Endothelin-1 Concentrations Research Articles

Zibotentan in microvascular angina: a randomized, placebo-controlled, crossover trial

Abstract Background/Introduction Microvascular angina is a chronic condition characterized by abnormal myocardial blood flow leading to ischemic symptoms. Endothelin-1, a peptide secreted by endothelial cells, is a highly potent constrictor of the human coronary arterioles. Microvascular angina is associated with elevated circulating concentrations of endothelin-1, and prolonged exposure to ‘excess’ endothelin causes vasoconstriction and vascular remodelling. The chronic elevation of circulating endothelin-1 in microvascular angina may be influenced by genetic factors. Purpose Zibotentan, the most selective antagonist of the endothelin A receptor with no off-target binding to the endothelin B receptor, was evaluated in oncology trials and did not improve survival. We identified zibotentan as a potential disease-modifying therapy for patients suffering from microvascular angina. We hypothesized that zibotentan 10 mg daily for 12 weeks in addition to background medical therapy could be an efficacious and safe treatment for patients with microvascular angina. We further hypothesized that the SNP regulator of EDN1 gene expression, rs9349379 (G allele), could be a novel theragnostic biomarker. Methods The trial involved a prospective, multicentre, randomized, double-blind, placebo-controlled, sequential crossover design to assess the effects of zibotentan 10 mg or matched placebo, once daily for 12 weeks. The primary outcome was treadmill exercise duration (seconds) using the Bruce protocol. The secondary outcomes included exercise test parameters, health status questionnaires, safety (frequency and severity of severe adverse events (SAEs) and adverse events), feasibility (withdrawal rate), and biomarkers of efficacy (pharmacokinetics, pharmacodynamics). Results The study found no significant difference in exercise duration with zibotentan (-4.26 seconds; 95% CI: -19.60 to 11.06; P=0.5871). There was no effect on the secondary outcomes. However, for exploratory (mechanistic) outcomes, zibotentan increased plasma big endothelin-1, endothelin-1, and global myocardial blood flow, while reducing hemoglobin, diastolic, and systolic blood pressure (all p<0.001). Adverse events were more common during the zibotentan period (60.2%) compared to placebo (14.4%, p<0.001). Conclusion(s) In conclusion, daily administration of 10 mg zibotentan for 12 weeks did not enhance exercise duration and was commonly associated with adverse effects related to fluid retention. Further trials exploring lower zibotentan doses in combination with agents to mitigate fluid retention, and longer treatment durations, are warranted.

The effect of eccentric arm cycling on muscle damage and injury-related biomarkers.

There is a scarcity of information regarding the effect of upper-body eccentric exercise on biomarkers of muscle damage. This study sought to investigate the effect of eccentric arm cycling on muscle damage [exercise-induced muscle damage (EIMD)]. Ten subjects performed a 15 min eccentric arm cycling protocol (cadence 49 ± 7 rpm, power absorbed 248 ± 34 W). Maximal voluntary contraction (MVC) of the elbow flexors was evaluated at rest and at 5 min, 24 h, and 48 h post-exercise. In addition, blood samples were drawn at rest and thereafter at 30 min, 24 h, and 48 h intervals after exercise for quantification of creatine kinase (CK), myoglobin, lactate dehydrogenase (LDH) and endothelin (ET-1) concentrations. Delayed onset muscle soreness (DOMS) was assessed using a category ratio scale (0-10). Myoglobin was increased from baseline at 30 min post-exercise (+114%, 46.08 ± 22.17 µg/L, p = 0.018). Individual peak values were higher than baseline values for CK (+72.8%, 204 ± 138 U/L, p = 0.046) and LDH (+17%, 3.3 ± 0.88 nmole/min/mL, p = 0.017), but not for ET-1 (+9%, 1.4 ± 0.48 pg/mL, p = 0.45). DOMS was reported at 24 h (median 4) and 48 h (median 4) post-exercise and MVC of the elbow flexors were reduced from baseline (216 ± 44 N) at 5 min (-34%, 147 ± 61 N, p < 0.001), 24 h (-17%, 181 ± 56 N, p = 0.005) and 48 h (-9%, 191 ± 54 N, p = 0.003). Eccentric arm cycling incites EIMD with reduced MVC and elevation of myoglobin, CK and LDH.

