Markers Of Endothelial Dysfunction Research Articles

#1554 The association between gut-derived metabolites and biomarkers of renal and cerebro-vascular damage in type 2 diabetes mellitus patients

Abstract Background and Aims Due to its numerous complications, type 2 diabetes mellitus (T2DM) has a major impact on the global economic burden and overall mortality. This condition modifies the metabolic microenvironment in targeted organs, such as the kidney and the brain, by its hyperglycemic nature. Gut microbiota seems to have significant interference with the renal-cerebral axis, especially in a dysbiosis state. The aim of the study was to quantify gut derived metabolites by metabolomic techniques and to evaluate their association with markers of endothelial, podocyte and proximal tubule damage and with cerebro-vascular hemodynamic indices. Method The metabolomic profiling was realized on serum and urine samples originated from 90 T2DM patients, divided into three subgroups, such as the following: 30 normal to mildly-, 30 moderately-, and 30 severely increased albuminuria, respectively, and 20 healthy subjects. The samples were examined by using untargeted and targeted ultra-high performance liquid chromatography coupled with electrospray-ionization quadroupole time-of-flight mass spectrometry (UHPLC-QTOF-ESI+-MS), in order to obtain the metabolic profile. The markers of renal damage such as synaptopodin (SP), podocalyxin (PD), N-acetyl-β-D-glucosaminidase (NAG), kidney injury molecule 1 (KIM-1), monocyte chemotactic protein 1 (MCP-1), and intercellular adhesion molecule 1 (ICAM-1) were assessed by ELISA technique. The hemodynamic cerebro-vascular indices were obtained by high resolution Doppler ultrasound of common carotid arteries (CCAs), internal carotid arteries (ICAs), and middle cerebral arteries (MCAs), bilaterally. The correlations between the metabolites, the markers of renal damage, and neurosonological indices were realized by univariable and multivariable linear regression analyses. Results UHPLC-QTOF-ESI+-MS targeted analysis and subsequent statistical assessments revealed a subset of metabolites with a specific pattern for the normal to mildly increased albuminuria subgroup. The metabolites identified as significant were, in serum: arginine (sArg), hippuric acid (sHA), indoxyl sulfate (sIS), butenoylcarnitine (sBCA), sorbitol (sSorb); and in urine, arginine (uArg), butenoylcarnitine (uBCA), indoxyl sulfate (uIS) and p-cresyl sulfate (uPCS). The univariable linear regression analysis revealed that sArg correlated positively with the breath-holding index (BHI) and negatively with intima media thickness (IMT) in ACI, MCP-1 and ICAM-1; sIS, sSorb, and sBCA correlated inversely with these parametes. The multivariable linear regression analysis displayed the specific correlations between metabolites, markers of endothelial dysfunction, and neurosonological indices, such as follows: sArg correlated with IMT and ICAM-1; sIS followed a predictive pattern along with resistance index (RI) in ACIs and ICAM-1; sBCA correlated with IMT and MCP-1 and sSorb correlated with ICAM-1 and BHI. The urine metabolites were correlated with markers of podocyte and proximal tubule dysfunction: uIS and uBCA were correlated with PD and urinary albumin to-creatinin ratio (uACR), and uPCR correlated with KIM-1 and uACR. Conclusion This study revealed a set of metabolites potentially derived from the intestinal microflora which may act as biomarkers for the early detection of both CMA and DKD in T2DM patients. SArg, sIS and, sBCA are indicators of renal endothelial dysfunction. Moreover, sArg and sIS reflect incipient common and internal carotid artery atherosclerosis, suggesting vascular remodeling at these levels. SSorb correlated with BHI, indicating blood-brain barrier dysfunction and CMA development. In urine, uBCA and uIS are indicators of podocytopathy, whereas uPCS is associated with proximal tubule damage in incipient DKD.

#2850 Elevation of serum indoxyl-sulfate in mice with normal kidney function triggers cardiac and vascular dysfunctions

