Positron emission tomography (PET) imaging has experienced rapid growth over the last few years since the introduction of hybrid PET/computed tomography (CT) scanners . Alhough much focus has been on the benefits of PET imaging [1,2] to enhance the management of patients with cancer, cardiac PET imaging can also be of great clinical benefit, as both viability and quantitative perfusion measurements can be obtained . Routinely, relative myocardial perfusion is estimated using 99mTc-SestaMIBI; however, this results in false negatives in cases where there is a widespread decrease in myocardial blood flow such as in triple vessel disease. Given the potential worldwide shortage of 99mTc and the need for more quantitative blood flow methods, a more complete assessment of alternative imaging methods is needed. The PET tracer 13N-ammonia provides improved resolution and quantification [3,4] over 99mTc-SestaMIBI, but is dependent on an on-site cyclotron. More recently, 18F compounds are showing considerable promise [5,6], but are dependent on being within a few hours of a medical cyclotron. Non-nuclear medicine approaches have also been explored including contrast-enhanced magnetic resonance imaging [7,8] and X-ray CT , but these still do not provide complete cardiac coverage using a single dose of contrast material and require multiple injections of contrast material for rest/stress assessments. Only rubidium-82 (82Rb) offers the potential for a quantitative method without access to a medical cyclotron. 82Rb is a positron-emitting myocardial perfusion tracer that, while having a very short half-life (76 s), can be produced using an on-site generator, which has a half-life of 25 days [10,11]. Given the increasing popularity of PET, the convenience of 82Rb as a perfusion tracer, the evolving shortage of 99mTc-based perfusion tracers, and some concern that 82Rb uptake may be affected when ischemia is present or when cell conditions are altered , investigation and validation of this tracer in different myocardial tissue states is necessary.
Although previous research has investigated the reliability and accuracy of blood flow measurements obtained with 82Rb or other perfusion tracers using PET [12–20], literature on 82Rb blood flow values in stunned and infarcted myocardium is limited to comparisons with other radiotracers . As the extraction of 82Rb by myocardium is dependent on the blood flow rate and the tissue's metabolic state, the accuracy of regional myocardial blood flow results obtained from dynamic 82Rb imaging during hyperemia or in metabolically challenged tissue has been questioned . Stunned myocardium, with reduced contractility but maintained blood flow, is of clinical importance as function will return spontaneously without the need for surgical intervention. The management of patients after infarction could be enhanced with the knowledge of blood flow in the infarct territory, providing information on the presence or extent of collateral circulation or success of reperfusion strategies. As such, this study investigated, in a canine model, regional myocardial blood flow quantified using dynamic 82Rb PET imaging in stunned and infarcted, both reperfused and nonreperfused, myocardium and in selected animals compared the flow values with those measured with radioactive microspheres. Furthermore, the reliability of 82Rb blood flow measurements during pharmacologic hyperemia using an agent that augments myocardial oxygen demand through inotropic stimulation (e.g. dobutamine) was also assessed.
Animal preparation and surgery
The canine studies reported here were approved by the Animal Use Subcommittee of the Canadian Council on Animal Care at the University of Western Ontario (ethics approval ♯2003-108-02). Anesthesia was induced using 1% propofol injected intravenously and maintained with 1.5–2% isoflurane. A left lateral thoracotomy was performed in the fourth intercostal space. A region of the left anterior descending (LAD) coronary artery was dissected free of the myocardium and a snare ligature was placed in this region. The snare was kept loose and externalized through an opening in the chest wall and the incision was closed. A femoral artery catheter was inserted using a 7F introducer sheath for reference blood withdrawal during microsphere blood flow measurements. The animals were then transported to the clinical PET/CT hybrid scanner. Once positioned on the PET/CT bed, a 6F pigtail catheter was inserted into the left ventricular cavity for administration of microspheres. The position of the pigtail catheter was confirmed by acquiring a scout CT image. A total of 12 mongrel dogs were used for this study.
Creation of stunned and infarcted myocardium
Stunned myocardium (STUN) was created by using the snare ligature to occlude the LAD coronary artery for 15 min followed by reperfusion [23–25]. Occlusion of the coronary artery was confirmed through changes in the ECG trace. Furthermore, a reduction in wall motion with maintained tissue viability was confirmed in a separate animal using magnetic resonance imaging, indicating the successful creation of stunned myocardium using this model. Resting blood flow measurements were acquired 45 min after release of the occlusion, and blood flow during dobutamine hyperemia was measured 30 min later. Dobutamine hyperemia was induced by 2-min stepwise increases (5, 10, 20 μg/kg/min) to 30 μg/kg/min, which was maintained throughout the 82Rb image acquisition and microsphere injection. Two hours after reperfusion, the LAD was again occluded and either released 2 h later (REP) or remained permanently occluded (OCC). Resting blood flow measurements were acquired 2.5 h after the release of the occlusion (or 4.5 h after occlusion in the group of animals with the permanent occlusion). Blood flow was measured again during dobutamine hyperemia 30 min later. After the last blood flow measurement on the day of surgery, the animals were recovered and brought back for rest (measured twice) and hyperemic (dobutamine) imaging 8 weeks later to measure blood flow in chronic reperfused or occluded myocardial infarction (CHRON REP or CHRON OCC). This protocol is shown schematically in Fig. 1.
