Characterizing the normal range of myocardial blood flow with 82rubidium and 13N-ammonia PET imaging

Background

Diagnosis of coronary disease and microvascular dysfunction may be improved by comparing myocardial perfusion scans with a database defining the lower limit of normal myocardial blood flow and flow reserve (MFR). To maximize disease detection sensitivity, a small normal range is desirable. Both ¹³N-ammonia and ⁸²Rb tracers are used to quantify blood flow and MFR using positron emission tomography (PET). The goal of this study was to investigate the trade-off between noise and accuracy in both ⁸²Rb and ¹³N-ammonia normal databases formed using a net retention model.

Methods

Fourteen subjects with <5% risk of CAD underwent rest and stress ⁸²Rb and ¹³N-ammonia dynamic PET imaging in a randomized order within 2 weeks. Myocardial blood flow was quantified using a one-compartment model for ⁸²Rb, and a two-compartment model for ¹³N-ammonia. A simplified model was used to estimate tracer retention, with tracer-specific net extraction functions derived to obtain flow estimates.

Results

Normal variability of retention reserve was equivalent for both tracers (±15% globally, ±16% regionally) and was lower in comparison to compartment model results (P < .05). The two-compartment model for ¹³N-ammonia had the smallest normal range of global blood flow resulting in a lower limit of normal MFR = 2.2 (mean ? 2 SD).

Conclusion

These results suggest that the retention model may have higher sensitivity for detection and localization of abnormal flow and MFR using ⁸²Rb and ¹³N-ammonia, whereas the ¹³N-ammonia two-compartment model has higher precision for absolute flow quantification.     

Simultaneous cardiac output and regional myocardial perfusion determination with PET and nitrogen 13 ammonia

BACKGROUND: The purpose of this study was to evaluate the possibility of measuring cardiac output during positron emission tomography (PET) examination of myocardial perfusion with nitrogen 13 ammonia. METHODS AND RESULTS: In 7 patients undergoing right-sided cardiac catheterization for evaluation of heart failure and 6 patients who had undergone heart transplantation, a thermodilution catheter for continuous measurement of cardiac output was inserted. An N-13 ammonia scan of the heart was subsequently performed, and with use of factor analysis, the time-activity curve from the right ventricle was derived from the dynamic image sequence. The PET-derived cardiac output was subsequently obtained according to the Stewart-Hamilton principle as the amount of injected tracer divided by the area under the time-activity curve. PET-acquired cardiac output measurements correlated closely with the invasively determined values for a wide range of cardiac output values (P < .0001). The mean difference was 0.12 L/min, with an SD of 0.74 L/min. The interobserver variation was low, with a mean difference of 0.06 L/min and an SD of 0.46 L/min. CONCLUSIONS: Cardiac output determination with N-13 ammonia and PET appears to be both accurate and precise and can be performed simultaneously with measurement of myocardial perfusion.     

The kinetics of copper-62-PTSM in the normal human heart.

Copper-62-labeled pyruvaldehyde bis(N-4-methylthiosemicarbazone) copper(II) (PTSM) is a generator-produced myocardial perfusion tracer. Animal studies have shown high myocardial tissue extraction and prolonged retention. The aim of this study was to define myocardial kinetics of 62Cu-PTSM and to determine its suitability for evaluating myocardial perfusion at rest and during pharmacological vasodilation in human subjects. In six healthy volunteers, 62Cu-PTSM was administered at baseline and during a 6-min adenosine infusion (140 micrograms/kg/min). Dynamic PET imaging with high temporal resolution was performed over 20 min. Good image quality was observed at rest and following adenosine. Myocardial kinetics demonstrated prolonged tissue retention with a clearance half-life of 105 +/- 49 min at rest and 101 +/- 65 min following adenosine (p = ns). Copper-62-PTSM tissue retention was quantified and showed only a 1.97-fold increase from rest to adenosine studies. This suggests attenuation of tracer retention at high flow rates. Copper-62-PTSM represents a promising new radiopharmaceutical for the evaluation of myocardial perfusion in the human heart.     

The suitability of gamma camera coincidence systems for nitrogen 13-labeled ammonia myocardial perfusion imaging: A quantitative comparison with full-ring PET

