Evaluation of attenuation correction in cardiac PET using PET/MR.

BACKGROUND: Simultaneous acquisition Positron emission tomography/magnetic resonance (PET/MR) is a new technology that has potential as a tool both in research and clinical diagnosis. However, cardiac PET acquisition has not yet been validated using MR imaging for attenuation correction (AC). The goal of this study is to evaluate the feasibility of PET imaging using a standard 2-point Dixon volume interpolated breathhold examination (VIBE) MR sequence for AC. METHODS AND RESULTS: Evaluation was performed in both phantom and patient data. A chest phantom containing heart, lungs, and a lesion insert was scanned by both PET/MR and PET/CT. In addition, 30 patients underwent whole-body 18F-fluorodeoxyglucose PET/CT followed by simultaneous cardiac PET/MR. Phantom study showed 3% reduction of activity values in the myocardium due to the non-inclusion of the phased array coil in the AC. In patient scans, average standardized uptake values (SUVs) obtained by PET/CT and PET/MR showed no significant difference (n = 30, 4.6 ± 3.5 vs 4.7 ± 2.8, P = 0.47). There was excellent per patient correlation between the values acquired by PET/CT and PET/MR (R 2 = 0.97). CONCLUSIONS: Myocardial SUVs PET imaging using MR for AC shows excellent correlation with myocardial SUVs obtained by standard PET/CT imaging. The 2-point Dixon VIBE MR technique can be used for AC in simultaneous PET/MR data acquisition.

Noninvasive Imaging of CCR2+ Cells in Ischemia-Reperfusion Injury After Lung Transplantation.

Ischemia-reperfusion injury-mediated primary graft dysfunction substantially hampers short- and long-term outcomes after lung transplantation. This condition continues to be diagnosed based on oxygen exchange parameters as well as radiological appearance, and therapeutic strategies are mostly supportive in nature. Identifying patients who may benefit from targeted therapy would therefore be highly desirable. Here, we show that C-C chemokine receptor type 2 (CCR2) expression in murine lung transplant recipients promotes monocyte infiltration into pulmonary grafts and mediates graft dysfunction. We have developed new positron emission tomography imaging agents using a CCR2 binding peptide, ECLi1, that can be used to monitor inflammatory responses after organ transplantation. Both 64 Cu-radiolabeled ECL1i peptide radiotracer (64 Cu-DOTA-ECL1i) and ECL1i-conjugated gold nanoclusters doped with 64 Cu (64 CuAuNCs-ECL1i) showed specific detection of CCR2, which is upregulated during ischemia-reperfusion injury after lung transplantation. Due to its fast pharmacokinetics, 64 Cu-DOTA-ECL1i functioned efficiently for rapid and serial imaging of CCR2. The multivalent 64 CuAuNCs-ECL1i with extended pharmacokinetics is favored for long-term CCR2 detection and potential targeted theranostics. This imaging may be applicable for diagnostic and therapeutic purposes for many immune-mediated diseases.

Functional recovery after coronary revascularization for chronic coronary artery disease is dependent on maintenance of oxidative metabolism.

