Edwin R. Wolfe

Noninvasive evaluation of sympathetic nervous system in human heart by positron emission tomography.

The noninvasive functional characterization of the cardiac sympathetic nervous system by imaging techniques may provide important pathophysiological information in various cardiac disease states. Hydroxyephedrine labeled with carbon 11 has been developed as a new catecholamine analogue to be used in the in vivo evaluation of presynaptic adrenergic nerve terminals by positron emission tomography (PET). To determine the feasibility of this imaging approach in the human heart, six normal volunteers and five patients with recent cardiac transplants underwent dynamic PET imaging after intravenous injection of 20 mCi [11C]hydroxyephedrine. Blood and myocardial tracer kinetics were assessed using a regions-of-interest approach. In normal volunteers, blood 11C activity cleared rapidly, whereas myocardium retained 11C activity with a long tissue half-life. Relative tracer retention in the myocardium averaged 79 +/- 31% of peak activity at 60 minutes after tracer injection. The heart-to-blood 11C activity ratio exceeded 6:1 as soon as 30 minutes after tracer injection, yielding excellent image quality. Little regional variation of tracer retention was observed, indicating homogeneous sympathetic innervation throughout the left ventricle. In the transplant recipients, myocardial [11C]hydroxyephedrine retention at 60 minutes was significantly less (-82%) than that of normal volunteers, indicating only little non-neuronal binding of the tracer in the denervated human heart. Thus, [11C]hydroxyephedrine, in combination with dynamic PET imaging, allows the noninvasive delineation of myocardial adrenergic nerve terminals. Tracer kinetic modeling may permit quantitative assessment of myocardial catecholamine uptake, which will in turn provide insights into the effects of various disease processes on the neuronal integrity of the heart.

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

BackgroundAnimal 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 ResultsA hyperinsulinemic-euglycemic clamp technique was used during PET data acquisition in nine healthy male volunteers and seven young male patients with a history ofIDDM 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, umol g−1 minm in normal subjects and 0.43 ± 0.16, mol· 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). ConclusionThese 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.

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.

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.

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.

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.

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.

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.

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 Patlaks 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

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.