BACKGROUND: The aim of this study was to examine the quality of nitrogen 13-labeled ammonia (NH(3)) perfusion data from coincidence-capable gamma camera positron emission tomography (GC-PET) systems compared with that from full-ring positron emission tomography (FR-PET). METHODS AND RESULTS: The performance parameters of the GC-PET system were examined and found adequate for imaging at the activity levels used clinically. We studied 15 patients who underwent stress and rest N-13-labeled NH(3) perfusion imaging on FR-PET and GC-PET systems. Quantitative analysis of perfusion values showed that GC-PET uptake was significantly lower than FR-PET uptake in 67.6% of segments. Bland-Altman analysis showed that the mean difference between FR-PET and GC-PET values was from 5.3% to 5.9%. Stress FR-PET identified 49 segments as having impaired perfusion, 46 (93.9%) of which were also identified by GC-PET. Fifty-six additional segments were identified as abnormal by GC-PET. These findings indicated a general overestimation of defect size on GC-PET. Analysis of the degree of perfusion reduction also found that GC-PET tended to overestimate defect contrast. These findings are similar to those previously found by workers examining fluorine 18-fluorodeoxyglucose uptake by both techniques. CONCLUSIONS: Good concordance was shown between GC-PET and FR-PET systems for N-13-labeled NH(3) perfusion imaging, although further work is required to optimize the technique.     

Assessment of myocardial perfusion by dynamic N-13 ammonia PET imaging: Comparison of 2 tracer kinetic models

BACKGROUND: Measurement of myocardial blood flow (MBF) by dynamic nitrogen 13 ammonia (NH(3)) positron emission tomography (PET) uses tracer kinetic modeling to analyze time-activity curves. We compared 2 commonly used models with 2 compartments (2C) and 3 compartments (3C) for quantification of MBF and coronary flow reserve (CFR). METHODS AND RESULTS: Seventy-seven patients underwent NH(3) PET at rest and during hyperemia. Time-activity curves for blood pool and myocardial segments were obtained from short-axis images of dynamic sequences. Model fitting of the 2C and 3C models was performed to estimate regional MBF. MBF values calculated by 2C and 3C models were 0.98 +/- 0.31 mL.min(-1).g(-1) and 1.11 +/- 0.37 mL.min(-1).g(-1), respectively, at rest (P < .0001) and 2.79 +/- 1.18 mL.min(-1).g(-1) and 2.46 +/- 1.02 mL.min(-1).g(-1), respectively, during hyperemia (P < .01), resulting in a CFR of 3.02 +/- 1.31 and 2.39 +/- 1.15 (P < .0001), respectively. Significant correlation was observed between the 2 models for calculation of resting MBF (r = 0.78), hyperemic MBF (r = 0.68), and CFR (r = 0.68). CONCLUSION: Measurements of MBF and CFR by 2C and 3C models are significantly related. However, quantification of MBF and CFR significantly differs between the methods. This difference needs to be considered when normal values are established or when measurements obtained with different methods need to be compared.     

Copper-62-labeled pyruvaldehyde bis(N4-methylthiosemicarbazonato)copper(II): synthesis and evaluation as a positron emission tomography tracer for cerebral and myocardial perfusion

Generator produced positron-emitting radionuclides could potentially expand the application of positron emission tomography (PET) to centers that do not have access to a local cyclotron. The zinc-62/copper-62 radionuclide generator system could serve as a source of positron-emitting copper-62 (62Cu) (t1/2 = 9.74 min) for physiologic imaging. Accordingly, we have prepared zinc-62/copper-62 generators capable of high output (greater than 300 mCi) and used the no-carrier-added eluate in a rapid high yield synthesis of [62Cu] Cu(PTSM) that provides the radiopharmaceutical in a form suitable for intravenous injection (where Cu(PTSM) = pyruvaldehyde bis(N4-methylthiosemicarbazonato) copper(II]. We then demonstrated in pilot studies that [62Cu]Cu(PTSM) provides high quality brain and heart images with PET, accurately delineating cerebral and myocardial perfusion in both experimental animals and in humans (corroborating results of previous experimental studies utilizing longer-lived copper isotopes). The results of this work demonstrate that 62Cu can be conveniently obtained from high-level generators and, when used to label Cu(PTSM), provides a generator-produced radiopharmaceutical capable of providing estimates of cerebral and myocardial perfusion independent of cyclotron-produced radionuclides.     

Uptake and turnover of L-(13N)-glutamate in the normal human heart and in patients with coronary artery disease

L-(13N)-glutamate (4-8 mCi) was administered IV to 27 patients with coronary artery disease and to 12 control subjects. Quantitative whole body imaging of the 13N label was performed in 31 individuals at different time intervals following the injection. Initial uptake of the total myocardium was estimated to be 5.0 +/- 0.88% of the dose. Standardized areas of reduced size on the projection plane contained 2.38 +2- 0.41% of the total dose in control subjects and 2.67 +/- 0.49% in coronary patients. Subsequent imaging exhibited significant differences in the dynamic behavior of both groups: 13N activity loss within 10 min was 3.2 +/- 4.2% of the initial value in control subjects and 16.0 +/- 9.8% in coronary patients. In individual cases a high myocardial accumulation of the 13N label was observed in regions of reduced 201Tl uptake. The findings are explained by an augmented extraction efficiency in cases of flow reduction. Glutamate utilization may be involved in metabolic adaptations of the myocardium to chronic or repetitive ischemia and may be worthy of further investigation by positron emission tomography.     