Abstract Background and Aims Acute kidney disease (AKD) is associated with a long-term risk of cardiovascular mortality and major cardiovascular events, particularly heart failure and acute myocardial infarction. To date, the underlying mechanisms responsible for this elevated cardiovascular risk remain poorly understood. Patients with AKD show increased circulating levels of indoxyl-sulfate (IS), a uremic toxin known to promote oxidative stress, inflammation and apoptosis in cultured vascular and cardiac cells. In this context, we hypothesized that IS elevation during AKD might promote acute myocardial and vascular lesions, which over time favour the onset of cardiovascular events. In a first attempt to test this hypothesis, we aimed to verify whether IS elevation in mice with normal renal function induces myocardial and vascular dysfunctions similar to that observed in AKD. Method Thirty female C57BL6J mice were divided into three groups: control (CT, n = 10), IS (n = 10) and AKD (n = 10). AKD was induced by 5/6 nephrectomy. Blank surgeries were performed in the CT and IS groups. IS was administered continuously for 15 days via drinking water (2.5 g/L) to reach, in IS mice, the IS serum concentrations found in AKD mice, as monitored by a validated high-performance liquid chromatography-tandem mass spectrometry method. Cardiac and vascular functions were assessed by echocardiography at baseline and at D15. Expression of markers of contractility (SERCA-2a for myocardium, αSMA for aorta), inflammation (TNF-α, IL-1β), and endothelial dysfunction (VCAM-1, ICAM-1, iNOS) were assessed by qRT-PCR and western blot. The presence of cardiac lesions was assessed histologically. Results Elevation of serum IS concentrations was similar in IS and AKD mice (serum IS: 10.7 ± 3.4 µg/mL in IS-group and 10.9 ± 5.8 µg/mL in AKD-group vs. 4.0 ± 2.1 µg/mL in CT-group (p < 0.001 in CT vs IS and AKD group). Compared with CT mice, IS and AKD mice showed systolic and diastolic dysfunctions as evidenced by decreased ejection fraction (EF: 62.4% [58.0-72.3] in CT vs. 50.1% [45.0-57.0] in IS (p < 0.05 vs CT) and 51.3% [45.6-57.1] in AKD (p < 0.01 vs CT)), decreased fractional shortening (FS: 33.6% [30.1-40.4] in CT vs. 24.8% [21.9-29.7] in IS (p < 0.05 vs CT) and 25.8% [22.4-29.6] in AKD (p < 0.01 vs CT)) and increased isovolumic relaxation time (IVRT: 17.2 ± 1.6 ms in CT vs. 20.7 ± 1.3 ms in IS (p < 0.001 vs CT) and 19.0 ± 1.7 ms in AKD (p < 0.05 vs CT)), respectively. For all echocardiographic parameters assessed, there were no significant differences observed between IS and AKD mice. Myocardium from IS and AKD mice showed decreased expression of SERCA-2a and elevated expression of both IL-1β and TNF-α at the mRNA and protein levels compared to CT mice. Aortas from IS and AKD mice also showed decreased mRNA expression of α-SMA and increased mRNA expression of IL-1β, VCAM-1, and iNOS compared to aortas from CT mice. The mRNA and protein expression of these inflammatory and contractile markers were not statistically different in the hearts and aortas from IS compared to AKD mice. No signs of vascular dysfunction were observed in either of the groups on ultrasound. Conclusion Systemic exposure to IS in mice without renal failure leads to significant cardiac and vascular dysfunctions that were similar to those observed in mice with AKD. Additional studies are needed to confirm the causal role of IS in the cardiovascular impact of AKD, and to determine whether IS could represent a valuable prognostic tool and therapeutic target for preventing AKD-associated cardiovascular complications.

#1411 Intrarenal hemodynamics in patients with coronary heart disease in the post-COVID-19 period

Abstract Background and Aims Coronary heart disease (CHD) and obesity are common pathologies in patients who have had COVID-19. Endothelial dysfunction (ED) markers determination has been important in such patients due to the high risk of cardiovascular diseases progression and complications development. THE AIM Assessment of endothelial dysfunction severity in patients with CHD and obesity in the post-COVID-19 period to improve the management of these patients. Method 49 patients were examined, who had COVID-19 a year ago. The first group (n=24) included patients with coronary artery disease in the post-COVID period. The second group (n=25) included patients with CHD and obesity who had COVID-19. We evaluated data from an ultrasound examination of the kidneys with duplex scanning of the renal arteries (resistance index (RI), pulsation index (PI)). We also studied the medical history, performed an objective examination, the results of a biochemical blood test, albuminuria levels. Results We demonstrated higher RI and PI of interlobar, segmental arteries in persons of the second group. An increase in RI and PI of segmental arteries accompanied by an increase in uric acid (p=0.001). The average level of microalbuminuria in the first group was 15.71 ± 4.51 μg/l, in the second group it was 24.38 ± 5.38 μg/l (p=0.110). Increasing glucose levels accompanied by an elevation of C-reactive protein levels. Obese patients had significantly higher levels of total cholesterol, triglycerides, low density lipoproteins than patients in the first group. Conclusion We observed changes in lipid metabolism, a higher incidence of diabetes mellitus in females, and changes in intrarenal hemodynamic parameters associated with uric acid levels in patients with coronary heart disease and obesity in the post-COVID-19 period.

