Oxidative Stress and Inflammation as Predictors of Mortality and Cardiovascular Events in Hemodialysis Patients: The DREAM Cohort.

AIM: Both oxidative stress and inflammation are involved in the pathogenesis of cardiovascular disease (CVD). The serum level of derivatives of reactive oxygen metabolites (d-ROMs) is a measure of the total amount of hydroperoxides serving as a marker of oxidative stress. We investigated whether d-ROMs could predict the clinical outcomes in hemodialysis patients and whether the associations of d-ROMs with the outcomes are independent of a marker of inflammation, C-reactive protein (CRP). METHODS: This was a prospective cohort study in hemodialysis patients. The key exposures were the serum levels of d-ROMs and CRP. The outcome measures were all-cause mortality and new CVD events. RESULTS: A total of 517 patients were analyzed. d-ROMs correlated positively with CRP. During follow-up for 5 years, 107 patients died, and 190 patients experienced new CVD events. In the Kaplan-Meier analyses, both higher d-ROMs and higher CRP levels predicted higher risks for mortality and CVD events. By Cox proportional-hazard regression analysis adjusted for potential confounders excluding CRP, d-ROMs exhibited a significant association with all-cause mortality, but this association was no longer significant after further adjustment for CRP. Using the same model, CRP exhibited a significant association with all-cause mortality, but this association was no longer significant after further adjustment for d-ROMs. When we analyzed new CVD events as the outcome, CRP was a significant predictor, whereas the level of d-ROMs was not. CONCLUSIONS: Although d-ROMs predicted mortality and CVD events in unadjusted models, the associations of d-ROMs with these outcomes were not independent of CRP. Oxidative stress and inflammation appear to share common causal pathways.

Visceral adiposity is associated with the discrepancy between glycated albumin and HbA1c in type 2 diabetes.

AIM: We investigated the association of visceral adiposity with glycated albumin (GA) as well as GA/hemoglobin A1c (HbA1c) in type 2 diabetes. METHODS: One hundred twenty-three patients (68 males, 55 females) with type 2 diabetes were enrolled in this cross-sectional study. Visceral fat area (VFA) was determined using an abdominal dual bioelectrical impedance analysis (dual BIA) instrument. The relationship of VFA with GA and GA/HbA1c was analyzed. RESULTS: Simple regression analysis showed that BMI was inversely correlated with GA as well as GA/HbA1c, but not with HbA1c, while VFA had a significant correlation with GA and GA/HbA1c. Furthermore, multiple regression analysis revealed VFA as an independent contributor to GA/HbA1c. These results suggest that visceral adiposity is a primary factor associated with GA and HbA1c level discrepancy in patients with type 2 diabetes. CONCLUSIONS: GA is a useful indicator for glycemic control, while visceral obesity should also be taken into consideration in type 2 diabetes cases.

Albuminuria rather than glomerular filtration rate is associated with vascular endothelial function in patients with type 2 diabetes.

AIMS: Albuminuria and reduced glomerular filtration rate (GFR) are manifestations of diabetic kidney disease and are both shown to be associated with cardiovascular outcomes. However, the differential association of albuminuria and reduced GFR with endothelial dysfunction, an early feature of atherosclerotic vascular damage, remains unclear. In this study, we investigated the association between albuminuria or estimated GFR (eGFR) and flow-mediated dilatation (FMD), a marker of endothelial function, in patients with type 2 diabetes. METHODS: This study included 633 patients with type 2 diabetes. The FMD of the brachial artery was measured by ultrasonography. Albuminuria was evaluated by urinary albumin-to-creatinine ratio (ACR). RESULTS: The mean FMD and eGFR, and the median value of ACR were 6.7%, 66.5 mL/min/1.73m2 and 12.5 mg/g creatinine, respectively. Impaired FMD was found in patients with advanced stages of chronic kidney disease based on both GFR and albuminuria categories. Multivariate analysis after adjusting for potential confounders revealed that ACR, but not eGFR, was significantly and inversely associated with FMD. CONCLUSIONS: Albuminuria is associated with FMD, independently of traditional cardiovascular risk factors in patients with type 2 diabetes. This study suggests a close relationship between albuminuria, rather than reduced GFR, and endothelial dysfunction in type 2 diabetes.

The Inhibitory Roles of Vitamin K in Progression of Vascular Calcification.

