Endothelial Biomarkers Research Articles

Endothelial Dysfunction Biomarkers and CKD Incidence in the REGARDS Cohort

IntroductionChronic kidney disease (CKD) is only partly caused by traditional risk factors. Endothelial dysfunction is common in CKD and may contribute to CKD incidence. We studied the association of circulating biomarkers reflecting endothelial dysfunction with incident CKD. MethodsREGARDS is a prospective cohort of 30,239 Black or White adults aged ≥45 years. Baseline levels of ICAM-1, VCAM-1, factor VIII, and E-selectin were measured in 3,300 participants without baseline CKD or albuminuria who attended a second visit 9.4 years later. Kidney outcomes were incident CKD (eGFR <60 mL/min/1.73m2 and ≥40% decline or onset of new end stage kidney disease), incident ≥30% eGFR decline, and incident albuminuria (albumin-to-creatinine ratio (ACR) ≥30 mg/g). Sequentially adjusted logistic regression models assessed the association of biomarkers with kidney outcomes. ResultsMedian age of participants was 62, 49% were women, and 46% identified as Black. 228 (6.9%) developed CKD, 613 (18.9%) experienced ≥30% decline in eGFR, and 356 (11.4%) developed albuminuria. The adjusted odds ratios for incident CKD per 1 standard deviation increment biomarker was 1.12 for ICAM-1 (95% CI 1.02-1.22), 1.10 for VCAM-1 (95% CI 1.01-1.20), 1.15 for factor VIII (95% CI 1.06-1.24), and 1.10 for E-selectin (95% CI 1.01-1.20). Results were similar for incident ≥30% eGFR decline but not albuminuria, where only higher factor VIII was positively associated. ConclusionsHigher concentration of ICAM-1, VCAM-1, factor VIII, and E-selectin were associated with incident CKD and ≥30% eGFR decline in a large cohort study. Higher factor VIII was also associated with incident albuminuria.

Association of endothelial dysfunction and peripheral arterial disease with sarcopenia in chronic kidney disease.

Endothelial dysfunction and peripheral arterial disease (PAD), which disturb skeletal muscle microperfusion, are highly prevalent in patients with chronic kidney disease (CKD). We evaluated the association of endothelial dysfunction and PAD with sarcopenia in patients with non-dialysis CKD. This cross-sectional study included 420 patients with stages 3-5 non-dialysis CKD aged 69.0±11.8years. Skeletal muscle index (skeletal muscle mass/height2), handgrip strength, 6-m gait speed and strength of hip flexion and knee extension were measured. Sarcopenia was defined according to the Asian Working Group for Sarcopenia 2019. Endothelial dysfunction and PAD were assessed using the vascular reactivity index (VRI) and ankle-brachial index (ABI), respectively. A VRI<1.0 was classified as poor endothelial function, and an ABI<0.9 was defined as PAD. Additionally, endothelial and inflammatory biomarkers, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), asymmetric dimethylarginine, endothelin-1 (ET-1) and interleukin-6, were measured in a subgroup of 262 patients. Among the participants, 103 (24.5%) were classified as having sarcopenia. Compared with patients without sarcopenia, those with sarcopenia had significantly lower ABI (1.04±0.16 vs. 1.08±0.15, P=0.028 for the right ABI; 1.01±0.16 vs. 1.06±0.16, P=0.002 for the left ABI) and VRI (0.83±0.57 vs. 1.08±0.56, P<0.001) and had higher serum levels of ICAM-1 (P<0.001), VCAM-1 (P=0.003) and ET-1 (P=0.037). Multivariate logistic regression revealed that, beyond age and body mass index, the average ABI (odds ratio [OR]: 0.81/0.1 increase; 95% confidence interval [CI]: 0.67-0.98; P=0.032) and VRI (OR: 0.93/0.1 increase; 95% CI: 0.88-0.98; P=0.010) were independently associated with sarcopenia. Among the endothelial biomarkers measured, ICAM-1 (OR: 2.47/1-SD increase; 95% CI: 1.62-3.75) and VCAM-1 (OR: 1.91/1-SD increase; 95% CI: 1.27-2.87) were independent predictors of sarcopenia. Group stratification based on the cut-offs of VRI and ABI showed that those with both poor VRI and ABI had the greatest risk for sarcopenia (OR: 4.22; 95% CI: 1.69-10.49), compared with those with normal VRI and ABI. Endothelial dysfunction and PAD are independently associated with sarcopenia in patients with stages 3-5 CKD, suggesting the dominant role of vascular dysfunction in sarcopenia.

