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1.  Microvascular dysfunction in the course of metabolic syndrome induced by high-fat diet 
Background
Metabolic syndrome (MetS) is associated with increased risk of cardiovascular disease (CVD). One important feature underlying the pathophysiology of many types of CVD is microvascular dysfunction. Although components of MetS are themselves CVD risk factors, the risk is increased when the syndrome is considered as one entity. We aimed to characterize microvascular function and some of its influencing factors in the course of MetS development.
Methods
Development of MetS in C57BL/6 mice on a high-fat diet (HFD, 51% of energy from fat) was studied. The initial phase of MetS (I-MetS) was defined as the first 2 weeks of HFD feeding, with the fully developed phase occurring after 8 weeks of HFD. We characterized these phases by assessing changes in adiposity, blood pressure, and microvascular function. All data are presented as mean ± standard error (SEM). Differences between cumulative dose–response curves of myograph experiments were calculated using non-linear regression analysis. In other experiments, comparisons between two groups were made with Student’s t-test. Comparisons between more than two groups were made using one-way ANOVA with Tukey post-hoc test. A probability value <0.05 was considered statistically significant.
Results
I-MetS mice presented with weight gain, blood pressure elevation, and microvascular dysfunction characterized by augmented vasoconstriction. This finding, contrary to those in mice with fully developed MetS, was not associated with endothelial dysfunction, insulin resistance, or systemic inflammation. In the initial phase, perivascular adipose tissue showed no sign of inflammation and had no influence on the pattern of vasoconstriction. These findings suggest that the onset of hypertension in MetS is strongly influenced by vascular smooth muscle cell dysfunction and independent of important factors known to influence microvascular function and consequently blood pressure levels.
Conclusion
We identified in I-MetS the occurrence of isolated augmented vasoconstriction along with blood pressure elevation, but not the presence of classical MetS components known to influence microvascular function. These findings increase our understanding of the pathophysiology of CVD risk associated with MetS.
doi:10.1186/1475-2840-13-31
PMCID: PMC3916304  PMID: 24490784
High-fat diet; Metabolic syndrome; Hypertension; Microvascular dysfunction; Vasoconstriction
2.  Associations of Fetuin-A levels with vascular disease in type 2 diabetes patients with early diabetic nephropathy 
Background
Ambigous results exist on fetuin-A as marker for vascular disease in type 2 diabetes. This study aims to define the role of fetuin-A as marker for micro- and macrovascular disease in a high risk population of patients with type 2 diabetes mellitus and early diabetic nephropathy.
Methods
Fetuin-A serum levels were assessed by ELISA in a cross-sectional setting in 153 patients with type 2 diabetes. Associations of fetuin-A with metabolic, inflammatory and vascular markers were studied. Atherosclerotic burden was assessed by ankle-brachial-index (ABI) as well as detection of common carotid artery intima-media thickness (IMT).
Results
Levels of fetuin-A were lower in male than in female patients (0.49 ± 0.15 vs. 0.56 ± 0.20 g/L, p = 0.02). In addition, there was an inverse correlation with age (r = -0.20, P = 0.01). Bivariate correlations adjusted for age and gender revealed no significant correlations with metabolic parameters, except for a weak inverse correlation with serum adiponectin (r = -0.19, p = 0.02). Regarding parameters of micro- and macrovascular disease, fetuin-A was significantly associated with ABI (r = 0.18, p = 0.04), while there was no association with IMT (r = -0.07, p = n.s). Patients with an ABI < 0.9 had lower fetuin A levels than patients with an ABI 0.9-1.3 or > 1.3 (0.43 ± 0.10 vs. 0.52 ± 0.17 vs. 0.54 ± 0.18 g/L p = 0.05). Neither GFR nor albuminuria were associated with fetuin-A serum levels. Patients with prevalent neuropathy did not have altered fetuin-A levels compared to diabetic controls. In step-wise logistic regression analysis including age, gender, HbA1c, total cholesterol, glomerular filtration rate and fetuin-A, only total cholesterol (β = 0.01, p = 0.02) and fetuin-A (β = -5.99, p = 0.03) proved to be independent predictors of an ABI < 0.9.