OBJECTIVES: This study was performed to define the importance of maintenance of oxidative metabolism as a descriptor and determinant of functional recovery after revascularization in patients with left ventricular dysfunction attributable to chronic coronary artery disease. BACKGROUND: Although myocardial accumulation of 18F-fluorodeoxyglucose indicates the presence of tissue that is metabolically active, it may not identify those metabolic processes required for restoration of myocardial contractility. Experimental studies suggest that, under conditions of ischemia and reperfusion, maintenance of myocardial oxidative metabolism is an important metabolic determinant of the capacity for functional recovery. METHODS: In 16 patients positron emission tomography was performed to characterize myocardial perfusion (with H(2)15O), oxidative metabolism (with 11C-acetate) and utilization of glucose (with 18F-fluorodeoxyglucose). Dysfunctional but viable myocardium was differentiated from nonviable myocardium on the basis of assessments of regional function before and after coronary revascularization. To define the importance of coronary revascularization on myocardial perfusion and metabolism, tomography was repeated in 11 patients after revascularization. RESULTS: Before revascularization, perfusion in 24 dysfunctional but viable myocardial segments and 29 nonviable segments averaged 79% and 74%, respectively, of that in 42 normal myocardial segments (both p less than 0.01). Dysfunctional but viable myocardium exhibited oxidative metabolism comparable to that in normal myocardium. In contrast, in nonviable myocardium, oxidative metabolism was only 66% of that in normal (p less than 0.01) and 69% of that in reversibly dysfunctional myocardium (p less than 0.003). Regional utilization of glucose normalized to regional perfusion in dysfunctional but viable myocardium was greater than that in normal myocardium (p less than 0.01). However, in both reversibly and persistently dysfunctional myocardium, utilization of glucose normalized to relative perfusion was markedly variable. CONCLUSIONS: The results indicate that preservation of oxidative metabolism is a necessary condition for recovery of function after coronary recanalization in patients with chronic coronary artery disease. Consequently, approaches that measure myocardial oxygen consumption, such as dynamic positron emission tomography with 11C-acetate, should facilitate the identification of those patients most likely to benefit from coronary revascularization.

Dependence of recovery of contractile function on maintenance of oxidative metabolism after myocardial infarction.

This study was performed to define the importance of maintenance of oxidative metabolism as a descriptor and determinant of the potential for functional recovery after revascularization in patients with recent myocardial infarction. In 11 patients (mean interval after infarction 6 days; 5 patients given thrombolytic therapy), positron emission tomography (PET) was performed to characterize myocardial perfusion (with oxygen-15-labeled water), glucose utilization (with fluorine-18-fluorodeoxyglucose) and oxidative metabolism (with carbon-11-acetate). Dysfunctional but viable myocardium was differentiated from nonviable myocardium by assessments of regional function before and after coronary revascularization. The impact of coronary revascularization on regional myocardial perfusion and metabolism was assessed in nine patients in whom tomography was repeated after revascularization. Before revascularization, dysfunctional but viable myocardium (19 segments) and nonviable myocardium (10 segments) exhibited relative perfusion equivalent to 74% and 63% of that of normal myocardium (33 segments), respectively (p less than 0.02). Dysfunctional but viable myocardium exhibited oxidative metabolism equivalent to 74% of that of normal myocardium (p less than 0.02). In contrast, in nonviable myocardium, oxidative metabolism was only 45% of that seen in normal (p less than 0.02) and 60% of that in reversibly dysfunctional myocardium (p less than 0.003). Regional glucose utilization (normalized to regional perfusion) in dysfunctional but viable myocardium was higher than that in normal myocardium (p less than 0.02). Nonviable myocardium exhibited lower levels of glucose utilization than did normal tissue (p less than 0.02). However, in both reversibly and persistently dysfunctional myocardium utilization of glucose normalized to relative perfusion was markedly variable.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of carbon-11-acetate with fluorine-18-fluorodeoxyglucose for delineating viable myocardium by positron emission tomography.