Inflammatory, metabolic, and endothelial biomarkers before and after pregnancy complications.

Women with gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), and preterm birth (PTB) have excess cardiovascular disease compared with those with uncomplicated births, perhaps related to prepregnancy inflammation, dysmetabolism, or endothelial dysfunction. We included 1238 women in the Coronary Artery Risk Development in Young Adults Study (1985-2011) with 2215 births classified according to outcomes (term, uncomplicated births were the referent). Using repeated measures analysis of variance, we estimated prepregnancy and postpregnancy biomarkers, as well as biomarker change according to pregnancy outcomes, adjusted for confounders. GDM and term HDP groups had higher prepregnancy high-sensitivity C-reactive protein (hsCRP) (+0.37 [95% CI, 0.08-0.65]; +0.29 [95% CI, 0.04-0.55] log mg/L), higher leptin (+0.29 [95% CI, 0.09-0.50]; +0.37 [95% CI, 0.17-0.56] log ng/ml), and lower adiponectin (-0.25 [95% CI, -0.36 to -0.13); -0.11 [95% CI, -0.22 to -0.01] log ng/ml) values than those with uncomplicated births, and these profiles persisted in magnitude postpregnancy. Controlling for body mass index attenuated most profiles, except that lower prepregnancy adiponectin remained associated with GDM. PTB without HDP or GDM was related to lower prepregnancy hsCRP and soluble intercellular adhesion molecule-1 (-0.31 [95% CI, -0.56 to -0.06] log mg/L; -0.05 [95% CI, -0.09 to -0.01] log ng/ml) and a larger leptin increase from before to after pregnancy (+0.20 [95% CI, 0.02-0.37] log ng/ml). Prepregnancy inflammation and metabolic dysfunction contributed to GDM and HDP, perhaps due to higher body mass index. PTB may be related to adverse metabolic changes postpregnancy, although the unexpected endothelial biomarker profile warrants further study.

Lipid profile, inflammatory biomarkers, endothelial dysfunction, and heart rate variability in adolescents with type 1 diabetes. A case-control study among UAE population

BackgroundType 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by the chronic inflammation and cause of endothelial dysfunction (ED). Heart rate variability (HRV) is a marker of sympathetic and parasympathetic autonomic nervous system dysfunction. We investigated the association of lipid profile, inflammatory biomarkers, endothelial dysfunction, and heart rate variability in adolescents with T1DM among UAE population. MethodIn this case-control study we recruited 126 adolescents (13–22 years) from Abu Dhabi, UAE (United Arab Emirates). Demographic, anthropometric, blood and urine samples were collected after an overnight fasting. HRV measurements were determined per Task Force recommendations. Independent t-test or Mann-Whitney U test and Pearson's Chi-squared test were used to compare groups. Adjusted conditional logistic regression model was used to identify the determinants independently associated with T1DM. ResultsThe mean ages in control (n = 47) and patient (n = 79) groups were 17.5 ± 4.6 and 18.6 ± 4.8 years, respectively. A family history of diabetes and waist and hip circumferences significantly differed between the groups (p = 0.030 and 0.010). The patients with T1DM exhibited significantly higher levels of atherogenic markers than control. Endothelial dysfunction biomarkers such as levels of sICAM-1 (p < 0.001), adiponectin (p < 0.001) and 25-hydroxyvitamin D (p < 0.001) were significantly different in the control group compared with those in the T1DM group. There was a significant difference in SDNN intervals, NN50, pNN50, and SD1/SD2 among the two groups. In adjusted analysis, total cholesterol (adjusted Odds Ratio (aOR): 2.78, 95 % CI:1.37–5.64; p = 0.005), LDL (2.66, 95%CI:1.19–5.92; p = 0.017), and triglycerides (5.51, 95%CI:1.57–19.41; p = 0.008) were significantly associated with developing T1DM. The HRV indicators were significantly associated with decrease odds of T1DM after controlling for SBP, BMI, and family history of DM. ConclusionIn this study, adolescents with T1DM showed a significant association with lipid profile, ED, and HRV compared with controls. Thus, an early attention to diabetes control is required to reduce the risk of cardiac autonomic neuropathy leading to various cardiovascular 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 Role of Vascular Endothelial Dysfunction in Hypertension With Hearing Loss

