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Background As a low grade systemic inflammation plays an important role in the pathogenesis of atherosclerosis-associated diseases and diabetes mellitus (DM) there is an interest in the relevance of circulating markers of immune inflammation to clinical manifestation of cardiovascular disease (CVD), especially in the setting of DM. Purpose Purpose of our investigation was to assess the predictive value of numerous immune markers (pro-inflammatory cytokines, anti-connective tissue antibodies) in relation with circulating markers of endothelial dysfunction (ED) in persons with documented ischemic heart disease (IHD), DM, and asymptomatic atherosclerosis (AA). Methods 393 persons (147 pts with IHD, 126 pts with T2DM, 120 pts with AA) were observed during 3-year period. The baseline levels of pro-inflammatory cytokines (IL1β, IL6, TNF-α), antibodies against connective tissue components (collagen – antiC-ab, hyaluronic acid – antiHA-ab, chondroitin sulfate antiCS-ab), soluble markers of ED: von Willebrand factor (vWf), endothelin 1 (ET-1), endogenous NO synthase (eNOs) were evaluated by ELISA. The incidence and severity of cardiovascular events (CVE) in the relation with baseline levels of measured markers were evaluated by cluster analysis in 4 cohorts formed according to presence of AA, current IHD and T2DM (AA, IHD, T2DM, IHD+T2DM). From 2 to 4 clusters were separated depending on the incidence and severity of CVE. Results We have defined that in AA the numerous of circulating markers: ET-1, IL-1β, TNFα, antiC-ab, antiCS-ab was associated with clinically significant CVE. In IHD the most severe clinical manifestations were documented in cluster, characterized by increased ET1, vWf, IL6, antiC-ab levels and decreased eNOs, In T2DM without evidenced IHD CVE were associated with next profile: ET1, eNOs, IL-6, antiC-ab, and antiHA-ab. In combination of IHD with T2DM the worst cluster was presented with raised levels of vWf, TNF-α, IL-6, antiC-ab, anti-HA and CRP as well as decreased eNOs. Conclusions Circulating markers of ED and immune-mediated inflammation reflect the clinical manifestation of IHD in high-risk persons with AA and T2DM. Cluster analysis has demonstrated the relationship between specific baseline profile of investigated biomarkers and clinical significant CVE. Obtained data broads our understanding regarding the inflammatory mechanism of atherosclerosis and also suggest a set of circulating markers as predictors of adverse cardiovascular events.

The article presents the results of a cluster analysis of the contribution of immune inflammationmarkers and endothelial dysfunction (ED) to the cardiovascular complicationsfrequency and severity in cohorts of patients with asymptomatic atherosclerosis (AAS), coronary artery disease (CAD), tyepe 2 diabetes mellitus (T2DM) and metabolic syndrome (MS) during 3 years of prospective observation. A comparative analysis of the spectrum of the examined markers was performed depending on the stage of the development of the disease, the presence of T2DM and the MS. It was revealed that the greatest contribution to the cardiovascular complications development in AAS is provided by such circulating markers of ED and immune inflammation as ET-1, IL-1β, TNF-α, total autoantibodies to type I and III collagen (a-Coll) and to Chondroitine-sulfate (a-ChS). With IHD, the greatest contribution is provided by ET-1, eNOs, antibodies a-Coll and also IL-6 and vWf.In T2DM patients without CAD, a profile of markers associated with the high rate of adverse events includes ET-1, eNOs, IL-6, a-Coll and antibodies against hyaluronic acid (a-HA). In a cohort of patients with chronic CAD in the setting of T2DM, a profile of markers associated with the development of adverse events includes vWf, TNF-α, as well as the level of eNOs, IL-6, a-Coll, a-HA and CRP. In the cases of AAS without concomitant MS, the greatest contribution is due to the increase in the level of ET-1, vWf, a-Coll and a-ChS content; in the presence of MS — IL-1β, TNF-α, a-Coll, anti-ChS, anti-HA and CRP. In CAD without MS profile of markers associated with the development of adverse events, includes ET-1, eNOs and a-HA, the presence of the MS — a-Coll, ET-1 and IL-6 levels.

Objective: to determine the level of circulating markers of endothelial dysfunction (endothelin‑1, von Willebrand factor (vfV), endothelial NO-synthase (e‑NOS)) in the blood serum of patients with type 2 diabetes mellitus (DM), as well as to assess the pathogenetic significance endothelial dysfunction in the development of diabetic nephropathy.Materials and methods: the study included 93 patients with type 2 DM, including 28 men (30.1%) and 65 women (69.9%), aged 30 to 79 years, the average age of patients was 59.7±8.4 of the year. The main group included patients with both newly diagnosed type 2 DM and a long-term diabetic history. The duration of the disease averaged 9.5±7.5 years. The majority of patients with DM type 2 (92.5%) at the time of inclusion in the study had various variants of microvascular complications of diabetes, only a small number of patientsin this group (7.5%) had no signs of diabetic angiopathy. Signs of various stages of diabetic nephropathy were observed in 60 patients (69.2%). The comparison group consisted of 30 patients with essential arterial hypertension, including 12 men (40%) and 18 women (60%), aged 34 to 70 years, on average 56.1 ± 8.1 years. The control group consisted of 32 apparently healthy individuals. In all patients, along with routine methods of clinical, laboratory and instrumental examination, the level of circulating markers of endothelial dysfunction (endothelin‑1, von Willebrand factor (vWF), endothelial NO-synthase (e‑NOS)) in blood serum was measured using enzyme-linked immunosorbent assay (ELISA).Results: in patients with DM type 2 and diabetic nephropathy, a statistically significant increase in the concentration of circulating markers of endothelial dysfunction was revealed in comparison with hypertensive patients and healthy individuals. An increase in the level of endothelin‑1 relative to the borderline reference value was found in 73 (78.5±4.1%), vfV in 63 (67.7±4.8%) and e‑NOS in 65 (69.9±4.7%) of patients with DM type 2. In the groups of participants with hypertension and healthy individuals, endothelial imbalance was noted by us significantly less often than in patients with DM type 2, the levels of endothelin‑1 and vfV in people with hypertension were increased in more cases than in healthy individuals. It was noted that the levels of circulating markers of endothelial dysfunction increase with an increase in the duration of DM type 2, and also significantly increase under conditions of carbohydrate decompensation.Conclusion: the results obtained confirm the pathogenetic role of endothelial dysfunction in the development of diabetic nephropathy in patients with type 2 diabetes, increasing endothelial imbalance in persons with a long diabetic history and lack of compensation for carbohydrate metabolism.