Sungeun Kim

Vascular Inflammation in Patients with Impaired Glucose Tolerance and Type 2 Diabetes: Analysis with 18F-Fluorodeoxyglucose Positron Emission Tomography

Background—Type 2 diabetes mellitus (T2DM) is associated with an increased risk of atherosclerotic cardiovascular disease. Vascular inflammation is a key factor in both the pathogenesis and outcome of atherosclerosis. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is a promising tool for indentifying and quantifying vascular inflammation within atherosclerotic plaques. This study was designed to examine the vascular inflammation measured using FDG-PET in patients with impaired glucose tolerance and T2DM, in comparison with age- and sex-matched control subjects with normal glucose tolerance. Methods and Results—We investigated vascular inflammation using FDG-PET in 90 age- and sex-matched subjects with different glucose tolerance (30 normal glucose tolerance subjects, 30 impaired glucose tolerance subjects, and 30 T2DM subjects). Vascular 18F-FDG uptake was measured as both the mean and maximum blood-normalized standardized uptake value, known as the target-to-background ratio (TBR). Both mean and maximum TBR measurements were significantly different, based on glucose tolerance, although the carotid intima-media thickness measurements were not significantly different. The maximum TBR values in patients with impaired glucose tolerance and T2DM were significantly increased compared with the normal subjects. In addition, subjects with metabolic syndrome had increased maximum TBR values compared with those without metabolic syndrome. Age-, sex-, and body mass index–adjusted maximum TBR levels were positively correlated with triglyceride, hemoglobin A1c, insulin resistance, high-sensitivity C-reactive protein, and Framingham risk score and were negatively correlated with high-density lipoprotein cholesterol and adiponectin levels. Conclusions—The results of the present study suggest that impaired glucose tolerance and T2DM are associated with vascular inflammation in carotid atherosclerosis detected by FDG-PET.Background— Type 2 diabetes mellitus (T2DM) is associated with an increased risk of atherosclerotic cardiovascular disease. Vascular inflammation is a key factor in both the pathogenesis and outcome of atherosclerosis. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is a promising tool for indentifying and quantifying vascular inflammation within atherosclerotic plaques. This study was designed to examine the vascular inflammation measured using FDG-PET in patients with impaired glucose tolerance and T2DM, in comparison with age- and sex-matched control subjects with normal glucose tolerance. Methods and Results— We investigated vascular inflammation using FDG-PET in 90 age- and sex-matched subjects with different glucose tolerance (30 normal glucose tolerance subjects, 30 impaired glucose tolerance subjects, and 30 T2DM subjects). Vascular 18F-FDG uptake was measured as both the mean and maximum blood-normalized standardized uptake value, known as the target-to-background ratio (TBR). Both mean and maximum TBR measurements were significantly different, based on glucose tolerance, although the carotid intima-media thickness measurements were not significantly different. The maximum TBR values in patients with impaired glucose tolerance and T2DM were significantly increased compared with the normal subjects. In addition, subjects with metabolic syndrome had increased maximum TBR values compared with those without metabolic syndrome. Age-, sex-, and body mass index–adjusted maximum TBR levels were positively correlated with triglyceride, hemoglobin A1c, insulin resistance, high-sensitivity C-reactive protein, and Framingham risk score and were negatively correlated with high-density lipoprotein cholesterol and adiponectin levels. Conclusions— The results of the present study suggest that impaired glucose tolerance and T2DM are associated with vascular inflammation in carotid atherosclerosis detected by FDG-PET. Received June 26, 2009; accepted December 14, 2009. # CLINICAL PERSPECTIVE {#article-title-2}

Metabolic Activity of the Spleen and Bone Marrow in Patients With Acute Myocardial Infarction Evaluated by 18F-Fluorodeoxyglucose Positron Emission Tomograpic Imaging