OBJECTIVES: This study was designed to determine in patients with advanced coronary disease whether prediction of recovery of mechanical function after coronary revascularization could be accomplished more effectively by positron emission tomography (PET) with carbon-11 (11C)-acetate than by PET with fluorine-18 (18F)-fluorodeoxyglucose. BACKGROUND: Results of previous studies have demonstrated that preservation of myocardial oxidative metabolism (measured by PET with 11C-acetate) is necessary for recovery of systolic function after coronary revascularization. METHODS: Myocardial oxidative metabolism was quantified before revascularization in 34 patients by the analysis of the rate of myocardial clearance of 11C-acetate. Metabolism of glucose was assessed by analysis of uptake of 18F-fluorodeoxyglucose. Receiver operating characteristic curves for predicting functional recovery were derived for the measurements of oxidative metabolism and glucose metabolism. In addition, criteria for prediction of recovery of function based on measurements of oxidative metabolism and glucose metabolism were developed and compared. RESULTS: Analysis of receiver operating characteristic curves indicated that estimates of oxidative metabolism were more robust in predicting functional recovery than were estimates of glucose metabolism (p < 0.02). Moreover, threshold criteria with 11C-acetate exhibited superior positive and negative predictive values (67% and 89%, respectively) than did the criteria with 18F-fluorodeoxyglucose (52% and 81%, respectively), p < 0.01. In segments with initially severe dysfunction, estimates of oxidative metabolism tended to be more robust than estimates of glucose metabolism in predicting functional recovery. Moreover, in such segments, the threshold criteria with 11C-acetate tended to exhibit superior positive and negative predictive values (85% and 87%, respectively) than did the criteria with 18F-fluorodeoxyglucose (72% and 82%, respectively), although statistical significance was not achieved. CONCLUSIONS: In patients with advanced coronary artery disease, the extent to which functional recovery can be anticipated after coronary revascularization can be delineated accurately by quantification of regional oxidative metabolism by PET with 11C-acetate.

Short-term oral estrogen replacement therapy does not augment endothelium-independent myocardial perfusion in postmenopausal women.

OBJECTIVES: The purpose of this study was to determine the effect of usual-dose estrogen replacement therapy (ERT) on myocardial perfusion and myocardial perfusion reserve (MPR) (evoked by an endothelium-independent vasodilator) in healthy postmenopausal women. Postmenopausal women have a decreased myocardial perfusion reserve compared with younger women. Estrogen infusions are known to enhance endothelium-dependent vasodilation of the epicardial coronary arteries in postmenopausal women, but whether ERT also enhances endothelium-independent myocardial perfusion and perfusion reserve is unclear. METHODS: In 24 healthy postmenopausal women who were not taking ERT, myocardial perfusion at rest, perfusion during the infusion of adenosine (a primarily endothelium-independent vasodilator), and MPR were determined by positron-emission tomography (PET) and oxygen 15-labeled water. The women were then randomly assigned in a double-blind fashion to receive either 0.625 mg of oral conjugated estrogens (Premarin) or placebo per day for 4 to 6 weeks, after which they underwent a repeat cardiac PET study. RESULTS: There was no statistical difference between those assigned to ERT and those assigned to placebo in the measurement of myocardial perfusion at rest (1.21 +/- 0.31 vs 1.16 +/- 0.18 mL/g/min, respectively) in response to adenosine (2.66 +/- 0.96 vs 3.3 +/- 0.45 mL/g/min) or MPR (2.24 +/- 0.83 vs 2.88 +/- 0.64 mL/g/min) after 4 to 6 weeks of oral ERT. There was also no difference between the groups in any of the myocardial perfusion measurements after correction for the rate-pressure product. CONCLUSIONS: Short-term oral ERT does not affect myocardial perfusion at rest in response to adenosine or MPR in healthy postmenopausal women. Thus potential beneficial effects of ERT on vasomotor function may be limited to enhancement of endothelium-dependent vasodilative mechanisms affecting conduit vessels.

Myocardial uptake of carbon-11-acetate as an indirect estimate of regional myocardial blood flow.

The rate of clearance of myocardial carbon-11 (11C) activity (after the administration of 11C-acetate) has been shown to correlate closely with myocardial oxygen consumption. In the present study, we hypothesized that regional net myocardial uptake of 11C-acetate, which reflects primarily delivery and extraction of tracer, would be markedly flow-dependent and potentially useful as an indirect index of regional myocardial blood flow. In 22 patients with stable coronary artery disease, the regional distribution of early net uptake of 11C-acetate was correlated with estimates of regional myocardial blood flow assessed with oxygen-15-water. The myocardial images of 11C-acetate uptake were of high quality. The correlation between the two approaches was close (r = 0.88) and not affected by the metabolic state of the tissue. Thus, in patients with stable coronary artery disease, under resting conditions, direct estimates of myocardial oxygen consumption in relation to the level of delivery of tracer to the tissue can now be obtained by PET with use of a single radiopharmaceutical, 11C-acetate. This approach may prove particularly useful in streamlining clinical protocols designed to assess myocardial oxygen consumption.