Vitamin K is a fat-soluble vitamin that is indispensable for the activation of vitamin K-dependent proteins (VKDPs) and may be implicated in cardiovascular disease (CVD). Vascular calcification is intimately associated with CV events and mortality and is a chronic inflammatory process in which activated macrophages promote osteoblastic differentiation of vascular smooth muscle cells (VSMCs) through the production of proinflammatory cytokines such as IL-1ß, IL-6, TNF-α, and oncostatin M (OSM) in both intimal and medial layers of arterial walls. This process may be mainly mediated through NF-κB signaling pathway. Vitamin K has been demonstrated to exert anti-inflammatory effects through antagonizing NF-κB signaling in both in vitro and in vivo studies, suggesting that vitamin K may prevent vascular calcification via anti-inflammatory mechanisms. Matrix Gla protein (MGP) is a major inhibitor of soft tissue calcification and contributes to preventing both intimal and medial vascular calcification. Vitamin K may also inhibit progression of vascular calcification by enhancing the activity of MGP through facilitating its γ-carboxylation. In support of this hypothesis, the procalcific effects of warfarin, an antagonist of vitamin K, on arterial calcification have been demonstrated in several clinical studies. Among the inactive MGP forms, dephospho-uncarboxylated MGP (dp-ucMGP) may be regarded as the most useful biomarker of not only vitamin K deficiency, but also vascular calcification and CVD. There have been several studies showing the association of circulating levels of dp-ucMGP with vitamin K intake, vascular calcification, mortality, and CVD. However, additional larger prospective studies including randomized controlled trials are necessary to confirm the beneficial effects of vitamin K supplementation on CV health.

Inter-Arm Blood Pressure Difference in Diabetes Mellitus and Its Preferential Association with Peripheral Artery Disease.

AIM: Inter-arm blood pressure difference (IAD) is known to be associated with a composite of cardiovascular disease (CVD) and with CVD risk factors. However, only limited information is available regarding the contribution of diabetes mellitus to IAD and the association of IAD with individual CVDs, such as coronary artery disease (CAD), stroke, and peripheral artery disease (PAD). METHODS: We addressed these issues in this cross-sectional study of 2580 participants who had simultaneous blood pressure measurements in both arms using an automated device. RESULTS: Compared with 1,264 nondiabetic subjects, 1316 patients with diabetes mellitus had a greater IAD (P=0.01) and a higher prevalence of IAD of ≥ 10 mmHg (8.4% vs. 5.4%, P=0.002). However, such difference was not significant after the adjustment for potential confounders. Among CAD, stroke, and PAD, only PAD was significantly associated with IAD in a model adjusted for the CVD risk factors. Age was found to modify the association between IAD and PAD, with the association being more prominent in the younger subgroup. CONCLUSION: Thus, diabetes mellitus itself was not an independent factor associated with IAD. A larger IAD was preferentially associated with the presence of PAD, and this association was modified by age.

Plasma omentin levels are inversely associated with atherosclerosis in type 2 diabetes patients with increased plasma adiponectin levels: a cross-sectional study.

BACKGROUND: Omentin and adiponectin are among the anti-inflammatory and anti-atherogenic adipokines that have potentially beneficial effects on cardiovascular disorders. Recent studies indicate a paradoxical relationship between adiponectin and cardiovascular mortality across many clinical settings including type 2 diabetes. In this study, we characterized the clinical features of type 2 diabetes patients with increased adiponectin levels and examined the association between omentin and atherosclerosis in those patients. METHODS: The subjects were 413 patients with type 2 diabetes. Fasting plasma omentin and total adiponectin levels were measured by enzyme-linked immunosorbent assay. The intima-media thickness (IMT) of the common carotid artery was measured by ultrasonography. The subjects were stratified according to the median value of plasma adiponectin. RESULTS: In high-adiponectin group, omentin levels were higher, while IMT tended to be greater than those in low-adiponectin group. The high-adiponectin group also exhibited older age, higher systolic blood pressure, lower kidney function, body mass index, and insulin resistance index compared to the low-adiponectin group. Multivariate analysis revealed that omentin levels were independently and negatively associated with IMT in high-adiponectin group, but not in low-adiponectin group, after adjusting for adiponectin levels and traditional cardiovascular risk factors. On the other hand, adiponectin levels were not significantly associated with IMT in either group. CONCLUSIONS: Plasma omentin levels are inversely associated with IMT in type 2 diabetes patients with increased adiponectin levels and multiple cardiovascular risk factors. This study suggests a protective role of omentin against atherosclerosis in type 2 diabetes patients, which is potentially influenced by adiponectin level and cardiovascular risk status.