Background—Atherosclerosis is considered to be an inflammatory disease associated with the activation of hematopoietic and immune-related organs such as the bone marrow (BM) and spleen. We evaluated the metabolic activity of those organs and of the carotid artery with 18F-fluorodeoxyglucose positron emission tomography in patients with coronary artery disease, including acute myocardial infarction. Methods and Results—Whole-body combined 18F-fluorodeoxyglucose positron emission tomography/computed tomography was performed in 32 patients with acute myocardial infarction, 33 patients with chronic stable angina, and 25 control subjects. The mean standard uptake value was calculated in the regions of interest in the spleen and the BM of lumbar vertebrae. The target-to-background ratio of the standard uptake values of the carotid artery and jugular vein was also calculated. In patients with acute myocardial infarction, the standard uptake values of the BM (1.67±0.16) and spleen (2.57±0.39), as well as the target-to-background ratio of the carotid artery (2.13±0.42), were significantly higher than the corresponding values of patients with angina (1.22±0.62; 2.03±0.35; 1.36±0.37; all P<0.001) and controls (0.80±0.44; 1.54±0.26; 1.22±0.22; all P<0.001), independent of traditional cardiovascular risk factors and high-sensitivity C-reactive protein. In all groups combined, the target-to-background ratio of the carotid artery was significantly associated with the standard uptake values of the BM (r=0.535; P<0.001), spleen (r=0.663; P<0.001), and high-sensitivity C-reactive protein (r=0.465; P<0.001). Conclusions—The metabolic activity of the BM and spleen, as well as of the carotid artery, was highest in patients with acute myocardial infarction, intermediate in patients with angina, and lowest in control subjects. The activation of the BM and spleen was significantly associated with inflammatory activity of the carotid artery.

The Metabolic Activity of the Spleen and Bone Marrow in Patients with Acute Myocardial Infarction Evaluated by 18F-FDG PET Imaging

Background—Atherosclerosis is considered to be an inflammatory disease associated with the activation of hematopoietic and immune-related organs such as the bone marrow (BM) and spleen. We evaluated the metabolic activity of those organs and of the carotid artery with 18F-fluorodeoxyglucose positron emission tomography in patients with coronary artery disease, including acute myocardial infarction. Methods and Results—Whole-body combined 18F-fluorodeoxyglucose positron emission tomography/computed tomography was performed in 32 patients with acute myocardial infarction, 33 patients with chronic stable angina, and 25 control subjects. The mean standard uptake value was calculated in the regions of interest in the spleen and the BM of lumbar vertebrae. The target-to-background ratio of the standard uptake values of the carotid artery and jugular vein was also calculated. In patients with acute myocardial infarction, the standard uptake values of the BM (1.67±0.16) and spleen (2.57±0.39), as well as the target-to-background ratio of the carotid artery (2.13±0.42), were significantly higher than the corresponding values of patients with angina (1.22±0.62; 2.03±0.35; 1.36±0.37; all P<0.001) and controls (0.80±0.44; 1.54±0.26; 1.22±0.22; all P<0.001), independent of traditional cardiovascular risk factors and high-sensitivity C-reactive protein. In all groups combined, the target-to-background ratio of the carotid artery was significantly associated with the standard uptake values of the BM (r=0.535; P<0.001), spleen (r=0.663; P<0.001), and high-sensitivity C-reactive protein (r=0.465; P<0.001). Conclusions—The metabolic activity of the BM and spleen, as well as of the carotid artery, was highest in patients with acute myocardial infarction, intermediate in patients with angina, and lowest in control subjects. The activation of the BM and spleen was significantly associated with inflammatory activity of the carotid artery.

