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.

Myocardial rubidium-82 tissue kinetics assessed by dynamic positron emission tomography as a marker of myocardial cell membrane integrity and viability.

BACKGROUND: Recent reports have demonstrated the clinical use of rubidium-82 chloride (Rb-82) in combination with positron emission tomography (PET) not only as a tracer of myocardial blood flow but also as a marker of cell membrane integrity using static imaging early and late after tracer injection. The purpose of this study was to compare myocardial Rb-82 kinetics assessed by dynamic PET imaging as a marker for tissue viability with regional fluorine-18 fluorodeoxyglucose (FDG) uptake in patients with coronary artery disease. METHODS AND RESULTS: Twenty-seven patients with angiographically proven coronary artery disease and 5 subjects with a low likelihood for coronary artery disease underwent dynamic PET imaging under resting conditions using Rb-82 and FDG. Both image sequences served as input data for a semiautomated regional analysis program. This program generated polar maps representing Rb-82 tissue half-life and FDG utilization assessed by Patlak's approach. Myocardial tissue viability was visually determined from static Rb-82 and FDG images. Regions were categorized as normal, ischemically compromised, and scar tissue. Their coordinates were subsequently copied to the functional polar maps for further analyses. In normal subjects, Rb-82 tissue half-life was homogeneous throughout the left ventricle (90 +/- 11 seconds). In coronary patients, differences between Rb-82 tissue half-lives in normal and scar tissue were highly significant (95 +/- 10 and 57 +/- 15 seconds, respectively; P < .0001). FDG uptake in these two tissue groups was 78 +/- 12% and 40 +/- 13%, respectively (P < .0001). Ischemically compromised tissue with reduced perfusion but maintained FDG uptake displayed an Rb-82 half-life of 75 +/- 9 seconds, indicating active cellular tracer retention, which was significantly different from scar tissue. Overall agreement of tissue categorization as either viable or scar was 86% between Rb-82 kinetics and FDG utilization. In a subgroup of 11 patients with all three tissue types within one image set, Rb-82 tissue half-life discriminated between normal, ischemic, and scar tissue (97 +/- 9, 75 +/- 9, and 60 +/- 15 seconds, respectively; P < .01). CONCLUSIONS: This study demonstrated a significant relationship between cell membrane integrity as assessed by dynamic Rb-82 PET imaging and myocardial glucose utilization as a marker for tissue viability. In regions with reduced perfusion, Rb-82 kinetics was different in compromised but metabolically active and irreversibly injured myocardium. The predictive value of this approach must be evaluated in follow-up studies.

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

BACKGROUND: Recent reports on 13N-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 of 13N-ammonia with 82Rb and 62Cu-labeled PTSM (62Cu-PTSM) to identify tracer-specific patterns that may be important in the clinical interpretation of cardiac flow studies. METHODS AND RESULTS: Twenty-eight healthy volunteers underwent PET imaging at rest with either 13N-ammonia (n = 14), 82Rb (n = 8), or 62Cu-PTSM (n = 6). Eight subjects given 13N-ammonia also underwent imaging after adenosine. Activity measured in the posterolateral wall on transaxial images was significantly lower than in the septum for 13N-ammonia, both at rest (p < 0.005) and after adenosine (p < 0.05). No differences were detected for 82Rb or 62Cu-PTSM. The septum/posterolateral wall activity ratios for 13N-ammonia, 82Rb, and 62Cu-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 for 13N-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). For 62Cu-PTSM, activity in the inferior wall was greater than that in other regions (p < 0.005). No regional differences were detected for 82Rb. CONCLUSIONS: The relatively increased wall activity with 13N-ammonia and 62Cu-PTSM is most likely due to cross-contamination of activity from the liver. The significant reduction in activity in the lateral wall with 13N-ammonia, which persists after adenosine, is most likely related to regional heterogeneity in 13N-ammonia retention and may reflect regional differences in metabolic-trapping mechanisms for 13N-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 clinical 13N-ammonia PET studies.

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 assessment of cardiac diabetic neuropathy by carbon-11 hydroxyephedrine and positron emission tomography.