The role of markers of endothelial dysfunction in the pathogenesis of coronary microvascular dysfunction in patients with non-obstructive coronary artery disease

Aim. To study the potential of non-invasive biomarkers in the diagnosis of coronary microvascular dysfunction (CMD) and prediction of the course of heart failure with preserved ejection fraction (HFpEF) in non-obstructive coronary artery disease.Materials and methods. The 12-month observational study included 118 consecutive patients (6 patients dropped out of the study due to contact loss) with non-obstructive coronary artery disease (CAD) and HFpEF (62 [59; 64]%). At the beginning of the study, serum levels of several biomarkers were assessed using the enzyme immunoassay: N-terminal pro-B-type natriuretic peptide (NT-proBNP), vascular endothelial growth factor (VEGF), and endothelin-1. Coronary flow reserve (CFR) was examined using dynamic single photon emission computed tomography. In the absence of obstructive CAD, CMD was defined as a global decrease in CFR ≤ 2. Echocardiography was used to determine parameters of hemodynamics, LV diastolic dysfunction, and myocardial stress. LV global longitudinal strain (GLS) was assessed using 2D speckle tracking.Results. The patients were divided into groups depending on the presence of CMD: group 1 included patients with CMD (n = 43), group 2 included those without it (n = 75). In patients in group 1, serum levels of endothelin-1 were 1.9 times higher (p = 0.012), levels of VEGF were 2.16 times higher (p = 0.008), and the concentration of NT-proBNP was 2.6 times higher (p = 0.004) than in patients in group 2. According to the ROC analysis, the concentrations of endothelin-1 ≥ 6.9 pg / ml (AUC = 0.711; p = 0.040) and VEGF ≥ 346.7 pg / ml (AUC = 0.756; p = 0.002) were considered as markers associated with the presence of CMD in patients with non-obstructive CAD. The multivariate regression analysis showed that only the presence of CMD (odds ratio (OR) 2.42; 95% confidence interval (95% CI) 1.26–5.85; p &lt; 0.001) and an increase in NT-proBNP ≥ 760.5 pg / ml (OR 1.33; 95% CI 1.08–3.19; p = 0.023) were factors associated with adverse events, and their combination increased the risk of HFpEF progression by more than 3 times (OR 3.18; 95% CI 2.76–7.98; p &lt; 0.001), whereas markers of endothelial dysfunction were not independent predictors. Conclusion. Endothelin-1 ≥ 6.9 pg / ml and VEGF ≥ 346.7 pg / ml can be used as non-invasive markers for the diagnosis of CMD. However, markers of endothelial dysfunction were not independent predictors of HFpEF progression in patients with non-obstructive CAD during 12-month follow-up.

Consumption of plant sterols-enriched soy milk with a healthy dietary pattern diet lowers blood pressure in adults with metabolic syndrome: A randomized controlled trial

Background & aimsPlant sterols (PS) have been shown to lower blood lipid-lipoproteins concentrations and may serve as a potential functional ingredient for cardiovascular disease (CVD) risk management. However, there are limited studies examining this effect in individuals with metabolic syndrome (MetS). The aim of this study was to evaluate the effects of PS-enriched food consumption as part of a healthy dietary pattern (HDP) on blood pressure and endothelial function in Singaporean adults with MetS. Methods and resultsThis was a 12-week, crossover, randomized controlled trial with a 4-week washout period. Thirteen subjects were instructed to consume an HDP diet either with normal soy milk (control group) or with PS (2 g/day)-enriched soy milk (PS group) for 4 weeks. Blood lipid-lipoproteins and glucose concentrations, blood pressure, and endothelial function-related indicators (flow-mediated dilation, total plasma nitrate/nitrite and endothelin-1 concentrations, circulating endothelial progenitor cells) were assessed before and after the intervention. Systolic blood pressure [mean change, PS group: -4.0 ± 3.7 mmHg; control group: 5.9 ± 2.5 mmHg (PInteraction =0.01)] and long-term CVD risk [mean change, PS group: -0.2 ± 1.0 %; control group: 2.7 ± 1.3 % (PInteraction =0.03)] decreased following PS consumption. No changes were observed in the other endothelial function-related outcomes. ConclusionsConsumption of PS-enriched food with an HDP diet may lower blood pressure and long-term CVD risk in adults with MetS. Clinical trial registrationNCT03723330, https://clinicaltrials.gov/.

Pharmacological efficacy study of the cardio-cerebral stasis transforming medicines on cerebral ischemia and myocardial infarction in rats

The purpose of this study was to investigate the efficacy and mechanisms of cardio-cerebral stasis transforming medicines (CCSTM) against cerebral infarction (CI) and myocardial infarction (MI). CI modeling was conducted using the refined Longa suture-occluded technique, while MI modeling was accomplished through the occlusion of the anterior descending branch of the left coronary artery. We found that compared with the model groups, CCSTM decreased the infarct size in models of CI and MI in a dose-dependent manner. After brain ischemia, CCSTM decreased the level of myeloperoxidase (MPO) and malondialdehyde (MDA), and increased the level of superoxide dismutase (SOD). Besides, CCSTM reduced the concentrations of lactate dehydrogenase (LDH), malondialdehyde MDA, and endothelin (ET) in the plasma of rats injured with MI. Histological examination of brain sections revealed that CCSTM alleviated cerebral damage after ischemia compared with the model group. CCSTM can reduce myocardial and cerebral infarction injury, and the oxidation level after myocardial and cerebral infarction in rats.