Heterogeneity of myocardial perfusion provides the physiological basis of perfusable tissue index.

UNLABELLED: Assessment of viable from nonviable myocardium is critical for the care of patients being considered for revascularization procedures. Recently, the perfusable tissue index (PTI) has been proposed as an index of myocardial viability. METHODS: Computer simulations were performed for homogeneously and heterogeneously perfused tissue over a wide range of flows (0.04-6.4 ml/g/min) using both bolus and infusion inputs. RESULTS: PTI estimated from simulated homogeneously perfused tissue did reflect the amount of tissue being perfused independent of absolute level of flow, type of input or model configuration, whereas PTI obtained from simulated heterogeneously perfused tissue was consistently lower than the simulated "true" PTI and varied with flow, type of input function and model configuration. Flow estimated with 15O-water was not significantly different from that measured with radio labeled microspheres. CONCLUSION: Oxygen-15-water can diffuse into both acutely and chronically ischemic myocardium irrespective of its functional status. The results suggest that PTI is most likely an index of the heterogeneity of myocardial flow rather than an index of the amount of tissue being perfused. Its utility for delineating myocardial viability is thus related to the amount of tissue perfused that has low absolute levels of perfusion or high degrees of flow heterogeneity.

Measurement of global and regional left ventricular function by cardiac PET.

UNLABELLED: To permit assessment by positron tomography of left ventricular mechanical function, methods were developed to measure ejection fraction and regional wall motion and produce realistic images of the beating heart from ECG-gated PET data. METHODS: Following red cell labeling with 15O-carbon monoxide, seven-slice PET data were collected in list mode and reformatted into 16 time frames. Volume-rendered cine images were created by the depth-weighted maximum-activity method. To determine the left ventricular ejection fraction, background was subtracted in voxels outside the heart and the cubic datasets were rotated to the angle with the best septal separation. Depth weighting was applied to stimulate a 99mTc study, and the beating images were rendered by summing counts along parallel projection rays. These techniques were validated in 16 patients by comparison with planar studies performed with 99mTc-red cells. RESULTS: Visual grading of regional wall motion yielded exact agreement between the PET and 99mTc methods in 62% of walls with agreement with one grade in 94%. Assessment of quantitative regional wall motion agreed closely with an independent threshold edge detection method. CONCLUSION: PET techniques have been developed to measure left-ventricular ejection fraction and regional wall motion and to produce realistic beating images of the cardiac blood pool. This information can be obtained at the same time as measurements of perfusion and metabolism and in the same spatial orientation, thereby permitting quantitative assessment by positron tomography of global and regional mechanical function in relation to flow and metabolism.

In vivo comparison of copper blood-pool agents: potential radiopharmaceuticals for use with copper-62.

Two techniques for labeling of albumin with copper-67 (67Cu) and 62Cu were investigated; one using the native Cu(II) binding site of the protein and the other employing a bifunctional chelate, 6-bromoacetamidobenzyl-1,4,8,11-tetraazacyclotetradecane- N,N'N",N"'-tetraacetic acid (Br-benzyl-TETA or BAT), conjugated to the protein. Rat biodistribution experiments with 67Cu demonstrated retention of i.v. 67Cu-benzyl-TETA-albumin in the blood pool identical to co-injected 125I-albumin. By contrast, i.v. administration of either [67Cu]-Cu-acetate or [67Cu]-Cu-acetate pre-mixed with albumin results in relatively rapid clearance of blood-pool radioactivity as the tracer is excreted into the urine. The 62Cu-benzyl-TETA-albumin radiopharmaceutical was obtained in ca. 17% radiochemical yield (end of synthesis, without decay correction) following a procedure that can be completed in 15-18 min. In PET experiments with a baboon, myocardial blood volume images with 62Cu-benzyl-TETA-albumin were identical to those obtained with C15O. Use of the 62Cu-benzyl-TETA-albumin image for blood-pool subtraction of a 62Cu-PTSM myocardial perfusion image is illustrated. Copper-62-benzyl-TETA-HSA should be a useful, generator-produced radiotracer for the detection of the vascular pool at PET facilities without cyclotrons.

