Atsuko Tahara

Heterogeneous myocardial FDG uptake and the disease activity in cardiac sarcoidosis.

OBJECTIVES This study evaluated the usefulness of fasting (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) in the diagnosis and management of cardiac sarcoidosis (CS) and compared it with FDG uptake in dilated cardiomyopathy (DCM). BACKGROUND Cardiac sarcoidosis may clinically present as DCM but is amenable to systemic corticosteroid therapy if disease activity is high. Although alterations of FDG uptake have been reported in CS, limited information is available on the quantitative estimates of FDG uptake. METHODS Fasting FDG-PET was performed in 24 systemic sarcoidosis patients and was compared with 8 age-matched DCM patients. FDG-PET was also performed in 15 age-matched healthy control subjects. Twelve of the 24 sarcoidosis patients had cardiac involvement based on criteria established by the Japanese Ministry of Health and Welfare; the remaining 12 of 24 patients revealed no evidence of cardiac involvement. The myocardial FDG uptake was quantified by measuring the standardized uptake value in 17 myocardial segments in each subject. Coefficient of variation (COV), which equals the standard deviation of uptake divided by the average uptake of 17 segments, was calculated as an index of heterogeneity in the heart. RESULTS The FDG uptake was distinctly heterogeneous in CS patients. The COV value was significantly greater in CS patients (0.25 ± 0.05) than control subjects (0.14 ± 0.03, p < 0.01), sarcoidosis patients without cardiac involvement (0.14 ± 0.03, p < 0.01), or DCM patients (0.15 ± 0.02, p < 0.01). The COV value in DCM patients was similar to control subjects or sarcoidosis patients without cardiac involvement. The cutoff COV value for the diagnosis of CS was 0.18 (sensitivity: 100%; specificity: 97%). After corticosteroid therapy in CS patients, the COV value was decreased to 0.14 ± 0.06 (p < 0.05) and became essentially similar to the other groups. CONCLUSIONS Heterogeneous myocardial FDG uptake may be a useful diagnostic marker of disease activity for CS.

Pioglitazone Attenuates Atherosclerotic Plaque Inflammation in Patients With Impaired Glucose Tolerance or Diabetes: A Prospective, Randomized, Comparator-Controlled Study Using Serial FDG PET/CT Imaging Study of Carotid Artery and Ascending Aorta

OBJECTIVES The aim of this study was to compare the effect of pioglitazone, an insulin sensitizer, with glimepiride, an insulin secretagogue, on atherosclerotic plaque inflammation by using serial (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging. BACKGROUND Atherosclerosis is intrinsically an inflammatory disease. Although hyperglycemia is associated with an increased risk of atherosclerotic cardiovascular disease, there are no clinical data to show the preference of any specific oral hypoglycemic agents to prevent atherosclerotic plaque inflammation. METHODS A total of 56 impaired glucose tolerant or diabetic patients with carotid atherosclerosis underwent a complete history, determinations of blood chemistries, anthropometric variables, and FDG-PET. They were randomly assigned to receive either pioglitazone (15 to 30 mg) or glimepiride (0.5 to 4.0 mg) for 4 months with titration to optimal dosage. Effects of the drugs on atherosclerotic plaque inflammation were evaluated by FDG-PET at study completion. Plaque inflammation was measured by blood-normalized standardized uptake value, known as a target-to-background ratio. RESULTS The study was completed in 31 pioglitazone-treated patients and 21 glimepiride-treated patients. Although both treatments reduced fasting plasma glucose and hemoglobin A1c values comparably, pioglitazone, but not glimepiride, decreased atherosclerotic plaque inflammation. Compared with glimepiride, pioglitazone significantly increased high-density lipoprotein cholesterol level. High-sensitivity C-reactive protein was decreased by pioglitazone, whereas it was increased by glimepiride. Multiple stepwise regression analysis revealed that the increase in high-density lipoprotein cholesterol level was independently associated with the attenuation of plaque inflammation. CONCLUSIONS Our present study suggests that pioglitazone could attenuate atherosclerotic plaque inflammation in patients with impaired glucose tolerance or in diabetic patients independent of glucose lowering effect. Pioglitazone may be a promising strategy for the treatment of atherosclerotic plaque inflammation in impaired glucose tolerance or diabetic patients. (Detection of Plaque Inflammation and Visualization of Anti-Inflammatory Effects of Pioglitazone on Plaque Inflammation in Subjects With Impaired Glucose Tolerance and Type 2 Diabetes Mellitus by FDG-PET/CT; NCT00722631).