ЭНДОТЕЛИН-1 В КОРТИКОЦИТАХ НАДПОЧЕЧНИКОВ ПРИ СОЧЕТАНИИ ЧЕРЕПНО-МОЗГОВОЙ ТРАВМЫ И ЭНДОТОКСЕМИИ

Neuroinflammation in traumatic brain injury (TBI) and endotoxemia caused by bacterial lipopolysaccharide have an indirect effect through blood vessels on paracrine and autocrine processes regulating steroidogenesis of adrenal corticocytes. The vasoconstrictor peptide endothelin-1 plays a key role in blood vessel homeostasis. This protein, as a regulator, may be involved in the integration of the listed mechanisms of action on the adrenal glands during endotoxemia and inflammation. Purpose of the study: immunohistochemical characterization of the localization sites and content of endothelin-1 in adrenal corticocytes during a combination of TBI and endotoxemia in the experiment. Materials and methods. Moderate TBI was reproduced in mature rats using a falling weight model weighing 200 g, endotoxemia was induced by intraperitoneal administration of pyrogenal at a total dose of 100 μg/kg body weight. Endothelin-1 was detected in adrenal tissues using the immunohistochemical method and morphometric analysis of the images was performed. Results. In all experimental groups, the stability of the morphometric characteristics of the ratio of the calving cortex and the adrenal medulla was found. With the combination of TBI and endotoxemia, there is a decrease in the area of the nucleus and cytoplasm of adrenal corticocytes and, as a consequence, the nuclear-cytoplasmic ratio. A morphological study revealed an increase in the content of endothelin-1 in the cells of the adrenal cortex, while in the adrenocytes of the medulla, a significant positive reaction to the presence of the peptide was not detected. Conclusion. The results obtained demonstrate that the combination of TBI and endotoxemia causes dysfunction of adrenal cortex cells with an increase in the synthesis of endothelin-1 in them.

Assessment of Specific Biomarkers' Profile and Structural, Functional Parameters of the Left Ventricle in Patients With Lymphomas Undergoing Antitumor Therapy.

To evaluate the dynamics of specific biomarkers for cardiotoxicity, endothelial dysfunction, fibrosis, systemic inflammation, and morpho-functional alterations in the left ventricular (LV) myocardium in patients with newly diagnosed lymphomas during 6 courses of polychemotherapy (PCT). The study included 30 patients with newly diagnosed lymphomas. All patients were evaluated for laboratory markers of cardiotoxicity at baseline and after 6 courses of chemotherapy (6 months), including N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin I (hsTnI), endothelin-1 (ET-1), circulating cardiac biomarker ST-2, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and LV structural and functional echocardiographic (EchoCG) parameters. The changes in NT-proBNP and hsTnI concentrations during 6 courses of PCT were not statistically significant. Comparison of the baseline values with those after 6 courses of PCT showed increases in the median concentrations of ET-1 (3.38 and 5.5 pg/ml, respectively; p=0.438) and ST-2 (12.21 and 26.75 ng/ml, respectively; p=0.687). Markers of systemic inflammation were significantly decreased after 6 courses of PCT: the median CRP decreased from 15.2 to 0.72 mg/ml (p=0.006), and the median IL-6 decreased from 12.2 to 5.1 pg/ml (p=0.034). EchoCG data revealed a statistically significant impairment of the LV diastolic function parameters (E/A; E/e' lateral; E/e' average; left atrial volume index; isovolumic relaxation time). A moderate direct correlation was found between the ET-1 concentration and the isovolumic relaxation time at baseline and after 6 courses of PCT, respectively (r1 = 0.387, p=0.047 and r2 = 0.391, p=0.035). No changes in the LV systolic function were observed. The study showed that patients with lymphoproliferative diseases had no signs of cardiotoxicity during PCT according to the accepted criteria. This study described and highlighted for the first time the interrelation of endothelial dysfunction, profibrotic status, and LV diastolic dysfunction as manifestations of cardiovascular toxicity in patients with lymphoproliferative diseases. It is advisable to supplement the integrated strategies for the prevention and monitoring of PCT cardiovascular toxicity with a thorough evaluation of instrumental parameters of diastolic dysfunction for timely initiation/correction of cardioprotective therapy.