Hypertension can cause hearing loss, but there is no clear definition of the mechanism(s) involved. The study aimed to explore the role of vascular endothelial dysfunction in hypertension with hearing loss. Patients with hypertension were divided into two groups based on hearing loss. Pure tone audiometry (PTA) and endothelial function testing were performed. A total of 216 (432 ears) hypertensive patients were divided into hypertension with hearing loss group (n = 104) and hypertension without hearing loss group (n = 112). The vascular endothelial biomarkers, ET-1 (endothelin-1) and vWF (von Willebrand factor) were significantly higher ( P &lt; .05) in the hypertension with hearing loss group. RHI (reactive hyperemia index), ET-1, and vWF were the factors related to hearing loss. The area under the receiver operating characteristic (ROC) curve (AUC) of RHI in the diagnosis of hypertension with hearing loss was .652 (95% CI .552-.751, P = .005), and the Youden index was 26.2%. The AUC of ET-1 was .706 (95% CI .612-.799, P = .001), and the Youden index was 38.9%. The AUC of vWF was .617 (95% CI .512-.721, P = .003), and the Youden index was 28.1%. Vascular endothelial dysfunction may play a role in the pathogenesis of hypertension with hearing loss.

Biomarker Assessment of a High-Risk, Data-Driven Pediatric Sepsis Phenotype Characterized by Persistent Hypoxemia, Encephalopathy, and Shock.

Identification of children with sepsis-associated multiple organ dysfunction syndrome (MODS) at risk for poor outcomes remains a challenge. We sought to the determine reproducibility of the data-driven "persistent hypoxemia, encephalopathy, and shock" (PHES) phenotype and determine its association with inflammatory and endothelial biomarkers, as well as biomarker-based pediatric risk strata. We retrained and validated a random forest classifier using organ dysfunction subscores in the 2012-2018 electronic health record (EHR) dataset used to derive the PHES phenotype. We used this classifier to assign phenotype membership in a test set consisting of prospectively (2003-2023) enrolled pediatric septic shock patients. We compared profiles of the PERSEVERE family of biomarkers among those with and without the PHES phenotype and determined the association with established biomarker-based mortality and MODS risk strata. Twenty-five PICUs across the United States. EHR data from 15,246 critically ill patients with sepsis-associated MODS split into derivation and validation sets and 1,270 pediatric septic shock patients in the test set of whom 615 had complete biomarker data. None. The area under the receiver operator characteristic curve of the modified classifier to predict PHES phenotype membership was 0.91 (95% CI, 0.90-0.92) in the EHR validation set. In the test set, PHES phenotype membership was associated with both increased adjusted odds of complicated course (adjusted odds ratio [aOR] 4.1; 95% CI, 3.2-5.4) and 28-day mortality (aOR of 4.8; 95% CI, 3.11-7.25) after controlling for age, severity of illness, and immunocompromised status. Patients belonging to the PHES phenotype were characterized by greater degree of systemic inflammation and endothelial activation, and were more likely to be stratified as high risk based on PERSEVERE biomarkers predictive of death and persistent MODS. The PHES trajectory-based phenotype is reproducible, independently associated with poor clinical outcomes, and overlapped with higher risk strata based on prospectively validated biomarker approaches.

Gut Microbiota and Biomarkers of Endothelial Dysfunction in Cirrhosis.

Our aim was to study the association of endothelial dysfunction biomarkers with cirrhosis manifestations, bacterial translocation, and gut microbiota taxa. The fecal microbiome was assessed using 16S rRNA gene sequencing. Plasma levels of nitrite, big endothelin-1, asymmetric dimethylarginine (ADMA), presepsin, and claudin were measured as biomarkers of endothelial dysfunction, bacterial translocation, and intestinal barrier dysfunction. An echocardiography with simultaneous determination of blood pressure and heart rate was performed to evaluate hemodynamic parameters. Presepsin, claudin 3, nitrite, and ADMA levels were higher in cirrhosis patients than in controls. Elevated nitrite levels were associated with high levels of presepsin and claudin 3, the development of hemodynamic circulation, hypoalbuminemia, grade 2-3 ascites, overt hepatic encephalopathy, high mean pulmonary artery pressure, increased abundance of Proteobacteria and Erysipelatoclostridium, and decreased abundance of Oscillospiraceae, Subdoligranulum, Rikenellaceae, Acidaminococcaceae, Christensenellaceae, and Anaerovoracaceae. Elevated ADMA levels were associated with higher Child-Pugh scores, lower serum sodium levels, hypoalbuminemia, grade 2-3 ascites, milder esophageal varices, overt hepatic encephalopathy, lower mean pulmonary artery pressure, and low abundance of Erysipelotrichia and Erysipelatoclostridiaceae. High big endothelin-1 levels were associated with high levels of presepsin and sodium, low levels of fibrinogen and cholesterol, hypocoagulation, increased Bilophila and Coprobacillus abundances, and decreased Alloprevotella abundance.

