Arterial-renal Syndrome in Patients with ESRD, a New Disease Paradigm

Background Patients with end-stage renal disease (ESRD) often present with an increased risk of cardiovascular disease. Conditions of compromised cardiovascular health such as atrial fibrillation (AFIB) and peripheral arterial disease (PAD) may alter biomarker levels in a way that reflects worsening ESRD. This study profiled biomarkers and laboratory parameters of endothelium dysfunction in patients with ESRD, categorized by additional AFIB and PAD conditions. Methods Citrated blood samples were collected from 95 patients with ESRD. Biomarker levels were measured from plasma samples using sandwich ELISAs, including tissue plasminogen activator (tPA), D-dimer, and nitrotyrosine. Lab parameters, including BUN, calcium, creatinine, parathyroid hormone, phosphate, alkaline phosphatase, ferritin, transferrin, and total iron capacity, and patient comorbidities were obtained from patient medical records. The comorbidities were determined through provider notes, and evidence of applicable testing. Results 14.89% of patients were found to have atrial fibrillation (n = 14), 30.85% of patients were found to have peripheral arterial disease (n = 29), and 6.38% of patients were found to have both peripheral arterial disease and atrial fibrillation (n = 6). When compared to patients with only ESRD, patients with ESRD and PAD showed elevated levels of D-Dimer (p = .0314) and nitrotyrosine (p = .0330). When compared to patients with only ESRD, patients with atrial fibrillation showed elevated levels of D-Dimer (p = .0372), nitrotyrosine (p = .0322), and tPA (p = .0198). Conclusion When compared to patients with just ESRD, patients with concomitant PAD had elevated levels of Nitrotyrosine and D-dimer; while patients with concomitant Afib had elevated levels of nitrotyrosine, D-dimer, as well as tPA.

Long COVID 19 Syndrome: Is It Related to Microcirculation and Endothelial Dysfunction? Insights From TUN-EndCOV Study

The COVID-19 disease is a multisystem disease due in part to the vascular endothelium injury. Lasting effects and long-term sequelae could persist after the infection and may be due to persistent endothelial dysfunction. Our study focused on the evaluation of endothelial quality index (EQI) by finger thermal monitoring with E4 diagnosis Polymath in a large cohort of long COVID-19 patients to determine whether long-covid 19 symptoms are associated with endothelial dysfunction. This is a cross-sectional multicenter observational study with prospective recruitment of patients. A total of 798 patients were included in this study. A total of 618 patients (77.4%) had long COVID-19 symptoms. The mean EQI was 2.02 ± 0.99 IC95% [1.95–2.08]. A total of 397 (49.7%) patients had impaired EQI. Fatigue, chest pain, and neuro-cognitive difficulties were significantly associated with endothelium dysfunction with an EQI <2 after adjustment for age, sex, diabetes, hypertension, dyslipidemia, coronary heart disease, and the severity of acute COVID-19 infection. In multivariate analysis, endothelial dysfunction (EQI <2), female gender, and severe clinical status at acute COVID-19 infection with a need for oxygen supplementation were independent risk factors of long COVID-19 syndrome. Long COVID-19 symptoms, specifically non-respiratory symptoms, are due to persistent endothelial dysfunction. These findings allow for better care of patients with long COVID-19 symptoms.

Urinary SARS-CoV-2 RNA Is an Indicator for the Progression and Prognosis of COVID-19

Background: We aimed to analyze clinical characteristics and find potential factors to predict poor prognosis in patients with coronavirus disease 2019 (COVID-19). Methods: We analyzed the clinical characteristics and laboratory tests of COVID-19 patients and detected SARS-CoV-2 RNA in urine sediments collected from 53 COVID-19 patients enrolled in Renmin Hospital of Wuhan University from 31 January 2020 to 18 February 2020 with qRT-PCR analysis. Then, we classified those patients based on clinical conditions (severe or non-severe syndrome) and urinary SARS-CoV-2 RNA (URNA− or URNA+). Results: We found that COVID-19 patients with severe syndrome (severe patients) showed significantly higher positive rate (11 of 23, 47.8%) of urinary SARS-CoV-2 RNA than non-severe patients (4 of 30, 13.3%, p = 0.006). URNA+ patients or severe URNA+ subgroup exhibited higher prevalence of inflammation and immune discord, cardiovascular diseases, liver damage and renal dysfunction, and higher risk of death than URNA− patients. To understand the potential mechanisms underlying the viral urine shedding, we performed renal histopathological analysis on postmortems of patients with COVID-19 and found severe renal vascular endothelium lesion characterized by an increase of the expression of thrombomodulin and von Willebrand factor, markers to assess the endothelium dysfunction. We proposed a theoretical and mathematic model to depict the potential factors that determine the urine shedding of SARS-CoV-2. Conclusions: This study indicated that urinary SARS-CoV-2 RNA detected in urine specimens can be used to predict the progression and prognosis of COVID-19 severity.