Genetic markers of endothelial dysfunction in chronic obstructive pulmonary disease

Objective. To analyze genetic markers of endothelial dysfunction in chronic obstructive pulmonary disease. Materials and methods. The study involved an examination of 285 patients with chronic obstructive pulmonary disease aged 67.12 ± 1.82, including males (73.68%) and females (26.32%). A control group consisted of 70 respondents, including 45 relatively healthy people, among whom males constituted 64.3% and females 35.7%. Polymorphisms of endothelial nitric oxide synthase NOS3 (C786T), endothelin-1 EDN1 Lys198Asn genes were examined by PCR method. Results. The cohort of COPD patients revealed a prevalence of pathological homozygous genotype 786SS NOS3 (χ2=12.84, df=1, p=0.0003). Carriage of heterozygous variant of LysAsn polymorphic marker Lys198Asn of EDN1 gene in COPD patients was detected in 32.5%. Conclusion. Manifestation of endothelial dysfunction in COPD patients is due to genotypic predisposition associated with carrying polymorphisms 786SS of NOS3 gene (OR 7.01, 95% CI 1.59-30.81) and Lys198Asn of EDN1 gene (OR 2.53, 95% CI 0.69-9.22)

Correlation of intracardiac hemodynamics indicators with von Willebrand factor – Marker of endothelial dysfunction in patients with coronary artery disease combined with coronavirus disease (COVID-19)

Correlation of intracardiac hemodynamics indicators with von Willebrand factor – Marker of endothelial dysfunction in patients with coronary artery disease combined with coronavirus disease (COVID-19)

Combined treatment of postmenopausal patients with pelvic organ prolapse and genitourinary syndrome

Background. Colpoptosis combined with stress urinary incontinence is one of the most common conditions in postmenopausal women. Menopause is also associated with the risk of genitourinary syndrome due to estrogen deficiency. Despite the variety of options for surgical correction of genital prolapse and urinary incontinence, there is no universal technique. The use of vaginal approach in pelvic floor surgery is associated with several controversies regarding the rates of recurrence and mesh-associated complications. Studies of the state of the endothelium in menopause have demonstrated a close relationship between age-related features and the frequency of adverse clinical outcomes, which requires an optimal intervention not only on the hormonal status but also on the microcirculatory system. Aim. To improve the principles of complex treatment of pelvic organ prolapse and genitourinary syndrome in postmenopausal patients. Materials and methods. The study included 48 postmenopausal patients with genital prolapse of stage II and above according to the POP-Q classification. All patients received continuous menopausal hormone therapy (MHT) with a combined estrogen-progestogen agent. The patients in group 1 (n=24) received MHT according to clinical guidelines for managing patients with genitourinary syndrome. The patients in group 2 (n=24), in addition to MHT, received sulodexide containing glucurono-2-amino-2-deoxyglucoglucan sulfate before the intended surgical treatment and for 30 days after surgery. Correction of colpocystocele, proctocele and stress urinary incontinence was performed using anterior and posterior colporrhaphy, perineoplasty, and urethral sling placement in case of stress urinary incontinence. Results. Six months after surgical treatment, signs of genital prolapse recurrence were detected in 3 patients (12.5%) in group 1, and 1 patient (4.2%) showed signs of mesh-associated complications (implant extrusion) after urethral sling placement. In group 2, only 4.2% of patients (n=1) showed signs of recurrence of stage II cystocele. All patients who underwent urethral sling surgery reported improved urinary incontinence (n=10). During complex therapy, 3 months after surgery, a more significant improvement of endothelial dysfunction markers was noted in group 2 patients (homocysteine level in group 1 after treatment was 12.27±0.34, in group 2 – 8.34±0.24). Conclusions. Combination therapy of genitourinary syndrome and genital prolapse using MHT, endotheliotropic drugs and vaginal surgical approach in postmenopausal patients contributes to effective and safe treatment associated with minimal risk of complications and recurrence rate. Endothelial dysfunction correction is an essential step in planning surgical intervention in menopausal patients, which contributes to improving tissue repair in the postoperative period.

Endothelial Dysfunction as a Key Link between Cardiovascular Disease and Frailty: A Systematic Review.

Background: Frailty is increasingly recognized as a significant health concern, particularly due to its association with cardiovascular pathologies. This study aims to examine how vascular endothelial dysfunction, a known premorbid stage in the pathophysiology of cardiovascular diseases, contributes to the link between cardiovascular illness and frailty. Methods: The inclusion criteria allowed us to focus on original clinical research articles published in English between January 2014 and January 2024, which reported quantitative assessments of the relationship between frailty and vascular endothelial dysfunction. Excluded from the study were systematic literature reviews, meta-analyses, editorials, conference articles, theses, methodological articles, and studies using animal or cell culture models. Searches were conducted of electronic databases, including Scopus, ScienceDirect, and Medline, up to 22 January 2024. The risk of bias was assessed using the Joanna Briggs Institute's critical appraisal tools. The methods used to present and synthesize the results involved data extraction and categorization based on biomolecular and clinical findings of endothelial dysfunction. Results: Following the application of the inclusion and exclusion criteria, a total of 29 studies were identified. Vascular endothelial dysfunction was associated with increased frailty phenotypes, and we also identified SGLT-2 inhibitors' potential role as an anti-fragility treatment that affects endothelial dysfunction. This study found that the physical and biomolecular markers of endothelial dysfunction are associated with frailty measures and have predictive value for incident frailty. Furthermore, some studies have shown inflammation to have an impact on endothelial dysfunction and frailty, and an innovative age-related chronic inflammation measure has been proven to predict frailty scores. Conclusions: The current evidence suggests an association between endothelial dysfunction and frailty, highlighting the need for further research to elucidate the underlying mechanisms.

