R Wells

Dynamic SPECT Measurement of Absolute Myocardial Blood Flow in a Porcine Model

Absolute myocardial blood flow (MBF) and myocardial flow reserve (MFR) provide incremental diagnostic and prognostic information over relative perfusion alone. Recent development of dedicated cardiac SPECT cameras with better sensitivity and temporal resolution make dynamic SPECT imaging more practical. In this study, we evaluate the measurement of MBF using a multipinhole dedicated cardiac SPECT camera in a pig model of rest and transient occlusion at stress using 3 common tracers: 201Tl, 99mTc-tetrofosmin, and 99mTc-sestamibi. Methods: Animals (n = 19) were injected at rest/stress with 99mTc radiotracers (370/1,100 MBq) or 201Tl (37/110 MBq) with a 1-h delay between rest and dipyridamole stress. With each tracer, microspheres were injected simultaneously as the gold standard measurement for MBF. Dynamic images were obtained for 11 min starting with each injection. Residual resting activity was subtracted from stress data and images reconstructed with CT-based attenuation correction and energy window–based scatter correction. Dynamic images were processed with kinetic analysis software using a 1-tissue-compartment model to obtain the uptake rate constant K1 as a function of microsphere MBF. Results: Measured extraction fractions agree with those obtained previously using ex vivo techniques. Converting K1 back to MBF using the measured extraction fractions produced accurate values and good correlations with microsphere MBF: r = 0.75–0.90 (P < 0.01 for all). The correlation in the MFR was between r = 0.57 and 0.94 (P < 0.01). Conclusion: Noninvasive measurement of absolute MBF with stationary dedicated cardiac SPECT is feasible using common perfusion tracers.

Repeatable Noninvasive Measurement of Mouse Myocardial Glucose Uptake with 18F-FDG: Evaluation of Tracer Kinetics in a Type 1 Diabetes Model

A noninvasive and repeatable method for assessing mouse myocardial glucose uptake with 18F-FDG PET and Patlak kinetic analysis was systematically assessed using the vena cava image–derived blood input function (IDIF). Methods: Contrast CT and computer modeling was used to determine the vena cava recovery coefficient. Vena cava IDIF (n = 7) was compared with the left ventricular cavity IDIF, with blood and liver activity measured ex vivo at 60 min. The test–retest repeatability (n = 9) of Patlak influx constant Ki at 10–40 min was assessed quantitatively using Bland–Altman analysis. Myocardial glucose uptake rates (rMGU) using the vena cava IDIF were calculated at baseline (n = 8), after induction of type 1 diabetes (streptozotocin [50 mg/kg] intraperitoneally, 5 d), and after acute insulin stimulation (0.08 mU/kg of body weight intraperitoneally). These changes were analyzed with a standardized uptake value calculation at 20 and 40 min after injection to correlate to the Patlak time interval. Results: The proximal mouse vena cava diameter was 2.54 ± 0.30 mm. The estimated recovery coefficient, calculated using nonlinear image reconstruction, decreased from 0.76 initially (time 0 to peak activity) to 0.61 for the duration of the scan. There was a 17% difference in the image-derived vena cava blood activity at 60 min, compared with the ex vivo blood activity measured in the γ-counter. The coefficient of variability for Patlak Ki values between mice was found to be 23% with the proposed method, compared with 51% when using the left ventricular cavity IDIF (P < 0.05). No significant bias in Ki was found between repeated scans with a coefficient of repeatability of 0.16 mL/min/g. Calculated rMGU values were reduced by 60% in type 1 diabetic mice from baseline scans (P < 0.03, ANOVA), with a subsequent increase of 40% to a level not significantly different from baseline after acute insulin treatment. These results were confirmed with a standardized uptake value measured at 20 and 40 min. Conclusion: The mouse vena cava IDIF provides repeatable assessment of the blood time–activity curve for Patlak kinetic modeling of rMGU. An expected significant reduction in myocardial glucose uptake was demonstrated in a type 1 diabetic mouse model, with significant recovery after acute insulin treatment, using a mouse vena cava IDIF approach.

Flow-Dependent Uptake of 123I-CMICE-013, a Novel SPECT Perfusion Agent, Compared with Standard Tracers

Rotenone derivatives have shown promise in myocardial perfusion imaging (MPI). CMICE-013 is a novel 123I-labeled rotenone derivative developed for SPECT MPI. The objective of this study was to assess the image quality of CMICE-013 and compare its uptake with tetrofosmin, sestamibi, and 201Tl in vivo in a porcine model of stress-induced myocardial ischemia. Methods: Microspheres were injected simultaneously with the radiotracer injections at rest and stress to measure blood flow. Mimicking a 1-d tetrofosmin protocol, stress imaging used 3 times as much activity and occurred 1 h after the rest injection. SPECT images were obtained at both rest and stress. After imaging, the heart was sectioned into 44–50 pieces. In each heart sample, the tracer uptake was measured in a γ counter. The images were aligned, and the decay-corrected ratio of the signals at rest and stress was used to separate the well-counter signal into rest and stress components. The uptake at rest and stress was compared with microsphere flow measurements. Results: The CMICE-013 images showed good contrast between the heart and surrounding organs, with heart-to-liver and heart-to-lung uptake ratios similar to those of the standard tracers. Uptake of CMICE-013 was 1.5% of the injected dose at rest and increased more rapidly with increased blood flow than did the standard SPECT tracers. The percentage injected dose of CMICE-013 taken up by the heart was greater (P < 0.05) than 201Tl, tetrofosmin, or sestamibi at flows greater than 1.5 mL/min/g. Conclusion: CMICE-013 is a promising new SPECT MPI agent.