Uptake and turnover of L-(13N)-glutamate in the normal human heart and in patients with coronary artery disease

L-(¹³N)-glutamate (4–8 mCi) was administered IV to 27 patients with coronary artery disease and to 12 control subjects.Quantitative whole body imaging of the ¹³N label was performed in 31 individuals at different time intervals following the injection. Initial uptake of the total myocardium was estimated to be 5.0±0.88% of the dose. Standardized areas of reduced size on the projection plane contained 2.38±0.41% of the total dose in control subjects and 2.67±0.49% in coronary patients. Subsequent imaging exhibited significant differences in the dynamic behavior of both groups: ¹³N activity loss within 10 min was 3.2±4.2% of the initial value in control subjects and 16.0±9.8% in coronary patients. In individual cases a high myocardial accumulation of the ¹³N label was observed in regions of reduced ²⁰¹Tl uptake. The findings are explained by an augmented extraction efficiency in cases of flow reduction.Glutamate utilization may be involved in metabolic adaptations of the myocardium to chronic or repetitive ischemia and may be worthy of further investigation by positron emission tomography.     

Dynamic positron computed tomography of the heart with a high sensitivity positron camera and nitrogen-13 ammonia

Dynamic positron computed tomography (PCT) of the heart was performed with a high-sensitivity, whole-body multislice PCT device and [13N]ammonia. Serial 15-sec dynamic study immediately after i.v. [13N]ammonia injection showed blood pool of the ventricular cavities in the first scan and myocardial images from the third scan in normal cases (n = 4). In patients with myocardial infarction (n = 8) and mitral valve disease (n = 2), tracer washout from the lung and myocardial peak time tended to be longer, suggesting presence of pulmonary congestion. PCT delineated tracer retention in the dorsal part of the lung. Serial 5-min late dynamic study in nine cases showed gradual increase in myocardial activity for 30 min in all normal segments and 42% of infarct segments, while less than 13% activity increase was observed in 50% of infarct segments. Thus, serial dynamic PCT with [13N]ammonia assessing tracer kinetics in the heart and lung is a valuable adjunct to the static myocardial perfusion imaging for evaluation of various cardiac disorders.     

Quantitation of the regional blood flow in the interventricular septum using positron emission tomography and nitrogen-13 ammonia

The purpose of the present study was to evaluate the effect of spillover of activity from the right ventricle (RV) on quantitation of the regional myocardial blood flow in the septum. Thirty-one healthy volunteers, 31 patients with ischemic heart disease, 7 patients with severe congestive heart failure, and 6 heart transplant patients underwent positron emission tomography (PET) with nitrogen-13 ammonia. Quantitation of the regional myocardial blood flow in the septum was performed using both a conventional two-compartment model and a previously validated two-compartment model taking RV spillover into account. Unaccounted RV spillover resulted in significant underestimation of the regional myocardial blood flow in the septum. The amount of underestimation was primarily dependent on the magnitude of spillover and the dispersion between the right and the left ventricular input functions. In healthy volunteers, the flow error was small but significant: on average 6% (range 5%-29%, P<0.00001), compared with 27% (range 0%-88%, P<0.002) in the group of patients with severe congestive heart failure, who had the most considerable amount of RV spillover. In the group of patients with ischemic heart disease and the group of heart transplant patients the flow errors were 10% (range 0%-55%, P<0.00001) and 6% (range 1%-19%, P<0.01), respectively. It is concluded that flow quantitation in the septum is significantly affected by RV spillover, resulting in a considerable underestimation of the septal blood flow unless correction is performed.     

Metabolic fate of [13N]ammonia in human and canine blood

Nitrogen-13- ([13N]) ammonia is a widely used tracer for PET myocardial blood flow studies. Quantification of blood flow using tracer kinetic principles requires accurate determination of [13N]ammonia activity in blood. Since [13N] ammonia is rapidly metabolized, the arterial input function may be contaminated by labeled metabolites. We, therefore, characterized the 13N-labeled metabolites in blood after intravenous (i.v.) injection of 20 mCi [13N]ammonia in nine healthy volunteers. Utilizing a series of ion exchange resins, 13N-labeled compounds were separated into four groups: ammonia, neutral amino acids, acidic amino acids, and urea. Analysis of the metabolic fate of [13N]ammonia indicates that over 90% of the blood activity within the first two minutes after injection is present as [13N]ammonia. However, there is considerable contamination of the blood activity at 3-5 min by [13N]glutamine (amide) and urea, which collectively represent 18%-50% of the blood activity. Thus, correction of the arterial input function for 13N-metabolites is required to accurately quantify the arterial input function of [13N]ammonia in myocardial blood flow studies.     

