Krzysztof Góralczyk

Triglycerides as an early pathophysiological marker of endothelial dysfunction in nondiabetic women with a previous history of gestational diabetes.

Abstract  Objective. To investigate whether baseline triglyceride levels are associated with early glucose dysregulation and/or cardiovascular risk in women with a previous history of gestational diabetes. Design. Prospective postpregnancy cohort study. Setting. Polish university hospitals. Sample. Participants included 125 women with previous gestational diabetes and 40 women with normal glucose regulation during pregnancy. Methods. All women were studied 2–24months (mean 12±10months) after the index pregnancy. Women with previous gestational diabetes were divided into tertiles in accordance with baseline triglyceride levels. Main Outcome Measures. We assessed glucose regulation (oral glucose tolerance test), insulin resistance (homeostasis model assessment), markers of endothelial dysfunction (soluble: intercellular adhesion molecule‐1, vascular cell adhesion molecule‐1, E‐selectin, tissue plasminogen activator antigen, von Willebrand factor antigen), fibrinolysis (plasminogen activator inhibitor antigen), inflammation (high‐sensitivity C‐reactive protein) and lipid levels. Results. Women with previous gestational diabetes (78% normal glucose regulation, 22% impaired glucose tolerance) had a high cardiometabolic risk profile compared with control women (100% normal glucose regulation). Baseline triglycerides >0.83mmol/l were associated with a higher prevalence of impaired glucose tolerance, higher high‐sensitivity C‐reactive protein and triglyceride/high‐density lipoprotein‐cholesterol ratio. Triglycerides >1.22mmol/l were associated with higher body fat indexes, higher insulin resistance, higher levels of endothelial dysfunction biomarkers, higher plasminogen activator inhibitor antigen and dyslipidemia. Only E‐selectin was independently associated with triglyceride levels. Conclusions. Baseline triglyceride levels are a cardiovascular risk marker as well as a pathophysiological parameter independently associated with endothelial dysfunction in nondiabetic women with previous gestational diabetes at 2–24months after an index pregnancy. Normalization of triglycerides should be included in preventive therapy after a pregnancy complicated by gestational diabetes.

A preliminary evaluation of VEGF-A, VEGFR1 and VEGFR2 in patients with well-controlled type 2 diabetes mellitus

Objective: Decompensated chronic hyperglycemia often leads to late microvascular complications such as retinopathy, diabetic foot syndrome, and diabetic kidney disease. The aim of this study was to determine the concentration of vascular endothelial growth factor A (VEGF-A) and its receptors in patients with well-controlled diabetes. Methods: The study was conducted on 31 patients with well-controlled type 2 diabetes without micro-or macroangiopathy. Thirty healthy volunteers were enrolled in a control group. Serum concentrations of VEGF-A, VEGF receptors 1 and 2 (VEGFR1 and VEGFR2), fasting glucose, and lipid profiles were measured, and the plasma concentration of glycated hemoglobin (HbA1c) was determined. Results: No significant differences were observed between the concentration of VEGF-A, VEGFR1 or VEGFR2 in the subject group and that in the control group. Positive correlations were noted between the levels of VEGF-A, VEGFR2, and triglyceride, and there was a negative correlation between the levels of VEGFR2 and high-density lipoprotein (HDL)-cholesterol in the study group. Conclusions: The concentrations of VEGF-A and its receptors 1 and 2 in patients with well-controlled diabetes are comparable to those of healthy individuals, which may indicate that appropriate control of glucose levels delays the occurrence of vascular complications. A negative correlation between VEGFR2 and HDL-cholesterol levels, and positive correlations between VEGF-A, VEGFR2, and triglyceride levels, suggest that lipid abnormalities occurring in diabetes may be involved in the modulation of angiogenesis.

Elevation of sE-Selectin Levels 2–24 Months following Gestational Diabetes Is Associated with Early Cardiometabolic Risk in Nondiabetic Women