The significance of Syndecan 1, a new marker for endothelial dysfunction, in cases of fetal growth retardation.

In the current study we aimed to investigate Syndecan 1 (SDC1) levels in pregnant women diagnosed with fetal growth restriction (FGR) and the relationship between SDC1 levels and clinical and doppler parameters in FGR cases associated with endothelial dysfunction, angiogenesis and uteroplacental insufficiency METHOD OF STUDY: A total of 90 pregnant women included in the study, (45 with FGR, 45 healthy control) matched by week of gestation and maternal age. Venous blood samples were collected and plasma concentrations of SDC1 were determined by a specific immunoassay. Doppler examination was performed to evaluate the relationship between the SDC1 levels and placental blood supply. Doppler parameters; meanUtA-PI(p <.001), CPR (p=.002) and CPUR (p <.001) were different between the groups, however MCA PI, umbilical artery PI and umbilical artery S/D were not (p>.05). While gestational age at delivery, birth weight, APGAR score at 1 and 5 min were significantly lower (all, p <.001) in the study group, non-reassure fetal heart rate tracing (p=.09) and NICU admission (p=.02) were significantly higher. SDC 1 level was 2,00±1,47ng/mL and 2,34±1,12ng/mL in the FGR and control groups, respectively (p=.008). In the study group SDC 1 level was 1,69±2,00 in those with gestational age below 32weeks and 2,13±1,18 in those with gestational age above 32weeks and there was a statistically significant difference between the groups (p=.015). Plasma SDC 1 concentration of 2,1850ng/mL or less had a sensitivity of 70%, a specificity of 72%, area under the ROC curve.65 (p<.005). Low maternal plasma SDC1 level may be associated with placental insufficiency and FGR. Low levels of SDC1 may be helpful as a predictor for the development of FGR during gestation.

Angiopoietins as Predictor Indexes in COVID-19 Patients in Delta and Omicron Waves.

This study aimed to explore the correlation between Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2) concentrations and the Angiopoietin-2/Angiopoietin-1 ratio (Ang-2/Ang-1) with clinical outcomes, potentially serving as disease severity and survival biomarkers. A study at AHEPA University Hospital involved 90 Coronavirus Disease 2019 (COVID-19) adult patients, 30 hospitalized intensive care units (ICU), 30 inward units (non-ICU), and 30 asymptomatic non-hospitalized individuals as controls. Estimated endothelial dysfunction markers related to angiogenesis were measured. There was a statistically significant difference only between outpatient and hospitalized patients (non-ICU-ICU groups) for the Ang-1 and Ang-2 indices. The Ang-2/Ang-1 ratio has differed significantly among the individual patient groups. An ROC analysis was conducted to find an optimal threshold for distinguishing between (outpatients-non-ICU) and (non-ICU-ICU) groups. It was based on Youden's index of 0.1122 and 0.3825, respectively. The Ang-1, Ang-2 levels, and Ang-2/Ang-1 ratio were analyzed as severity indicators in COVID-19 patients. The Ang-2/Ang-1 ratio demonstrated better prognostic and diagnostic utility than individual biomarker levels. Monitoring the Ang-2/Ang-1 ratio can identify COVID-19 patients at risk and assist clinicians in tailoring treatment strategies to improve outcomes.

Replicative senescence and high glucose induce the accrual of self-derived cytosolic nucleic acids in human endothelial cells.

Recent literature shows that loss of replicative ability and acquisition of a proinflammatory secretory phenotype in senescent cells is coupled with the build-in of nucleic acids in the cytoplasm. Its implication in human age-related diseases is under scrutiny. In human endothelial cells (ECs), we assessed the accumulation of intracellular nucleic acids during in vitro replicative senescence and after exposure to high glucose concentrations, which mimic an in vivo condition of hyperglycemia. We showed that exposure to high glucose induces senescent-like features in ECs, including telomere shortening and proinflammatory cytokine release, coupled with the accrual in the cytoplasm of telomeres, double-stranded DNA and RNA (dsDNA, dsRNA), as well as RNA:DNA hybrid molecules. Senescent ECs showed an activation of the dsRNA sensors RIG-I and MDA5 and of the DNA sensor TLR9, which was not paralleled by the involvement of the canonical (cGAS) and non-canonical (IFI16) activation of the STING pathway. Under high glucose conditions, only a sustained activation of TLR9 was observed. Notably, senescent cells exhibit increased proinflammatory cytokine (IL-1β, IL-6, IL-8) production without a detectable secretion of type I interferon (IFN), a phenomenon that can be explained, at least in part, by the accumulation of methyl-adenosine containing RNAs. At variance, exposure to exogenous nucleic acids enhances both IL-6 and IFN-β1 expression in senescent cells. This study highlights the accrual of cytoplasmic nucleic acids as a marker of senescence-related endothelial dysfunction, that may play a role in dysmetabolic age-related diseases.