Rubidium-82 positron emission tomography imaging and blood flow measurements
Three-dimensional dynamic PET imaging was performed on a GE Discovery LS PET/CT hybrid scanner (GE Healthcare, Milwaukee, Wisconsin, USA), with 18 frames acquired over 10.5 min (12×10 s, 3×30 s, 1×60 s, 1×120 s, 1×240 s). 82Rb was infused intravenously using a custom-built infusion system [26,27] and the scan was started when counts were first observed in the field-of-view. On average, 378 MBq was infused. For attenuation correction, a 10-min 68Ge static transmission scan was acquired. Image sets were reconstructed using the Fourier-rebinning (FORE)+OSEM  iterative reconstruction software (version 16.01) available on the commercial system (GE Medical Systems, GE Healthcare), which corrected for attenuation, randoms, and scatter. Images were reconstructed into a 128×128 array with a 15 cm diameter field-of-view, 5.5 mm full-width at half-maximum Gaussian postfilter, pixel size of 1.17 mm, and 35 slices with a slice thickness of 4.25 mm.
An automatic program reoriented the dynamic 82Rb images into the short axis plane  to sample the left ventricular myocardium. The left ventricular and atrial cavities were identified automatically to obtain a median arterial input function, used for compartmental modeling and correction of partial volume effects, as follows. In each of 496 midmyocardial sectors, dynamic polar maps containing myocardial time–activity curves were generated. For each time activity curve, a one-tissue-compartment tracer kinetic model was used to quantify regional myocardial blood flow in ml/min/g [30,31] using an extraction fraction correction of the uptake rate . The blood flow polar maps were analyzed using a standard 17-segment model .
Absolute measurements of myocardial blood flow were made using radioactively labeled microspheres, one of 46Sc, 51Cr, 57Co, 85Sr, 95Nb, 103Ru, 141Ce, or 153Gd (PerkinElmer New England Nuclear, Waltham, Massachusetts, USA), which were injected concurrently with the start of the infusion of 82Rb. After sacrifice of the animals, the hearts were sliced into 5–8 short axis slices, which were sectioned into 0.25–1.5 g pieces. Each section was counted using a high-purity germanium well counter (Dspec, Ortec, Oak Ridge, Tennessee, USA) and counts per second (CPS) for each sample for each radionuclide injected were determined. Regional myocardial blood flow (in units of ml/min/g) was calculated as (CPStissue/CPSblood)(WR/Masssample), where WR is the blood withdrawal rate (1.96 ml/min). The microsphere blood flow values were compiled into 17 segments for comparison with the 82Rb blood flow results.
As the experimental design of these experiments was extended over an 8-week period to investigate blood flow in chronic myocardial infarction, leaching of radioactive label from the microspheres was possible [33,34]. Separate experiments were performed in vitro to determine which microspheres were most susceptible to loss of label. This experiment consisted of adding 1 ml of lactated Ringers to a known activity of each sphere, agitating the mixture weekly for 8 weeks, spinning the solutions for 5 min, and then counting the supernatant. 85Sr, 57Co, 153Gd, and 95Nb had, on average, 13% of total activity in the supernatant. Therefore, early data points acquired with any one of these microspheres were removed in an unbiased fashion. Furthermore, one animal was euthanized 2 days after surgery and six animals did not have a complete set of chronic image acquisitions because of sudden cardiac death subsequent to arrhythmias. This left a total of 35 image sets (24 rest and 11 hyperemia image sets) with 17 segments in each set for comparison of 82Rb to microsphere blood flow results: STUN rest (n = 9), STUN stress (n = 2), REP rest (n = 4), REP stress (n = 2), OCC rest (n = 4), OCC stress (n = 1), CHRON REP rest (n = 3), CHRON REP stress (n = 3), CHRON OCC rest (n = 4), CHRON OCC stress (n = 3). For each chronic rest or stress condition, repeated measurements (same or next day) were combined. These matched results were used for statistical comparisons between microspheres and 82Rb. The unmatched 82Rb results, where microsphere data were not necessarily present, were also included for further comparison.
