Endothelial dysfunction and inflammation predict development of diabetic nephropathy in the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA 2) study

Objective. To evaluate risk factors for progression from persistent microalbuminuria to diabetic nephropathy in the Irbesartan in Patients with Type 2 diabetes and Microalbuminuria (IRMA 2) study, including biomarkers of endothelial dysfunction, chronic low‐grade inflammation, growth factors and advanced glycation end products (AGE peptides). Methods. IRMA 2 was a 2‐year multicentre, randomized, double‐blind trial comparing irbesartan (150 and 300?mg once daily) versus placebo. The primary end‐point was time to onset of diabetic nephropathy. Samples from a subgroup from the placebo and the 300?mg irbesartan treatment group were used in this post‐hoc analysis (n = 269, 68?%). Nine biomarkers were analysed: high sensitivity C‐reactive protein (hs‐CRP), interleukin 6 (IL‐6), fibrinogen, von Willebrand Factor (vWf), soluble vascular cell adhesion molecule‐1 (sVCAM‐1), soluble intercellular cell adhesion molecule‐1 (sICAM‐1), sE‐selectin, transforming growth factor‐beta (TGF‐β) and AGE peptides. Mean standard deviation scores (Z‐scores) were used to combine biomarker information. Results. In a Cox enter model with combined Z‐scores for biomarkers of endothelial dysfunction (vWf, sVCAM‐1, sICAM‐1, sE‐selectin) and for biomarkers of inflammation (hs‐CRP, IL‐6, fibrinogen), endothelial dysfunction (hazard ratio for a 28?% increase ( = 1 SD) in Z‐score) 3.20 (1.56 to 6.56), p = 0.001) and UAER (HR for a 75?% increase ( = 1 SD) in UAER) 2.61 (1.30 to 5.23), p = 0.007) were found as independent predictors. Independently, IL‐6 and vWf predicted the end‐point. In addition, endothelial Z‐score was associated with progression of albuminuria (p = 0.038). Conclusion. Endothelial dysfunction and possibly inflammation are novel predictors of progression to diabetic nephropathy in patients with type 2 diabetes and microalbuminuria independently of traditional risk factors.

Trial registration: ClinicalTrials.gov identifier: NCT00317915.     

Fecal levels of leukocyte markers reflect disease activity in patients with ulcerative colitis

Objective. A prominent feature of inflammatory bowel disease (IBD) is the presence of inflammatory cells in the gut mucosa, and which contribute to the ongoing inflammatory process. The aim of the study was to evaluate fecal neutrophil, eosinophil, mast cell and macrophage markers in the assessment of disease activity in patients with ulcerative colitis (UC). Methods. Twenty‐eight patients with active UC; 4 with proctitis, 16 with left‐side colitis and 8 with total colitis, were included in the study. Patient history, endoscopy and histopathology were examined and fecal and serum samples were evaluated at inclusion and after 4 and 8 weeks of treatment. Fecal samples were analysed for myeloperoxidase (MPO), eosinophil protein X (EPX), mast cell tryptase, IL‐1β and TNF‐α using immunoassays. Blood samples were analysed for MPO, EPX, C‐reactive protein, orosomucoid and leucocyte counts. Results. Fecal MPO and IL‐1β levels were elevated in all patients at inclusion despite different disease extensions. Striking reductions in fecal levels of MPO, EPX, tryptase and IL‐1β were observed after 4 weeks of treatment in 20/28 patients with complete remission after 8 weeks. No further reductions were seen in 20/27 patients at 8 weeks. Endoscopic score correlated to IL‐1β at all visits (p<0.01), to MPO at visits 2 and 3 (p<0.05, p<0.001), EPX at visit 2 (p<0.05) and tryptase at visit 3 (p<0.01). Levels of fecal markers also related to histological indices of the disease. Conclusions. Measurements of fecal MPO, EPX and IL‐1β could be objective complements to endoscopical and histopathological evaluations in the daily care of patients with UC.     