Transgenic human C-reactive protein affects oxidative stress but not inflammation biomarkers in the aorta of spontaneously hypertensive rats

BackgroundC-reactive protein (CRP) is an acute inflammatory protein detected in obese patients with metabolic syndrome. Moreover, increased CRP levels have been linked with atherosclerotic disease, congestive heart failure, and ischemic heart disease, suggesting that it is not only a biomarker but also plays an active role in the pathophysiology of cardiovascular diseases. Since endothelial dysfunction plays an essential role in various cardiovascular pathologies and is characterized by increased expression of cell adhesion molecules and inflammatory markers, we aimed to detect specific markers of endothelial dysfunction, inflammation, and oxidative stress in spontaneously hypertensive rats (SHR) expressing human CRP. This model is genetically predisposed to the development of the metabolic syndrome.MethodsTransgenic SHR male rats (SHR-CRP) and non-transgenic SHR (SHR) at the age of 8 months were used. Metabolic profile (including serum and tissue triglyceride (TAG), serum insulin concentrations, insulin-stimulated incorporation of glucose, and serum non-esterified fatty acids (NEFA) levels) was measured. In addition, human serum CRP, MCP-1 (monocyte chemoattractant protein-1), and adiponectin were evaluated by means of ELISA, histological analysis was used to study morphological changes in the aorta, and western blot analysis of aortic tissue was performed to detect expression of endothelial, inflammatory, and oxidative stress markers.ResultsThe presence of human CRP was associated with significantly decreased insulin-stimulated glycogenesis in skeletal muscle, increased muscle and hepatic accumulation of TAG and decreased plasmatic cGMP concentrations, reduced adiponectin levels, and increased monocyte chemoattractant protein-1 (MCP-1) levels in the blood, suggesting pro-inflammatory and presence of multiple features of metabolic syndrome in SHR-CRP animals. Histological analysis of aortic sections did not reveal any visible morphological changes in animals from both SHR and SHR-CRP rats. Western blot analysis of the expression of proteins related to the proper function of endothelium demonstrated significant differences in the expression of p-eNOS/eNOS in the aorta, although endoglin (ENG) protein expression remained unaffected. In addition, the presence of human CRP in SHR in this study did not affect the expression of inflammatory markers, namely p-NFkB, P-selectin, and COX2 in the aorta. On the other hand, biomarkers related to oxidative stress, such as HO-1 and SOD3, were significantly changed, indicating the induction of oxidative stress.ConclusionsOur findings demonstrate that CRP alone cannot fully induce the expression of endothelial dysfunction biomarkers, suggesting other risk factors of cardiovascular disorders are necessary to be involved to induce endothelial dysfunction with CRP.

The soluble (pro)renin receptor promotes a preeclampsia-like phenotype both in vitro and in vivo.

Preeclampsia is classified as new-onset hypertension coupled with gross endothelial dysfunction. Placental (pro)renin receptor ((P)RR) and plasma soluble (P)RR (s(P)RR) are elevated in patients with preeclampsia. Thus, we aimed to interrogate the role (P)RR may play in the pathogenesis of preeclampsia. Human uterine microvascular endothelial cells (HUtMECs, n = 4) were cultured with either; vehicle (PBS), 25-100 nM recombinant s(P)RR, or 10 ng/ml TNF-a (positive control) for 24 h. Conditioned media and cells were assessed for endothelial dysfunction markers via qPCR, ELISA, and immunoblot. Angiogenic capacity was assessed through tube formation and adhesion assays. Additionally, pregnant rats were injected with an adenovirus overexpressing s(P)RR from mid-pregnancy (day 8.5), until term (n = 6-7 dams/treatment). Maternal and fetal tissues were assessed. HUtMECs treated with recombinant s(P)RR displayed increased expression of endothelial dysfunction makers including vascular cell adhesion molecule-1, intracellular adhesion molecule-1, and endothelin-1 mRNA expression (P = 0.003, P = 0.001, P = 0.009, respectively), along with elevated endothelin-1 protein secretion (P < 0.001) compared with controls. Recombinant s(P)RR impaired angiogenic capacity decreasing the number of branches, total branch length, and mesh area (P < 0.001, P = 0.004, and P = 0.009, respectively), while also increasing vascular adhesion (P = 0.032). +ADV rats exhibited increased systolic (P = 0.001), diastolic (P = 0.010), and mean arterial pressures (P = 0.012), compared with -ADV pregnancies. Renal arteries from +ADV-treated rats had decreased sensitivity to acetylcholine-induced relaxation (P = 0.030), compared with -ADV pregnancies. Our data show that treatment with s(P)RR caused hypertension and growth restriction in vivo and caused marked endothelial dysfunction in vitro. These findings demonstrate the significant adverse actions of s(P)RR on vascular dysfunction that is characteristic of the preeclamptic phenotype.