Vitamin D role in endothelial dysfunction development in patients with polycystic ovarian syndrome

Background. The study was aimed to determine the correlation between the blood concentration of vitamin D and factors that influence the function of the endothelium and the hemodynamic of gonads in women with polycystic ovary syndrome (PCOS). Material and methods. Sixty women aged from 18 to 26 years were examined: 30 women with a diagnosis of PCOS and 30 healthy women. The blood serum concentration of vitamin D, C-reactive protein (CRP), interleukin-6 (IL-6), homocysteine (Hcy), nitrites/nitrates (NOx), and arginine were investigated. Maximum systolic velocity (Vmax), resistance index (RI), and pulsatility index (PI) were measured with Doppler ultrasound. Cholecalciferol was used in a dose of 4000 IU per day for 12 weeks for the correction of deficiency of vitamin D. Results. The patients with PCOS were found to have a lower (Р < 0.001) average vitamin D than healthy women. The reduction of vitamin D concentration was combined with an increase (P < 0.001) in the average concentration of NOx and a decrease in arginine. It was found a positive association between vitamin D and arginine (r = 0.391; P < 0.05), between NOx and CRP (r = 0.432; P < 0.02), IL-6 (r = 0.476; P < 0.01), Vmax (r = 0.383; P < 0.05), RI (r = 0.369; P < 0.05), PI (r = 0.380; P < 0.05) and reverse correlation with arginine (r = –0.375; P < 0.05). It was not found an association between NOx and vitamin D (r = 0.207; P > 0.05), Hcy (r = 0.176; P > 0.05); between vitamin D and Vmax (r = 0.231; P > 0.05), RI (r = 0.201; P > 0.05), PI (r = 0.181; P > 0.05). The therapy of cholecalciferol level was accompanied by an increase (P < 0.001) in concentrations of vitamin D, arginine (P < 0.05) and a decrease in NOx (P < 0.02), IL-6 (P < 0.05), SRP (P < 0.001), Hcy (P < 0.001), Vmax (P < 0.001), RI (P < 0.001), PI (P < 0.01), quantity of antral follicles (P < 0.001), and the growth of follicles (P < 0.001). However, none of the studied indicators reached the indicators in healthy women. Conclusions. The deficiency of vitamin D is associated with increased markers of chronic inflammation, homocysteine, nitrate/nitrites, reduced concentration of arginine that provokes the development of endothelium dysfunction and, therefore, the hemodynamics disorders and folliculogenesis in the ovary.

Endothelial dysfunction in patients with hereditary spherocytosis and b-thalassemia

Patients with hereditary spherocytosis and b-Thalassemia are characterized by the increased risk of thrombosis. The early manifestation of thrombotic complications can occur even in childhood especially after surgery. Hypercoagulability can be associated with endothelial dysfunction. The aim of this study was to investigate the hemostatic state and endothelial function in children with hereditary spherocytosis and b-thalassemia. The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. The hemostatic status of 18 children (10 boys and 8 girls from 1 to 13 years) with hereditary spherocytosis and of 8 children (4 boys and 4 girls from 3 to 8 years) with b-thalassemia was assessed using clotting times (activated partial thromboplastin time – APTT, thrombin time – TT, prothrombin time PT), fibrinogen levels and markers of endothelium dysfunction: endothelin-1 and thrombomodulin levels. Patients with hereditary spherocytosis were divided into 2 groups: during the hemolytic crisis (11 patients) and without the hemolytic crisis (7 patients). Patients with b-Thalassemia were divided into 3 groups: b-thalassemia major, b-thalassemia intermedia and b-thalassemia minor. APTT, TT and PT were not changed significantly between groups. We find the decreased fibrinogen levels in patients with severe condition: in hereditary spherocytosis patients during hemolytic crisis (1.9 ± 0.3 ng/ml with normal range 2–3.9 ng/ml) and in b-thalassemia major patients (1.8 ± 0.3 ng/ml with normal range 2–3.9 ng/ml). This could be caused by consumption of fibrinogen during acute hemolysis. The Thrombomodulin levels were increased in all hereditary spherocytosis patients, but median value was higher in group with hemolytic crisis (6665 pg/ml vs 5976 pg/ml with ormal value 275–909 pg/ml) indicating endothelium dysfunction and activation of blood clotting. In b-thalassemia patients Thrombomodulin levels were more elevated in b-thalassemia major and b-thalassemia intermedia (6389 ± 537 pg/ml и 6804 ± 120 pg/ml) compared to b-thalassemia minor (2727 ± 213 pg/ml) which is still higher than normal range. Endothelin-1 levels were elevated on 55% with hereditary spherocytosis patients during crisis vs 43% without. In general Endothelin-1 levels were more elevated in b-thalassemia patients (were normal in b-thalassemia minor) vs hereditary spherocytosis patients (2.33 ± 2.89 fmol/ml vs 0.95 ± 0.35 fmol/ml). Thrombomodulin and endothelin-1 levels revealed endothelium dysfunction in children with hemolysis. More dramatic changes observed in severe condition: in hereditary spherocytosis patients during hemolytic crisis and in b-thalassemia major and b-thalassemia intermedia patients.

