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.

Double-blind, placebo-controlled clinical trial with a rho-kinase inhibitor in pulmonary arterial hypertension.

BACKGROUND: We have previously demonstrated that long-term inhibition of Rho-kinase ameliorates pulmonary arterial hypertension (PAH) in animal models. In the present study, we examined the clinical effects of mid-term oral treatment with an extended release formulation of AT-877 (fasudil hydrochloride), a specific Rho-kinase inhibitor (AT-877ER) on PAH. METHODS AND RESULTS: 23 PAH patients were treated with either placebo (10/2 females/males, 51 ± 16 years, idiopathic PAH (IPAH) in 6, PAH associated with connective tissue disease (CTD-PAH) in 3, PAH with congenital heart disease (CHD-PAH) in 2, and portal PAH in 1) or AT-877ER (6/5 females/males, 47 ± 14 years, IPAH in 2, CTD-PAH in 5, and CHD-PAH in 4); 3 patients were excluded. We performed a 6-min walk test and right heart catheterization in the remaining 20 patients, before and 3 months after the treatment (placebo n=11, AT-877ER n=9). Although there were no significant differences between the 2 groups for the 6-min walk distance, pulmonary hemodynamics tended to be improved in the AT-877ER group, especially the prevalence of improved cardiac index from baseline, which was significantly higher in the AT-877ER than in the placebo group. In the AT-877ER group, serum levels of hydroxyfasudil, an active metabolite of AT-877ER tended to correlate with improvements in the cardiac index and mean pulmonary artery pressure. CONCLUSIONS: Mid-term treatment with oral AT-877ER showed additional improvement in pulmonary hemodynamics in patients with PAH.

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.

Positive association between serum level of glyceraldehyde-derived advanced glycation end products and vascular inflammation evaluated by [(18)F]fluorodeoxyglucose positron emission tomography.

OBJECTIVE: Advanced glycation end products (AGEs) evoke inflammatory reactions, contributing to the development and progression of atherosclerosis. We investigated the relationship between serum AGE level and vascular inflammation. RESEARCH DESIGN AND METHODS: The study involved 275 outpatients at Kurume University, Japan (189 males and 86 females; mean age 61.2 ± 8.8 years) who underwent complete history and physical examinations and determinations of blood chemistry and anthropometric variables, including AGEs. Serum AGE level was examined by enzyme-linked immunosorbent assay. Vascular [(18)F]fluorodeoxyglucose (FDG) uptake, an index of vascular inflammation, was measured as blood-normalized standardized uptake value, known as the target-to-background ratio (TBR), by FDG-positron emission tomography (FDG-PET). Furthermore, we examined whether the changes in serum AGE level after treatment with oral hypoglycemia agents (OHAs) were correlated with those of TBR in another 18 subjects whose AGE value was >14.2 units/mL (mean ± 2 SD). RESULTS: Mean serum AGE level and carotid TBR values were 9.15 ± 2.53 and 1.43 ± 0.22 units/mL, respectively. Multiple stepwise regression analysis revealed that TBR was independently correlated with AGEs (P < 0.001), carotid intima-media thickness (P < 0.01), and BMI (P < 0.02). When age- and sex-adjusted AGE values stratified by TBR tertiles were compared using ANCOVA, a significant trend was observed (P < 0.01). In addition, the changes in AGEs after OHA treatment were positively (r = 0.50, P < 0.05) correlated with those in TBR value. CONCLUSIONS: The current study reveals that serum AGE level is independently associated with vascular inflammation evaluated by FDG-PET, suggesting that circulating AGE value may be a biomarker that could reflect vascular inflammation within an area of atherosclerosis.

Serum levels of advanced glycation end products (AGEs) are independent correlates of insulin resistance in nondiabetic subjects.

BACKGROUND: Advanced glycation end products (AGEs) evoke oxidative stress generation and inflammatory reactions, thus being involved in vascular complications in diabetes. Since oxidative stress and inflammation impair insulin actions as well, it is conceivable that AGEs may play some role in insulin resistance. However, there is no clinical study to examine the relationship between serum levels of AGEs and insulin resistance. This study investigated whether serum AGE levels were independent correlates of insulin resistance in humans. METHODS: Three hundred twenty-two nondiabetic Japanese subjects (216 male and 106 female; mean age 61.5 ± 9.1 years) underwent a complete history and physical examination, determinations of blood chemistries, anthropometric and metabolic variables, including AGEs. Serum AGE levels were examined with an enzyme-linked immunosorbent assay. RESULTS: Mean serum AGE levels were 8.96 ± 2.57 U/mL. In univariate analysis, waist circumference, diastolic blood pressure (BP), mean BP, AGEs, low-density lipoprotein (LDL) cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol (inversely), hemoglobin A1c (GHb), creatinine clearance, uric acid, and high sensitivity C-reactive protein were significantly associated with insulin resistance evaluated by homeostasis model assessment of insulin resistance (HOMA-IR) index. After performing multiple regression analysis, waist circumference (P < 0.001), GHb (P < 0.001), triglycerides (P < 0.001), and AGEs (P < 0.01) still remained significant independently. When age-adjusted HOMA-IR levels stratified by AGE tertiles were compared using ANCOVA, a significant trend was demonstrated in both males and females. CONCLUSION: The present study demonstrated for the first time that serum AGE levels were one of the independent correlates of HOMA-IR index, thus suggesting that AGEs may play some pathological role in insulin resistance in humans.