Association of Adiponectin, Resistin, and Vascular Inflammation Analysis With 18F-Fluorodeoxyglucose Positron Emission Tomography

Objective—Adiponectin and resistin are adipokines that are linked to obesity, inflammation, and atherosclerosis. 18F-Fluorodeoxyglucose (FDG) positron emission tomography is a promising imaging technique that can be used to evaluate vascular inflammation. Methods and Results—We measured adiponectin and resistin levels, as well as traditional cardiovascular risk factors, in 60 obese subjects and 60 nonobese controls. In addition, we compared carotid intima-media thickness and target-to-background ratio (TBR) measured using 18F-fluorodeoxyglucose-positron emission tomography/computed tomography. The mean TBR values were significantly higher in the obese group compared with normal subjects, although their mean carotid intima-media thickness levels were not significantly different. Serum adiponectin levels showed a significant negative correlation with mean TBR values (r=−0.215, P=0.020), whereas resistin levels were positively correlated with mean TBR values (r=0.214, P=0.021). Multiple linear regression analysis showed that mean TBR values were independently associated with body mass index, high-sensitivity C-reactive protein, and resistin levels (R2=0.308). Conclusion—Adiponectin and resistin may be useful as biomarkers to reflect vascular inflammation. In particular, resistin levels were independently associated with vascular inflammation even after adjusting for other cardiovascular risk factors.

Serum Adipocyte Fatty Acid-Binding Protein Is Associated Independently with Vascular Inflammation: Analysis with 18F-Fluorodeoxyglucose Positron Emission Tomography

CONTEXT The inflammatory status of atherosclerotic lesions is a major factor triggering acute cardiovascular events. Growing evidence has shown that adipocyte fatty acid-binding protein (A-FABP) has an important role in the development of atherosclerosis. OBJECTIVE The objective of the study was to determine the association between circulating A-FABP levels with vascular inflammation as measured using [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography (PET), which is a novel imaging technique for noninvasive measurement of atherosclerotic inflammation. DESIGN This was a cross-sectional study. PARTICIPANTS Eighty-seven men without previously diagnosed cardiovascular disease or diabetes participated in the study. MAIN OUTCOME MEASURE We measured the serum A-FABP, adiponectin, and leptin levels as well as other cardiovascular risk factors. Vascular inflammation in the carotid arterial wall, as indicated by the target to background ratio (TBR), was analyzed using FDG-PET. RESULTS The circulating A-FABP and leptin levels had positive correlations with maximum TBR values (r = 0.38, P < 0.001; and r = 0.28, P = 0.010, respectively), whereas the adiponectin levels had a negative correlation (r = -0.31, P = 0.004). The maximum TBR levels exhibited an additive linear increment according to the rise in tertiles of the A-FABP levels in subjects with and without metabolic syndrome. Multiple regression analysis showed that serum A-FABP levels were independently associated with maximum TBR after adjustment for other cardiovascular risk factors (P = 0.006). CONCLUSIONS Circulating A-FABP, adiponectin, and leptin levels were shown to be associated with vascular inflammation, as measured using FDG-PET. Specifically, the A-FABP level was an independent risk factor for vascular inflammation in Korean men without cardiovascular disease or diabetes.

Implication of circulating irisin levels with brown adipose tissue and sarcopenia in humans.

CONTEXT Irisin is an exercise-induced novel myokine that drives brown-fat-like conversion of white adipose tissue and has been suggested to be a promising target for the treatment of obesity-related metabolic disorders. OBJECTIVE To assess the association of circulating irisin concentrations with brown adipose tissue (BAT) and/or sarcopenia in humans. SETTING AND DESIGN We examined irisin levels in 40 BAT-positive and 40 BAT-negative women detected by (18)F-fluorodeoxyglucose positron emission tomography ((18)FDG-PET). In a separate study, we also examined 401 subjects with or without sarcopenia defined by skeletal muscle mass index (SMMI) and appendicular skeletal muscle (ASM)/height(2) using dual-energy x-ray absorptiometry. RESULTS Among 6877 consecutive (18)FDG-PET scans in 4736 subjects, 146 subjects (3.1%) had positive BAT scans. The BAT-detectable group and the matched BAT-undetectable group did not differ in circulating irisin levels measured using two different ELISA kits (P = .747 and P = .160, respectively). Serum irisin levels were not different between individuals with sarcopenia and those without sarcopenia using either kit (P = .305 and P = .569, respectively). Also, serum irisin levels were not different between groups defined by ASM/height(2) using either kit (P = .352 and P = .134, respectively). Although visceral fat area and skeletal muscle mass showed significant difference according to tertiles of SMMI levels, irisin concentrations did not differ. CONCLUSIONS Circulating irisin levels were not different in individuals with detectable BAT or those with sarcopenia compared with control subjects and were not correlated with SMMI.