Adenosine Attenuates Aortic Smooth Muscle Cell Calcification through A3 Adenosine Receptor.

Vascular calcification is a typical feature of atherosclerosis and is associated with adverse cardiovascular events such as myocardial infarction and stroke. Several studies have suggested that adenosine, an ATP metabolite may function as an endogenous regulator of arterial calcification. However, its effects on vascular smooth muscle cell calcification have not been clarified. In this study, we investigated the inhibitory effects of adenosine on vascular calcification in vitro by utilizing the culture of human aortic smooth muscle cells (HASMCs). Osteoblastic differentiation of HASMCs was induced by the treatment with oncostatin M and osteogenic differentiation medium. Adenosine and its metabolically stable analogue, 2-chloroadenosine (CADO) significantly reduced matrix mineralization and alkaline phosphatase (ALP) activities in HASMCs. The mRNA expression of tissue non-specific alkaline phosphatase (TNAP) was down-regulated by adenosine and CADO, but the mRNA expression of other osteoblastic differentiation markers, such as Runt-related transcription factor 2 (RUNX2) and bone sialoprotein (BSP)-II, was not significantly affected by these two reagents. Among the adenosine receptor (AR) subtype-selective agonists used, only IB-MECA (A3 AR-selective agonist) significantly decreased in vitro mineralization and ALP activities in HASMCs, but not with CCPA (A1 AR-selective agonist), CGS21680 (A2a AR-selective agonist), or BAY60-6583 (A2b AR-selective agonist). Importantly, IB-MECA also down-regulated expression of TNAP mRNA. Finally, knockdown of A3 AR, but not A1 AR, A2a AR, or A2b AR, significantly reversed the inhibitory actions of adenosine, CADO, or IB-MECA on in vitro calcification and ALP activities in HASMCs. These data suggest that adenosine attenuates HASMC calcification through A3 AR.

Oncostatin M induces C2C12 myotube atrophy by modulating muscle differentiation and degradation.

Oncostatin M (OSM) is a cytokine of the interleukin-6 family and plays a role in various disorders such as cancer and inflammatory diseases, which are often accompanied by skeletal muscle atrophy, or sarcopenia. However, the role of OSM in the regulation of skeletal muscle mass remains to be identified. In this study, we investigated the effect of OSM on C2C12 myotube formation in vitro. C2C12 myoblasts were induced to differentiate into myotubes for 3 days and then treated with OSM for 24 or 48 h. The diameter of differentiated C2C12 myotubes were reduced by 18.7% and 23.3% compared to control cells after treatment with OSM for 24 and 48 h, respectively. The expression levels of MyoD and myogenin were decreased, while those of atrogin-1, CCAAT/enhancer binding protein δ, and OSM receptor were increased in C2C12 myotubes treated with OSM for 24 h compared to control cells. Furthermore, the inhibitory effect of OSM on myotube formation was significantly attenuated by pretreatment with an inhibitor of signal transducer and activator of transcription (STAT) 3 or by knockdown of Stat3. Finally, the OSM-induced changes in the expression levels of MyoD, myogenin, and atrogin-1 were reversed by pretreatment with an inhibitor of STAT3 or by Stat3 knockdown in C2C12 myotubes. In conclusion, OSM induces C2C12 myotube atrophy by inhibiting myogenic differentiation and activating muscle degradation in a STAT3-dependent manner.

Plasma omentin levels are associated with vascular endothelial function in patients with type 2 diabetes at elevated cardiovascular risk.

AIMS: Omentin is an adipokine that has protective effects against cardiovascular damage. Previous studies showed an inverse relationship between omentin and obesity, diabetes, and cardiovascular disease. This study aimed to investigate the association between omentin and vascular endothelial function in patients with type 2 diabetes (T2D). METHODS: The subjects were 425 patients with T2D and 223 non-diabetic controls. Fasting plasma omentin levels were measured by enzyme-linked immunosorbent assay, and the endothelium-dependent, flow-mediated dilatation (FMD) was measured by ultrasonography. RESULTS: Plasma omentin levels were higher, while FMD was lower in participants with T2D than in non-diabetic controls. No significant correlation was found between plasma omentin levels and FMD in either non-diabetic controls or participants with T2D on multivariate analysis. However, stratified analysis in T2D patients revealed that plasma omentin levels were independently and positively associated with FMD in high cardiovascular risk subgroups according to age (≥65 years), estimated glomerular filtration rate (<60 mL/min/1.73 m2), or preexisting cardiovascular diseases but not in low-risk subgroups. CONCLUSIONS: Plasma omentin levels are independently associated with endothelial function in subgroups of patients with T2D at elevated cardiovascular risk. This study suggests a protective role of omentin against endothelial dysfunction, particularly in high-risk patients.

