Rob S.B. Beanlands

Positron emission tomography detects evidence of viability in rest technetium-99m sestamibi defects.

OBJECTIVES The purpose of this study was to determine the relative value of single-photon emission computed tomographic (SPECT) imaging at rest using technetium-99m methoxyisobutyl isonitrile (technetium-99m sestamibi) with positron emission tomography for detection of viable myocardium. BACKGROUND Recent studies comparing positron emission tomography and thallium-201 reinjection with rest technetium-99m sestamibi imaging have suggested that the latter technique underestimates myocardial viability. METHODS Twenty patients with a previous myocardial infarction underwent rest technetium-99m sestamibi imaging and positron emission tomography using fluorine (F)-18 deoxyglucose and nitrogen (N)-13 ammonia. In each patient, circumferential profile analysis was used to determine technetium-99m sestamibi, F-18 deoxyglucose and N-13 ammonia activity (expressed as percent of peak activity) in nine cardiac segments and in the perfusion defect defined by the area having technetium-99m sestamibi activity < 60%. Technetium-99m sestamibi defects were graded as moderate (50% to 59% of peak activity) and severe (< 50% of peak activity). Estimates of perfusion defect size were compared between technetium-99m sestamibi and N-13 ammonia. RESULTS Sixteen (53%) of 30 segments with moderate defects and 16 (47%) of 34 segments with severe defects had > or = 60% F-18 deoxyglucose activity considered indicative of viability. Fluorine-18 deoxyglucose evidence of viability was still present in 50% of segments with technetium-99m sestamibi activity < 40%. There was no significant difference in the mean (+/- SD) technetium-99m sestamibi activity in segments with viable (40 +/- 7%) and nonviable segments (49 +/- 7%, p = 0.84). Of the 18 patients who had adequate F-18 deoxyglucose studies, the area of the technetium-99m sestamibi defect was viable in 5 (28%). In 16 patients (80%), perfusion defect size determined by technetium-99m sestamibi exceeded that measured by N-13 ammonia. The difference in defect size between technetium-99m sestamibi and N-13 ammonia was significantly greater in patients with viable (21 +/- 9%) versus nonviable segments (7 +/- 9%, p = 0.007). CONCLUSIONS Moderate and severe rest technetium-99m sestamibi defects frequently have metabolic evidence of viability. Technetium-99m sestamibi SPECT yields larger perfusion defects than does N-13 ammonia positron emission tomography when the same threshold values are used.

Noninvasive quantification of regional myocardial flow reserve in patients with coronary atherosclerosis using nitrogen-13 ammonia positron emission tomography. Determination of extent of altered vascular reactivity.

OBJECTIVES The aim of this study was to evaluate patients with coronary artery disease to 1) determine the relation between flow reserve measured by nitrogen-13 (N-13) ammonia kinetic modeling and stenosis severity assessed by quantitative angiography, and 2) examine whether flow reserve is impaired in regions supplied by vessels without significant angiographic disease. BACKGROUND With the advent of new therapeutic approaches for coronary disease, an accurate noninvasive approach for absolute quantification of flow and flow reserve is needed to evaluate functional severity and extent of atherosclerosis. Nitrogen-13 ammonia kinetic modeling may permit such evaluation. METHODS Twenty-seven subjects were classified into three groups: group 1 = 5 young volunteers: group 2 = 7 middle-aged volunteers; and group 3 = 15 patients with coronary artery disease. Dynamic N-13 ammonia positron emission tomographic imaging was performed at rest and during adenosine infusion. A three-compartment model was fit to regional N-13 ammonia kinetic data to determine myocardial flow. Group 3 patients underwent quantitative coronary angiography. RESULTS The regional blood flow results in patients with coronary disease were classified into four subgroups: no significant detectable disease and mild (50% to 69.9% area stenosis), moderate (70% to 94.9% area stenosis) or severe (95% to 100% area stenosis) coronary disease. Flow reserve was 2.95 +/- 0.65; 2.09 +/- 0.47; 2.02 +/- 0.51; 1.3 +/- 0.32, respectively (p < or = 0.01 except mild vs. moderate). Flow reserve was correlated with percent area stenosis (r = -0.56) and minimal lumen diameter (r = 0.75). In volunteers (groups 1 and 2), flow reserves were greater than in segments without detectable disease in group 3 patients (4.10 +/- 0.71 and 3.79 +/- 0.42, respectively, vs. 2.88 +/- 0.56, p < or = 0.02). CONCLUSIONS The functional severity of coronary disease measured by N-13 ammonia positron emission tomography varied for a given stenosis but was significantly related to angiographic severity. Among patients with coronary disease, myocardial regions without significant angiographic stenoses displayed reduced flow reserve than did regions in control subjects, indicating that vascular reactivity was more diffusely impaired in group 3 than was suggested by angiography. Noninvasive quantification of myocardial flow reserve using dynamic N-13 ammonia positron emission tomography yields important functional data that permit definition of the extent of disease even when disease is not apparent by angiography.