Myocardial ischaemia of non-obstructive origin as a cause of new onset anginal chest pain in the long COVID syndrome

Background New-onset chest pain occurs in around 20% of patients with long COVID syndrome (LCS). Being the vascular endothelium one of the targets of the SARS-CoV-2 virus, we hypothesized that new onset anginal symptoms in LCS could be due to endothelium dysfunction and other non-obstructive causes of myocardial ischaemia. Methods We investigated 11 consecutive patients who developed new onset anginal chest pain, suggestive of myocardial ischaemia, after documented SARS-CoV-2 infection. Intracoronary assessment included endothelium-dependent evaluation with acetylcholine testing (Ach), and endothelium-independent assessment with coronary flow reserve (CFR) and microcirculatory resistance (MR). Criteria for positiveness of these tests and medical treatment recommendation were obtained from 2019 ESC guidelines and 2020 EAPCI consensus document on ischaemia with non-obstructive coronary arteries (INOCA). Results Mean patient age was 56 years (SD ± 15); 10 (91%) were female. In the acute COVID-19 phase, 4 patients (36%) had had pulmonary infiltrates and 2 (18%) required hospitalization. Conclusive non-invasive tests were obtained in 7 (64%), showing exercise-related myocardial ischaemia in 6 (86%). Coronary angiography ruled out obstructive epicardial stenoses in all the patients. Ach testing revealed abnormal endothelium-dependent responses in 9 (82%) patients: 5 (56%) had epicardial vessel and 4 (44%) microvascular spasm. Endothelium-independent assessment was abnormal in 6 (54%) cases, with abnormal CFR in 2 (33%), abnormal MR in 2 (33) and both abnormal CFR and MR in 2 (33%) patients. The most frequent endotype was combined endothelium dependent- and independent abnormalities (6/9, 67%). Stratified medical treatment according to endotype led to significant improvement in Seattle Angina Scores for angina frequency (+22 points, p=0.013) and a notable trend towards angina stability (+25 points, p=0.093) at a mean follow-up time of 222 days. Conclusions Myocardial ischaemia of non-obstructive origin is common in patients with chest pain and LCS. Vasomotor abnormalities related to endothelial dysfunction occurred in 82% of patients, frequently associated to impaired microvascular vasodilation or high microvascular resistance. Stratified medical treatment led to significant improvement in angina stability and frequency. FUNDunding Acknowledgement Type of funding sources: None.

The Influence of Maternal Obesity on Cell-Free Fetal DNA and Blood Pressure Regulation in Pregnancies with Hypertensive Disorders

Background and Objectives: obesity and blood pressure disorders are one of the main risk factors for antenatal, intra, postpartum, and neonatal complications. In preeclampsia (PE), the placental hypoxia leads to vascular endothelium dysfunction, cell necrosis, and apoptosis. This condition is associated with the release of free fetal DNA (cffDNA) circulating in plasma. The disturbance of the efficiency of vasodilatation and blood pressure regulation in PE can be confirmed by analyzing the apelin, salusin, and prosalusin. This study aimed to assess the influence of obesity on cffDNA, and the effectiveness of maintaining normal blood pressure in patients with preeclampsia and gestational hypertension. Material and Methods: the research material was blood serum and oral mucosa swabs, obtained from 168 patients. Pregnant women were divided into the following: a control group (C)—67 women; a gestational hypertension group (GH)—35 patients; a preeclampsia with obesity group (PE + O) (pre-gravid BMI > 30)—23 patients. The rest were lean preeclamptic women (PE)—66 patients—(pre-gravid BMI < 25 in 43 women). Results: the cffDNA was observed in 1.50% of women in the C group, in 2.45% in the GH group, but in 18.18% of lean patients with preeclampsia. The cffDNA was detected in 58% of obese pregnant women with PE. The greater the placental hypoxia was in preeclampsia, the less efficient the hypotensive mechanisms, according to an analysis of the studied adipokines. The prosalusin concentration was significantly lower in the PE group with cffDNA than in the PE group without it (p = 0.008). Apelin was higher in the PE group with cffDNA (p = 0.006) compared to other groups. The same results were also observed in the subgroup with obesity. Conclusion: in preeclamptic women, obesity seems to act as an additive factor of placental damage by means of the dysregulation of hypotensive mechanisms.