Plasma polyunsaturated fatty acid profile is associated with vascular endothelial function in patients with type 2 diabetes.

Decreased plasma n-3 polyunsaturated fatty acid levels or the n-3/n-6 polyunsaturated fatty acid ratios are associated with a risk of cardiovascular events. In this cross-sectional study, we measured plasma levels of eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid and investigated the association between the plasma polyunsaturated fatty acid profile and vascular endothelial function in 396 patients with type 2 diabetes. Endothelium-dependent, flow-mediated dilatation of the brachial artery was measured using ultrasonography. Multiple regression analyses, including age, sex, body mass index, and other cardiovascular risk factors, revealed that plasma eicosapentaenoic acid levels ( ß = 0.140, p = 0.008) and the eicosapentaenoic acid/arachidonic acid ratio ( ß = 0.127, p = 0.019), but not plasma docosahexaenoic acid levels ( ß = 0.067, p = 0.220) or the docosahexaenoic acid/arachidonic acid ratio ( ß = 0.034, p = 0.559), were independently and positively associated with flow-mediated dilatation. In conclusion, plasma eicosapentaenoic acid levels and the eicosapentaenoic acid/arachidonic acid ratio are independently associated with endothelial function in patients with type 2 diabetes. This study indicates a positive association between eicosapentaenoic acid, rather than docosahexaenoic acid, and endothelial function in type 2 diabetes.

Plasma soluble leptin receptor levels are associated with pancreatic ß-cell dysfunction in patients with type 2 diabetes.

AIMS/INTRODUCTION: A soluble form of the leptin receptor (soluble Ob-R) in the circulation regulates leptin's bioactivity, and is inversely associated with body adiposity and circulating leptin levels. However, no study has examined the clinical impact of soluble Ob-R on glucose metabolism in diabetes. The present study aimed to investigate the association of plasma soluble Ob-R levels with insulin resistance and pancreatic ß-cell function in patients with type 2 diabetes. MATERIALS AND METHODS: A total of 289 Japanese patients with type 2 diabetes were included in the present study. Fasting plasma soluble Ob-R levels and plasma leptin levels were measured by enzyme-linked immunosorbent assay. Insulin resistance and pancreatic ß-cell function were estimated by homeostasis model assessment of insulin resistance, homeostasis model assessment of ß-cell function and fasting C-peptide index. RESULTS: The median plasma soluble Ob-R level and plasma leptin level were 3.4 ng/mL and 23.6 ng/mL, respectively. Plasma soluble Ob-R levels were negatively correlated with homeostasis model assessment of insulin resistance, homeostasis model assessment of ß-cell function and the C-peptide index, whereas plasma leptin levels were positively correlated with each index in univariate analyses. Multivariate analyses including plasma soluble Ob-R levels, plasma leptin levels and use of sulfonylureas, along with age, sex, body mass index and other covariates, showed that soluble Ob-R levels were independently and negatively associated with homeostasis model assessment of ß-cell function and the C-peptide index, but not significantly associated with homeostasis model assessment of insulin resistance. CONCLUSIONS: Plasma soluble Ob-R levels are independently associated with pancreatic ß-cell function, but not with insulin resistance, in patients with type 2 diabetes. The present study implicates the role of soluble Ob-R in pancreatic ß-cell dysfunction in type 2 diabetes.

Altered Serum n-6 Polyunsaturated Fatty Acid Profile and Risks of Mortality and Cardiovascular Events in a Cohort of Hemodialysis Patients.

