. Figure 3. Coronary flow reserve (CFR) in segments with coronary stenosis vs. segments with normal perfusion without coronary stenosis. MBF Measurements Using Rb PET Quantitative MBF measurements using Rb PET have been validated through the use of other PET flow tracers 21 and animal models. 33 Lortie et al reported that Rb MBF measurements at rest and during pharmacological stress correlated with those for 13 N-ammonia PET in humans. 21 Manabe et al showed good repeatability of Rb MBF measurements during stress and at rest. 18 Thus, Rb MBF measurements may be useful in the clinical setting for the diagnosis of CAD in patients. In the present study, segmental rest MBF ranged from 0.89 to 1.09 ml min 1 g 1 among the 4 groups. These rest MBF values were similar to typical rest MBF values obtained through Figure 4. Correlation between the hyperemic MBF, RPP-corrected CFR, and % coronary artery diameter stenosis. (A) Inverse correlation between hyperemic MBF and % coronary stenosis. (B) Inverse correlation between RPP-corrected CFR and % coronary stenosis. CFR, coronary flow reserve; MBF, myocardial blood flow; RPP, rate pressure-product.

6 YOSHINAGA K et al. standard approaches using 15 O-water or 13 N-ammonia PET. 13,14 Hyperemic MBF in the segments without coronary stenosis was more than 2.5 ml min 1 g 1. In contrast, hyperemic MBF in the segments with coronary stenosis was less than 2.0 ml min 1 g 1. A CFR 2.0 is generally considered normal 13 and is associated with a low risk of cardiovascular events. Therefore, the current MBF measurements are considered to be accurate. Moreover, the hyperemic MBF and CFR inversely correlated with percent diameter stenosis on QCA, which is in agreement with previously reported findings. 34 Additional Diagnostic Value of MBF Quantification Over Relative Perfusion Imaging Our group previously reported that MBF quantification using 15 O-water PET provided additional diagnostic value over SPECT MPI. 16 Herzog et al reported that CFR also had longterm prognostic value. 35 Myocardial perfusion PET has higher diagnostic accuracy than does SPECT. 6,9,36 However, even when using PET, relative perfusion imaging still has limited ability to detect myocardial ischemia, especially in cases of multivessel disease. 12 Thus, routine MBF quantification has been sought for clinical application O-water and 13 N-ammonia require immediate access to an on-site cyclotron and therefore these PET flow tracers have not seen wide clinical usage. In contrast, Rb is a generatorproduced PET flow tracer and has been widely used in clinical settings in North America. 10,17,23 The additional diagnostic value of MBF quantification using Rb has been predicted, 17,38 but to date supporting data have been limited. Parkash et al showed the additional diagnostic value of Rb MBF quantification in patients with 3-vessel CAD. 24 However, they evaluated MBF using a retention index, which has high statistical noise and is now considered a less accurate approach. Moreover, they evaluated a reduced MBF in the whole LV and did not evaluate regional MBF. In the present study, we used a single-tissue compartment model for MBF quantification, which a standard and accurate approach. 31 In fact, previous studies showed that the repeatability of MBF measurements using this approach is excellent. 18 In the clinical setting, it is important to detect critical coronary stenosis not only for diagnosis but also with regard to performing coronary intervention. Therefore, the current data may provide additional insight over that obtained through previous studies and thus contribute to CAD patient care. Study Limitations First, the sample size of the present study was small. Rb is produced from a strontium- ( Sr)/ Rb generator in the United States and Canada, but there is no radiopharmaceutical company that provides this generator in Japan. Thus, it is very difficult to perform additional Rb PET studies in our facility. Moreover, current radioisotope providers guarantee the quality of the generator for only 4 8 weeks. Sufficient Rb radioactivity can be obtained for clinical imaging within this period only. Thus, study duration was quite limited in our facility, and we do not currently have a usable Rb generator. Thus, it is not possible to perform additional data acquisition and to increase the study population. However, the current data clearly showed differences between hyperemic MBF and CFR among the regions with a range of disease severity (Groups A, B, and C). Although the findings from the present study were sufficient to detect significant differences, further studies involving a larger cohort or more centers are required to confirm our results and support the wider use of this approach in Japan. Second, this study aimed to show the diagnostic value of Rb MBF quantification and did not have long-term follow-up data. Further study is required to determine the additional prognostic value of Rb MBF quantification. Third, the number of segments in Group D (abnormal perfusion without coronary stenosis) was small, so it was not possible to evaluate the clinical role of this group based on the present data. However, a larger sample size may show that this type of segment has clinical meaning. Previous reports have shown that this pattern is associated with early vascular dysfunction. CFR was reduced in myocardium subtended by normal coronary arteries in patients with CAD. 16,39 The magnitude of CFR reduction was lower than that in segments supplied by stenotic coronary arteries. Because relative perfusion images depend on blood flow distribution, this small vasodilator capacity reduction may (sometimes) induce perfusion abnormalities. Herzog et al reported that perfusion defects and reduced CFR were independently associated with cardiovascular events. 35 Although the population of Group D was small, the current data showed reduced CFR in Group D compared to that in Group C (no stenosis without ischemia), consistent with previous reports. Thus, this finding of abnormal CFR may be associated with an increased risk of cardiac events. Further investigation is required to evaluate such a possibility. Conclusions In the present study, hyperemic MBF and CFR measured by Rb PET inversely correlated with percent diameter stenosis on quantitative CAG. Segments with reversible ischemia and coronary stenosis had reduced hyperemic MBF. Even segments with coronary stenosis, but normal stress perfusion, had reduced hyperemic MBF compared with that of non-stenotic segments. Thus, MBF quantification by Rb PET may provide additional diagnostic information over that obtained through standard visual analysis in patients with CAD. Acknowledgments The authors thank Kazumasa Noriyasu, MD, PhD, Sayaka Takamori, RT, Keiichi Magota, RT, Hiroshi Arai, RT, Hidehiko Omote, RT, Kyotaro Suzuma, MS, Katsuhiko Kasai, MSc, and Ken-ichi Nishijima, PhD for their technical expertise and Eriko Suzuki for her administrative support of this study. This study was supported in part by grants from the Ministry of Education, Science and Culture (No and No ), Northern Advancement Center for Science & Technology (Sapporo, Japan) (Grant #H19-C-068) and Adult Cardiovascular Research Foundation (Kyoto, Japan) (#H-22-23). Ran Klein was supported by the Japan Society for the Promotion of Science (JSPS) and Natural Sciences and Engineering Research Council of Canada (NSERC) Summer Program (2008) (Tokyo, Japan and Ottawa, Ontario, Canada). References 1. 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