A combined abnormality in heart rate variation and QT corrected interval is a strong predictor of cardiovascular death in type 1 diabetes

Objective. Long‐term diabetes is associated with excess morbidity and mortality, and cardiovascular autonomic neuropathy and QTc interval abnormalities are both predictive of early cardiovascular death in diabetes. We aimed to investigate the effect of these risk factors in a large cohort of type 1 diabetic patients followed prospectively for 10 years. Material and methods. Three‐hundred‐and‐ninety‐one type 1 diabetic mellitus patients (240?M and 151?F, age 41.8 years±9.9 (mean±SD), duration of DM 27.3 years±8.2) were followed in an outpatient setting. Results. Patients with decreased heart rate variability had an excess overall mortality that diminished after adjusting for conventional cardiovascular risk factors; hazard ratio 2.5 (0.9–6.8; p = 0.071) compared to patients with normal heart rate variability. Likewise, prolonged QTc interval was associated with premature death with an adjusted hazard ratio of 2.3 (1.3–4.0; p = 0.005). In a combined analysis, patients with abnormal values for heart rate variability and QTc had a poorer prognosis compared to patients with normal test values for both parameters (adjusted hazard ratio 6.7 (1.8–25; p = 0.005)). Of the 34 patients with both test values abnormal, 15 died and 14 of these from cardiovascular causes. Conclusions. We conclude that combined abnormality in heart rate variability and QTc is a strong predictor of mortality in type 1 diabetes independently of conventional risk factors. These results have implications for future screening and treatment programmes for cardiovascular disease in type 1 diabetes.     

Hyperproinsulinemia segregates young adult patients with newly diagnosed autoimmune (type 1) and non‐autoimmune (type 2) diabetes

ObjectiveTo investigate whether measurements of proinsulin and/or intermediate proinsulin degradation products could be used to differentiate between autoimmune (type 1) and non‐autoimmune (type 2) diabetes in young adults. Material and methods Total proinsulin, intact proinsulin and 32,33 split proinsulin concentrations were measured in 25 patients aged 15–34 years with type 1 diabetes, as defined by the presence of at least two positive islet autoantibodies, and in 23 antibody‐negative patients of similar age with type 2 diabetes, at the time of clinical onset of diabetes and at 3–4 months thereafter. Comparisons were made with data from 25 healthy subjects matched for gender and age. Results Plasma levels of total proinsulin, intact proinsulin and 32,33 split proinsulin were significantly increased 2–3‐fold in the patients with newly diagnosed type 2 diabetes as compared with the controls, both in absolute terms (p<0.0001) and when related to circulating insulin (p<0.01–0.0002). In contrast, absolute proinsulin and 32,33 split proinsulin concentrations were significantly lower in patients with onset of type 1 diabetes than in controls. When proinsulin and split proinsulin release were related to plasma insulin, however, similar ratios were found in the type 1 diabetes patients and in controls. Using the 90th percentile for total proinsulin in the control group as the cut‐off, the sensitivity and specificity for differentiation between autoimmune and non‐autoimmune diabetes were 87% and 92%, respectively. At 3–4 months after clinical onset of diabetes, proinsulin secretion was still 2–3 times higher in type 2 than in type 1 diabetes patients (p<0.001). Conclusions. Young adult patients with newly diagnosed type 2 diabetes display disproportionate hyperproinsulinemia, whereas proinsulin secretion appears to be normal in patients with clinical onset of type 1 diabetes. Evaluation of proinsulin and 32,33 split proinsulin concentrations may be useful as a diagnostic tool in differentiating between autoimmune and non‐autoimmune diabetes in young adults, particularly in those lacking islet autoantibodies at diagnosis.     

The relationship between inflammation,endothelial dysfunction and proteinuria in patients with diabetic nephropathy

Abstract

Objectives. Diabetic nephropathy (DN) is a major manifestation of microangiopathy in patients with Diabetes Mellitus (DM). Inflammation is one of the major factors in the formation of endothelial dysfunction. Endothelial dysfunction is a major contributor to the complications of DM. The aim of the present study was to investigate the possible relationship between inflammation, endothelial dysfunction and proteinuria in patients with diabetic nephropathy. Materials and methods. Plasma TNF-α and IL-6, pro-inflammatory cytokines, concentrations were measured in 25 patients with DN and in 30 diabetic control subjects. Also, we evaluated the markers of endothelial dysfunction such as flow mediated dilatation (FMD), nitrate-mediated dilatation (NMD) and carotid intima-media thickness (CIMT). Results. TNF-α, IL-6 and high-sensitivity C-reactive protein concentrations were significantly higher (p = 0.012, p = 0.006 and p < 0.001, respectively) in the patients with DN than the controls. And, urinary protein concentrations were significantly higher (p < 0.001) but eGFR levels were significantly lower (p < 0.001) in the patients with DN. FMD was significantly lower in DN patients (p < 0.001). We have observed that FMD correlated negatively with body mass index (r = ?0.424, p < 0.05). And there was also a positive correlation between TNF-α and urinary protein concentrations in the patients with DN (p < 0.05). Conclusion. TNF-α, IL-6, hsCRP and urinary protein concentrations are higher in the DN patients. There were no correlations among pro-inflammatory cytokines concentrations and markers of vascular endotelial disfunction. These findings did not show vascular endothelial dysfunction, but may indicate glomerular endothelial dysfunction.     