Assessment of diagnostic performance of quantitative flow measurements in normal subjects and patients with angiographically documented coronary artery disease by means of nitrogen-13 ammonia and positron emission tomography

OBJECTIVES Regional myocardial blood flow (MBF) and flow reserve measurements using nitrogen-13 (N-13) ammonia positron emission tomography (PET) were compared with quantitative coronary angiography to determine their utility in the detection of significant coronary artery disease (CAD). BACKGROUND Dynamic PET protocols using N-13 ammonia allow regional quantification of MBF and flow reserve. To establish the diagnostic performance of this method, the sensitivity and specificity must be known for varying decision thresholds. METHODS MBF and flow reserve for three coronary territories were determined in 20 normal subjects and 31 patients with angiographically documented CAD by means of dynamic PET and a three-compartment model for N-13 ammonia kinetics. Ten normal subjects defined the normal mean and SD of MBF and flow reserve, and 10 normal subjects were compared with patients. PET flow obtained in the territory with the most severe stenosis in each patient was correlated with the angiographic assessment of the stenosis (severity > or = 50%, > or = 70%, > or = 90%). Receiver operating characteristic (ROC) curve analysis was performed for 1.5, 2.0, 2.5, 3.0 and 4.0 SD of flow abnormalities. RESULTS MBF and flow reserve values from the normal subjects and from territories with documented stenoses > or = 50% were significantly different (p < 0.05). A significant difference was found between normal subjects and angiographically normal territories of patients with CAD. High diagnostic accuracy and sensitivity, with moderately high specificity, were demonstrated for detection of all stenoses. CONCLUSIONS Quantification of myocardial perfusion using dynamic PET and N-13 ammonia provides a high performance level for the detection and localization of CAD. The specificity of dynamic PET was excellent in patients with a low likelihood of CAD, whereas an abnormal flow reserve in angiographically normal territories was postulated to represent early functional abnormalities of vascular reactivity.

Acute effects of dobutamine on myocardial oxygen consumption and cardiac efficiency measured using carbon-11 acetate kinetics in patients with dilated cardiomyopathy☆