Effects of Dezocine and Propofol Combination on Plasma 5-HT and ET Levels in Stroke Patients Undergoing Thrombolysis

Objective: To investigate the effect of dezocine combined with propofol on brain metabolism in patients undergoing cerebral thrombosis thrombolysis. Methods: A total of 86 stroke patients admitted between July 2022 and December 2023 were randomly divided into two groups: Group A (study group) and Group B (control group), with 43 patients in each group. Both groups underwent intra-arterial thrombolysis therapy. Group B received dezocine for anesthesia, while Group A received a combination of dezocine and propofol. Plasma concentrations of 5-hydroxytryptamine and endothelin, as well as brain metabolic indicators, were compared between the two groups immediately after anesthesia, at 1 hour post-reperfusion, and 3 hours post-reperfusion. Results: There were no significant differences in the levels of 5-hydroxytryptamine and endothelin between the two groups immediately after anesthesia and at 1 hour post-reperfusion (P &gt; 0.05). However, at 3 hours post-reperfusion, the levels of 5-hydroxytryptamine and endothelin in Group A were significantly lower than those in Group B. Furthermore, in Group A, the levels of 5-hydroxytryptamine and endothelin at 3 hours post-reperfusion were lower compared to the levels at 1 hour post-reperfusion (P &lt; 0.05). Conclusion: Dezocine combined with propofol can effectively improve the quality of anesthesia and has a minimal effect on brain metabolic indices, suggesting reduced damage to brain metabolism.

Right Ventricular Hypertrophy in Spontaneously Hypertensive Rats (SHR/NHsd) Is Associated with Inter-Individual Variations of the Pulmonary Endothelin System.

Spontaneously hypertensive rats (SHRs) develop severe hypertension and subsequently left ventricular hypertrophy. Whether they also develop right ventricular hypertrophy is not clear. We analyzed 76 female SHRs (strain SHR/NHsd) and observed severe right ventricular hypertrophy in 7% of these rats (SHR-RVH). Right ventricular hypertrophy did not correlate with the age of the rats and was already seen in one rat at the pre-hypertensive state. The current study investigated the molecular fingerprint of the lung and right ventricle from SHR-RVH and compared this first to SHRs that did develop left but not right ventricular hypertrophy, and second to normotensive rats without hypertrophy. Rats with right ventricular hypertrophy had a decreased expression of the endothelin-B receptor (EDNRB) in the lung, together with an increased protein content of endothelin-1 and an increased expression of ACTA2A. Furthermore, in the right ventricle, a down-regulation of the endothelin-A receptor (EDNRA) was found, consistent with a mild phenotype. The data suggest that in a sub-group of SHR/NHsd rats, low expression of the endothelin clearance receptor (endothelin-B receptor) in the lung triggers an increase in vascular resistance to the right ventricle that then triggers hypertrophy. Our study is the first description of a genetic variant in a defined SHR strain.

The Predictive Value of PKC and ET-1 Levels in Cerebrospinal Fluid for Vasospasm and Prognosis in Patients with Aneurysmal Subarachnoid Hemorrhage.

To analyze the predictive value of protein kinase C (PKC) and endothelin-1 (ET-1) in cerebrospinal fluid for vasospasm and prognosis in patients with aneurysmal subarachnoid hemorrhage (ASH). One hundred and forty-eight ASH patients hospitalized in our hospital during February 2019 to February 2022 were optioned as observation subjects. These subjects were graded into good prognosis group (mRS score 0-2, n = 102) and poor prognosis group (mRS score 3-6, n = 46) according to the Rankin Revised Scale Score (mRS) after 6 months of follow-up. Cerebrospinal fluid was collected from patients to detect the content of ET-1 and PKC. The prognostic factors were analyzed using multifactorial logistic regression. The predictive value was assessed using receiver operating characteristic (ROC) curve. The patients with poor prognosis had a higher age level and a higher proportion of ≥2 aneurysms, aneurysm diameter ≥6 mm, cerebral vasospasm, and Hunt-Hess grade ≥III than those with good prognosis (P < 0.05). The patients with poor prognosis had higher content of PKC and ET-1 than those with good prognosis (P < 0.05). Age, aneurysm diameter ≥6 mm, cerebral vasospasm, Hunt-Hess classification ≥grade III, PKC and ET-1 were all risk factors related to the prognosis of ASH (P < 0.05). The area under the curve (AUC) of PKC and ET-1 for diagnosing poor prognosis of ASH was 0.803 and 0.720, respectively. The AUC of the combined detection was 0.873 (P < 0.05). Patients with cerebrovascular spasm had higher content of PKC and ET-1 than those without (P < 0.05). The AUC of PKC and ET-1 for diagnosing cerebral vasospasm in ASH was 0.891 and 0.816, respectively, which was 0.932 for combined detection (P < 0.05). The combination of PKC and ET-1 in cerebrospinal fluid had certain value in predicting the poor prognosis of patients with ASH.

Investigation of pulmonary artery and circulating endothelin-1 expression in dogs with pulmonary hypertension secondary to myxomatous mitral valve disease.