OBJECTIVE: Alterations in the balance between serum n-3 and n-6 polyunsaturated fatty acids (PUFAs) is predictive of cardiovascular events among hemodialysis patients, although little is known about the serum ratio of n-6 arachidonic acid (AA) to n-6 dihomo-γ-linoleic acid (DGLA) in renal failure. We hypothesized that AA/DGLA ratio is altered in hemodialysis patients resulting in poor clinical outcomes. METHODS: This was a single center cohort study in an urban area in Japan with cross-sectional analyses. Subjects were 517 hemodialysis patients and 122 control subjects. The main exposure was serum AA/DGLA ratio, and the main outcome measures were all-cause mortality and cardiovascular events during 5 years. RESULTS: The hemodialysis patients showed a higher median (interquartile range) AA/DGLA ratio than the control subjects (6.46 [5.22-7.81] versus 4.56 [3.74-6.34], P < .001). In a Cox proportional hazard model adjusted for age, sex, dialysis duration, diabetic nephropathy, prior cardiovascular disease, and the ratio of serum n-3 polyunsaturated fatty acids (eicosapentaenoic acid plus docosahexaenoic acid) to AA, the higher quartiles of AA/DGLA ratio were associated with higher risk for all-cause mortality with hazard ratios (95% confidence interval) of 1.50 (0.84-2.76) for quartile 2, 2.10 (1.18-3.86) for quartile 3, and 2.02 (1.10-3.78) for quartile 4 compared with quartile 1. AA/DGLA ratio showed a similar association with the risk of cardiovascular events. CONCLUSIONS: AA/DGLA ratio was elevated in patients with end-stage renal disease requiring hemodialysis, and a high AA/DGLA ratio was an independent predictor of poor clinical outcomes in this population.

Plaque Calcification During Atherosclerosis Progression and Regression.

Plaque calcification develops by the inflammation-dependent mechanisms involved in progression and regression of atherosclerosis. Macrophages can undergo two distinct polarization states, that is, pro-inflammatory M1 phenotype in progression and anti-inflammatory M2 phenotype in regression. In plaque progression, predominant M1 macrophages promote the initial calcium deposition within the necrotic core of the lesions, called as microcalcification, through not only vesicle-mediated mineralization as the result of apoptosis of macrophages and vascular smooth muscle cells (VSMCs), but also VSMC differentiation into early phase osteoblasts. On the other hand, in plaque regression M2 macrophages are engaged in the healing response to plaque inflammation. In association with the resolution of chronic inflammation, M2 macrophages may facilitate macroscopic calcium deposition, called as macrocalcification, through induction of osteoblastic differentiation and maturation of VSMCs. Oncostatin M, which has been shown to promote osteoblast differentiation in bone, may play a pivotal role in the development of plaque calcification. Clinically, two types of plaque calcification have distinct implications. Macrocalcification leads to plaque stability, while microcalcification is more likely to be associated with plaque rupture. Statin therapy, which reduces cardiovascular mortality, has been shown to exert its dual actions on plaque morphology, that is, regression of atheroma and increment of macroscopic calcium deposits. Statins may facilitate the healing process against plaque inflammation by enhancing M2 polarization of macrophages. Vascular calcification has pleiotropic properties as pro-inflammatory "microcalcification" and anti-inflammatory "macrocalcification". The molecular mechanisms of this process in relation with plaque progression as well as plaque regression should be intensively elucidated.

Plasma homocysteine and cerebral small vessel disease as possible mediators between kidney and cognitive functions in patients with diabetes mellitus.

Cognitive impairment is more prevalent in those with decreased kidney function. We tested a hypothesis that an increased homocysteine and/or cerebral small vessel diseases (SVDs) mediate the link between kidney and cognitive functions in a cross-sectional study in 143 type 2 diabetes patients without diagnosis of dementia or prior stroke. The exposure and outcome variables were estimated glomerular filtration rate (eGFR) and cognitive performance evaluated with Modified Mini-Mental State (3 MS) examination, respectively. The candidate mediators were plasma homocysteine concentration, and SVDs including silent cerebral infarction, cerebral microbleed, periventricular hyperintensity, and deep and subcortical white matter hyperintensity by magnetic resonance imaging. In multiple regression models adjusted for 12 potential confounders, eGFR was positively associated with 3 MS score, inversely with homocysteine, but not significantly with the presence of any type of SVD. The association of eGFR with 3 MS remained significant when each of the SVDs was added to the model, whereas it disappeared when homocysteine was included in place of SVD. Mediation analysis indicated nearly significant mediation of homocysteine (P = 0.062) but no meaningful mediations of SVDs (P = 0.842-0.930). Thus, homocysteine, not SVDs, was shown to be the possible mediator between kidney and cognitive functions in patients with type 2 diabetes mellitus.