OBJECTIVES The aim of this study was to use positron emission tomography (PET)-derived carbon (C)-11 acetate kinetics to determine the effects of dobutamine on oxidative metabolism and its effects on myocardial efficiency in a group of patients with dilated cardiomyopathy. BACKGROUND Dobutamine is known to improve myocardial function but may do so at the expense of myocardial oxygen consumption, which could be a potential deleterious effect. Carbon-11 acetate kinetics correlate with myocardial oxygen consumption as shown in animal models. Combining these scintigraphic measurements of oxygen consumption with estimates of cardiac work results in a work-metabolic index, which reflects cardiac efficiency. METHODS Eight patients with nonischemic dilated cardiomyopathy underwent dynamic PET imaging, echocardiography and hemodynamic measurements. Seven of these patients were also studied while receiving dobutamine. Direct measurements of myocardial oxygen consumption using coronary sinus catheterization were obtained with eight of the PET studies to validate C-11 acetate in patients with cardiomyopathy. RESULTS The mean (+/- SD) C-11 clearance rate significantly increased with dobutamine from 0.105 +/- 0.027 to 0.155 +/- 0.023 min-1 (p = 0.001). Directly measured myocardial oxygen consumption had a linear relation to the mean C-11 clearance rate (r = 0.8, p = 0.018). Dobutamine was noted to significantly reduce systemic vascular resistance as well as the severity of mitral regurgitation. The work-metabolic index determined using hemodynamic variables and PET data increased from 2 +/- 0.7 x 10(4) to 2.6 +/- 0.6 x 10(4) (p = 0.04). Efficiency, estimated by employing the oxygen consumption to k2 relation, also increased from 13 +/- 4.5% to 16.9 +/- 6.4% (p = 0.04). CONCLUSIONS Despite an increase in myocardial oxygen consumption, dobutamine led to an increase in work-metabolic index in patients with dilated nonischemic cardiomyopathy. Dobutamine reduced systemic vascular resistance and mitral regurgitation, suggesting that in this group of patients, it had important vasodilatory action in addition to its inotropic effects. The use of the C-11 acetate PET for determining myocardial oxygen consumption and estimating efficiency could potentially complement existing clinical measures of ventricular performance and may allow improved and objective evaluation of therapy in patients with heart failure.

Interobserver and interstudy variability of myocardial blood flow and flow-reserve measurements with nitrogen 13 ammonia—labeled positron emission tomography*

BackgroundExperimental studies have shown that positron emission tomography (PET) with 13N-labeled ammonia provides accurate quantification of regional myocardial blood flow (MBF) under rest and stress conditions. To establish the clinical utility of this method, the interobserver variability and the temporal variability of serial measurements of blood flow and coronary flow reserve (CFR) must be known. This study investigated the interobserver and temporal reproducibility of 13N-labeled PET for measurement of MBF and CFR.Methods and ResultsInitial and follow-up 13N-labeled ammonia PET studies were performed at rest and during adenosine infusion in six normal volunteers and six patients with stable coronary artery disease. Two investigators analyzed dynamically acquired data from the initial studies and one investigator analyzed the follow-up studies. Time-activity curves of tissue tracer activity were derived by a semiautomated sampling routine. A three-compartment model and curve-fitting algorithm were used to determine estimates of MBF in five myocardial regions. The interobserver correlations for MBF and CFR were excellent (r=0.96 and 0.93, respectively). The interstudy correlation was good for rest and stress MBF (r=0.87). The estimates of CFR on the initial and follow-up studies demonstrated a fair correlation (r=0.72). For individual myocardial regions, there was considerable interstudy variability of stress MBF and CFR, with a mean percent difference for CFR of 19%±19% in normal volunteers and 38%±16% in patients with coronary disease. In normal subjects, regional CFR was highly reproducible (95%) when the values were defined as either normal (≥2.5) or reduced (<2.5).ConclusionsThe interobserver of reproducibility of 13N-labeled ammonia PET estimates of regional MBF was excellent. The temporal reproducibility of MBF and CFR was fair, with individual regions demonstrating substantial interstudy variability.

Heterogeneity of ventricular function and myocardial oxidative metabolism in nonischemic dilated cardiomyopathy.