Characteristics Of Pathogenetic Links In Vascular Remodeling And Bone Tissue Destruction In Postmenopausal Women With Arterial Hypertension

Background — Much attention is drawn to the role of the nonspecific immune inflammatory vascular response as a link of general pathogenetic mechanisms with changes in the elastic properties of arteries and the phenomena of destructive changes in bones. Objective — We aimed to study the role of nonspecific immune inflammatory markers, parathyroid hormone and female sex hormones as predictors of cardiovascular and degenerative bone changes in postmenopausal women with arterial hypertension (AH) and osteoporosis (OP). Methods — We examined 104 patients (mean age: 54.03±9.56 years) distributed among three groups: healthy women, females with AH and osteopenia, and women with AH and OP. The markers of immune inflammatory response, endothelial dysfunction, hormonal, mineral, and vitamin statuses were analyzed simultaneously with 24-hour ambulatory monitoring of blood pressure, and parameters of vascular wall stiffness and densitometry to elucidate the predictors of cardiovascular and degenerative bone changes in postmenopausal women. Results — For patients with AH and osteopenia, a significant parameter associated with the risk of OP was pulse wave velocity (PWV); its increase exceeding 12.05 m/s was associated with a 3.8-fold increase in the risk of OP. Levels of proinflammatory indicators, interleukins IL-6 and IL-8, tumor necrosis factor-α, high-sensitivity C-reactive protein, and parathyroid hormone were elevated, while levels of progesterone and IL-10 were decreased. Conclusion — Timely specialized multidirectional research of biochemical and instrumental parameters (PWV and densitometry) could become the basis for the development of a personalized strategy for the prevention and treatment of women in order to avoid dangerous cardiovascular and bone complications.

DYNAMICS OF THE LEVELS OF ASYMMETRIC DIMETHYLARGININE AND PLASMINOGEN ACTIVATOR INHIBITOR TYPE 1 IN PATIENTS WITH ACUTE ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION AND TYPE 2 DIABETES MELLITUS DEPENDING ON THE REPERFUSION STRATEGY

Introduction. Despite the major successes achieved in the treatment of acute coronary syndromes (ACS), acute myocardial infarction (AMI) remains the main cause of death among the working-age population of Ukraine. The means of treatment of interventional cardiology can actually reduce the mortality of patients with ACS, improve the course of the acute period of the disease and ensure less reduction in the functional capabilities of the heart in the future. Among the many pathogenetic mechanisms of vascular inflammation in coronary heart disease and type 2 diabetes, endothelial dysfunction is the determining factor.&#x0D; The aim of the study. To evaluate the levels of plasminogen activator inhibitor type 1, asymmetric dimethylarginine and endothelial nitric oxide synthase on the 10-14th day in patients depending on the presence or absence of concomitant diabetes type 2 and the type of reperfusion therapy.&#x0D; Materials and methods. 130 patients with acute myocardial infarction were examined, who were divided into 2 groups: 1 group consisted of patients with acute myocardial infarction with accompanying type 2 diabetes (n=73), 2 group – patients with acute myocardial infarction without type 2 diabetes (n =57). The quantitative content of the plasminogen activator inhibitor type 1 (PAI-1) was determined by the immunoenzymatic method using a commercial test system manufactured by Technoclone PAI-1 ELISA Kit (Austria), endothelial nitric oxide synthase (NOS) – Enzyme-Linked Immunosorbent Assay (ELISA) Kit For Nitric Oxide Synthase Endothelial, asymmetric dimethylarginine (ADMA) – Immunodiagnostik ADMA ELISA Kit (Austria).&#x0D; Results. Percutaneous coronary intervention (PCI) contributes to a more significant decrease in the content of the marker of endothelial dysfunction – ADMA and an increase in NOS on the 10-14th day of acute myocardial infarction in comparison with standard therapy. During PCI, the level of PAI-1 did not reliably change during treatment due to post-inflammatory and post-traumatic activation of platelets in the vascular wall.&#x0D; Conclusions. In patients with acute myocardial infarction with type 2 diabetes mellitus, percutaneous coronary intervention contributes to a significant decrease in the content of asymmetric dimethylarginine and an increase in NOS on the 10-14th day of acute myocardial infarction, but was not accompanied by a significant decrease in the level of PAI-1, which in general indicates positive effect of performed myocardial revascularization.

Markers of Endothelial Dysfunction in Kawasaki Disease: An Update.

Kawasaki disease (KD) is a medium vessel vasculitis that has a special predilection for coronary arteries. Cardiovascular complications include the development of coronary artery abnormalities (CAAs) and myocarditis. Endothelial dysfunction (ED) is now recognized to be a key component in the pathogenesis of KD and is believed to contribute to the development of CAAs. ED has been evaluated by several clinical parameters. However, there is paucity of literature on laboratory markers for ED in KD. The evaluation of ED can be aided by the identification of biomarkers such as oxidative stress markers, circulating cells and their progenitors, angiogenesis factors, cytokines, chemokines, cell-adhesion molecules, and adipokines. If validated in multicentric studies, these biomarkers may be useful for monitoring the disease course of KD. They may also provide a useful predictive marker for the development of premature atherosclerosis that is often a concern during long-term follow-up of KD. This review provides insights into the current understanding of the significance of ED in KD.