Pulmonary hypertension (PH) is a condition characterized by abnormally elevated pressure in the pulmonary vasculature. It is a common complication of myxomatous mitral valve disease (MMVD) in dogs. Several vasoactive substances, including endothelin-1 (ET-1), have been suggested to contribute to pathological changes in the pulmonary arteries of patients with PH. This study aimed to examine the local and systemic expression of ET-1 in dogs with PH secondary to MMVD. Lung tissues were collected from 20 client-owned dogs during the first stage of the study and divided into three groups: normal dogs (n = 5), MMVD dogs (n = 8), and MMVD+PH dogs (n = 7). The expression of ET-1 and endothelin A receptor (ETAR) in the pulmonary arteries was determined using immunohistochemistry. Blood samples were collected from 61 client-owned dogs for the second stage of the study and divided into three groups: normal (n = 22), MMVD (n = 20), and MMVD+PH (n = 19). Plasma ET-1 concentration was measured using a sandwich enzyme-linked immunosorbent assay. There was no difference in ET-1 and ETAR expression in the pulmonary arteries among the three groups. Similarly, there was no difference in the plasma ET-1 concentration between the groups. In addition, no correlation was found between the immunohistochemical expression of ET-1 and ETAR and the thickness of the pulmonary arteries or between the plasma ET-1 level and echocardiographic variables. The lack of difference in the expression of ET-1 and ETAR in the pulmonary arteries and in the circulating ET-1 concentration among the studied groups suggests that ET-1 may not be related to the pathological development of PH secondary to MMVD in dogs. Due to the small sample size in this study, further research is needed to confirm these findings.

Abstract 19: Effect of the endothelin receptor antagonist aprocitentan on plasma endothelin, renin and aldosterone concentrations in patients with resistant hypertension. A biomarker analysis of the PRECISION study.

Hypothesis: Dual endothelin (ET) ET A /ET B receptor antagonist aprocitentan significantly reduced blood pressure in patients with resistant hypertension, who were still hypertensive despite standard background anti-hypertensive drugs including a diuretic, an ARB and a CCB (PRECISION trial, NCT03541174). The effect of aprocitentan in this population, characterized with low renin and elevated aldosterone levels, was assessed on a panel of plasma biomarkers: ET-1, CT-proET-1 (a stable peptide and biomarker for ET-1 production), renin, aldosterone. Methods: From the 730 randomized patients in PRECISION, ET-1 (n=700), CT-proET-1 (n=100, randomly selected), immunoreactive renin (n=679) and aldosterone (n=703) were measured in plasma samples collected at randomization (baseline) and after 4 weeks for either placebo, aprocitentan 12.5 or 25 mg. Results: Four-week placebo treatment had no effect on the studied biomarkers compared to baseline. Treatment with aprocitentan 12.5 and 25 mg increased plasma ET-1 by +34% and +53% and CT-proET-1 by +38% and +47% vs. baseline respectively. Aprocitentan had no effect on renin levels (p&gt;0.05) while decreasing plasma aldosterone by -17% and -24% at the 12.5 and 25 mg dose respectively. Importantly, the reduction in aldosterone did not result in a change in kalemia (see Table ). Conclusions: Aprocitentan caused reactive dose-dependent increases in plasma CT-proET-1 and ET-1, resulting from effective ET receptor blockade. The increase in CT-proET-1 may indicate a compensatory increase in ET-1 de novo synthesis, while the increase in ET-1 may reflect a reduced clearance due to blockade of ET B and increased production. The decrease of aldosterone by aprocitentan confirms the secretagogue role of ET-1 on aldosterone production by adrenal cortical cells via both ET A and ET B receptors This decrease of aldosterone was observed on top of the known decrease induced by an ARB but did not induce hyperkalemia nor aggravation of renal function.

Zibotentan in Microvascular Angina: A Randomized, Placebo-Controlled, Crossover Trial.

Background: Microvascular angina is associated with dysregulation of the endothelin system and impairments in myocardial blood flow, exercise capacity, and health-related quality of life. The G allele of the noncoding single nucleotide polymorphism RS9349379 enhances expression of the endothelin-1 gene (EDN1) in human vascular cells, potentially increasing circulating concentrations of Endothelin-1 (ET-1). Whether zibotentan, an oral ET-A receptor selective antagonist, is efficacious and safe for the treatment of microvascular angina is unknown. Methods: Patients with microvascular angina were enrolled in this double-blind, placebo-controlled, sequential crossover trial of zibotentan (10 mg daily for 12 weeks). The trial population was enriched to ensure a G allele frequency of 50% for the RS9349379 single nucleotide polymorphism. Participants and investigators were blinded to genotype. The primary outcome was treadmill exercise duration (seconds) using the Bruce protocol. The primary analysis estimated the mean within-participant difference in exercise duration after treatment with zibotentan versus placebo. Results: A total of 118 participants (mean ±SD; years of age 63.5 [9.2 ]; 71 [60.2% ] females; 25 [21.2% ] with diabetes) were randomized. Among 103 participants with complete data, the mean exercise duration with zibotentan treatment compared with placebo was not different (between-treatment difference, -4.26 seconds [95 ] CI, -19.60 to 11.06] P=0.5871). Secondary outcomes showed no improvement with zibotentan. Zibotentan reduced blood pressure and increased plasma concentrations of ET-1. Adverse events were more common with zibotentan (60.2%) compared with placebo (14.4%; P<0.001). Conclusions: Among patients with microvascular angina, short-term treatment with a relatively high dose (10 mg daily) of zibotentan was not beneficial. Target-related adverse effects were common.