H2S as a Bridge Linking Inflammation, Oxidative Stress and Endothelial Biology: A Possible Defense in the Fight against SARS-CoV-2 Infection?

The endothelium controls vascular homeostasis through a delicate balance between secretion of vasodilators and vasoconstrictors. The loss of physiological homeostasis leads to endothelial dysfunction, for which inflammatory events represent critical determinants. In this context, therapeutic approaches targeting inflammation-related vascular injury may help for the treatment of cardiovascular disease and a multitude of other conditions related to endothelium dysfunction, including COVID-19. In recent years, within the complexity of the inflammatory scenario related to loss of vessel integrity, hydrogen sulfide (H2S) has aroused great interest due to its importance in different signaling pathways at the endothelial level. In this review, we discuss the effects of H2S, a molecule which has been reported to demonstrate anti-inflammatory activity, in addition to many other biological functions related to endothelium and sulfur-drugs as new possible therapeutic options in diseases involving vascular pathobiology, such as in SARS-CoV-2 infection.

THE ROLE OF ENDOTHELIAL DYSFUNCTION IN INFLAMMATORY BOWEL DISEASES

The purpose of the study – to assess the disorders’ degree of endothelium dysfunction inpatients with nonspecific ulcerative colitis (NUC) and Crohn's disease (CD), dependingon the severity of inflammation.Material and methods. 34 patients with NUC and 18 people with CD with continuousrecurrent courses, 15 patients with NUC and 15 patients with CD in remission wereobserved. The control group included 30 healthy volunteers.Results. It has been established that patients with active NUC had a significantly higherlevel of markers characterizing changes of proliferative (VEGF-165) and adhesive(VCAM-1) endothelial functions vs. control (in 4.62 and 2.01 times) and patients whohad an inactive disease (at 3.95 and 4.62) (p<0.05). In the active course of NUC, VEGF-165 level increased by 3.27 and 5.03 times, the level of VCAM by 1.83 and 2.09 times vs.inactive and control group (p<0.05).In patients with severe and moderate degrees of NUC, we have set an increase in theconcentration of VEGF-165 compared with mild degree, p<0.05. It has been proven thatin severe degree of CD, the concentration of VEGF-165 increased 21.5% vs. moderateactivity and 63.1% vs. mild activity, p<0.05.It has been established that adhesive phenotype of endothelial dysfunction with severeactivity of NUC was associated with an elevated content of adhesion molecule, dependingof activity, p<0.05. The adhesive phenotype of endothelial dysfunction is proved forpatients with severe activity of CD compared with moderate and mild activity, p<0.05.We have revealed a reliable direct regression relationship between the concentration ofthe vascular endothelial growth factor and the activity of UC according to the TrueloveWitts scale (R=0.29, p<0.05), between the CDAI index level in CD and the content ofVCAM-1 (R=0.29, p<0.05).Conclusions. Inflammatory bowel diseases - NUC and CD are accompanied withendothelium dysfunction, proliferative and adhesive phenotypes, associated with theactivity of process.

Worse Course and Bad Prognosis of COVID-19 in Hyper-Homocysteinemia: Role of Some B-Group Vitamins and of Other Compounds

Background: Increased homocysteine serum levels (HHcy) induce Endothelium Dysfunction (ED), responsible of the activation of some proinflammatory agents (“cytokine storm”), the imbalance between vasodilation and vasoconstriction with vasoconstrictive prevalence, increased oxidative stress and hyper-coagulability. Methods: All these events can worsen the course of COVID-19 in HHcy- patients, favoring the evolution towards vasculitis, thromboembolic complications, multi-organ dysfunction until acute respiratory distress and failure. Results: Therefore, Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) also called COVID-19, elapses more dangerously in patients affected by HHcy and can easily complicate with thromboembolic events. But, some vitamins of B-group and other substances could positively affect both high Hcy levels and thrombotic complications of SARS-CoV-2 happening in lungs and other districts. Conclusions: COVID-19 can have a dangerous evolution and a bad prognosis in patients with HHcy. Concerning this, some compounds seem to exert beneficial effects on HHcy, inflammatory and coagulopathic complications.