Soluble urokinase plasminogen activator receptor (suPAR) in children with obesity or type 1 diabetes as a marker of endothelial dysfunction: a cross-sectional study.

Pediatric obesity and type 1 diabetes mellitus (T1DM) represent two common chronic diseases associated with chronic inflammation, endothelial dysfunction and long-term complications. The aim of the present study was to assess the possible diagnostic and prognostic value of soluble urokinase plasminogen activator receptor (suPAR), a marker of inflammation and impaired endothelial function, in children with the diseases.In this cross-sectional study, children and adolescents with T1DM (N = 41) or obesity (N = 37), aged < 18 years old, and without proteinuria were included, together with children of similar age and without evident morbidity that served as controls (N = 42). Serum samples were obtained during standard outpatient follow up and the urokinase-type plasminogen activator receptor (suPAR) concentrations were measured using a commercially available sandwich ELISA kit (DUP00, R&D systems). Clinical and biochemical indices that were also assessed include body mass index (BMI) z-score, Tanner stages, glycosylated haemoglobin (HbA1c), fasting lipid profile and serum creatinine. Mean serum suPAR levels were significantly higher in patients with obesity compared to patients with T1DM and controls, while children with T1DM had similar suPAR levels to controls. Also, serum suPAR levels showed a negative correlation with age (Spearman rho -0.359, p < 0.001) and serum creatinine levels (Spearman rho -0.334, p = 0.005), and a positive correlation with BMI z-score (Spearman rho 0.354, p = 0.009) in the whole cohort. Conclusion: Serum suPAR may be a useful predictive marker of inflammation or endothelial dysfunction for children with obesity and T1DM, as well as a promising therapeutic target. Further studies are needed in order to clarify whether the reported differences in suPAR levels could reflect a greater impairment of the inflammation status and endothelial function in children with obesity compared to children with T1DM. What is Known: • Paediatric obesity and type 1 diabetes are characterised by chronic inflammation and metabolic dysregulation. • Urokinase plasminogen activator receptor (uPAR) has been proposed as a useful biomarker for chronic inflammation and cardiovascular risk in adults. What is New: • Serum suPAR levels were increased in children and adolescents with obesity compared to those with T1DM and healthy controls; thus, obesity may affect the inflammatory status and endothelial function to a higher degree than T1DM during childhood. • Serum suPAR may serve as a diagnostic and predictive marker of inflammation and endothelial dysfunction for children and adolescents with obesity and T1DM.

Investigation of Serum Endocan Levels in SARS-CoV-2 Patients.

Endocan is an endothelial-cell-specific proteoglycan (ESM-1) and has emerged as an endothelial dysfunction and inflammatory marker in recent years. Endocan can be used as a marker of inflammatory endothelial dysfunction in endothelium-dependent disease: cardiovascular disease, sepsis, lung and kidney disease and malignancies. Recent data suggest that endothelial dysfunction is a key mechanism in COVID-19 pathogenesis. Endotheliitis and thrombo-inflammation are associated with severe forms of SARS-CoV-2 infection, and endocan is currently under investigation as a potential diagnostic and prognostic marker. The aim of this study was to determine serum endocan levels in patients with COVID-19 to evaluate the correlation between endocan levels and clinical disease diagnosis and prognosis. This study enrolled 56 patients, divided into three groups depending on disease severity: mild (15), moderate (25) and severe (16). The biochemical, demographic, clinical and imagistic data were collected and evaluated in correlation with the endocan levels. Serum endocan levels were significantly higher in the COVID-19 patients compared to the control group; also, endocan concentration correlated with vaccination status. The results revealed significantly elevated serum endocan levels in COVID-19 patients compared to the control group, with a correlation observed between endocan concentration and vaccination status. These findings suggest that endocan may serve as a novel biomarker for detecting inflammation and endothelial dysfunction risk in COVID-19 patients. There was no significant relationship between serum endocan levels and disease severity or the presence of cardiovascular diseases. Endocan can be considered a novel biomarker for the detection of inflammation and endothelial dysfunction risk in COVID-19 patients.

Correction of endothelial dysfunction in patients with type 2 diabetes mellitus, diabetic kidney disease and non-alcoholic steatohepatitis