Nonuniformity in myocardial accumulation of fluorine-18-fluorodeoxyglucose in normal fasted humans.

In initial studies using fluorine-18-fluorodeoxyglucose (FDG) in normal fasted subjects, we observed disparities in the regional myocardial accumulation of this tracer. Accordingly, we systematically evaluated regional myocardial FDG accumulation in comparison with regional myocardial perfusion assessed with oxygen-15-water and oxidative metabolism assessed with carbon-11-acetate in nine normal subjects (four studied after a 5-hr fast and five studied both fasted and following glucose loading). Under fasting conditions, myocardial accumulation of FDG in the septum and anterior wall averaged 80% of that in the lateral and posterior walls (p less than 0.03). In contrast, after glucose loading the regional distribution of myocardial FDG accumulation became more homogeneous. Regional myocardial perfusion, oxidative metabolism, and accumulation of carbon-11-acetate were homogeneous under both conditions. Thus, under fasting conditions there are regional variations in myocardial accumulation of FDG, which are visually apparent, are not associated with concomitant changes in oxidative metabolism or perfusion, and cannot be attributed to partial-volume effects. This significant heterogeneity may limit the specificity of PET with FDG for detecting myocardial ischemia in fasting subjects.

Superiority of C-11 acetate compared with F-18 fluorodeoxyglucose in predicting myocardial functional recovery by positron emission tomography in patients with acute myocardial infarction.

In patients with chronic coronary artery disease, preservation of myocardial oxidative metabolism measured by positron emission tomography (PET) with 11C-acetate is a more accurate predictor of subsequent myocardial functional recovery than is maintenance of glucose metabolism estimated with 18F-fluorodeoxyglucose. However, whether measurements of myocardial oxidative metabolism are more accurate than measurements of glucose metabolism in predicting functional recovery in patients with recent myocardial infarction is unknown. Myocardial oxidative metabolism was measured within 10 days of infarction in 19 patients by analysis of the rate of myocardial clearance of 11C-acetate. Metabolism of glucose was assessed by analysis of the uptake of 18F-fluorodeoxyglucose. Criteria for prediction of the recovery of function based on measurements of oxidative metabolism and glucose metabolism were compared. Threshold criteria with 11C-acetate exhibited superior positive and negative predictive values (89% and 73%, respectively) compared with the criteria of 18F-fluorodeoxyglucose (65% and 57%, respectively) (p <0.025). In addition, the magnitude of functional recovery after revascularization correlated with the severity of the metabolic abnormality present initially. In patients with recent myocardial infarction, the extent of functional recovery can be predicted accurately by measurement of regional oxidative metabolism by PET with 11C-acetate, and these measurements are superior to those of 18-fluorodeoxyglucose.

Distinguishing left ventricular aneurysm from pseudoaneurysm. A review of the literature.

A postmyocardial infarction left ventricular pseudoaneurysm occurs when a rupture of the ventricular free wall is contained by overlying, adherent pericardium. A postinfarction aneurysm, in contrast, is caused by scar formation resulting in thinning of the myocardium. Although the usual treatment for patients with pseudoaneurysm is urgent surgical repair, the imaging characteristics of pseudoaneurysm and aneurysm, for which treatment is more conservative, are quite similar. The literature on the natural history and imaging characteristics of the two entities is reviewed, and an approach to distinguishing between the two entities is proposed.

Coronary MR angiography.