OBJECTIVES This study was performed to test the hypothesis that regional variation in ventricular function in patients with nonischemic dilated cardiomyopathy is related to regional variation in oxidative metabolism. BACKGROUND Heterogeneity in regional left ventricular function has long been noted in patients with nonischemic dilated cardiomyopathy. Regional variation in wall stress has been proposed as the pathophysiologic mechanism. By correlating regional function with oxidative metabolism, one can test the hypothesis that heterogeneity in wall stress is responsible for heterogeneity in function. We hypothesized that preserved function as a result of more favorable loading conditions would be associated with regional oxidative metabolism that is equal to or lower than that in other regions. METHODS Fifteen patients with nonischemic dilated cardiomyopathy (mean [+/- SD] ejection fraction 20.7 +/- 4.0%) were studied. Regional ventricular function was determined using short-axis chordal shortening on two-dimensional echocardiography. Regional oxidative metabolism was assessed by carbon-11 acetate clearance kinetics on dynamic positron emission tomography. An eight-segment model of the left ventricle was used. Segmental function and oxidative metabolism were defined as increased if they varied at least 1 SD from the respective mean value for that patient. RESULTS Thirteen (87%) of 15 patients exhibited segments with increased function. In 7 (54%) of 13 patients, regional function was increased in the proximal lateral wall. Multivariate linear regression analysis showed a direct relation between regional function and oxidative metabolism (p = 0.02). The average concordance between increased function and increased oxidative metabolism among patients was 0.87 +/- 0.11 (95% confidence interval 0.70 to 1.00). CONCLUSIONS Patients with nonischemic dilated cardiomyopathy display heterogeneity in regional ventricular function. Relative preservation is observed most frequently in the proximal lateral wall. Relative preservation of function is associated with higher regional oxidative metabolism, suggesting that mechanisms other than or in addition to local loading conditions may be responsible for heterogeneity in function.

Comparison of technetium-99m sestamibi and thallium-201 retention characteristics in canine myocardium

OBJECTIVES The aim of this study was to compare the myocardial retention of technetium-99m (Tc-99m) sestamibi and thallium-201 over a wide range of blood flow at different time points after tracer injection. BACKGROUND Technetium-99m sestamibi has been proposed as a new perfusion tracer with better physical characteristics than those of thallium-201 for scintigraphic imaging. However, no studies have simultaneously compared the ability of both tracers to assess myocardial blood flow during pharmacologic vasodilation. METHODS The myocardial retention of Tc-99m sestamibi and thallium-201 were compared over a wide range of blood flow induced by regional coronary occlusion and dipyridamole infusion in an open chest dog model. Myocardial retention of both tracers was determined by in vitro tissue counting at 2, 5, and 20 min after tracer injection and was correlated with microsphere-determined blood flow. RESULTS Thallium-201 demonstrated greater absolute tissue retention than did Tc-99m sestamibi. At 2 min after tracer injection, there was an almost linear relation between the retention of both tracers and myocardial blood flow over a wide flow range. However, this relation was not maintained over time. At 20 min after injection, the retention of both tracers underestimated myocardial blood flow at higher flow rates. At 2, 5 and 20 min after injection, increments of relative tracer retention between the different levels of flow were always greater for thallium-201 than for Tc-99m sestamibi. CONCLUSIONS Thallium-201 displays more suitable physiologic characteristics as a flow tracer and may allow better differentiation of myocardial regions with different levels of coronary flow reserve. For both tracers, early cardiac imaging may minimize underestimation of blood flow at higher flow rates.

The relationship between myocardial retention of technetium-99m teboroxime and myocardial blood flow

OBJECTIVES The aim of this study was to define the temporal changes in the relationship between technetium-99m teboroxime tissue retention and myocardial blood flow in a canine model. BACKGROUND Technetium-99m teboroxime is a new neutral lipophilic myocardial perfusion agent. It is known to be highly extracted by the myocardium but to have a rapid clearance rate. METHODS A wide range of myocardial blood flow was induced in each experiment by regional coronary occlusion and dipyridamole infusion. Myocardial retention of technetium-99m teboroxime was determined by in vitro tissue counting at 1, 2 or 5 min after injection of the tracer. Tracer retention was correlated with microsphere-determined blood flow and the data were fitted to nonlinear functions. RESULTS Correlation coefficients for these functions were 0.92, 0.95 and 0.95 at 1, 2, and 5 min, respectively. At 1 min after injection, the relationship of technetium-99m teboroxime retention to blood flow was linear over a wide flow range, becoming nonlinear at flow rates greater than 4.5 ml/min per g. After 5 min the retention-flow relationship was linear only to 2.5 ml/min per g, above which little change in retention was noted. Normalized myocardial retention, expressed as a percent of the retention at 1 ml/min per g, was also calculated. At flow rates of 1, 2, 3, 4 and 5 ml/min per g, normalized retention was 100, 169, 228, 277 and 317% at 1 min and 100, 171, 217, 239 and 237% at 5 min after injection. CONCLUSIONS At 1 min after injection, the relationship of technetium-99m teboroxime myocardial retention to blood flow is well maintained over a wide range of flow. However, after only 5 min, tracer retention underestimates flow changes at moderate and high flow rates. Thus, rapid acquisition protocols are necessary to fully exploit the potential of this promising new tracer in the evaluation of myocardial perfusion.