Background. Non-alcoholic fatty liver disease and chronic kidney disease are public health concerns worldwide due to their increasing prevalence, adverse prognosis, and health care burden. The purpose of the study was to determine the probable effect of a combination of metformin, rosuvastatin, essential phospholipids and quercetin on the blood lipids, endothelial function, fibrinolysis system and platelet hemostasis, which are factors for the progression of nonalcoholic steatohepatitis. Materials and methods. Studies were performed on the dynamics of treatment in 60 patients with non-alcoholic fatty liver disease, type 2 diabetes mellitus and diabetic kidney disease (stage I–III). Depending on the prescribed treatment at random, the examined patients were divided into 2 groups. Twenty-eight persons of the first group received a low-calorie diet with dietary restrictions, essential phospholipids, metformin hydrochloride, rosuvastatin. Thirty-two patients from the second group received quercetin in addition to similar dietary recommendations, essential phospholipids, hypoglycemic and hypolipidemic therapy. The mean age of patients was 53.80 ± 3.52 years. The comparison group consisted of 30 healthy individuals of the corresponding age. Results. To evaluate the degree of endothelial-protective effect of quercetin on the background of the recommended protocol therapy, markers of endothelial dysfunction, fibrinolysis and platelet hemostasis were studied. NO content significantly reduced (1.7 times) in patients of group 2 before treatment, increased by 1.5 times (p &lt; 0.05). This can be explained by the effect of quercetin, as well as the use of metformin, which reduces the degree of insulin resistance and the level of hyperlipidemia. Conclusions. The effectiveness of a combination therapy for non-alcoholic steatohepatitis and type 2 diabetes mellitus with diabetic kidney disease using essential phospholi­pids, statins and metformin with the addition of quercetin is higher than that of traditional therapy, as it significantly restores the functional state of the endothelium, eliminates the phenomena of hypercoagulation syndrome without the additional prescription of antiplatelet agents.

Asymmetric and symmetric dimethylarginine as markers of endothelial dysfunction in cerebrovascular disease: A prospective study

Background and aimAsymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) have been proposed as mediators of endothelial dysfunction. In this study, we aimed to investigate the diagnostic and prognostic role of ADMA and SDMA in acute cerebrovascular disease. Methods and resultsA prospective case-control study was performed, enrolling 48 patients affected by ischemic stroke with no cardioembolic origin, 20 patients affected by TIA, 40 subjects at high cardiovascular risk and 68 healthy subjects.ADMA levels were significantly lower in high-risk subjects (18.85 [11.78–22.83] μmol/L) than in patients with brain ischemic event, both transient (25.70 [13.15–40.20] μmol/L; p = 0.032) and permanent (24.50 [18.0–41.33] μmol/L; p = 0.001). SDMA levels were different not only between high-risk subjects and ischemic patients, but also between TIA and stroke patients, reaching higher levels in TIA group and lower levels in stroke group (1.15 [0.90–2.0] vs 0.68 [0.30–1.07] μmol/L; p < 0.001). SDMA was also correlated with short-term prognosis, with lower levels in case of adverse clinical course, evaluated by type of discharge (p = 0.009) and need of prolonged rehabilitation (p = 0.042). ConclusionsThe present study highlights the relationship between l-arginine, ADMA, SDMA and acute cerebrovascular events. Therefore, our results suggested a potential role of SDMA as a specific marker of transient ischemic damage and as a short-term positive prognostic marker.

Association of hepatokines with markers of endothelial dysfunction and vascular reactivity in obese adolescents.

Obesity-induced insulin resistance (IR) is known to influence hepatic cytokines (hepatokines), including fibroblast growth factor (FGF-21), fetuin-A, and chemerin. This study aimed to investigate the association between hepatokines and markers of endothelial dysfunction and vascular reactivity in obese adolescents. A total of 45 obese adolescents were categorized into three groups based on glucose tolerance: normal glucose tolerance (NGT), prediabetes (PD), and type 2 diabetes (T2D). We examined the relationships between FGF-21, fetuin-A, and chemerin with endothelial markers (plasminogen activator inhibitor-1 [PAI-1], intercellular adhesion molecule-1 [ICAM-1], and vascular cell adhesion marker-1 [VCAM-1]) and vascular surrogates (brachial artery reactivity testing [BART] and peak reactive hyperemia [PRH]). Obese adolescents (age 16.2±1.2 years; 62 % female, 65 % Hispanic) with NGT (n=20), PD (n=14), and T2D (n=11) had significant differences between groups in BMI; waist-hip ratio (p=0.05), systolic BP (p=0.008), LDL-C (p=0.02), PAI-1 (p<0.001). FGF-21 pg/mL (mean±SD: NGT vs. PD vs. T2D 54±42; 266±286; 160±126 p=0.006) and fetuin-A ng/mL (266±80; 253±66; 313±50 p=0.018), were significantly different while chemerin ng/mL (26±5; 31±10; 28±2) did not significantly differ between the groups. Positive correlations were found between chemerin and both PAI-1 (r=0.6; p=0.05) and ICAM-1 (r=0.6; p=0.05), FGF-21 and PAI-1 (r=0.6; p<0.001), and fetuin-A with TNFα (r=-0.4; p=0.05). Negative correlations were found between chemerin and PRH (r= -0.5; p=0.017) and fetuin-A and PRH (r=-0.4; p=0.05). In our cohort, IR predicted higher FGF-21 levels suggesting a linear relationship may exist between the two parameters. Hepatokines can augment alterations in the microvascular milieu in obese adolescents as demonstrated by their associations with the markers PAI-1, ICAM-1, and PRH.