A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

Left Ventricular Systolic Function in Patients with Systemic Lupus Erythematosus and Its Association with Cardiovascular Events

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder with potential cardiovascular involvement. The aim of this study was to assess left ventricular (LV) systolic function in a large cohort of patients with SLE using standard echocardiographic measurements and global longitudinal strain (GLS) by two-dimensional speckle-tracking analysis. Furthermore, the association between echocardiographic parameters and the occurrence of cardiovascular events was assessed.Methods: A total of 102 patients with SLE (88% women; mean age, 43 +/- 14 years) undergoing a dedicated multidisciplinary assessment were analyzed, including echocardiography, at the time of their first visit. A control group consisted of 50 age- and sex-matched healthy subjects.Results: Compared with control subjects, patients with SLE showed impaired LV systolic function on the basis of LV ejection fraction (51 +/- 6% vs 62 +/- 6%, P < .001) and by LV GLS (-15 +/- 3% vs -19 +/- 2%, P < .001). During a median follow-up period of 2 years (interquartile range, 1-6 years), 38 patients (37%) developed cardiovascular events. Kaplan-Meier survival curves showed that patients with SLE with more impaired LV GLS (on the basis of the median value of -15%) experienced higher cumulative rates of cardiovascular events compared with those with less impaired LV GLS (chi(2) = 8.292, log-rank P = .004). On multivariate Cox regression analysis, LV GLS demonstrated an independent association with cardiovascular events (hazard ratio, 2.171; 95% CI, 1.015-4.642; P = .046), whereas LV ejection fraction was not significantly associated with the outcome.Conclusions: In patients with SLE, LV systolic function as measured by LV GLS is significantly impaired and associated with cardiovascular events, potentially representing a new tool to improve risk stratification in these patients.Cardiolog

N-TERMINAL PROPEPTIDE OF COLLAGEN TYPE III AS A PROPOSED MARKER OF MYOCARDIAL FIBROSIS IN TYPE 2 DIABETES

Aim. To evaluate the role of N-terminal procollagen type III propeptide (P3NP) as a proposed marker of myocardial fibrosis in type 2 diabetes (DM2) patients.Material and methods. In the study, 2 groups of patients participated: with DM2 and non-DM2 (both n=32). All patients underwent clinical and laboratory assessment, including P3NP, electrocardiography, echocardiography. Statistics was done with Mann-Whitney criteria and Spearman correlation.Results. The level P3NP is significantly higher in DM2 patients (р&lt;0,00001). In DM2 patients, the level of P3NP significantly correlates with increased myocardial mass of the left ventricle (р=0,00026) and myocardial mass index of the left ventricle (р=0,03685).Conclusion. Echo- and electrocardiographic signs characteristic for myocardial fibrosis (mass increase, voltage decline) in DM2 patients are concomitant with the increase of P3NP. Significant correlation of P3NP and the size of myocardium makes it to propose P3NP as one of possible markers of myocardial fibrosis in DM2 persons

A SELECTIVE ANTAGONIST OF MINERALOCORTICOID RECEPTOR EPLERENONE IN CARDIOLOGY PRACTICE

The role of aldosterone in pathophysiological processes is considered. The effects of the selective antagonist of mineralocorticoid receptor eplerenone are analyzed. The advantages of eplerenone compared with spironolactone are discussed.</p

MODIFIED LOW-DENSITY LIPOPROT EINS IN DI ABETES MELLITUS TYPE 2

Objective: to compare the level of modified low-density lipoproteins (mLDL) in patients with diabetes mellitus type 2 (DM2) and without DM2; to identify the factors affecting mLDL сontent.Materials and methods. The study involved 64 patients; they were divided into 2 groups. The main group included 32 patients with DM2 (15 men and 17 women, median age – 65 years), the control group 2 included 32 patients without DM2 (15 men and 17 women, median age – 60.5 years). All patients (100 %) had arterial hypertension. Both groups were generally comparable in the main clinical and laboratory characteristics. Mann–Whitney test, Spearman correlation coefficient were used for statistical data processing.Results. In patients with DM2 mLDL level was significantly higher (р &lt;0.001) and correlated with blood glucose concentration (p = 0.021), glycated hemoglobin values (p &lt;0.001) and body-weight index (p = 0.007). In patients without DM2 mLDL level correlated with bodyweight index (p &lt;0.001). No correlation between mLDL level and standard LDL content was found in patients with DM2 and in patients without DM2 (p = 0.714 and p = 0.758 respectively).Conclusion. DM2 is significantly associated with an increased mLDL level that is affected by parameters of carbohydrate metabolism and body-weight index. In persons without hyperlipidemia mLDL level increases in case of hyperglycemia

Shrinking Lung Syndrome Diagnostic and Therapeutic Challenges in 3 Patients With Systemic Lupus Erythematosus

Pathophysiology and treatment of rheumatic disease

MYOCARDIAL FIBROSIS IN PATIENTS WITH DIABETES MELLITUS

The mechanism of myocardial damage in diabetes mellitus is considered. The pathogenesis of myocardial fibrosis, leading to diabetic cardiomyopathy, is described in details. Management tactics aimed at the prevention of heart failure in patients with diabetes is proposed.</p

MYOCARDIAL FIBROSIS IN PATIENTS WITH DIABETES MELLITUS

The mechanism of myocardial damage in diabetes mellitus is considered. The pathogenesis of myocardial fibrosis, leading to diabetic cardiomyopathy, is described in details. Management tactics aimed at the prevention of heart failure in patients with diabetes is proposed

ENDOVASCULAR TREATMENT FOR DISORDERS OF THE VENOUS SYSTEM

The annual rate of deep vein thrombosis in general population is from 5 to 9 cases per 10 000, whereas for venous thromboembolism (deep vein thrombosis and pulmonary embolism taken together) amounts to 14 cases per 10 000. To improve longterm results of therapy for thrombosis of deep veins of the lower extremities, it is important to restore venous function and outflow. Anticoagulant therapy with low weight or non-fractionated heparin preparations remains the most widely used method of management. However, total or partial thrombosis resolution under anticoagulant treatment is achieved only in 4 and 14% of cases, respectively. Thrombolysis allows for early resorption of the thrombus by means of a minimally invasive procedure with lower risk of complication. After the venous flow is restored, the aim of treatment is to prevent damage to the venous valves, venous hypertension and repeated thrombosis with development of the post-thrombotic syndrome. Compared to anticoagulation, systemic thrombolysis has the benefit of more rapid clot resorption and less damage to the venous valve. One of its serious limitations is a high bleeding risk related to higher doses of the drug administered through a peripheral vein catheter. Therefore, selective intra-clot administration of thombolytics (direct catheter thrombolysis) has been suggested as an alternative. For more effective therapy with the use of lower doses of thrombolytics, the so called pharmaco-mechanical thrombectomy has been developed. Venous stenosis hindering the venous outflow is frequently seen after direct catheter or pharmaco-mechanical thrombolysis. Angioplasty with stent placement is recommended in the cases with residual venous abnormality after successful thrombolysis and thrombectomy