Peptide hormones and risk for future cardiovascular events among prediabetics: a 20-year follow-up in the OPERA study

Abstract

Background: Prediabetes has proven to have many unfavourable impacts on the cardiovascular system.

Methods: The OPERA (Oulu Project Elucidating Risk of Atherosclerosis) study included 1045 middle-aged subjects followed from the years 1990–1993 to 2014. The focus was on peptide hormones.

Results: Plasma resistin levels were higher among prediabetics (p?=?.001), particularly impaired glucose tolerance (IGT) (p?<?.001), but not impaired fasting glucose (IFG) patients than among normal glucose tolerance (NGT) or diabetes groups. Diabetics showed lower resistin levels than IGT subjects (p?<?.001). IGT or diabetes groups showed lower adiponectin and higher leptin levels compared to the NGT group (p?<?.001). The IFG group had the highest blood pressure and left ventricular mass index, even higher than the diabetic group. Diabetics had the highest, prediabetics (IFG?+?IGT) intermediate and NGT the lowest risk for CVD events during follow-up (p?<?.001). Among prediabetics, high plasma ghrelin was an independent predictor of CVD events (p?<?.05) in the Cox regression analysis although it did not significantly improve either classification or discrimination of the patients.

Conclusions: Among glucose tolerance groups, patients with IGT had the highest resistin, but equally high leptin and low adiponectin levels as diabetics. Among prediabetics, ghrelin seems to predict independently cardiovascular events in the long term.

• KEY MESSAGE

• Among glucose tolerance groups, patients with IGT had the highest resistin, but equally high leptin and low adiponectin levels as diabetics.

• Among prediabetics, ghrelin seems to predict independently cardiovascular events in the long term.

     

Effect of smoking cessation on markers of inflammation and endothelial cell activation among individuals with high risk for cardiovascular disease

Objective. To prospectively determine the effect of smoking cessation on markers of inflammation and endothelial cell activation. Material and methods: Thirty male and 22 female smokers of >7 cigarettes daily, aged 32–64 years with cardiovascular disease (CVD) or additional risk factors to smoking, participated in a program of smoking cessation with a follow‐up period of 1 year. Cessation was validated by carbon monoxide measurement in expired breath, and 41 of the patients completed the study (17 quitters and 24 non‐quitters). Plasma samples were drawn at baseline and after 1 year, and inflammatory markers were analyzed by enzyme immunoassays. Peripheral blood mononuclear cells (PBMCs) were isolated at baseline and 1 year in 6 quitters and 6 smokers and mRNA levels of interleukin‐8 (IL‐8), tumor necrosis factor α (TNFα) and intercellular adhesion molecule 1 (ICAM‐1) were analyzed by real‐time quantitative RT‐PCR. Results. Our main findings were: (i) While the concentration of soluble (s) ICAM‐1 decreased in quitters, it increased in smokers, with a significant difference in changes between the groups (p = 0.04). (ii) While there was only minor change in mRNA levels of IL‐8 in smokers, those who stopped smoking showed a decrease in the gene expression of IL‐8 (p<0.09; comparing difference in changes). (iii) Concentrations of the other measured parameters (E‐selectin, IL‐6, sCD40 ligand, TNFα, von Willebrand factor, and C‐reactive protein) were unchanged during follow‐up in both groups. Conclusion. Smoking cessation induced a reduction in ICAM‐1, suggesting a novel mechanism for the rapid reduction in the risk of CVD following smoking cessation.     