Lipopolysaccharide-binding protein is associated with arterial stiffness in patients with type 2 diabetes: a cross-sectional study.

BACKGROUND: Lipopolysaccharide (LPS)-binding protein (LBP) is an acute-phase reactant that mediates immune responses triggered by LPS. Recent evidence indicates the association of circulating LBP levels with obesity, diabetes, and cardiovascular diseases. In this study, we aimed to investigate the relationship between serum LBP levels and arterial stiffness in patients with type 2 diabetes. METHODS: A total of 196 patients with type 2 diabetes, including 101 men and 95 women, were enrolled in this cross-sectional study. Fasting serum LBP levels were determined by enzyme-linked immunosorbent assay. Arterial stiffness was assessed by measuring the aortic pulse wave velocity (PWV). RESULTS: The mean values of serum LBP and aortic PWV were 18.2 µg/mL and 1194 cm/s, respectively. Serum LBP levels were positively correlated with body mass index, triglycerides, high-sensitivity C-reactive protein, and insulin resistance index and were negatively correlated with high-density lipoprotein cholesterol. They were, however, not significantly correlated with aortic PWV in univariate analyses. Multivariate analysis revealed that serum LBP levels were independently and positively associated with aortic PWV (ß = 0.135, p = 0.026) after adjusting for age, sex, body mass index, albumin, high-sensitivity C-reactive protein, and other cardiovascular risk factors. Further analyses revealed that the impact of serum LBP levels on aortic PWV was modified by sex, and the association between serum LBP levels and aortic PWV was found to be significant only in men. CONCLUSIONS: Serum LBP levels are associated with arterial stiffness, independent of obesity and traditional cardiovascular risk factors, especially in men with type 2 diabetes. This study indicates a potential role of the LPS/LBP-induced innate immunity in the development and progression of arterial stiffness in type 2 diabetes.

Cardiothoracic Ratio as a Predictor of Cardiovascular Events in a Cohort of Hemodialysis Patients.

AIM: The cardiothoracic ratio (CTR) on a chest X-ray is an indicator of cardiac enlargement, although its predictive power for cardiovascular disease (CVD) events in chronic kidney disease is unknown. We examined it in a cohort of hemodialysis patients, as compared with an N-terminal fragment of probrain natriuretic peptide (NT-proBNP). METHOD: This was an observational study with cross-sectional and longitudinal analyses including 517 maintenance hemodialysis patients and 122 healthy control subjects. The main predictors were CTR and serum NT-proBNP, and the main outcome was CVD events in 5 years. RESULTS: At baseline, the hemodialysis patients had higher median (interquartile range) levels of CTR [0.487 (0.457-0.520)] than the control group [0.458 (0.432-0.497)]. In the hemodialysis group, CTR was positively correlated with NT-proBNP (Spearman's r=0.44, P＜0.001). During follow-up, 190 CVD events occurred. CTR was significantly associated with the risk of CVD [HR 2.12 (95% CI, 1.38-3.25) for the fourth quartile as compared with the second quartile of CTR] in a multivariate Cox model. In the same model, NT-proBNP (fourth versus first quartile) showed a HR of 3.27 (2.02-5.31). When CTR and NT-proBNP were simultaneously included as predictors, only NT-proBNP remained a significant predictor of CVD events, all-cause mortality and composite of CVD plus all-cause mortality. CONCLUSIONS: We showed that CTR was a significant and independent predictor of CVD in hemodialysis patients. CTR can be used for CVD risk stratification in hemodialysis patients when NT-proBNP is not available.

The Association between Monocyte Surface CD163 and Insulin Resistance in Patients with Type 2 Diabetes.

AIM: To investigate the association between monocyte CD163 and insulin resistance in patients with type 2 diabetes. METHODS: One hundred sixty-six patients with type 2 diabetes without inflammatory or chronic kidney disease were recruited. The monocyte CD163 levels were measured by flow cytometry and soluble CD163 (sCD163) by ELISA. Insulin resistance was evaluated by the index of the homeostasis model assessment (HOMA-R). RESULTS: The median sCD163 and monocyte CD163 expression levels were 582.9 (472.4-720.0) ng/ml and 6061 (4486-7876) mean fluorescent intensity (MFI), respectively. In a simple regression analysis, monocyte CD163 was inversely correlated with log [HOMA-R] (r = -0.257, p = 0.010), and sCD163 was positively correlated with log [HOMA-R] (r = 0.198, p = 0.042). In multiple regression analyses, monocyte CD163 was an independent contributor to log [HOMA-R] (ß = -0.220, p = 0.020) even after adjustment of various clinical factors for HOMA-R (R2 = 0.281, p = 0.001), whereas sCD163 was not. CONCLUSIONS: Monocyte surface CD163 expression levels were more significantly associated with insulin resistance than sCD163 in patients with type 2 diabetes, suggesting a novel pathophysiological role of CD163.