Efficacy and Safety of a Probiotic Containing Saccharomyces boulardii CNCM I-745 in the Treatment of Small Intestinal Bacterial Overgrowth in Decompensated Cirrhosis: Randomized, Placebo-Controlled Study

(1) Background: The aim was to evaluate the effectiveness of the probiotic containing Saccharomyces boulardii in the treatment of small intestinal bacterial overgrowth (SIBO) in patients with decompensated cirrhosis. (2) Methods: This was a blinded, randomized, placebo-controlled study. (3) Results: After 3 months of treatment, SIBO was absent in 80.0% of patients in the probiotic group and in 23.1% of patients in the placebo group (p = 0.002). The patients with eliminated SIBO had decreased frequency of ascites and hepatic encephalopathy, the increased platelets and albumin levels, the decreased blood levels of total bilirubin, biomarkers of bacterial translocation (lipopolysaccharide [LPS]) and systemic inflammation (C-reactive protein), and positive changes in markers of hyperdynamic circulation compared with the state at inclusion. There were no significant changes in the claudin 3 level (the intestinal barrier biomarker) in these patients. No significant changes were observed in the group of patients with persistent SIBO. The serum level of nitrate (endothelial dysfunction biomarker) was lower in patients with eradicated SIBO than in patients with persistent SIBO. One (5.3%) patient with eradicated SIBO and six (42.9%) patients with persistent SIBO died within the first year of follow-up (p = 0.007). (4) Conclusions: SIBO eradication was an independent predictor of a favorable prognosis during the first year of follow-up.

ITRI Biofilm Prevented Thoracic Adhesion in Pigs That Received Myocardial Ischemic Induction Treated by Myocardial Implantation of EPCs and ECSW Treatment.

This study tested the hypothesis that ITRI Biofilm prevents adhesion of the chest cavity. Combined extracorporeal shock wave (ECSW) + bone marrow-derived autologous endothelial progenitor cell (EPC) therapy was superior to monotherapy for improving heart function (left ventricular ejection fraction [LVEF]) in minipigs with ischemic cardiomyopathy (IC) induced by an ameroid constrictor applied to the mid-left anterior descending artery. The minipigs (n = 30) were equally designed into group 1 (sham-operated control), group 2 (IC), group 3 (IC + EPCs/by directly implanted into the left ventricular [LV] myocardium; 3 [+]/3[-] ITRI Biofilm), group 4 (IC + ECSW; 3 [+]/[3] - ITRI Biofilm), and group 5 (IC + EPCs-ECSW; 3 [+]/[3] - ITRI Biofilm). EPC/ECSW therapy was administered by day 90, and the animals were euthanized, followed by heart harvesting by day 180. In vitro studies demonstrated that cell viability/angiogenesis/cell migratory abilities/mitochondrial concentrations were upregulated in EPCs treated with ECSW compared with those in EPCs only (all Ps < 0.001). The LVEF was highest in group 1/lowest in group 2/significantly higher in group 5 than in groups 3/4 (all Ps < 0.0001) by day 180, but there was no difference in groups 3/4. The adhesion score was remarkably lower in patients who received ITRI Biofilm treatment than in those who did not (all Ps <0.01). The protein expressions of oxidative stress (NOX-1/NOX-2/oxidized protein)/apoptotic (mitochondrial-Bax/caspase3/PARP)/fibrotic (TGF-β/Smad3)/DNA/mitochondria-damaged (γ-H2AX/cytosolic-cytochrome-C/p-DRP1), and heart failure/pressure-overload (BNP [brain natriuretic peptide]/β-MHC [beta myosin heavy chain]) biomarkers displayed a contradictory manner of LVEF among the groups (all Ps < 0.0001). The protein expression of endothelial biomarkers (CD31/vWF)/small-vessel density revealed a similar LVEF within the groups (all Ps < 0.0001). ITRI Biofilm treatment prevented chest cavity adhesion and was superior in restoring IC-related LV dysfunction when combined with EPC/ECSW therapy compared with EPC/ECSW therapy alone.