Serum level of pigment epithelium-derived factor is a marker of atherosclerosis in humans

OBJECTIVE Pigment epithelium-derived factor (PEDF) could play a protective role against atherosclerosis. However, there is no clinical study to examine the relationship between serum level of PEDF and atherosclerosis in humans. METHODS/RESULTS The study involved 317 consecutive outpatients in Kurume University Hospital (220 male and 97 female) with a mean age of 62.1±9.1. We examined whether serum level of PEDF were independently associated with vascular inflammation evaluated by [(18)F]-fluorodeoxyglucose positron emission tomography (FDG-PET) and intima-media thickness (IMT) in carotid artery in humans. Carotid [(18)F]-FDG uptake, an index of vascular inflammation within the atherosclerotic plaques, was measured as standardized uptake value (SUV). Mean serum PEDF level, carotid SUV and IMT values were 13.5±1.1 μg/mL, 1.34±0.19, and 0.71±0.15 mm, respectively. In multiple stepwise regression analysis, estimated glomerular filtration rate (p<0.001), males (p<0.001), homeostasis model assessment of insulin resistance index (p<0.05), heart rate (p<0.05), triglycerides (p<0.05), carotid IMT (p<0.05), waist circumference (p<0.05) and carotid SUV (p<0.05) were independently correlated to PEDF level (R(2)=0.332). CONCLUSION The present study reveals that serum level of PEDF is independently associated with vascular inflammation and IMT, thus suggesting that PEDF level is a novel biomarker that could reflect atherosclerosis in humans.

Pioglitazone Decreases Coronary Artery Inflammation in Impaired Glucose Tolerance and Diabetes Mellitus : Evaluation by FDG-PET/CT Imaging

OBJECTIVES The aim of this study was to compare the effect of pioglitazone with glimepiride on coronary arterial inflammation with serial (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) combined with computed tomography (CT) angiography. BACKGROUND Recent studies have shown that FDG-PET combined with CT is a reliable tool to visualize and quantify vascular inflammation. Although pioglitazone significantly prevented the progression of coronary atherosclerosis and reduced the recurrence of myocardial infarction in patients with type 2 diabetes mellitus (DM), it remains unclear whether pioglitazone could attenuate coronary artery inflammation. METHODS Fifty atherosclerotic patients with impaired glucose tolerance or type 2 DM underwent determination of blood chemistries, anthropometric and inflammatory variables, and FDG-PET/CT angiography, and then were randomized to receive either pioglitazone or glimepiride for 16 weeks. Effects of the treatments on vascular inflammation of the left main trunk were evaluated by FDG-PET/CT angiography at baseline and end of the study. Vascular inflammation of the left main trunk was measured by blood-normalized standardized uptake value, known as a target-to-background ratio. RESULTS Three patients dropped out of the study during the assessment or treatment. Finally, 25 pioglitazone-treated patients and 22 glimepiride-treated patients (37 men; mean age: 68.1 ± 8.3 years; glycosylated hemoglobin: 6.72 ± 0.70%) completed the study. After 16-week treatments, fasting plasma glucose and glycosylated hemoglobin values were comparably reduced in both groups. Changes in target-to-background ratio values from baseline were significantly greater in the pioglitazone group than in the glimepiride group (-0.12 ± 0.06 vs. 0.09 ± 0.07, p = 0.032), as well as changes in high-sensitivity C-reactive protein (pioglitazone vs. glimepiride group: median: -0.24 [interquartile range (IQR): -1.58 to -0.04] mg/l vs. 0.08 [IQR: -0.07 to 0.79] mg/l, p = 0.031). CONCLUSIONS Our study indicated that pioglitazone attenuated left main trunk inflammation in patients with impaired glucose tolerance or DM in a glucose-lowering independent manner, suggesting that pioglitazone may protect against cardiac events in patients with impaired glucose tolerance or DM by suppressing coronary inflammation. (Anti-Inflammatory Effects of Pioglitazone; NCT00722631).

Effects of pioglitazone on visceral fat metabolic activity in impaired glucose tolerance or type 2 diabetes mellitus.