Increased levels of C‐reactive protein and interleukin‐6 in hyperhomocysteinemic subjects

Objective. Elevated plasma homocysteine concentration is considered to be an independent risk factor for cardiovascular disease. However, the mechanisms by which hyperhomocysteinemia are related to vascular disease are unclear. High‐sensitivity C‐reactive protein (CRP), a marker of inflammation, has been reported to be an independent predictor of future myocardial infarction among clinically healthy individuals. Interleukin (IL)‐6 is a regulator of CRP and has a key role in initiation of inflammation. The aim of this study was to investigate whether individuals with increased plasma homocysteine concentrations have altered levels of serum CRP and IL‐6. Material and methods. Serum concentrations of CRP and IL‐6 were measured in 39 individuals with hyperhomocysteinemia and in 39 control subjects matched for gender, age and body mass index (BMI). In addition, the inflammatory effect of IL‐6 on peripheral blood mononuclear cells was measured. Results. Compared to controls, hyperhomocysteinemic subjects have elevated serum levels of CRP and IL‐6 (p?0.001 and p<0.005, respectively). Importantly, this raised level of IL‐6 was also seen in hyperhomocysteinemic individuals without accompanying hypercholesterolemia or cardiovascular disease. IL‐6 increased the release of monocyte chemoattractant protein‐1 from peripheral blood mononuclear cells, with particularly enhancing effects in cells from patients with hyperhomocysteinemia. Conclusions. These data suggest that enhanced inflammation may be associated with homocysteine‐related cardiovascular disease, possibly involving IL‐6‐related mechanisms.     

Renal tubulointerstitial expansion is associated with endothelial dysfunction and inflammation in type 1 diabetes

Objective. Diabetic nephropathy has been considered to be primarily of glomerular origin, but there is now compelling evidence that disruption of the tubulointerstitial architecture determines the outcome of diabetic nephropathy in interplay with the glomerular damage. We investigated whether reactive oxidative species, pro‐inflammatory cytokines and endothelial dysfunction were implicated in the progression of tubulointerstitial damage in young subjects with type 1 diabetes. Material and methods. In a prospective study, we investigated 18 young subjects (mean age 21 years) with type 1 diabetes and microalbuminuria. Quantitative morphometry concerning glomerular and tubulointerstitial changes was performed at baseline (i.e. mean duration of diabetes 10 years) and 2.5 and 8 years later. Markers of endothelial activation and inflammation, intercellular adhesion molecule‐1, vascular cell adhesion molecule‐1, tumour necrosis factor‐α, interleukin‐6, interleukin‐8 and highly sensitive C‐reactive protein were measured at baseline and after 8 years. Tissue plasminogen activator antigen and plasminogen activator inhibitor (PAI‐1 activity) and asymmetric dimethylargine (ADMA) were measured at baseline and after 2.5 years. Results. PAI‐1 activity at baseline was a significant independent variable of the 8‐year increment in interstitial volume fraction (Vv(Int/cortex)). ADMA/L‐arginine ratio at baseline was associated with the increment in Vv(Int/cortex) during 2.5 years (p<0.01), still significant after adjustment for covariates (p = 0.02). No associations between Vv(Int/cortex) and glomerular parameters, HaemoglobinA1c and urinary albumin excretion were observed. Conclusions. Biomarkers involved in interstitial volume expansion seem to be different from those of mesangial expansion in early diabetic nephropathy. PAI‐1 activity may have a predictive role in the development of the tubulointerstitial expansion.     

HPLC determination of plasma dimethylarginines: Method validation and preliminary clinical application

BackgroundAsymmetric dimethylarginine (ADMA) has been suggested as a possible marker of endothelial dysfunction, and interest in its use in clinical practice is increasing. However, the potential role of symmetric dimethylarginine (SDMA) as an endogenous marker of renal function, has been less widely investigated. The aims of the present study were therefore to determine reference values for dimethylarginines in plasma after method validation, and to ascertain ADMA plasma concentrations in patients with disorders characterized by endothelial dysfunction; a further end-point was to investigate the relationship between SDMA plasma concentrations and estimated GFR (eGFR) as well as plasmatic creatinine in patients with chronic kidney disease (CKD).Materials and methodsHPLC with fluorescence detection was used for the determination of plasma dimethylarginines. To verify the clinical usefulness of ADMA and SDMA, values from 4 groups of patients at a high risk of cardiovascular complications as well renal dysfunction (chronic heart failure n = 126; type II diabetes n = 43; pulmonary arterial hypertension n = 17; chronic kidney disease n = 42) were evaluated, and compared with the reference values, obtained from 225 blood donors.ResultsThe intra- and inter-assay CVs (< 5.2%), the absolute and relative recoveries (96–106%) were highly satisfactory. ADMA levels were significantly elevated in all groups of patients compared with controls (p < 0.001) with the exception of samples from patients with type II diabetes. SDMA levels were significantly elevated both in the patients with chronic kidney disease and in the patients with type II diabetes complicated by renal insufficiency, the values being closely correlated with both eGFR (R = 0.740) and plasmatic creatinine (R = 0.700).ConclusionsThe findings made in the present study shows that ADMA levels are significantly increased in patients with diseases associated with endothelial dysfunction This molecule might, therefore, be used as a biochemical marker for the evaluation of endothelial function. Furthermore, the preliminary results reported suggest that SDMA might be a reliable marker of renal function, especially in peadiatric populations, for which the use of eGFR is not recommended.     