Role of biomarkers and molecular signaling pathways in acute lung injury.

Acute lung injury (ALI) is caused by bacterial, fungal, and viral infections. When pathogens invade the lungs, the immune system responds by producing cytokines, chemokines, and interferons to promote the infiltration of phagocytic cells, which are essential for pathogen clearance. Their excess production causes an overactive immune response and a pathological hyper-inflammatory state, which leads to ALI. Until now, there is no particular pharmaceutical treatment available for ALI despite known inflammatory mediators like neutrophil extracellular traps (NETs) and reactive oxygen species (ROS). Therefore, the primary objective of this review is to provide the clear overview on the mechanisms controlling NETs, ROS formation, and other relevant processes during the pathogenesis of ALI. In addition, we have discussed the significance of epithelial and endothelial damage indicators and several molecular signaling pathways associated with ALI. The literature review was done from Web of Science, Scopus, PubMed, and Google Scholar for ALI, NETs, ROS, inflammation, biomarkers, Toll- and nucleotide-binding oligomerization domain (NOD)-like receptors, alveolar damage, pro-inflammatory cytokines, and epithelial/endothelial damage alone or in combination. This review summarized the main clinical signs of ALI, including the regulation and distinct function of epithelial and endothelial biomarkers, NETs, ROS, and pattern recognition receptors (PRRs). However, no particular drugs including vaccine for ALI has been established. Furthermore, there is a lack of validated diagnostic tools and a poor predictive rationality of current therapeutic biomarkers. Hence, extensive and precise research is required to speed up the process of drug testing and development by the application of artificial intelligence technologies, structure-based drug design, in-silico approaches, and drug repurposing.

The association between prolonged capillary refill time and microcirculation changes in children with sepsis

BackgroundsIn children with sepsis, circulatory shock and multi-organ failure remain major contributors to mortality. Prolonged capillary refill time (PCRT) is a clinical tool associated with disease severity and tissue hypoperfusion. Microcirculation assessment with videomicroscopy represents a promising candidate for assessing and improving hemodynamic management strategies in children with sepsis. Particularly when there is loss of coherence between the macro and microcirculation (hemodynamic incoherence). We sought to evaluate the association between PCRT and microcirculation changes in sepsis.MethodsThis was a prospective cohort study in children hospitalized with sepsis. Microcirculation was measured using sublingual video microscopy (capillary density and flow and perfused boundary region [PBR]—a parameter inversely proportional to vascular endothelial glycocalyx thickness), phalangeal tissue perfusion, and endothelial activation and glycocalyx injury biomarkers. The primary outcome was the association between PCRT and microcirculation changes.ResultsA total of 132 children with sepsis were included, with a median age of two years (IQR 0.6–12.2). PCRT was associated with increased glycocalyx degradation (PBR 2.21 vs. 2.08 microns; aOR 2.65, 95% CI 1.09–6.34; p = 0.02) and fewer 4–6 micron capillaries recruited (p = 0.03), with no changes in the percentage of capillary blood volume (p = 0.13). Patients with hemodynamic incoherence had more PBR abnormalities (78.4% vs. 60.8%; aOR 2.58, 95% CI 1.06–6.29; p = 0.03) and the persistence of these abnormalities after six hours was associated with higher mortality (16.5% vs. 6.1%; p < 0.01). Children with an elevated arterio-venous CO2 difference (DCO2) had an abnormal PBR (aOR 1.13, 95% CI 1.01–1.26; p = 0.03) and a lower density of small capillaries (p < 0.05). Prolonged capillary refill time predicted an abnormal PBR (AUROC 0.81, 95% CI 0.64–0.98; p = 0.03) and relative percentage of blood in the capillaries (AUROC 0.82, 95% CI 0.58–1.00; p = 0.03) on admission. A normal CRT at 24 h predicted a shorter hospital stay (aOR 0.96, 95% CI 0.94–0.99; p < 0.05).ConclusionsWe found an association between PCRT and microcirculation changes in children with sepsis. These patients had fewer small capillaries recruited and more endothelial glycocalyx degradation. This leads to nonperfused capillaries, affecting oxygen delivery to the tissues. These disorders were associated with hemodynamic incoherence and worse clinical outcomes when the CRT continued to be abnormal 24 h after admission.