OBJECTIVES: The purpose of this investigation was to evaluate the sympathetic nervous system of the heart by positron emission tomographic (PET) imaging in patients with diabetes mellitus with and without diabetic autonomic neuropathy. BACKGROUND: The clinical assessment of cardiac involvement in diabetic autonomic neuropathy has been limited to cardiovascular reflex testing. With the recent introduction of radiolabeled catecholamines such as carbon (C)-11 hydroxyephedrine, the sympathetic innervation of the heart can be specifically visualized with PET imaging. METHODS: Positron emission tomographic imaging was performed with C-11 hydroxyephedrine and rest myocardial blood flow imaging with nitrogen-13 ammonia. Three patient groups were studied, including healthy volunteers as control subjects, diabetic patients with normal autonomic function testing and diabetic patients with varying severity of autonomic neuropathy. Homogeneity of cardiac tracer retention as well as absolute tracer retention was determined by relating myocardial tracer retention to an arterial C-11 activity input function. RESULTS: Abnormal regional C-11 hydroxyephedrine retention was seen in seven of eight patients with autonomic neuropathy. Relative tracer retention was significantly reduced in apical, inferior and lateral segments. The extent of the abnormality correlated with the severity of conventional markers of autonomic dysfunction. Absolute myocardial tracer retention index measurements showed a 45 +/- 21% decrease in distal compared with proximal myocardial segments in autonomic neuropathy (0.069 +/- 0.037 min-1 vs. 0.13 +/- 0.052 min-1, p = 0.02). CONCLUSIONS: This study demonstrates a heterogeneous pattern of neuronal abnormalities in patients with diabetic cardiac neuropathy. The extent of this abnormality correlated with the severity of neuropathy assessed by conventional tests. Future studies in larger groups of patients are required to define the relative sensitivity of this imaging approach in detecting cardiac neuropathy and to determine the clinical significance of these scintigraphic findings in comparison with conventional markers of autonomic innervation.

Myocardial glucose uptake in patients with insulin-dependent diabetes mellitus assessed quantitatively by dynamic positron emission tomography.

BACKGROUND: Animal studies have demonstrated reduced myocardial glucose utilization in the diabetic heart, suggesting abnormalities in glucose transport. This study was designed to evaluate myocardial glucose uptake as assessed by 2-fluoro-(fluorine-18)2-deoxy-D-glucose (FDG) and positron emission tomography (PET) in patients with insulin-dependent diabetes mellitus (IDDM) under standardized metabolic conditions. METHODS AND RESULTS: A hyperinsulinemic-euglycemic clamp technique was used during PET data acquisition in nine healthy male volunteers and seven young male patients with a history of IDDM for less than 5 years. Oxidative metabolism was assessed with C-11 acetate, and glucose uptake was quantitatively measured with FDG using Patlak graphic analysis. Hemodynamic data and C-11 acetate kinetics were comparable. Myocardial glucose uptake averaged 0.44 +/- 0.12 mumol.g-1.min-1 in normal subjects and 0.43 +/- 0.16 mumol.g-1.min-1 in patients with IDDM (P = NS). Blood tracer clearance was also similar in both groups as determined by the ratio of peak blood tracer activity to the activity at 55 to 60 minutes after tracer injection. F-18 activity ratio between myocardium and blood pool averaged 7.2 +/- 3.4 in the normal heart and 7.5 +/- 3.0 in the diabetic heart (P = NS). CONCLUSIONS: These data indicate that metabolic standardization and supplementation with insulin in young patients with IDDM is associated with myocardial glucose uptake similar to that observed in the normal heart. Chronic therapy with insulin may prevent the metabolic abnormalities observed in diabetic animal models.

Carbon-11 hydroxyephedrine with positron emission tomography for serial assessment of cardiac adrenergic neuronal function after acute myocardial infarction in humans.