Evaluation of Apoptosis with 99mTc-rhAnnexin V-128 and Inflammation with 18F-FDG in a Low-Dose Irradiation Model of Atherosclerosis in Apolipoprotein E–Deficient Mice

Low-dose radiation in apolipoprotein E–deficient (ApoE−/−) mice has a protective effect with less subsequent atherosclerosis. Inflammation and apoptosis play major roles in the development of atherosclerosis. We evaluated the temporal pattern of the development of histologic atherosclerosis, inflammation with 18F-FDG, and apoptosis with 99mTc-rhAnnexin V-128 at 3 time points. Methods: ApoE−/− mice were fed a high-fat diet, exposed to low-dose 60Co γ-radiation of 25 mGy at 2 mo of age, and evaluated within 1 wk (2-mo group), 1 mo (3-mo group), and 2 mo (4-mo group) from the time of radiation. Mice were divided into 3 subgroups and each received 18F-FDG, 99mTc-rhAnnexin V-128, or no radiotracer for autoradiography. Mice underwent euthanasia and aortic root dissection. The extent of atherosclerosis was determined by en face and Oil red O imaging. Aortic arch inflammation (18F-FDG) and apoptosis (99mTc-rhAnnexin V-128) were determined with digital autoradiography. Aortic sinus sections were stained with Sudan IV for assessment of lesion area and stage, antiCD68 antibody for inflammation and anti–cleaved-caspase 3 antibody for apoptosis. Results: The extent of aortic atherosclerosis increased from 2 to 3 mo and from 3 to 4 mo. Inflammation (CD68) decreased and apoptosis (anti–cleaved-caspase 3 antibody) increased in aortic sinus slices measured as percentage of lesion by 4 mo. With increasing lesion stage, lesion inflammation decreased and lesion apoptosis increased. Aortic arch inflammation (18F-FDG uptake) did not differ over time and did not correlate with average lesion stage. However, aortic arch apoptosis (99mTc-rhAnnexin V-128) increased significantly by 4 mo and correlated with average lesion stage. There were no differences between the treatment subgroups (18F-FDG, 99mTc-rhAnnexin V-128, or no radiotracer). Conclusion: The temporal pattern of development of inflammation and apoptosis differ during the development of atherosclerosis in ApoE−/− mice treated with low-dose radiation. Advanced lesions are characterized by increased apoptosis and either less or similar amounts of inflammation, shown on immunohistochemistry and autoradiography. Treatment with radiotracers had no significant effects on extent of atherosclerosis, inflammation, or apoptosis.

Reply: Noninvasive measurement of mouse myocardial glucose uptake with 18F-FDG.

TO THE EDITOR: I read with interest the recent publication by Thorn et al. (1) using vena cava image-derived input functions for quantification of myocardial glucose uptake (MGU). The authors demonstrated that using vena cava PET image–derived input functions permits reproducible noninvasive measurement of regional MGU using 18F-FDG and Patlak kinetic modeling and shows the expected reduction of MGU in type 1 diabetic mice. However, for accurate quantification of MGU, it is critical that plasma glucose time–activity curves be used rather than wholeblood time–activity curves. As discussed previously in this journal (2,3), whereas glucose equilibrates extremely rapidly across the erythrocyte plasma membrane in primates, this is not true in adult nonprimates (4,5). Transport of glucose into human erythrocytes was too fast to measure at 37 C, whereas in rat erythrocytes transport was more than 3 orders of magnitude slower, even when compared with human erythrocytes at 4 C (5). Slower glucose transport rates result in lower erythrocyte-to-plasma glucose distribution ratios in nonhuman primates; ratios ranged from 0 in pigs to 0.45 in calves (4). More recently, Wu et al. confirmed that 18FFDG transport was also slow in mice; the 18F-FDG concentration in plasma was initially significantly higher than in whole blood and did not reach steady state until approximately 20 min after injection (6). There was little animal-to-animal variability; estimation of plasma 18F-FDG from whole blood values was possible using an empirically derived exponential function, but this would need validation for different experimental conditions such as diabetes (6). The slow transport of 18F-FDG across the erythrocyte plasma membrane also has implications for the lumped constant (LC) of 0.67 used by Thorn et al. to account for differences in uptake and phosphorylation of 18F-FDG versus glucose. As discussed previously (2,3,7), the study by Ratib that established the widely used value of 0.67 for the LC calculated MGU as the product of plasma glucose and myocardial blood flow, assuming equal plasma and whole-blood glucose concentrations and rapid equilibration of glucose across the erythrocyte (8). However, whereas this would be valid in primates, in dogs the erythrocyte glucose concentration is much lower than the plasma glucose concentration, 1.5 mM versus 4.4 mM (9), and the erythrocyte glucose transport rate much slower than cardiac glucose uptake, and so cardiac glucose utilization is essentially derived exclusively from the plasma compartment. MGU can therefore be estimated as the product of plasma flow and the arteriovenous plasma glucose concentration difference (7). Using whole-blood flow to calculate MGU will result in artificially high values, resulting in underestimation of the LC. Kofoed et al. found an LC of 1.1 in healthy dogs using plasma flow to calculate MGU (7). Estimates of the LC obtained in human volunteers ranged from 1 during insulin infusion to 1.4 in the fasted state (10). In summary, for nonprimates slow transport of glucose across the erythrocyte membrane makes it critical to use plasma rather than whole-blood 18F-FDG time–activity curves when determining MGU rates with 18F-FDG and PET. The value of 0.67 for the LC used to account for differences in the uptake and phosphorylation of 18F-FDG versus glucose is an underestimate, which will result in overestimation of MGU.