CONTEXT Excess visceral fat is associated with chronic systemic inflammation and cardiovascular complications. Pioglitazone has been reported to variably influence visceral fat volume; however, its effect on metabolic activity of the visceral fat remains uncharacterized. OBJECTIVE The aim of this study was to assess the effects of pioglitazone on glucose metabolism of fat tissue by using (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) and computed tomography imaging. DESIGN, SETTING, AND PARTICIPANTS FDG-PET and computed tomography imaging were performed in 56 patients with impaired glucose tolerance or type 2 diabetes mellitus; lipid and glycemic profiles and inflammatory biomarkers were obtained in all patients. These patients were randomized to treatment with either pioglitazone or glimepiride for 16 weeks. MAIN OUTCOME MEASURES The metabolic activity of the visceral fat tissues as assessed by FDG uptake was expressed as a target-to-background ratio (TBR) of blood-normalized standardized uptake value. RESULTS The study was completed in 32 pioglitazone-treated and 21 glimepiride-treated patients (40 men and 13 women; mean age, 67.7 ± 8.1 y; body mass index, 25.0 ± 3.6 kg/m(2); glycated hemoglobin, 6.78 ± 0.70%). Both treatments were well-tolerated and comparably improved glycemic control. At baseline, visceral fat exhibited a higher TBR value than subcutaneous fat (0.55 ± 0.14 vs 0.30 ± 0.07, P < .001). Pioglitazone, but not glimepiride, significantly decreased the visceral fat volume (130.5 ± 53.0 to 122.1 ± 51.0 cm(2), P = .013) and TBR values (0.57 ± 0.16 to 0.50 ± 0.11, P = .007). Neither pioglitazone nor glimepiride treatment showed any effect on the volume or TBR values of subcutaneous fat. After 16 weeks of treatment with pioglitazone, reduction in visceral fat TBR was correlated to the increase in high-density lipoprotein cholesterol levels. CONCLUSIONS Our study indicated that pioglitazone decreased the visceral fat volume and its metabolic activity in patients with impaired glucose tolerance or type 2 diabetes mellitus. The beneficial effects of pioglitazone on visceral fat may be independent of its glucose-lowering effect.

Serum levels of advanced glycation end products (AGEs) are independently correlated with circulating levels of dipeptidyl peptidase-4 (DPP-4) in humans.

OBJECTIVES Inhibition of dipeptidyl peptidase-4 (DPP-4) has been proposed as a potential therapeutic target for type 2 diabetes. Although soluble DPP-4 has been identified in human serum and could be associated with DPP-4 activity, the kinetics and regulation of circulating DPP-4 levels remain unknown. In this study, we examined which anthropometric and metabolic variables, including serum levels of advanced glycation end products (AGEs), were independently associated with serum DPP-4 levels. Further, we investigated the effects of AGEs on DPP-4 expression in, and soluble DPP-4 release from human cultured proximal tubular epithelial cells. DESIGN AND METHODS The study involved 432 consecutive outpatients (301 males and 131 females; mean ages 61.8 ± 8.8) who underwent complete history and physical examinations, and determinations of blood chemistry and anthropometric variables. Serum DPP-4 and AGE levels were examined by enzyme-linked immunosorbent assay. Protein expression levels of DPP-4 and its release from the cells were analyzed with western blot analysis. RESULTS Mean serum levels of DPP-4 and AGEs were 520.2 ± 39.9 ng/mL and 8.96 ± 2.57 U/mL, respectively. In multiple regression analysis, female (p<0.001), HDL-cholesterol (p<0.001), glycated hemoglobin (p<0.001), AGEs (p<0.03), and the absence of hypertension medication (p<0.05) are independently associated with DPP-4 levels (R(2)=0.167). Western blot analysis revealed that AGEs significantly increased DPP-4 expression in, and soluble DPP-4 release from tubular cells. CONCLUSIONS The present study reveals that serum levels of DPP-4 are independently associated with various metabolic parameters in a general population. AGEs may up-regulate cellular DPP-4 expression and subsequently increase circulating levels of DPP-4 in humans.

Adiponectin is inversely associated with ratio of serum levels of AGEs to sRAGE and vascular inflammation

vascular inflammation Nobuhiro Tahara , Sho-ichi Yamagishi ⁎, Atsuko Tahara , Masatoshi Ishibashi , Naofumi Hayabuchi , Masayoshi Takeuchi , Tsutomu Imaizumi a a Department of Medicine, Division of Cardio-Vascular Medicine, Kurume University School of Medicine, Kurume, Japan b Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan c Division of Nuclear Medicine, PET Center and Department of Radiology, Kurume University School of Medicine, Kurume, Japan d Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Kanazawa, Japan

Clinical and Biochemical Factors Associated With Area and Metabolic Activity in the Visceral and Subcutaneous Adipose Tissues by FDG-PET/CT