Objective. We hypothesised that the endothelial dysfunction is associated with early glucose dysregulation and/or atherosclerosis risk factors in nondiabetic women with a previous history of gestational diabetes (pGDM). Material/Methods. Anthropometric parameters, glucose regulation (OGTT), insulin resistance (HOMA), lipids, biomarkers of endothelial dysfunction, and inflammation were evaluated in 85 women with pGDM and in 40 controls 2–24 months postpartum. Results. The pGDM group consisted of 67% normoglycemic women (pGDM-N) and 33% with prediabetic state (pGDM-P). The BMI, waist circumference, fasting and 2 h glucose (OGTT), soluble adhesion molecules, tissue plasminogen activator antigen, high sensitivity C-reactive protein, total-, LDL-cholesterol, and triglycerides/HDL-cholesterol ratio were higher in the pGDM women compared with the controls. After adjustment for BMI and fasting glucose, only higher triglycerides, higher TG/HDL and lower HDL-cholesterol were associated with pGDM. The pGDM-P differed from pGDM-N for only higher triglycerides and TG/HDL. The plasma level of sE-selectin was not independently associated with glucose concentration in pGDM group. sE-selectin level correlated with triglycerides, TG/HDL, plasminogen activator inhibitor-1 antigen, and sICAM-1. Conclusions. sE-selectin level correlated with components of metabolic syndrome, but only the atherogenic lipid profile was independently associated with a previous history of GDM in nondiabetic women 2–24 months postpartum.

Effect of uncontrolled hyperglycemia on levels of adhesion molecules in patients with diabetes mellitus type 2.

ObjectiveUncontrolled diabetes has become a major cause of mortality and morbidity by reason of vascular angiopathy. The aim of this study was to evaluate the concentrations of soluble forms of vascular adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), E-selectin, and thrombomodulin in patients with well-controlled and uncontrolled diabetes type 2.MethodsThe study was conducted on 62 patients with diabetes. Group I consisted of 35 patients with well-controlled diabetes. The second group included 27 patients with uncontrolled diabetes with micro-albuminuria. A control group was made up of 25 healthy volunteers. The concentrations of sVCAM-1, sICAM-1, sE-selectin, and soluble thrombomodulin were assayed in plasma. Serum concentration of creatinine was measured and the plasma concentrations of fasting glucose and glycated hemoglobin (HbA1c) determined.ResultsLower concentrations of ICAM-1 were found in the group of uncontrolled diabetes patients compared with those with well-controlled disease. In patients with uncontrolled diabetes, VCAM-1 levels were significantly higher compared with the group with well-controlled diabetes. In patients with uncontrolled diabetes a positive correlation was obtained between glomerular filtration rate and sE-selectin and a negative correlation between the levels of creatinine and ICAM-1, although there was a positive correlation between (HbA1c) and ICAM-1.ConclusionThe study confirmed the participation of the inflammatory process associated with impaired vascular endothelial function in the pathogenesis of type 2 diabetes. The opposite effect of uncontrolled hyperglycemia on adhesion molecules suggests different functions of VCAM-1 and ICAM-1 in complications of diabetes.概要目的评估可溶性血管细胞间黏附分子 (sVCAM-1)、可溶性细胞间黏附分子 (sICAM-1)、可溶性选择素E 和可溶性血栓调节蛋白在血糖控制良好和不受控制的2 型糖尿病患者中的水平。创新点对2 型糖尿病患者的血管内皮炎症标记物进行评估。方法62 例糖尿病患者分成两组: 第一组包括35 个血糖控制良好的糖尿病患者, 第二组包括27 个未控制血糖并伴有微蛋白尿的糖尿病患者。对照组由25 名健康志愿者组成。测定血浆中sVCAM-1、sICAM-1、可溶性选择素E 和可溶性血栓调节蛋白的浓度, 同时测定血清肌酐及血浆中空腹血糖和糖化血红蛋白 (HbA1c) 的浓度。结论与血糖控制良好的糖尿病组相比, 未控制血糖组具有相对低的ICAM-1 水平和更高的VCAM-1 水平。未控制血糖组中患者的糖化血红蛋白和ICAM-1 之间呈正相关, 肾小球滤过率和可溶性选择素E 之间呈正相关, 而肌酐和ICAM-1 之间呈负相关。研究证实2 型糖尿病的发病机理中炎症过程的出现与血管内皮功能受损有关。未受控制的高血糖对粘附分子的反向作用表明, 在糖尿病的并发症中VCAM-1和ICAM-1具有不同功能。

Low-grade risk of hypercoagulable state in patients suffering from diabetes mellitus type 2 *