Coronary MR angiography has developed rapidly over the past several years. Not only is research being performed at academic centers but industry is also investing in dedicated contrast agents and cardiac MR imaging platforms. Although current coronary MR angiography has limited clinical utility, its place within the assessment of ischemic cardiac disease is evolving. The technology currently under investigation holds much promise, especially when one considers that MR has the potential to provide information currently supplied by the performance of a number of screening tests. It would be far more cost-effective to perform a single MR examination than to perform a stress echo, rest-stress nuclear medicine examination and a conventional coronary angiogram. In addition, clinicians need information about coronary flow and myocardial perfusion. Although some of this information can be currently obtained with an intravascular Doppler flow wire or by positron emission tomography, MR angiography offers the advantages of being both noninvasive and more easily accessible in comparison to either method. The combined information promised by a comprehensive cardiac MR examination that includes coronary MR angiography as a component is an exciting prospect.

Methodology governing the assessment of myocardial glucose metabolism by positron emission tomography and fluorine 18-labeled fluorodeoxyglucose.

Positron emission tomography (PET) with fluorine 18-labeled fluorodeoxyglucose (FDG) has provided important insights into the alterations in myocardial glucose metabolism associated with normal cardiac physiology and pathophysiology. In patients with left ventricular dysfunction caused by coronary artery disease, PET-FDG studies have identified certain patterns of myocardial glucose metabolism relative to flow that are associated with viable myocardium. Consequently, in many centers, PET-FDG imaging is being used to identify patients with left ventricular dysfunction who are likely to benefit from coronary revascularization. However, myocardial glucose metabolism (and thus myocardial uptake of FDG) is markedly dependent on a variety of factors, particularly the substrate environment and level of myocardial perfusion. These and other factors must be considered to obtain and interpret myocardial FDG images accurately with respect to the underlying pathophysiologic process. In this review the impact of these factors on myocardial FDG imaging, as well as the relative advantages and disadvantages of approaches designed to optimize myocardial PET-FDG studies, will be discussed.

Imaging to distinguish between viable and nonviable myocardium: pathophysiologic basis and importance of positron emission tomography.

One goal of strategies designed to restore nutritive perfusion in patients with left ventricular dysfunction attributable to coronary artery disease is salvage of reversibly ischemic myocardium in an effort to improve patients' left ventricular function, signs and symptoms, and survival. Accurate identification of patients likely to benefit from interventions such as coronary revascularization requires the differentiation of viable (reversibly dysfunctional) myocardium from nonviable (persistently dysfunctional) tissue. To date, no consensus has been reached regarding the best approach for achieving this differentiation. In this review, the pathophysiologic characteristics of viable and nonviable myocardium are summarized, and diagnostic methods that exploit these characteristics for the purposes of detecting viable myocardium are discussed. Emphasis is placed on approaches that use positron emission tomography because of its usefulness in quantifying those specific metabolic processes that support both tissue viability and the capacity for functional recovery.

Myocardial signal response to dipyridamole and dobutamine: demonstration of the BOLD effect using a double-echo gradient-echo sequence.

The purpose of this study was to examine the differential myocardial signal responses due to the blood oxygen level dependent (BOLD) effect in magnetic resonance imaging (MRI) under differing conditions of myocardial oxygen supply and demand. The signal response was measured when myocardial blood flow was increased in excess of oxygen demand or when flow was increased in response to increased myocardial oxygen demand. Normal volunteers were studied using a segmented, interleaved, double-echo, gradient-echo sequence at baseline conditions and during pharmacological stress with either dipyridamole (n = 5) or dobutamine (n = 6). Changes in T2* in the myocardium during stress were calculated. Peak coronary flow velocity was measured at rest and during stress using a breath-hold phase contrast technique. Administration of dipyridamole induced a 124 +/- 27% increase in coronary blood flow which resulted in a 46 +/- 22% increase in T2*, consistent with a decrease in myocardial venous deoxyhemoglobin concentration as myocardial oxygen supply exceeds demand. In contrast, the administration of dobutamine resulted in a 41 +/- 25% increase in coronary blood flow but no significant change in T2* (-5 +/- 19%), consistent with a lack of change in myocardial venous deoxyhemoglobin concentration and balanced oxygen supply and demand. Thus, alterations in the relationship between myocardial oxygen supply and demand appear to be detectable using BOLD MRI.