THE ASSESSMENT OF MECHANICAL RV DYSSYNCHRONY USING PHASE ANALYSIS OF RNV IMAGING IN SUBJECTS WITH NORMAL AND SEVERELY REDUCED LV FUNCTION

Phase analysis during radionuclide ventriculography (RNV) is an evolving and promising technique for measuring left ventricular (LV) mechanical dyssynchrony. However, the feasibility of phase analysis to assess right ventricle (RV) synchrony in normal population and RV dyssynchrony pre and post

Sci—Fri AM: Imaging — 09: Serial estimation of cross‐talk for correction in dual‐isotope imaging with dynamic tracers

The recent radioisotope shortage has led to interest in non-Tc99m-based tracers. We have developed a novel I-123-labelled myocardial perfusion imaging tracer. We compare the I123-tracer to the clinical standard of Tc99m tetrofosmin in vivo in a rat model using a small-animal SPECT/CT camera. SPECT distinguishes different isotopes based on the different energies of the emitted gamma rays and thus allows simultaneous comparison of two tracer distributions in the same animal. Dual-isotope imaging is complicated by cross-talk between the energy windows of the isotopes. Standard energy-window-based correction methods are difficult to employ because of the proximity in energy of Tc99m (140keV) and I123 (159keV). Imaging the second tracers energy window prior to its injection provides an estimate of the cross-talk. However, this estimate is only accurate if the tracer distribution is static. We use serial imaging prior to the introduction of the second tracer to estimate the dynamics of the first tracer and interpolate the cross-talk images to provide a more accurate correction. We used rat models of myocardial disease (n=3). I123 tracer was injected and imaged for one hour at 20min intervals. The Tc99m tetrofosmin was then injected and 30min later, a dual-isotope image was obtained. The impact of this approach is assessed by comparing the differences in the Tc99m-tetrofosmin image using this method with correction by simple correction for physical decay. The interpolative approach improves the accuracy of the correction by 2%-5% and thereby enhances the comparison of the two tracers.

Poster — Thur Eve — 02: Evaluation of Cross‐Talk for Dual‐Isotope Myocardial Perfusion Imaging Using a New Dedicated Cardiac CZT SPECT Camera

Myocardial perfusion imaging (MPI) with single‐photon emission computed tomography(SPECT) is an important tool in the clinical management of heart disease. Simultaneous dual‐istope imaging offers a means to greatly reduce the time required for this test, but is limited by interference between the signals of the two isotopes. Newly developed dedicated cardiacSPECTcameras based on CZT detectors may reduce the interference between isotopes due to improved energy resolution. Our objective is to measure in clinical patients the magnitude of cross‐talk expected for simultaneous perfusion imaging with Tl‐201 and Tc‐99m‐tetrofosmin on a new CZT‐based multi‐pinhole dedicated cardiacSPECTcamera. We retrospectively examined 25 matched pairs of Tl‐201 and Tc‐99m‐tetrofosmin patients. Reprocessing the listmode data, we determined the cross‐talk fraction for typical energy windows as well as for a Tc‐99m energy window that was reduced from 20% to 12%. Two protocols were considered: Tl‐rest/Tc‐stress and Tc‐rest / Tl‐stress. Cross‐talk into the Tl window was 74% and 36% respectively for the two protocols. Cross‐talk into the 10% Tc‐99m window was 2.4% and 11% respectively. The cross‐talk into the Tc‐99m window was reduced by 25% using a +/−6% window. Cross‐talk between Tc‐99m‐tetrofosmin and Tl‐201 has been assessed for the new dedicated CZT‐based cardiacSPECTcameras and the improved energy resolution of the CZT detectors decreases cross‐talk interference.