ObjectiveDiabetes, including type 1 and type 2, is associated with the hypercoagulable state. The aim of this study is to evaluate the concentration of selected hemostatic parameters and vascular endothelial growth factor-A (VEGF-A) in diabetic subjects.MethodsThe study was conducted in 62 patients with diabetes. Group I consisted of 27 patients having uncontrolled diabetes with microalbuminuria and Group II included 35 well-controlled diabetic patients. The control group was made up of 25 healthy volunteers. In the citrate plasma, the concentrations of tissue factor (TF), tissue factor pathway inhibitor (TFPI), thrombin-antithrombin (TAT) complexes, and D-dimer were assayed. Serum concentrations of VEGF-A, lipid profile, creatinine, and plasma fasting glucose were measured and in the versene plasma the concentration of HbA1c was determined.ResultsIn the patients with uncontrolled diabetes, higher concentrations of TF, TFPI, and VEGF-A were observed, as compared with the well-controlled diabetics group and the control group. A significantly lower activity of antiplasmin was reported in patients from Group I as compared with the control group. In Group I, using the multivariate regression analysis, the glomerular filtration rate was independently associated with VEGF-A and dependently associated with total cholesterol.ConclusionsThe study showed higher concentrations of TF and TFPI in the patients with uncontrolled diabetes with microalbuminuria, which is associated with rapid neutralization of the thrombin formation, since TFPI inhibits the complex of TF/VIIa/Ca2+. The manifestation of the above suggestions is the correct TAT complexes and D-dimer, which indicates a low grade of prothrombotic risk in this group of patients, but a higher risk of vascular complications.中文概要目的评估糖尿病病人的止血参数和血管内皮生长因子的浓度。方法62例糖尿病患者分成两组:第一组包括35个血糖控制良好的糖尿病患者,第二组包括27个未控制血糖并伴有微蛋白尿的糖尿病患者。对照组由25名健康志愿者组成。测定血浆中组织因子(TF)、组织因子途径抑制剂(TFPI)、凝血酶抗凝血酶复合物(TAT)和D-二聚体的浓度。同时测定血清中内皮生长因子A(VEGF-A)、血脂、肌酐和血浆空腹血糖及糖化血红蛋白(HbA1c)的浓度。结论研究表明,未控制血糖并伴有微蛋白尿的糖尿病患者具有更高的浓度的TF和TFPI,这与凝血酶形成的快速中和有关。TAT复合物和D-二聚体的正确形成,能保证患者具有一个相对较低级凝血风险,但同时会带来更高的血管并发症的风险。

Does mobilisation of CD34+ stem cells along with VEGF, angiogenin, IL-6, IL-8, and hsCRP levels allow predicting the direction of left ventricular ejection fraction and wall motion score index changes in patients with myocardial infarction?

BACKGROUND Left ventricular (LV) systolic function is a significant prognostic factor in patients after myocardial infarction (MI). Multiple angiogenic and inflammatory factors are involved in postinfarction LV remodelling process. In addition, CD34+progenitor cells mobilised from bone marrow and tissue niches participate in regeneration of the infarcted myocardium. AIM To examine relationships between LV ejection fraction (LVEF) and wall motion score index (WMSI) and the number of CD34+ cells and plasma levels of vascular endothelial growth factor (VEGF), angiogenin and such inflammatory factors as interleukin 6 (IL-6), interleukin 8 (IL-8), and high-sensitivity C-reactive protein (hsCRP) in patients with ST-elevation MI (STEMI). METHODS The study group included 61 patients with STEMI treated with primary percutaneous coronary intervention (PCI)involving bare metal stent implantation. Plasma levels of the evaluated angiogenic and inflammatory factors were measured by flow cytometry at 4 time points (just before PCI, 24 h later, at hospital discharge, and 30 days after STEMI). LVEF and WMSI were measured by echocardiography at hospital discharge, 1 month later, and 6 months later. We compared angiogenic and inflammatory factor levels in patients with no improvement of the LV systolic function during the follow-up (group 1, n = 22)vs. those with improved LV systolic function (group 2, n = 39). RESULTS No differences in the levels of VEGF, angiogenin, IL-6, IL-8, and hsCRP, and the number of CD34+ cells were observed between the two groups. Despite this, we found significant negative correlations between hsCRP level and LVEF,and positive correlations between hsCRP level and WMSI in both patient groups, but these correlations were much stronger in group 1. We also found a significant negative correlation between WMSI at 6 months and the number of CD34+ cells measured 24 h after PCI. CONCLUSIONS 1. Evaluation of plasma VEGF, angiogenin, IL-6, IL-8, and hsCRP levels and the number of CD34+ cells at different time points in patients with STEMI did not allow predicting the direction of changes in LVEF and WMSI. 2. Observed significant correlations between hsCRP level and LVEF and WMSI may suggest a harmful effect of inflammation on postinfarction myocardial remodelling. 3. A significant negative correlation between the number of CD34+ and WMSI suggests that increased mobilisation of these cells might have a beneficial effect on systolic function after MI.