OBJECTIVES: The purpose of this study was to assess the extent and reversibility of neuronal abnormalities in patients with an acute myocardial infarction. BACKGROUND: Previous experimental studies have described ischemic injury to sympathetic neurons exceeding the area of myocardial necrosis. Carbon-11 (C-11) hydroxyephedrine (HED) is a norepinephrine analogue that can be used for the noninvasive evaluation of neuronal integrity using positron emission tomography. METHODS: We studied 14 volunteers and 16 patients experiencing a first acute myocardial infarction. Positron emission tomographic imaging was used to quantitatively compare regional perfusion, as assessed with nitrogen-13 ammonia, with myocardial retention of C-11 hydroxyephedrine early after myocardial infarction as well as > 6 months after the acute event. RESULTS: C-11 hydroxyephedrine and flow images demonstrated homogeneous tracer retention in volunteers but were abnormal in all patients. C-11 hydroxyephedrine abnormalities were more extensive than those for blood flow assessed by semiquantitative polar map analysis (31 +/- 15% vs. 17 +/- 17% left ventricle; p < 0.05), particularly in five patients with non-Q wave infarction (31 +/- 11% vs. 3.5 +/- 2.5% left ventricle; p = 0.008). Eleven patients with Q wave infarction had matched defects (28 +/- 17% vs. 21 +/- 17% left ventricle; p = NS). C-11 hydroxyephedrine tissue retention fraction was quantified in three tissue zones: zone 1 (abnormal rest flow) had retention fraction 0.037 +/- 0.022-min; zone 2 (normal rest flow but decreased carbon-11 hydroxyephedrine retention) had retention fraction 0.068 +/- .034-min, and zone 3 (normal flow and carbon-11 hydroxyephedrine retention) had retention fraction 0.087 +/- 0.041-min (p = 0.0004). Follow-up studies at 8 +/- 3 months in eight patients revealed no change in extent of abnormalities or absolute tissue tracer retention in infarct and peri-infarct territories. CONCLUSIONS: The results of abnormal regional sympathetic innervation in patients with infarction confirm previous experimental data and suggest persistent neuronal damage in infarct and peri-infarct territories, without evidence of reinnervation of reversibly injured myocardium.

Quantitative evaluation of regional substrate metabolism in the human heart by positron emission tomography.

Meaning interpretation of metabolic images obtained by positron emission tomography for evaluation of cardiac disease requires a knowledge of the normal variation in regional myocardial substrate metabolism. Recent studies with fluorine-18 (F-18) fluorodeoxyglucose suggest inhomogeneity of myocardial glucose metabolism in the normal human heart, which may relate to substrate availability. Therefore, quantitative evaluation of myocardial oxidative metabolism and glucose metabolism, as derived by dynamic positron emission tomography with carbon-11 (C-11) acetate and F-18 fluorodeoxyglucose, was performed in nine healthy male volunteers. All were studied under tightly controlled metabolic conditions of hyperinsulinemic-euglycemic clamping with and without a concurrent lipid emulsion infusion. Significant inhomogeneity of regional glucose metabolism was noted although it was less than that described under fasting conditions. Glucose utilization was 13% lower in the septum compared with the lateral wall both without and with lipid infusion (0.34 vs. 0.39 mumol/g per min, respectively, p less than 0.05; and 0.33 vs. 0.38 mumol/g per min, respectively, (p less than 0.05). Relatively decreased septal glucose utilization could not be explained by decreased metabolic demand because C-11 clearance constants were marginally higher in the septum than in the lateral wall in both studies (0.055 vs. 0.054 per min, respectively, p = NS; and 0.061 vs. 0.056 per min, respectively, p less than 0.05). Relatively decreased septal glucose utilization could reflect regional variation in substrate use and possible preferential free fatty acid utilization by the septum. These data provide a useful framework for assessing altered cardiac metabolism in disease and support standardization of metabolic conditions during metabolic imaging with positron emission tomography.

Accuracy of automatically determined borders in digital two-dimensional echocardiography using a cardiac phantom.

Although two-dimensional echocardiography (2-D echo) is a useful technique for evaluation of global and regional left ventricular function, the main limitation is the inability to easily extract reliable and accurate quantitative information throughout all phases of the cardiac cycle. We sought to develop suitable automated techniques for the objective determination of endocardial and epicardial borders in two-dimensional echocardiographic images. To test algorithms for the automatic detection of myocardial borders we constructed a cardiac ultrasound phantom consisting of 16 echogenic annuli of known dimensions embedded in a material of low echogenicity which allowed imaging without partial volume effects. An algorithm based on Gaussian filtering followed by a difference gradient operator was applied to detect edges in the 2-D echo images of these annuli. The radii of the automatically determined inner borders were within 0.44 mm root meansquared error over a range of 15-25 mm true radius. This lower boundary for the error in our approach to automatic placement of myocardial borders in 2-D echocardiograms suggests the potential to extract more information concerning left ventricular function than is available with current techniques.