Prognostic value of plasma big endothelin-1 in patients with light chain cardiac amyloidosis

BackgroundLight chain cardiac amyloidosis (AL-CA) is associated with a high incidence of mortality. Big endothelin-1 (ET-1), the precursor of endothelial-vasoconstrictive ET-1, is closely related to the concentration of bioactive ET-1....

Clinical and pathogenetic features of the development of endothelial dysfunction in patients with chronic kidney disease and its contribution to the development of cognitive impairments

THE AIM: to study the clinical and pathogenetic features of the development of endothelial dysfunction (ED) in patients with chronic kidney disease stages 3A-5D and its contribution to the development of cognitive impairment.PATIENTS AND METHODS: The study included 80 patients with CKD stages 3A-5D aged from 26 to 79 years (average age 58.9 ± 1.4 years): 43 women (average age 60.1 ± 1.9 years) and 37 men (average age 57.4±2.3 years). The patients were divided into 2 groups: group 1 included 40 patients with CKD 3A-5 (average age 59.9 ± 2.1 years), group 2 included 40 patients with CKD 5D (average age 58.1 ± 2 years). All patients underwent common and biochemical blood tests, the levels of endothelial nitric oxide synthase 3 (eNOS-3) and endothelin-1 (END-1) were determined, an endothelium-dependent vasodilation test (EDVD) was performed, testing for the presence and severity of cognitive disorders using the Montreal Cognitive Assessment Scale (MoCA) and the Mini Mental State Examination (MMSE).RESULTS: The prevalence of ED in the overall cohort of patients based on the results of a positive test with EDVD was 55 % of cases. ED was statistically significantly more often detected in the group of patients receiving hemodialysis treatment compared to patients in group 1: 70 % versus 40 %, respectively (p=0.007). The level of eNOS-3 in group 1 was higher compared to group 2 and amounted to 1.01±0.5 ng/ml versus 0.76±0.3 ng/ml (p=0.008). While the level of END-1 was statistically significantly lower in patients of group 1 compared to group 2 and amounted to 45.4±9.1 pg/ml versus 54.9±4.7 pg/ml (p&lt;0.001). Cognitive impairments were identified in the general cohort: according to MMSE – in 67.5 % of cases, according to MoCA – in 71.3 %, and were more common in group 2. There were no statistically significant relationships between the results of the EDVD test and testing on the MoCA and MMSE scales. The level of eNOS-3 was lower in the subgroup of patients with cognitive impairment according to MoCA compared to the subgroup without it: 0.73±0.1 ng/ ml versus 0.94±0.2 ng/ml (p=0.127). The content of END-1 was statistically significantly higher in the subgroup of patients with cognitive impairment according to MoCA – 52.98±1.2 pg/ml compared to the subgroup without it – 47.67±1.5 pg/ml (p=0.043). When assessing the relationship between the levels of eNOS-3 and END-1 and the results of the EDVD test, it was found that in patients with a positive test in group 1, the level of eNOS-3 was statistically significantly higher compared to group 2 (p=0.01). An inverse relationship was observed for END-1; its level was lower in patients of group 1 compared to group 2 (p&lt;0.01).CONCLUSION. Thus, the study revealed a high prevalence of endothelial dysfunction in patients with CKD stages 3A-5D. Progressive loss of renal function leads to dysregulation of the molecular mechanisms controlling vascular tone and the development of ED. eNOS-3 and END-1 have demonstrated high sensitivity for ED verification, and their detection improves the quality of the EDVD test. The development and progression of ED in patients with CKD is a multifactorial process that leads to hemodynamic disturbances in various organs and tissues, their damage and has a negative impact on the patient’s quality of life, his cognitive status and life expectancy.