Impact of menaquinone-4 supplementation on coronary artery calcification and arterial stiffness: an open label single arm study.

BACKGROUND: Dietary intake of vitamin K has been reported to reduce coronary artery calcification (CAC) and cardiovascular events. However, it is unknown whether supplemental menaquinone (MK)-4 can reduce CAC or arterial stiffness. To study the effect of MK-4 supplementation on CAC and brachial ankle pulse wave velocity (baPWV). METHODS: This study is a single arm design to take 45 mg/day MK-4 daily as a therapeutic drug for 1 year. Primary endpoint was CAC score determined using 64-slice multislice CT (Siemens), and the secondary endpoint was baPWV measured before and 1 year after MK-4 therapy. RESULTS: A total of 26 patients were enrolled. The average age was 69 ± 8 years and 65 % were female. Plasma levels of phylloquinone (PK), MK-7, and MK4 were 1.94 ± 1.38 ng/ml, 14.2 ± 11.9 ng/ml and 0.4 ± 2.0 ng/ml, respectively, suggesting that MK-7 was the dominant vitamin K in the studied population. Baseline CAC and baPWV were 513 ± 773 and 1834 ± 289 cm/s, respectively. At 1 year following MK-4 supplementation, the values were 588 ± 872 (+14 %) and 1821 ± 378 cm/s (-0.7 %), respectively. In patients with high PIVKA-2, -18 % annual reduction of baPWV was observed. CONCLUSION: Despite high dose MK-4 supplementation, CAC increased +14 % annually, but baPWV did not change (-0.7 %). The benefits of MK-4 supplementation were only observed in patients with vitamin K insufficiencies correlated with high PIVKA-2 baseline levels, reducing baPWV but not CAC. TRIAL REGISTRATION: This study was registered as UMIN 000002760.

[Vascular diseases in CKD-MBD].

Vascular calcification is an important component of CKD-MBD and occurs in association with vascular lesions of CKD-MBD such as atherosclerosis and arteriosclerosis. Atherosclerotic intimal calcification and medial calcification contribute to the development and progression of cardiovascular disease. Epidemiological data suggest that it is not atherothrombotic disease but myocardal disease including left ventricular hypertrophy with fibrosis and diastolic dysfunction which is the principal cause of cardiovascular death in CKD. Arteriosclerosis is characterized by thickening and calcification of the medial arterial layer. Medial calcification results in increased arterial stiffness and contributes to the development of myocardial disease. Therefore, it is important to develop novel therapeutics for medial calcification.

Plasma C1q/TNF-Related Protein-9 Levels Are Associated with Atherosclerosis in Patients with Type 2 Diabetes without Renal Dysfunction.

Aim. C1q/tumor necrosis factor-related protein-9 (CTRP9), a paralog of adiponectin, is expressed in adipose tissue. CTRP9 exerts protective effects against obesity and atherosclerosis in rodents. We investigated the association between plasma CTRP9 levels and atherosclerosis in patients with type 2 diabetes. Methods. We included 419 patients with type 2 diabetes, 161 of whom had chronic kidney disease (CKD). Fasting plasma CTRP9 and total adiponectin levels were measured with enzyme-linked immunosorbent assay. The intima-media thickness (IMT) of the common carotid artery was measured with ultrasonography. Results. Plasma CTRP9 levels were higher in the CKD group than in the non-CKD group. Plasma CTRP9 levels were positively correlated with carotid IMT in the non-CKD group. Multivariate analyses revealed that plasma CTRP9 levels were positively associated with carotid IMT in the non-CKD group, independent of age, sex, body mass index, adiponectin, and other cardiovascular risk factors. However, plasma CTRP9 levels were not associated with carotid IMT in the CKD group. Conclusion. Plasma CTRP9 levels are associated with atherosclerosis in diabetic patients without CKD, independently of obesity, adiponectin, and traditional cardiovascular risk factors. This study indicates a potential role of CTRP9 in atherosclerosis progression in human type 2 diabetes.