Registration and comparison of data
To reduce misregistration errors between the 82Rb and microsphere blood flow results, the region-at-risk (RAR) was determined in all animals. Once determined, the RAR was used to subsequently define the stunned and infarcted tissue in subsequent data analyses. In the REP animals, the RAR was determined by measuring blood flow using microspheres and 82Rb dynamic PET during the 2 h occlusion. In the OCC animals, the RAR was determined during the resting blood flow measurements acquired 4.5-h postocclusion. Average segmental flow values of less than 0.4 ml/min/g defined the RAR for all 82Rb and microsphere analyses.
Statistical analysis was performed using GraphPad Prism (GraphPad, San Diego, California, USA). Analysis of variance (ANOVA) with Bonferroni post-hoc testing (Kruskal–Wallis with Dunn's comparison post-hoc testing for nonparametric data) was performed on all 82Rb and microsphere flow in the different tissue types to evaluate significance. Spearman correlation analysis compared all 82Rb results to microsphere flow data. Correlations were considered strong if 1.0>ρ>0.7; moderate if 0.7>ρ>0.3; weak if 0.3>ρ>0.1. Average values are reported as mean±standard error of the mean. NS, not significantly different (P≥0.05).
On average, the RAR determined using microspheres and 82Rb imaging was 23±3% and 20±2% of the left ventricle, respectively (P = NS). Spearman correlation analyses showed the presence of a strong and significant correlation between microsphere and 82Rb blood flow results (ρ = 0.72; P<0.0001). Average resting microsphere results in remote nonischemic and at-risk tissue in the STUN, REP, OCC, CHRON REP, and CHRON OCC groups as well as all 82Rb blood flow results with or without matching microsphere results are shown in Fig. 2a–e. These results show that 82Rb blood flow closely matches blood flow measured with microspheres in most tissue types, with mild overestimation in the acute STUN and REP groups at rest. Similar differences were observed between the at-risk and remote tissues, using 82Rb and microspheres (Fig. 2a–d). The CHRON OCC data (Fig. 2e) showed a significant flow reduction in the infarct zone with 82Rb compared with the remote tissue, but not with microspheres. The unmatched 82Rb blood flow results, with an increased number of animals to increase the power of the analysis, further affirm the matched results, with similar trends and lower blood flow in the at-risk tissue compared with remote tissues on average.
When all remote and RAR tissues were considered together, significant differences between the two techniques were noted at rest. The 82Rb PET technique yielded flow values slightly higher than microspheres in the remote tissue (0.73±0.01 vs. 0.68±0.02; P<0.001) and lower in the RAR tissue (0.42±0.02 vs. 0.53±0.03; P<0.001) at rest. This underestimation in the RAR tissue was, in part, because of two animals with reactive hyperemia, one in the STUN group and the other in the REP group, shown in Fig. 3a and b. Better agreement was seen in all other animals in the STUN and REP groups, representatives of which are shown in Fig. 3c and d.
Average hyperemic microsphere blood flow results in remote nonischemic and at-risk tissue in the STUN, REP, OCC, CHRON REP, and CHRON OCC groups as well as all 82Rb blood flow results with or without matching microsphere results are shown in Fig. 4a–e. When all remote and RAR tissues were considered together, 82Rb blood flow values in the remote tissue were significantly higher than the microsphere flow results (3.53±0.16 vs. 2.77±0.15; P<0.05), but no significant difference was noted in the RAR tissue between the 82Rb and microsphere results (2.31±0.26 vs. 1.90±0.20; P = NS). Comparing RAR to remote regions, similar trends were observed using 82Rb and microsphere flows. The unmatched 82Rb flow results showed significantly reduced blood flow in the RAR tissues compared with the remote tissue, except in the CHRON REP group as observed at rest. Given the increased number of animals included with the unmatched 82Rb flow results, these results give a more statistically powerful indication of the ability of 82Rb to measure blood flow in various tissue types during dobutamine hyperemia. The 82Rb rest and stress results together are consistent with the expected patterns of flow impairment after acute and chronic occlusion, with some restoration of flow observed late after reperfusion in the CHRON REP group.
This study investigated segmental blood flow values obtained from dynamic 82Rb PET imaging in various tissue states and compared these values to selected microsphere flow values. The results suggest that 82Rb PET imaging is able to define the at-risk region and measure segmental blood flow at rest and during inotropic stimulation with values similar to those obtained with microspheres. These results provide evidence that dynamic 82Rb PET imaging can serve as a surrogate for microsphere blood flow measurements for serial blood flow measurements in chronic large animal models. Furthermore, 82Rb PET imaging seems to be an adequate method for measuring blood flow in animals with stunned and/or acutely or chronically infarcted tissue, whether reperfused or permanently occluded, although regions of reactive hyperemia, as defined by microsphere flow, may not be observed with 82Rb blood flow imaging (Fig. 3a and b).