Association of vascular indices with novel circulating biomarkers as prognostic factors for cardiovascular complications in patients with type 2 diabetes mellitus

BackgroundThe pathophysiology of atherosclerosis in type 2 diabetes mellitus (T2DM) is multifactorial. The association of vascular indices with circulating biomarkers of inflammation and insulin resistance and their role in the long-term cardiovascular prognosis in T2DM patients were currently investigated.Patients and methodsPatients with T2DM and poor glycemic control without known cardiovascular diseases (n = 119) at baseline were enrolled and followed for about 9 years. The end-point was the occurrence of any cardiovascular event (coronary heart disease, stroke, peripheral artery disease or cardiovascular death). Aortic pulse wave velocity (PWV), augmentation index (AIx), brachial flow-mediated dilation (FMD), hsCRP, Chitinase-3-like protein 1 (YKL-40), Neutrophil Gelatinase-Associated Lipocalin (NGAL), Fatty Acid Binding Protein (FABP-4) were assessed.ResultsHigher YKL-40 and NGAL were associated with higher PWV, while higher YKL-40 and FABP-4 were related to higher AIx (p < 0.05 for all). In univariate Cox regression analysis, PWV > 10 m/s, YKL-40 > 78 ng/ml and NGAL > 42 ng/ml were associated with cardiovascular events (p < 0.05 for all). In multivariate analysis, after adjusting for classical risk factors and glycemic control, increased NGAL, YKL-40 and PWV and decreased FMD (i.e. ≤ 2.2%) (p < 0.05 for all) were independently associated with cardiovascular events.ConclusionIn T2DM patients without established cardiovascular disease, novel indices of vascular inflammation (NGAL and YKL-40) were associated with subclinical atherosclerosis (arterial stiffness) but also with adverse clinical prognosis. Arterial stiffness and endothelial dysfunction were also independently related to adverse prognosis.     

Postload hyperglycemia is associated with increased subclinical inflammation in patients with prediabetes

Abstract

Background/aims. In this present study, we aimed: (i) To clarify if prediabetes is associated with subclinical inflammation independent of underlying obesity, and (ii) to evaluate the effect of postload glucose concentration on subclinical inflammation markers in a group of patients with elevated fasting glucose. Material and methods. In a cohort of 165 patients with newly detected fasting hyperglycemia, according to 75 g oral glucose tolerance test (OGTT), subjects were classified either as newly diagnosed type 2 diabetes (diabetes group, n = 40), impaired fasting glucose (IFG) plus impaired glucose tolerance (IGT) (IFG/IGT group, n = 42) or IFG only (IFG group, n = 83). A control group (n = 47) consisted of age- and body mass index (BMI)-matched healthy subjects with a normal OGTT. Circulating concentrations of lipids, insulin, interleukin-6 (IL-6), interleukin-8 (IL-8) and high sensitive C-reactive protein (hsCRP) were measured. HOMA index was calculated. Results. Subclinical inflammation markers were elevated in patients with diabetes and IFG/IGT compared to healthy controls and also IFG patients (diabetes vs. control: p < 0.05 for hsCRP, IL-8, and IL-6; IFG/IGT vs. control: p < 0.05 for hsCRP, and IL-6; diabetes vs. IFG: p < 0.05 for hsCRP, and IL-6; IFG/IGT vs. IFG: p < 0.05 for hsCRP, and IL-6). In multiple regression analysis, postload glucose concentration was independently associated with circulating hsCRP and IL-6 concentrations when the data was controlled for age, gender, BMI and lipid concentrations (p < 0.05 for hsCRP, and IL-6). Conclusion. Our results suggest that patients with prediabetes, independent of underlying obesity, have increased concentrations of subclinical inflammation which is mostly driven by postload glucose concentrations.     