Adiponectin and endothelial markers in postmenopausal women taking oral or transdermal hormone therapy

To assess the concentration of adiponectin, soluble E‐selectin, soluble thrombomodulin and tissue activator plasminogen antigen in postmenopausal women who received oral or transdermal hormone therapy.

Assessment of ghrelin and leptin receptor levels in postmenopausal women who received oral or transdermal menopausal hormonal therapy

ObjectiveIn postmenopausal women, an increased leptin concentration and reduced levels of ghrelin and adiponectin were observed. The aim of this study was to evaluate the concentrations of the active form of ghrelin, total ghrelin, leptin receptor, lipoprotein(a) (Lp(a)), and plasminogen activator inhibitor type 1 (PAI-1) in postmenopausal women who received oral or transdermal menopausal hormonal therapy (MHT).MethodsThe study involved 76 healthy women: 46 women aged from 44 to 58 years who received oral (26) or transdermal (20) MHT; the control group consisted of 30 women aged from 44 to 54 years who did not receive MHT. The plasma concentrations of total ghrelin, the active form of ghrelin, Lp(a), and PAI-1:Ag were measured by enzyme-linked immunosorbent assay (ELISA). The concentration of the leptin receptor was measured by enzyme immunometric assay (EIA).ResultsWe observed a significantly higher concentration of total ghrelin and the active form of ghrelin in women who received transdermal MHT in comparison with those who took oral MHT. We also found a significantly lower concentration of total ghrelin in women who received oral MHT compared with the control group. A higher concentration of PAI-1:Ag was found in the group of women who took transdermal MHT in comparison with those who took oral MHT and with the control group. The differences were statistically significant. Additionally, we found a significant negative correlation between the concentrations of total ghrelin and PAI-1:Ag and a positive correlation between the concentrations of total ghrelin and leptin receptor in women who received transdermal MHT.ConclusionsThe study showed that women who used transdermal MHT had higher levels of total ghrelin than women who took oral MHT. This indicates a beneficial effect of the transdermal route of MHT. However, transdermal therapy was associated with adverse effects with regard to the observed higher levels of PAI-1:Ag, which in turn, can lead to a reduction in fibrinolytic activity.

The influence of lovastatin on thrombomodulin gene expression in vascular endothelial cells--in vitro study.

OBJECTIVE Statins reduce lipids concentration in blood. The latest investigations show they also improved the function of vascular endothelial cells (ECs). Thrombomodulin (TM) is particularly important marker of ECs activity. We investigated the in vitro effect of lovastatin on the expression level of TM gene. METHODS AND RESULTS ECs were incubated for 24 h in culture medium including lovastatin in 3 concentrations: 0.1, 1.0, 10.0 mol/l. The mRNA level of TM increased in correlation with rising concentrations of lovastatin to 600 % vs. control group. CONCLUSIONS TM is essential antithrombotic factor in endothelial cells. Lovastatin significantly raises thrombomodulin gene expression. It is important characteristics of this medicine, which prevents cardiovascular events.

Cardiomyopathy in the mouse model of Duchenne muscular dystrophy caused by disordered secretion of vascular endothelial growth factor.

Summary Background Duchenne muscular dystrophy (DMD) is a genetic neuromuscular disorder that affects skeletal muscles and cardiac muscle tissue. In some cases, myocardial injury secondary to hypoxia can lead to dilative cardiomyopathy (DCM). A genetic defect in the dystrophin gene may increase the susceptibility of myocardium to hypoxia. Available data suggest that this may be caused by impaired secretion of NO, which is bound with secretion of VEGF-A. Material/Methods Male mice C57BI/10ScSn mdx (animal model of DMD) and healthy mice C57BI/10ScSn were exposed to hypobaric hypoxia in low-pressure chambers. Their hearts were harvested immediately after and 1, 3, 7, and 21 days after exposure to hypoxia. Normobaric mice were used as controls. The expression of VEGF-A in myocardium and cardiac vessel walls was evaluated using immunohistochemistry, Western blotting, and in situ hybridization. Results VEGF-A expression in myocardium and vessel walls of healthy mice peaked 24 hours after exposure to hypoxia. The expression of VEGF-A in vessel walls was similar in dystrophic and healthy mice; however, VEGF-A expression in the myocardium of dystrophic mice was impaired, peaking around day 7. In the heart, the total level of VEGF depends on VEGF expression in myocardium, not in vessel endothelium, and our research demonstrates that the expression of VEGF is dystrophin-dependent. Conclusions Disordered secretion of VEGF-A in hypoxic myocardium caused the total level of this factor to be impaired in the heart. This factor, which in normal situations protect against hypoxia, promotes the gradual progression of cardiomyopathy.