The blood flow results shown in Fig. 3a and b suggest that blood flow measured with 82Rb shortly following reperfusion of an acute (15 min) or more prolonged (2 h) occlusion does not show the reactive hyperemic response to reperfusion seen in the microsphere data. The cause of this could perhaps be a combination of decreased extraction during reactive hyperemia and/or metabolic derangements during recently reperfused myocardium as a consequence of reperfusion injury, where intracellular concentration of Na+ is increased substantially and may compete with K+ [35,36]. This in turn could limit uptake of potassium analogs such as thallium and rubidium. Other groups have not seen any changes in tracer kinetics of 201Tl during stunning , but these results were compared with another radioactive tracer that might be influenced in a similar manner as the 201Tl, whereas our results were compared with radioactive microspheres.
Although the results indicate good agreement between the microsphere and 82Rb techniques in various tissue states, some trends and significant differences were present. A trend for underestimation of resting blood flow in chronically infarcted tissue with 82Rb imaging compared with microspheres was seen in the CHRON REP and CHRON OCC groups (shown in Fig. 2d and e). As 82Rb is a potassium analog, its uptake in the myocardium is dependent on a functioning sodium–potassium ATPase pump in a manner similar to 201Tl, both of which have been used for assessment of myocardial viability [38–40]. Thus, although the blood flow may have increased over 8 weeks, extraction of the tracer in the chronically infarcted tissue may remain low because of reduced metabolic ability of infarcted myocardium to sequester the flow tracer. Alternatively, the apparent reduction in chronic resting 82Rb blood flow could result from residual partial volume effects because of the finite spatial resolution of PET  as the infarct-related scar tissue tends to shrink and the myocardial wall thins over the 8-week period. Although the rubidium compartment model does include a regional partial-volume correction, the accuracy may be limited in cases of extreme wall-thinning postinfarction.
The acute resting results (Fig. 2a–c) are consistent with either of these hypotheses. Microsphere and 82Rb blood flow values in the RAR tissue are both reduced compared with the remote tissue. Microvascular repair has not started, therefore blood flow is reduced, as measured by microspheres and 82Rb. Early after infarction or reperfusion, myocardial thinning or remodeling would not have started and thus partial volume effects during PET imaging would not be an issue. Although the microsphere and 82Rb flow values are quite similar, the slight trend for decreased 82Rb blood flow at the acute time points in RAR tissue may be a result of an artificial increase in microsphere blood flow results because of shrinkage of the infarcted tissue over the 8 weeks, as we have shown earlier . If the microsphere results had been corrected for shrinkage, which was not possible as baseline microspheres were not available , we expect that the flow results in the stunned and acutely infarcted tissue may have been more similar to the 82Rb values.
It has been recognized for some time that the quantification of myocardial blood flow with 82Rb has some limitations. These include: (i) decreasing extraction fraction, similar to 201Tl at hyperemic flow rates resulting in underestimation of flow, (ii) low spatial resolution because of limited count statistics and high positron range, and (iii) emission of a 777 keV prompt γ-photon which can increase the apparent background or scatter fraction with three-dimensional acquisition, although this is usually compensated in current approaches [43,44]. The first limitation can be corrected with accurate kinetic modeling . The spatial resolution of 82Rb perfusion images is comparable to or better than those obtained using 99mTc and 201Tl SPECT imaging . Finally, the good overall agreement between 82Rb and microspheres suggests that the effect of the 777 keV prompt γ-photon was negligible on the scanner used in this study. Despite these limitations, absolute determination of myocardial blood flow by 82Rb may be a better choice over 99mTc-SestaMIBI, which only provides relative estimates and is dependent on a reliable source of 99mTc.
The results from this study suggest that 82Rb is a suitable perfusion tracer for investigating myocardial blood flow and its detection of disease in a canine model of stunned and acutely and chronically infarcted myocardium at rest and during dobutamine hyperemia. 82Rb can thus be used as a surrogate for microsphere blood flow measurements in animal models as well as in patients with stunned and/or acutely or chronically infarcted tissue.
The authors acknowledge the financial assistance of the Nuclear Medicine Department (Dr Jean-Luc Urbain). Lela Deans, Huafu Kong, Jennifer Hadway, Dominique Ouimet, Terrie Ann Campbell, and Andrew McLellan provided experimental and animal assistance and expertise. They thank Dr Janice DeMoor and Dr Jean De Serres for editorial assistance. This study was funded by Canadian Institutes of Health Research (grant ♯R-04-368), Ontario Consortium of Cardiac Imaging (OCCI), which is supported by the Ontario Research and Development Challenge Fund. and DRAXIMAGE, Kirkland, Quebec, Canada. Dr Lekx was supported by a co-institution, co-supervisor fellowship from OCCI (F.P., R.B., R.dK.).
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