High serum ACE activity predicts severe hypoglycaemia over time in patients with type 1 diabetes

Abstract

Aims/hypothesis. High serum angiotensin-converting enzyme (ACE) activity is associated with increased risk of severe hypoglycaemia (SH) within 1 year in type 1 diabetes. We wanted to find out whether ACE activity is stable over time and predicts SH beyond 1 year, and if gender differences exist in the association between ACE activity and risk of SH. Methods. A follow-up study of 128 adult patients with type 1 diabetes was conducted. At entry, ACE activity was measured. For 12 months, patients prospectively recorded events of severe hypoglycaemia (SH). At a median of 40 months, ACE activity was measured again and participants recalled the number of SH in the last year. Results. ACE activity is reproducible over 40 months (p < 0.00001). Patients with SH during the baseline study also had SH during follow-up (p < 0.00001). Serum ACE activity measured at baseline was positively associated with the rate of SH at follow-up (p = 0.0003) with a 3.2-fold increased rate of SH in subjects belonging to the upper ACE quartile compared to subjects in the three lowest quartiles (p < 0.00001). The association between high serum ACE activity and increased risk of SH did not differ significantly in women and men. Conclusion. In type 1 diabetes individual serum ACE activity is reproducible over time. High ACE activity predicts recurrent SH over at least 40 months with no differences between genders.     

Physical activity and sedentary behavior in adolescents with type 1 diabetes

The purpose of this study was to describe the associations between levels of physical activity measured by accelerometry and changes in fitness, body composition, lipids, and glucose control (i.e., glycosolated hemoglobin [A1C]) in a sample of 16 adolescents with type 1 diabetes participating in a personalized exercise program. More sedentary activity was associated with lower fitness and fat free mass and increased total cholesterol, low‐density lipoprotein (LDL‐c), and triglycerides (p < .05). Greater amounts of moderate to vigorous activity were associated with higher fitness and fat free mass, and decreased total cholesterol, LDL‐c, triglycerides, and A1C (p < .05). Findings support the beneficial effects of increased moderate activity and decreased sedentary behavior to reduce cardiovascular risks and improve glucose control in adolescents with type 1 diabetes. © 2010 Wiley Periodicals, Inc. Res Nurs Health 33:441–449, 2010     

Parameters of antioxidative defense in type 2 diabetic patients with cardiovascular complications

OBJECTIVE. Diabetes‐associated oxidative stress is a consequence of both increased production of free radicals and reduced capacity of antioxidative defense. Prolonged hyperglycemia is the major factor in the pathogenesis of atherosclerosis in diabetes which can lead to cardiovascular complications. The aim of this study was to test the parameters of antioxidative defense in type 2 diabetic patients.

METHODS. A total of 117 type 2 diabetics with and without cardiovascular complications were examined in order to find out the influence of hyperglycemia, type and duration of complications and duration of diabetes on the extent of disorder of antioxidative parameter values: superoxide dismutase (SOD), glutathione peroxidase (GSH‐Px), glutathione reductase (GR) and total antioxidant status (TAS).

RESULTS. Compared to healthy control subjects, type 2 diabetic patients with cardiovascular complications (CVC) had significantly lower SOD (P<0.0001), GSH‐Px (P<0.0001), GR ( P = 0.0002) and TAS values (P<0.0001). In type 2 diabetic subjects with CVC, males had significantly lower SOD (778.7±103.2?U/gHb, P<0.01) and GR activities (52.2±8.9?U/L, P<0.001) compared to females (839.3±94.9?U/gHb; 58.5±9.1?U/L). Significant and positive correlation was found between glucose levels and SOD (r = 0.375 for P<0.05) and GSH‐Px (r = 0.384, P<0.05 ) activity in the group of complications‐free diabetics, while significant negative correlation between glucose and GSH‐Px values (r = ?0.382, P<0.05) was found in the group of type 2 diabetics with coronary artery disease (CAD) and hypertension (HTA) and with CAD and acute myocardial infarction (AMI) (r = ?0.860 P<0.05), and highly negative correlation between glucose and SOD levels (r = ?0.590, P<0.05) in the group of diabetic subjects with CAD, AMI and HTA. Likewise, there was highly significant negative correlation of SOD (r = ?0.949, P<0.05) and TAS (r = ?0.393 for P = 0.038) with duration of diabetes in the group of diabetics with CAD and HTA.