Modelling of the early stage of retinal neurodegeneration via a topical injection of dopaminergic neurotoxin

Purpose: to develop a model of the early stage of retinal neurodegeneration via an intravitreal injection of the dopaminergic neurotoxin. Material and methods. The experiment was carried out on 20 Chinchilla rabbits. The experimental groups received intravitreal injection of 0.1 ml of 6-hydroxydopamine (6-OHDA) in NaCl 0.9 % with 0.5 % ascorbate, containing 0.25 or 0.5 mg 6-OHDA. The control group received injections of 0.1 ml of NaCl-ascorbate solution without neurotoxin. On the 7th and the 14th days after the injection, intraocular pressure (IOP), pupillary light reaction and ocular blood flow were estimated and the fundus was examined. On the 7th day after an injection of 0.25 mg 6-OHDA, we used ELISA to measure dopamine concentration in retinal homogenates, while on the 14th day after an injection of 0.5 mg 6-OHDA, the concentrations of dopamine, norepinephrine, TNF-a and endothelin-1 were measured by the same method. Results. On the 7th day after a 0,25 mg injection of neurotoxine, we revealed a decrease of dopamine in the retina (0.043 ± 0.130 pg/mg protein compared with 0.10 ± 0,03 pg/mg protein in the controls, р &lt; 0.01). On the 14th day, dopamine and norepinephrine levels showed a fourfold increase (р &lt; 0.05). An injection of 0.5 mg of 6-OHDA caused a threefold increase of dopamine (р &lt; 0.05) and a fivefold increase of norepinephrine (р &lt; 0.01) concentration in comparison with the controls. On the 14th day, endotheline-1 level was 65 % higher than in the controls after a 0.25 mg 6-OHDA injection (р &lt; 0.01) and 45 % higher after a 0,5 mg injection (р&lt;0.05). At the same time, TNF-α levels increased by 43 % (р &lt; 0.05) and 20 % (р &lt; 0.05) respectively. We also revealed a dose-dependent change of IOP, a disturbance of pupillary light reaction and decreased ocular blood flow after an injection of neurotoxin. Conclusion. A single intravitreal injection of dopaminergic neurotoxin 6-OHDA in the amount of 0.25 or 0.5 mg per eye leads to a neuroinflammation and vascular disorders, which are the main pathogenetic pathways of neurodegeneration. To model its early phase, the 0.25 mg dose is preferable as it causes less dramatic functional disorders. The latter model can be useful for the investigation of retinal neurodegeneration pathogenesis, the search for early diagnostic and prognostic markers thereof and the estimation of therapy effectiveness.

Blood serum biomarkers in the dynamics of treatment for cerebrovascular pathology in post-COVID-19 patients

Neurological manifestations after COVID-19 infections can be attributed to chronic immune and inflammatory reactions induced by SARS-CoV-2, as well as endothelial dysfunction and other vascular issues. This study included 24 patients with cerebrovascular disease (CVD) who had contracted COVID-19 1 &amp;ndash; 1.5 years before the examination (experimental group) and 20 patients with CVD who had not previously been infected with the coronavirus (comparison group). Both groups were representative in terms of age and gender. Blood serum biomarkers, including interleukin (IL)-6, endothelin-1 (ET-1), and vascular endothelial growth factor A (VEGF-A), were tested before and after a 14-day standard complex therapy in the hospital at our institute using appropriate enzyme-linked immunosorbent assay reagent kits. Increases in the levels of IL-6 (by 20%), ET-1 (by 200%), and VEGF-A (by 100%) were observed in patients with CVD who had contracted COVID-19 1 &amp;ndash; 1.5 years earlier compared to the comparison group. The effectiveness of a 2-week therapeutic intervention in patients with a history of COVID-19 was found only for VEGF-A: its serum level decreased twofold, leading to the normalization of this indicator. The concentrations of IL-6 and ET-1 were not affected by the treatment. In addition, the serum levels of ET-1 and VEGF-A in unvaccinated individuals exceeded those in vaccinated patients.

Specific features of arterial stiffness and endothelial vasomotor dysfunction in patients with joint hypermobility syndrome

Introduction. Joint hypermobility syndrome (JHS) is characterized by a multisystem lesion of organs, including the cardiovascular system, which determines the presence of cardiovascular risks in this pathology. Aim. Studying of arterial stiffness and endothelial dysfunction parameters in patients with JHS. Material and methods. Study population included 105 adults with JHS (90 women and 15 men) and 57 healthy controls (49 women and 8 men) aged 20 to 28 years (mean age 22 [21; 23] years). All persons underwent a general clinical examination; examination of endothelial vasomotor function (EVF) and pulse wave velocity at the carotid-radial segment (PWVcr) by rheography (IMPECARD-M, Belarus); investigation of arterial stiffness parameters: cardio-ankle vascular index (CAVI), cardio-ankle pulse wave velocity (PWVha), ankle-brachial index (ABI), augmentation index (AI) by sphygmography (VaSeraVS-1500N Fukuda Denshi, Japan); determination of T786C polymorphism of the eNOS gene by polymerase chain reaction (Litech, Russia), determination of endothelin-1 and transforming growth factor beta-1 (TGF-β1) levels by enzyme immunoassay (Fine Test, Wuhan Fine Biotech Co., China). Results. According to the main clinical and laboratory indicators, the groups were matched. In patients with JHS, the values of PWV at the carotid-radial and cardio-ankle segments were higher, in other parameters (EVF, CAVI, ABI, AI) the groups were matched. In the group with JHS, pathological values of EVF, PWVcr, CAVI, AI were more often determined. Among patients with JHS, an excess of vascular age over the passport age is detected 8.6 times more often (95% CI from 1.103 to 67.321). These changes are not associated with mutations of the eNOS T786C gene and changes in endothelin-1 and TGF-β1 concentrations. Conclusion. These data indicate the importance of further study of the mechanisms of early vascular changes in the arteries in JHS, in order to develop optimal methods of therapy and improve the cardiovascular prognosis of patients with this pathology