Intra-operative sentinel lymph node identification using a novel receptor-binding agent (technetium-99m neomannosyl human serum albumin, 99mTc-MSA) in stage I non-small cell lung cancer

OBJECTIVE In the previous report, to simplify the synthesis and labelling procedures and to improve the biological properties, we developed a novel mannose receptor-binding agent, technetium-99m human serum albumin (99mTc-MSA), for sentinel lymph node detection. This study is the first clinical trial designed to test the reliability and feasibility of sentinel node detection using this new radioactive agent in patients with stage I non-small cell lung cancer. METHODS Forty-two patients (30 men, 12 women; mean age 63.3 + or - 8.9 years) that were candidates for lobectomy with mediastinal lymph node dissection for stage I non-small cell lung cancer were enrolled. A total dose of 1mCi of 99mTc-MSA in 0.2 ml was administered in one shot at the peritumoural region approximately 3h before surgery. The radioactivity in the lymph nodes was counted before (in vivo) and after (ex vivo) dissection with a hand-held gamma probe. A sentinel lymph node was defined as any node for which the radioactivity count was 5 times that of the resected lung tissue with the lowest count for the ex vivo counts. All harvested lymph nodes were cut into 2-mm slices and ultimately diagnosed by using formalin-fixed and paraffin-embedded sections with haematoxylin and eosin staining. RESULTS 99mTc-MSA was taken up by the lymph nodes and its detection did not change until 21 h after the injection. The number of dissected lymph nodes per patient was 22.1 + or - 11.6 (range 4-57). Among 42 patients, the sentinel lymph nodes could be identified in 40 patients (95.2%). The number of sentinel lymph nodes identified was 2.3 + or - 1.1 stations (range 1-5) per patient. Ten out of 40 patients (25.0%) had metastases in 11 sentinel lymph nodes. Three of these 11 sentinel lymph nodes (27.3%) had skip metastases. No false-negative sentinel lymph nodes were detected in any of the 10 patients with N1 or N2 disease (0%). The relationship between in vivo and ex vivo results for mediastinal sentinel lymph nodes showed concurrence in 29 out of 40 patients (72.5%). CONCLUSIONS Intra-operative sentinel lymph node identification using 99mTc-MSA appears to be feasible and reliable in stage I non-small cell lung cancer.

Association between sRAGE, esRAGE levels and vascular inflammation: Analysis with 18F-fluorodeoxyglucose positron emission tomography

BACKGROUND The receptor for advanced glycation end-products (RAGE) and its diverse ligands play a pivotal role in the development of cardiovascular disease. Soluble forms of RAGE (sRAGE), including the splice variant endogenous secretory RAGE (esRAGE), may neutralize AGE-RAGE mediated vascular damage by acting as a decoy. (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) is a novel imaging technique for detecting vascular inflammation. METHODS We examined vascular inflammation measured using FDG-PET in 41 type 2 diabetes patients and 41 healthy control subjects in the right carotid artery. Vascular (18)F-FDG uptake was measured as the blood-normalized standardized uptake value (SUV), known as the target-to-background ratio (TBR). In addition, their relationship with carotid intima-media thickness (CIMT), estimated GFR (eGFR), and other cardiovascular risk factors was evaluated. RESULTS Both mean and maximum TBR values were significantly higher in patients with type 2 diabetes compared to healthy subjects. After adjusting for age and gender, sRAGE levels were significantly correlated with both mean and maximum TBR values, but not with CIMT values. Multiple linear regression analysis showed that maximum TBR values were independently associated with sRAGE levels in addition to HbA1c and eGFR. CONCLUSIONS Circulating sRAGE showed significant association with TBR values measured using FDG-PET, which reflect vascular inflammation.