The effects of afterload reduction on myocardial carbon 11-labeled acetate kinetics and noninvasively estimated mechanical efficiency in patients with dilated cardiomyopathy.

Methods and ResultsWith echocardiography and dynamic carbon 11-labeled acetate (C-11 acetate) positron emission tomographic imaging, C-11 acetate kinetics and a parameter that estimates mechanical ventricular efficiency (the work metabolic index) were defined in eight patients with dilated cardiomyopathy. The effect of afterload reduction with nitroprusside on these parameters was evaluated in six of these patients. Nitroprusside increased stroke work index but decreased the C-11 clearance rate. The work metabolic index determined noninvasively increased and correlated well with an invasive approach. The work metabolic index was inversely correlated with systemic vascular resistance. Nitroprusside shifted this relationship upward and to the left.ConclusionThis method of estimating efficiency is feasible and may represent a unique noninvasive approach for the evaluation of cardiac performance and responses to therapy.

Heterogeneity of regional nitrogen 13-labeled ammonia tracer distribution in the normal human heart:Comparison with rubidium 82 and copper 62-labeled PTSM

BackgroundRecent reports on13N-labeled ammonia (13N-ammonia) positron emission tomographic (PET) imaging have suggested a relative reduction of measured tracer activity in the posterolateral wall. Such inhomogeneity of tracer distribution could potentially affect accuracy for detection of disease. The aim of this study was to compare the regional distribution of13N-ammonia with82Rb and62Cu-labeled PTSM (62Cu-PTSM) to identify tracer-specific patterns that may be important in the clinical interpretation of cardiac flow studies.Methods and ResultsTwenty-eight healthy volunteers underwent PET imaging at rest with either13N-ammonia (n=14),82Rb (n=8), or62Cu-PTSM (n=6). Eight subjects given13N-ammonia also underwent imaging after adenosine. Activity measured in the posterolateral wall on transaxial images was significantly lower than in the septum for13N-ammonia, both at rest (p<0.005) and after adenosine (p<0.05). No differences were detected for82Rb or62Cu-PTSM. The septum/posterolateral wall activity ratios for13N-ammonia,82Rb, and62Cu-PTSM were 1.15±0.07, 1.00±0.06, and 0.97±0.08, respectively (p<0.001). Regional analysis of image data showed the percent of maximal activity data for13N-ammonia in the lateral wall to be less than that of other regions (p<0.001) and in the inferior wall to be greater than in the anterior and lateral walls (p<0.001). For62Cu-PTSM, activity in the inferior wall was greater than that in other regions (p<0.005). No regional differences were detected for82Rb.ConclusionsThe relatively increased wall activity with13N-ammonia and62Cu-PTSM is most likely due to cross-contamination of activity from the liver. The significant reduction in activity in the lateral wall with13N-ammonia, which persists after adenosine, is most likely related to regional heterogeneity in13N-ammonia retention and may reflect regional differences in metabolic-trapping mechanisms for13N-ammonia. Further investigation is required to elucidate the underlying mechanism of this phenomenon. Reduced tracer retention in the lateral wall segment as a normal variant must be considered when evaluating clinical13N-ammonia PET studies.