Conclusions
The results of this cross-sectional study suggest that lower fetuin-A levels are associated with macrovascular late complications in high-risk type 2 diabetes patients while there are no associations of fetuin-A with metabolic status or microvascular complications.
doi:10.1186/1475-2840-9-48
PMCID: PMC2949712  PMID: 20822519
3.  Association between carotid diameter and the advanced glycation endproduct Nε-Carboxymethyllysine (CML) 
Background
Nε-Carboxymethyllysine (CML) is the major non-cross linking advanced glycation end product (AGE). CML is elevated in diabetic patients and apparent in atherosclerotic lesions. AGEs are associated with hypertension and arterial stiffness potentially by qualitative changes of elastic fibers. We investigated whether CML affects carotid and aortic properties in normoglycemic subjects.
Methods
Hundred-two subjects (age 48.2 ± 11.3 years) of the FLEMENGHO study were stratified according to the median of the plasma CML level (200.8 ng/ml; 25th percentile: 181.6 ng/ml, 75th percentile: 226.1 ng/ml) into "high CML" versus "low CML" as determined by ELISA. Local carotid artery properties, carotid intima media thickness (IMT), aortic pulse wave velocity (PWV), blood pressure and fetuin-A were analyzed. In 26 patients after carotidectomy, CML was visualized using immunohistochemistry.
Results
According to the CML median, groups were similar for anthropometric and biochemical data. Carotid diameter was enlarged in the "high" CML group (485.7 ± 122.2 versus 421.2 ± 133.2 μm; P < 0.05), in particular in participants with elevated blood pressure and with "high" CML ("low" CML: 377.9 ± 122.2 μm and "high" CML: 514.5 ± 151.6 μm; P < 0.001). CML was associated fetuin-A as marker of vascular inflammation in the whole cohort (r = 0.28; P < 0.01) and with carotid diameter in hypertensive subjects (r = 0.42; P < 0.01). CML level had no effect on aortic stiffness. CML was detected in the subendothelial space of human carotid arteries.
Conclusion
In normoglycemic subjects CML was associated with carotid diameter without adaptive changes of elastic properties and with fetuin-A as vascular inflammation marker, in particular in subjects with elevated blood pressure. This may suggest qualitative changes of elastic fibers resulting in a defective mechanotransduction, in particular as CML is present in human carotid arteries.
doi:10.1186/1475-2840-8-45
PMCID: PMC2733133  PMID: 19660101
4.  Myeloid-related protein 8/14 complex describes microcirculatory alterations in patients with type 2 diabetes and nephropathy 
Background
Inflammation contributes to cardiovascular complications in type 2 diabetes, which are often characterized by microvascular alterations. We investigated whether myeloid-related protein 8/14 complex (MRP8/14) secreted by transmigrating monocytes and granulocytes may represent a biomarker for microvascular alterations in patients with type 2 diabetes and nephropathy.
Methods
MRP8/14 was measured in 43 patients with type 2 diabetes and nephropathy. Additionally, the inflammatory markers Interleukin-6 (IL-6), Tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) were quantified. To detect microvascular alterations proteinuria and retinal vessel caliber were used as classical and novel marker, respectively. Proteinuria was quantified by protein-creatinine ratio (PCR); retinal vessel caliber was quantified after retina photography on digitalized retina pictures.
Results
MRP8/14 was positively associated with inflammation (r = 0.57), proteinuria (r = 0.40) and retinal arterial caliber (r = 0.48). Type 2 diabetic patients with MRP8/14 values above the median of 5.8 μg/ml demonstrated higher proteinuria and larger retinal artery caliber than patients with MRP8/14 values below the median (logPCR: -0.51 ± 0.52 versus -0.96 ± 0.46, P < 0.01; retinal artery lumen (μm): 178.3 ± 14.1 versus 162.7 ± 14.9 P < 0.01). Both groups did not differ with regard to metabolic factors and blood pressure. MRP8/14 was an independent predictor of retinal artery caliber in multivariate stepwise regression analysis (β = 0.607) and was positively associated with IL-6 (r = 0.57, P < 0.001) and TNF-α (r = 0.36, P < 0.05).
Conclusion
MRP8/14 – a marker for transendothelial migration – describes not only the state of inflammation in diabetic nephropathy, but additionally the degree of microvascular alterations in the glomerular and retinal bed. Therefore, MRP8/14 may be a potentially selective novel biomarker for microcirculatory defects in diabetic nephropathy.
doi:10.1186/1475-2840-8-10
PMCID: PMC2654885  PMID: 19232095

Results 1-4 (4)