High-sensitivity C-reactive protein in the low- and intermediate-Framingham risk score groups: Analysis with 18F-fluorodeoxyglucose positron emission tomography

OBJECTIVES To evaluate vascular inflammation according to high-sensitivity C-reactive protein (hsCRP) levels in the low- (<10%) and intermediate- (10%-20%) Framingham risk score (FRS) groups using (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT, which reflects vascular inflammation and vulnerable atherosclerotic plaque. METHODS We measured hsCRP levels and traditional cardiovascular risk factors in 142 non-diabetic subjects without history of cardiovascular disease. To assess the vascular influence of hsCRP on each FRS category, we compared carotid intima-media thickness (CIMT), brachial-ankle pulse wave velocity (baPWV), and vascular inflammation, which was represented as the target-to-background ratio (TBR) measured using FDG-PET/CT. RESULTS In both low- and intermediate-FRS categories, mean TBR values in subjects with higher hsCRP levels (≥2mg/L) were significantly increased compared to those with lower hsCRP levels (<2mg/L) (P=0.001, P<0.001, respectively). However, baPWV and CIMT values did not significantly differ according to hsCRP levels in the same FRS categories. Mean TBR levels positively correlated with FRS, body mass index (BMI), whereas negatively correlated with HDL-cholesterol. Multiple stepwise regression analyses showed that hsCRP, LDL-cholesterol, BMI, and insulin resistance were independently associated with mean TBR values (R(2)=0.414). CONCLUSIONS In both intermediate and low FRS risk groups, vascular inflammation measured using FDG-PET/CT was increased in individuals with higher hsCRP levels compared to those with lower hsCRP.

Novel PET imaging of atherosclerosis with 68Ga-labeled NOTA-Neomannosylated Human Serum Albumin

Activated macrophages take up 18F-FDG via glucose transporters, so this compound is useful for atherosclerosis imaging by PET. However, 18F-FDG application is limited for imaging of the heart and brain, in which glucose uptake is high, and in patients with aberrant glucose metabolism. The aims of this study were to confirm that mannosylated human serum albumin (MSA) specifically binds to the mannose receptor (MR) on macrophages and to test the feasibility of 68Ga-labeled NOTA-MSA for PET imaging of atherosclerotic plaques. Methods: The peritoneal macrophages of C57/B6 mice were collected, incubated with rhodamine B isothiocyanate-MSA (10 μg/mL), and evaluated by confocal microscopy and flow cytometry. The same evaluations were performed after preincubation of the macrophages with anti-CD206 MR blocking antibodies. NOTA-MSA was synthesized by conjugating 2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid to MSA, followed by labeling with 68Ga. Rabbits with atherosclerotic aorta induced by a 3-mo cholesterol diet and chronic inflammation underwent consecutive PET/CT with 18F-FDG and 68Ga-NOTA-MSA at 2-d intervals. Results: The binding of MSA to MR and its dose-dependent reduction by preincubation with anti-CD206 MR blocking antibody were confirmed. Rhodamine B isothiocyanate and fluorescein isothiocyanate fluorescence colocalized at the atherosclerotic plaque. The 68Ga-NOTA-MSA SUVs of the atherosclerotic aorta were significantly higher than those of the healthy arteries and inferior vena cava and were comparable to those obtained with 18F-FDG. Conclusion: These findings suggest that MR-specific 68Ga-NOTA-MSA is effective for detecting atherosclerosis in the aorta and is a promising radiopharmaceutical for imaging atherosclerosis because of the presence of M2 macrophages in atherosclerotic plaques.