Evaluation of endothelial glycocalyx injury biomarkers in feline hemotropic mycoplasmosis

The present study aimed to investigate endothelial glycocalyx (eGCx) damage in cats with feline hemotropic mycoplasmosis caused by Mycoplasma haemofelis using selected biomarkers and to determine the diagnostic and prognostic significance of these biomarkers. The study included 25 cats with feline hemotropic mycoplasmosis and 10 healthy cats. Clinical examination, blood gas analysis, complete blood count, and biochemical analysis were performed. Hemotropic mycoplasmosis diagnosed by microscopic examination and molecularly confirmed by PCR targeting the Mycoplasma haemofelis 16s rRNA gene. To evaluate endothelial glycocalyx damage, syndecan-1, endothelin-1 (ET-1), asymmetric dimethylarginine (ADMA), and vascular endothelial growth factor-A (VEGF-A) concentrations were measured using cat-specific commercial ELISA kits. Of the cats with feline hemotropic mycoplasmosis, 14 (56%) survived and 11 (44%) died. While syndecan-1 and ET-1 concentrations were significantly higher in cats with hemotropic mycoplasmosis compared to the control group (p < 0.001), no statistically significant difference was found for ADMA and VEGF-A concentrations (p > 0.05). Endothelial glycocalyx biomarkers showed significant correlations with each other and with hematological parameters (p < 0.01). The results of the ROC analysis showed that ET-1 with area under the curve (AUC) of 0.821 (p < 0.01) and VEGF-A with AUC of 0.805 (p < 0.010) were found to be significant prognostic indicators. In conclusion, this study demonstrated that serum syndecan-1 and ET-1 can be used as diagnostic and serum ET-1 and VEGF-A as prognostic biomarkers in cats with hemotropic mycoplasmosis. Our results indicate the development of eGCx damage in feline hemotropic mycoplasmosis and suggest that glycocalyx disruption may contribute to the pathogenesis of the disease.

#50 The relationship between pre-dialysis plasma endothelin-1 and the intradialytic decline in blood pressure

Abstract Background and Aims Endothelin-1 (ET-1), a potent vasoconstrictor, may play an important role in the blood pressure (BP) response to hemodialysis (HD). Patients receiving maintenance HD have higher concentrations of plasma endothelin-1 than non-HD patients with advanced chronic kidney disease or patients receiving peritoneal dialysis. We wished to examine the association between the pre-HD level of ET-1 and the magnitude of intradialytic systolic BP decline. Methods Data was collected in a prospective study of 50 patients receiving maintenance HD admitted to Brigham and Women's Hospital in Boston, MA, USA. BP was measured before and every 15 min during a single HD session using an automated BP cuff. The systolic BP decline was calculated as the pre-HD minus the lowest intradialytic systolic BP. Blood samples were collected pre-HD. Patients with missing data, HD &amp;lt;3 h, or pre-dialysis BP &amp;lt;85/55 mmHg were excluded from the analysis (n = 8). Spearman's rho (ρ) was used to assess the correlation between pre-HD ET-1 and intradialytic systolic BP decline. Results Of the 42 included patients, 17 were females, median age 62 [25th, 75th percentile: 50, 70] years. The median HD duration was 232 [210, 242] min and median ultrafiltration was 2.1 [2, 3] L. Before HD, the median ET-1 was 2.4 [1.9, 3.0] pg/mL, the median systolic BP was 141 [119, 167] mmHg, and the median diastolic BP was 68 [63, 84] mmHg. A moderate negative correlation was observed between the baseline ET-1 and the intradialytic decline in systolic BP (ρ = –0.34, P = 0.03). This correlation was stronger in patients with baseline systolic BP &amp;gt;120 mmHg (ρ = –0.51, P = 0.004, n = 30) and much stronger in patients with baseline systolic BP &amp;gt;140 mmHg (ρ = –0.66, P = 0.001, n = 21). Almost all cases (8 out of 9) with an intradialytic decline in systolic BP of &amp;gt;50 mmHg occurred in patients with baseline ET-1 below the pre-HD median level. Conclusions Our results suggest that hospitalized patients with pre-HD systolic BP &amp;gt;140 mmHg and lower baseline ET-1 may be more likely to experience larger intradialytic declines in systolic BP. Whether measurement of pre-HD ET-1 could help identify hypotensive-prone patients requires further investigation in larger studies.