CONTEXT Body fat distribution and inflammation may play a role in metabolic derangements and cardiovascular disease in obesity. OBJECTIVE The aim of this study is to investigate clinical and biochemical factors associated with area and metabolic activity in the visceral and subcutaneous adipose tissues (VAT and SAT). PARTICIPANTS (18)F-fluorodeoxyglucose-positron emission tomography and computed tomography imaging was performed in 251 consecutive subjects (62.6 ± 9.3 y) for risk screening. MAIN OUTCOME MEASURES We examined which clinical, anthropometric, metabolic, and inflammatory variables including advanced glycation end products (AGEs) and pigment epithelium-derived factor (PEDF) were independently associated with area and metabolic activity in VAT and SAT. Adipose tissue area was determined with computed tomography, whereas metabolic activity was assessed by (18)F-fluorodeoxyglucose uptake expressed as a target to background ratio (TBR) of blood-normalized standardized uptake. RESULTS Serum levels of AGEs and PEDF were 9.81 ± 3.21 U/mL and 14.0 (range 10.8-17.7) μg/mL, respectively. Although the area in VAT and SAT was associated with waist circumference and sex, each adipose tissue area and TBR had different metabolic risk profiles. The TBR value in VAT was higher than that in SAT. In a multiple stepwise regression analysis, AGEs and medication for hypertension were independently associated with VAT TBR (R(2) = 0.102), whereas medication for diabetes, mean intima-media thickness, AGEs, and PEDF were the independent correlates of SAT TBR (R(2) = 0.132). CONCLUSIONS The present study demonstrated that area and metabolic activity in VAT and SAT could be differently regulated, suggesting the involvement of AGEs and PEDF in adipose tissue inflammation.

Pioglitazone Decreases Asymmetric Dimethylarginine Levels in Patients with Impaired Glucose Tolerance or Type 2 Diabetes

BACKGROUND AND AIMS Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is a biomarker and mediator of cardiovascular disease in patients with impaired glucose tolerance (IGT) or diabetes mellitus (DM). Advanced glycation end products (AGEs) and their receptor (RAGE) axis is involved in ADMA generation as well. However, it remains unclear whether pioglitazone could decrease ADMA levels by reducing RAGE expression in humans. DESIGN AND METHODS Forty-eight IGT or type 2 DM (T2DM) patients were assigned to receive either pioglitazone (n=29) or glimepiride (n=19) and evaluated at baseline and 16 weeks of follow-up. We compared the effects of pioglitazone and glimepride on ADMA and soluble form of RAGE (sRAGE) levels and then studied whether the changes in serum ADMA level (ΔADMA) after treatment with pioglitazone were correlated with ΔsRAGE. We further examined which Δclinical variables were independently associated with ΔADMA. RESULTS After 16-week treatments, fasting plasma glucose and glycated hemoglobin (HbA1c) values were comparably reduced in both groups. Compared with glimepiride, pioglitazone treatment significantly decreased ADMA levels and improved insulin sensitivity, while it elevated high-density lipoprotein cholesterol (HDL-C) and sRAGE values and increased body weight and waist circumference. In multiple stepwise regression analysis, log-transformed Δfibronectin were a sole independent determinant of log-transformed ΔADMA (r=-0.551, R²=0.303). CONCLUSIONS This study demonstrated that pioglitazone decreased serum ADMA levels in a glucose-lowering independent manner. Elevation of fibronectin by pioglitazone may contribute to the reduction of serum levels of ADMA in IGT or T2DM subjects, thus playing a protective role against cardiovascular disease.

Molecular imaging of vascular inflammation.

Atherosclerosis and its thrombotic complications represent the major cause of morbidity and mortality in the industrialized countries. Despite recent advances in the diagnosis and management of cardiovascular disease, a substantial number of patients still die from acute coronary syndromes. Recently, atherosclerotic plaque composition rather than the degree of arterial stenosis has been shown to reflect the plaque vulnerability, thus contributing to the pathogenesis of cardiovascular disease. Vulnerable plaques have a large lipidrich necrotic core, a thin-fibrous cap and numerous inflammatory cells. Among them, macrophage activation plays a central role in vascular inflammation and plaque instability within the atherosclerosis, being strongly involved in acute coronary syndromes. Various morphologic features of plaque vulnerability have been described by computed tomography angiography, magnetic resonance imaging, intravascular ultrasound, and optical coherence tomography. Molecular imaging is the tool best suited for identifying metabolically active macrophages. Indeed, positron emission tomography (PET) imaging with 18F-fluorodeoxyglucose (FDG) is capable of identifying and quantifying vascular inflammation characterized by macrophage activation within the atherosclerotic plaques. So, FDG-PET might be a feasible clinical tool for detecting vulnerable plaques and evaluating the efficacy of drugs in plaque instability. In this paper, we review the clinical utility of FDG-PET imaging in identifying patients at risk of plaque rupture and resultantly prone to cardiovascular disease.