CONCLUSION. Our results confirm the hypothesis that there is reduced antioxidative defense in type 2 diabetics with prominent cardiovascular complications, which negatively correlates with glucose concentrations and duration of diabetes and cardiovascular complications.     

Prognostic Value of Serum Von Willebrand Factor,but Not Soluble ICAM and VCAM,for Mortality and Cardiovascular Events is Independent of Residual Renal Function in Peritoneal Dialysis Patients

♦ Objective: We explored associations between markers of endothelial dysfunction and outcome events, and whether those associations were independent of residual renal function (RRF) in patients on peritoneal dialysis.♦ Methods: The study enrolled 261 incident patients and 68 healthy control subjects who were followed till death, censoring, or study end. Demographics, biochemistry, markers of inflammation (C-reactive protein) and endothelial dysfunction [soluble intercellular adhesion molecule 1 (sICAM), soluble vascular adhesion molecule 1 (sVCAM), and von Willebrand factor (vWf)] were examined at baseline. Outcome events included all-cause death and fatal and nonfatal cardiovascular (CV) events.♦ Results: Mean levels of vWf, sICAM, and sVCAM were significantly higher in patients than in healthy control subjects. Levels of sICAM and sVCAM, but not vWf, were significantly correlated with RRF. Levels of sICAM and vWf both predicted all-cause mortality and fatal and nonfatal CV events after adjustment for recognizable CV risk factors. The association between sICAM and outcome events disappeared after further adjustment for RRF. However, RRF did not change the predictive role of vWf for outcome events. Compared with the lowest vWf quartile (6.6% - 73.9%), the highest vWf quartile (240.9% - 1161%) predicted the highest risk for fatal and nonfatal CV events (adjusted hazard ratio: 2.05; 95% confidence interval: 1.15 to 3.64; p = 0.014). We observed no associations between sVCAM and RRF, or sVCAM and any outcome event.♦ Conclusions: The prognostic value of vWf, but not sICAM, is independent of RRF in predicting mortality and CV events.     

Metabolic syndrome aggravates the increased endothelial activation and low‐grade inflammation in subjects with familial low HDL

Background. Inhibition of cytokine‐induced expression of adhesion molecules is one of the atheroprotective mechanisms of high‐density lipoprotein (HDL).

Aim. We investigated whether increased endothelial activation and low‐grade inflammation are present in Finnish subjects with familial low HDL, and which factors contribute to the inflammatory parameters.

Method. High‐sensitivity C‐reactive protein (hsCRP), soluble intercellular adhesion molecule‐1 (sICAM‐1), vascular cell adhesion molecule‐1 (sVCAM‐1), and sE‐selectin were measured in 91 subjects with low HDL‐cholesterol from 41 low‐HDL families and in 112 normolipidemic controls with comparable age‐ and gender distribution. Presence of the features of the metabolic syndrome (MetS) was recorded.

Results. sVCAM‐1, sICAM‐1, sE‐selectin, and hsCRP were significantly higher in low‐HDL subjects than in the controls (sVCAM‐1: 560±147?ng/mL versus 496±95?ng/mL, P = 0.001; sICAM‐1: 247±60?ng/mL versus 215±47?ng/mL, P<0.001; sE‐selectin: 52±20?ng/mL versus 44±16?ng/mL, P = 0.022; and hsCRP: 1.73±2.05?mg/L versus 0.85±1.10?mg/L, P<0.001). Low‐HDL subjects had increased body mass index (BMI) and waist, and elevated insulin and triglyceride levels. Adhesion molecules and hsCRP increased according to the number of the features of the MetS.

Conclusions. The presence of the MetS in subjects with familial low HDL‐cholesterol aggravates the low‐grade inflammation and endothelial activation, and ultimately may add to the higher susceptibility for atherosclerotic disease in these individuals.     

Acute hyperglycaemia induces an inflammatory response in young patients with type 1 diabetes

Background. Patients with type 1 diabetes (T1D) are at a substantially increased risk of cardiovascular disease. Stress-induced hyperglycaemia in turn is shown to worsen the prognosis of patients suffering from an acute myocardial infarction. However, the mechanisms behind these findings are incompletely known.

Aim. To investigate whether markers of chronic inflammation, and oxidative stress respond to acute hyperglycaemia in patients with T1D.