Observations with SPECT on the normal regional distribution of pulmonary blood flow in gravity independent planes

While the effect of gravity on the pulmonary circulation is well documented, the distribution of pulmonary flow under gravity independent conditions is not as well understood. Single photon emission computed tomography was applied to the study of regional pulmonary blood flow in slices where the effect of gravity was constant. Lung tomography, after the injection of [99mTc]MAA, was carried out in six normal volunteers and in the fully inflated and isolated lungs from six dogs that had been killed. Our tomographic results suggest that pulmonary perfusion in isogravitational planes is inherently nonuniform with preferential flow centrally and reduced circulation more peripherally. Planar imaging of the dissected isogravitational slices from the animals further confirmed the uneven perfusion noted on the tomographic slices.     

Comparison of gated N-13 ammonia PET and gated Tc-99m sestamibi SPECT for quantitative analysis of global and regional left ventricular function

Background  The aim of this study was to compare global and regional left ventricular function in patients with coronary artery disease (CAD), obtained by use of Cedars-Sinai quantitative gated single photon emission computed tomography (QGS), for gated nitrogen 13 ammonia (NH₃) positron emission tomography (PET) and technetium 99m sestamibi (MIBI) single photon emission computed tomography (SPECT). Methods and Results  Fifty-one patients with CAD underwent gated N-13 NH₃ PET and gated MIBI SPECT. The end-diastolic volume, end-systolic volume, and ejection fraction were calculated by use of QGS. The quantitative regional wall motion (WM) and wall thickening (WT) scores for 20 segments in the myocardium were also measured by QGS. The end-diastolic volume, end-systolic volume, and ejection fraction measured by N-13 NH₃ PET showed highly significant correlation with those measured by MIBI SPECT (r=0.97, r=0.97, and r=0.84, respectively). The mean correlation of WM and WT on an individual patient basis between N-13 NH₃ PET and MIBI SPECT was 0.81 and 0.84, respectively. The circumferential variation of WM and TT in 20 segments showed a similar pattern with N-13 NH₃ PET and MIBI SPECT. Conclusion  Gated N-13 NH₃ PET combined with QGS provides information on both global and regional left ventricular function comparable to that obtained by gated Tc-99m perfusion myocardial SPECT in CAD patients.     

Evaluation of ammonia metabolism in the skeletal muscles of patients with cirrhosis using N-13 ammonia PET

OBJECTIVE: Skeletal muscle is said to compensate for the decreased ammonia metabolism in patients with cirrhosis. Branched-chain amino acids (BCAA) are being used as a treatment for hyperammonemia, and are believed to decrease blood ammonia by consumption of BCAA in skeletal muscles. We examined ammonia metabolism of the skeletal muscles in patients with liver cirrhosis after administration of BCAA using 13N-ammonia positron emission tomography (PET). METHODS: The subjects were patients with compensated or decompensated liver cirrhosis. PET studies were performed before and 2 hours after injection of BCAA. Serial dynamic PET scans (2 min x 10 frames) were started simultaneously with 13N-ammonia injection. The standardized uptake value (SUV) of both thighs was calculated. RESULTS: In the patient with compensated liver cirrhosis, there was little difference in the rate of increase in SUV before to after administration of BCAA. However, in the patient with decompensated liver cirrhosis, the rate of increase in SUV after administration was higher than that before administration of BCAA. CONCLUSION: Ammonia metabolism in the muscle of patients with liver cirrhosis could be examined noninvasively under physiological conditions using 13N-ammonia PET. The muscles were found to metabolize ammonia partially, and the role of this contribution to metabolism of ammonia in patients with decompensated liver cirrhosis is particularly important.     

Semiquantitative in vitro binding assay of indium-111-labeled monoclonal antibodies to human cancer and normal tissues

We have developed a simple in vitro method for the semiquantitative assessment of the radiolabeled antibody binding to cancer and normal tissues. Indium-111-labeled F(ab')2 fragments of 17-1A and 19-9 monoclonal antibodies with well-characterized specificity for gastrointestinal cancer demonstrated similar binding properties between cultured cancer cells and membrane fractions of homogenates prepared from tumor tissues. All of the 17 colon cancer specimens and seven (64%) of 11 gastric cancer specimens obtained by surgery showed positive binding with 17-1A. Specific binding of 19-9 was observed in 9 (53%) colon cancers and 4 (36%) gastric cancers. However, some normal colon tissues were also positive with 111In-labeled 17-1A. Relative levels of CA 19-9 antigen expression, determined by the binding with radiolabeled antibodies, correlated with percent positive cells determined by the immunohistochemical assays. Furthermore, membrane fractions could be cryopreserved without losing antibody-binding activity. These results indicate that this assay can be used for testing the immunoreactivity of radiolabeled anti-tumor antibodies and in vitro binding properties to cancer and normal tissues.