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.

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.

Long-term treatment with valsartan improved cyclic variation of the myocardial integral backscatter signal and diastolic dysfunction in hypertensive patients: the echocardiographic assessment.

Myocardial fibrosis is the major determinant of diastolic property of the left ventricle (LV). Experimental and clinical studies have suggested that angiotensin receptor blockers attenuate myocardial fibrosis in various heart diseases. The integrated backscatter signal (IBS) represents a promising ultrasonic method for assessing the characterization of myocardial tissue: cardiac cycle-dependent variation of the IBS (IBS-CV) is negatively correlated with myocardial collagen deposition in hypertensive hearts. Using non-invasive echocardiographic techniques, we performed a prospective, multi-center trial to examine whether long-term treatment with valsartan would improve myocardial fibrosis and diastolic dysfunction in hypertensives. This study included 43 hypertensive patients who had impaired diastolic function (transmitral Doppler flow early to late filling velocity ratio [E/A ratio] <1.0) and preserved systolic function (LV ejection fraction [LVEF] >50%). Twelve-month valsartan treatment reduced blood pressure (BP) and LV mass index. Valsartan significantly increased not only IBS-CV but also E/A ratio without changing LVEF. The effects of valsartan were compared between two subgroups: one with low IBS-CV (IBS-CV <5.08 dB [the average of 43 patients at baseline]), the other with high IBS-CV (IBS-CV >5.08 dB). At baseline, BP, LV mass index, LVEF, and E/A ratio were similar in the two groups. Valsartan significantly increased IBS-CV and E/A ratio in the low IBS-CV group, but not in the high IBS-CV group, despite comparable reductions in BP and LV mass. In conclusion, long-term valsartan treatment attenuated myocardial fibrosis and improved diastolic dysfunction in hypertensives. It is suggested that in the low IBS-CV group, improvement of diastolic dysfunction by valsartan may be caused by attenuation of myocardial fibrosis, and not by regression of LV hypertrophy.

The prevalence of inflammation in carotid atherosclerosis: analysis with fluorodeoxyglucose-positron emission tomography.

AIMS: There is increasing evidence that (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging can be useful for non-invasive measurement of atherosclerotic plaque inflammation in humans. However, it is unknown how often atherosclerosis has inflammation in humans. Thus, we examined the prevalence of inflammation in documented carotid atherosclerosis using FDG-PET imaging. METHODS AND RESULTS: FDG-PET imaging was performed in 100 consecutive patients who underwent carotid artery ultrasonography (CA-US) for screening of carotid atherosclerosis. Carotid atherosclerosis was considered when patients had the plaque score >or=5 and/or the focal thickening of the maximum intima-media complex >or=2 mm (localized plaque) by CA-US. The inflammation of carotid atherosclerosis was quantified by measuring the standardized uptake value (SUV) of FDG of the carotid artery. Inflammation was defined as present if the SUV score was >or=1.60 (>or=1 x standard deviation above the average). FDG-PET imaging revealed inflammation in 12 of 41 (29%) patients having carotid atherosclerosis, whereas in 6 of 59 (10%) patients not having carotid atherosclerosis (P < 0.01). In patients with documented atherosclerosis by CA-US, body mass index, waist circumference, and the number of localized plaques were greater in a subset with inflammation than in a subset without. CONCLUSION: Inflammation was visualized by FDG-PET imaging in approximately 30% of patients with documented carotid atherosclerosis.

Vascular inflammation evaluated by [18F]-fluorodeoxyglucose positron emission tomography is associated with the metabolic syndrome.

OBJECTIVES: We investigated factors for carotid artery inflammation by [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography (PET). BACKGROUND: Inflammation is present in some atherosclerotic plaques. The FDG-PET is capable of identifying and quantifying vascular inflammation within atherosclerotic plaques. METHODS: The FDG-PET imaging was performed in 216 consecutive patients (63 +/- 9 years, men:women 147:69) for cancer screening. Vascular inflammation in carotid atherosclerosis was quantified by measuring the standardized uptake value (SUV) of FDG into the artery. RESULTS: Multiple stepwise regression analysis revealed significant relationships between SUV and waist circumference (p < 0.001), hypertensive medication (p < 0.001), carotid intima-media thickness (p < 0.001), high-density lipoprotein cholesterol (p < 0.01, inversely), homeostasis model assessment of insulin resistance (p < 0.05), or high sensitivity C-reactive protein (p < 0.05). Age- and gender-adjusted SUV of FDG was significantly higher (p < 0.0001) in proportion to the accumulation of the number of the components of the metabolic syndrome. Thus, the metabolic syndrome was associated with increased FDG uptake in carotid atherosclerosis. CONCLUSIONS: Our present study may suggest that the metabolic syndrome is associated with inflammation in carotid atherosclerosis. (Detection of Plaque Inflammation by Positron Emission Tomography (PET); http://www.clinicaltrials.gov/ct/show/NCT00114504; NCT00114504).