Methods. The plasma glucose concentration was rapidly raised from 5 to 15 mmol/L in 35 males (22 men with T1D and 13 age-matched non-diabetic volunteers) and maintained for 2 h. All participants were young non-smokers without any signs of diabetic or other complications. Markers of chronic inflammation, and oxidative stress were analysed in serum/plasma samples drawn at base-line and after 120 min of hyperglycaemia.

Results. Compared to normoglycaemia, acute hyperglycaemia increased the interleukin (IL)-6 concentrations by 39% in patients with T1D (P<0.01) and 26% in healthy volunteers (P<0.05). During hyperglycaemia the superoxide dismutase concentration was increased by 17% in the healthy volunteers (P<0.01) and 5% in the patients with type 1 diabetes (P=NS). The increase in tumour necrosis factor (TNF)-α was larger in patients with type 1 diabetes than in non-diabetic volunteers (35% versus ?10%, P<0.05).

Conclusions. This study shows that acute hyperglycaemia induces an inflammatory response in patients with type 1 diabetes.     

Cardiovascular autonomic regulation in patients with 3243A>G mitochondrial DNA mutation

BACKGROUND. Patients with the 3243A>G mutation in mitochondrial DNA (mtDNA) have an increased risk for cardiovascular morbidity and mortality. The function of the autonomic nervous system has not been evaluated in these patients.

PATIENTS AND METHODS. Indices of 24‐hour heart rate variability (HRV) and baroreflex sensitivity (BRS) were measured in 28 patients with 3243A>G. The results were compared to controls matched with respect to age, sex, the presence of hypertension and diabetes mellitus and the use of cardiac medication. Conventional time and spectral domain indices and fractal correlation properties of HRV were analysed.

RESULTS. In spectral analysis of HRV, the ultra‐low and very‐low‐frequency spectral components were lower in the patients than the controls (P?<?0.05 for both). Furthermore, the short‐term fractal scaling exponent was lower in the patients with 3243A>G compared to the controls (1.16?±?0.18 versus 1.28?±?0.13, P?<?0.01). No significant associations were found between the HRV indices and the other characteristics of the patients with 3243A>G, such as the presence of diabetes or left ventricular hypertrophy, left ventricular systolic function, the severity of the disease or the degree of 3243A>G heteroplasmy.

CONCLUSIONS. Patients with the 3243A>G mutation in mtDNA have abnormalities in the spectral and fractal characteristics of HRV suggesting altered cardiac autonomic regulation. The abnormalities are not clearly associated with clinical manifestations related to 3243A>G suggesting that mitochondrial dysfunction may affect the autonomic regulatory systems more directly.     

Association of growth factors with arterial recanalization and clinical outcome in patients with ischemic stroke treated with tPA

Summary. Background: Growth factors (GF) such as vascular endothelial growth factor (VEGF), angiopoietin‐1 (Ang‐1) and granulocyte‐colony stimulating factor (G‐CSF) have been associated with greater efficacy of tissue plasminogen activator (tPA) in experimental studies. Objectives: To study the association of these GF with arterial recanalization and clinical outcome in patients with acute ischemic stroke treated with tPA. Methods: We prospectively studied 79 patients with ischemic stroke attributable to MCA occlusion treated with i.v. tPA within the first 3 h from onset of symptoms. Continuous transcranial color‐coded sonography (TCCS) was performed during the first 2 h after tPA bolus to assess early MCA recanalization. Hemorrhagic transformation (HT) was classified according to ECASS II definitions. Good functional outcome was defined as a Rankin scale score of 0–2 at 90 days. GF levels were determined by ELISA. Results: Mean serum levels of VEGF, G‐CSF and Ang‐1 at baseline were significantly higher in patients with early MCA recanalization (n = 30) (all P < 0.0001). In the multivariate analysis, serum levels of VEGF (OR, 1.03), G‐CSF (OR, 1.02) and Ang‐1 (OR, 1.07) were independently associated with early MCA recanalization (all P < 0.0001). On the other hand, patients with parenchymal hematoma (PH) (n = 20) showed higher levels of Ang‐1 (P < 0.0001). Ang‐1 (OR, 1.12; P < 0.0001) was independently associated with PH, whereas patients with good outcome (n = 38) had higher levels of G‐CSF (P < 0.0001). G‐CSF was independently associated with good outcome (OR, 1.12; P = 0.036). Conclusions: These findings suggest that GF may enhance arterial recanalization in patients with ischemic stroke treated with t‐PA, although they might increase the HT.