Liposomal-Associated Phospholipase A 2 Is More Effective in Predicting Cardiac Risk in Law Enforcement Than Framingham Risk Score and Coronary Artery Calcium Score Calculation.

To clarify the methods for identifying officers at high risk for cardiac events. This retrospective review included 3330 patient charts. Classic cardiovascular risk factors, coronary artery calcium (CAC) scores, and endothelial inflammatory biomarker levels were compared between civilians and law enforcement officers (LEOs). The Framingham Risk Score (FRS) was compared with risk assessment using inflammatory biomarkers. The FRS failed to identify more than 90% of LEOs at high risk of cardiovascular events. Similarly, the use of the CAC score was ineffective. Inflammatory biomarker analysis measuring the lipoprotein-associated phospholipase A 2 activity was the most reliable method for identifying LEOs at high risk of cardiovascular events. The use of the standard FRS and CAC scores is less effective than that of inflammatory biomarkers in identifying LEOs at high risk of cardiovascular events.

Empagliflozin improves vascular insulin sensitivity and muscle perfusion in persons with type 2 diabetes.

Sodium glucose cotransporter 2 inhibitors (SGLT2is) improved major adverse cardiovascular events (MACE), heart failure, and renal outcomes in large trials; however, a thorough understanding of the vascular physiological changes contributing to these responses is lacking. We hypothesized that SGLT2i therapy would diminish vascular insulin resistance and improve hemodynamic function, which could improve clinical outcomes. To test this, we treated 11 persons with type 2 diabetes for 12 wk with 10 mg/day empagliflozin and measured vascular stiffness, endothelial function, peripheral and central arterial pressures, skeletal and cardiac muscle perfusion, and vascular biomarkers before and at 120 min of a euglycemic hyperinsulinemic clamp at weeks 0 and 12. We found that before empagliflozin treatment, insulin infusion lowered peripheral and central aortic systolic pressure (P < 0.05) and muscle microvascular blood flow (P < 0.01), but showed no effect on other vascular measures. Following empagliflozin, insulin infusion improved endothelial function (P = 0.02), lowered peripheral and aortic systolic (each P < 0.01), diastolic (each P < 0.05), mean arterial (each P < 0.01), and pulse pressures (each P < 0.02), altered endothelial biomarker expression, and decreased radial artery forward and backward pressure amplitude (each P = 0.02). Empagliflozin also improved insulin-mediated skeletal and cardiac muscle microvascular perfusion (each P < 0.05). We conclude that empagliflozin enhances insulin's vascular actions, which could contribute to the improved cardiorenal outcomes seen with SGLT2i therapy.NEW & NOTEWORTHY The physiological underpinnings of the cardiovascular benefits of SGLT2 inhibitors remain uncertain. We tested whether empagliflozin mitigates vascular insulin resistance in patients with type 2 diabetes. Aortic and peripheral systolic, diastolic, mean and pulse pressures, endothelial function, vascular stiffness, and heart and muscle microvascular perfusion were measured before and during an insulin infusion at baseline and after 12 wk of empagliflozin. After empagliflozin, vascular responses to insulin improved dramatically.

Astragaloside IV Mediates the PI3K/Akt/mTOR Pathway to Alleviate Injury and Modulate the Composition of Intestinal Flora in ApoE-/- Atherosclerosis Model Rats.

Atherosclerosis (AS) is a chronic inflammatory vascular disease with a complex pathogenesis. Astragaloside IV (AST IV), the primary active component of Astragalus, possesses anti-inflammatory, antioxidant, and immunomodulatory properties. This research aims to investigate the outcome of AST IV on AS and its potential molecular mechanism. A high-fat diet (21% fat, 50% carbohydrate, 20% protein, 0.15% cholesterol, and 34% sucrose) was utilized to feed Apolipoprotein E deficient (ApoE-/-) SD rats for 8 weeks, followed by continuous intragastric administration of AST IV for 8 weeks. Biochemical detection was conducted for serum lipid levels and changes in vasoactive substances. After Masson staining, aortic root oil red O staining, and Hematoxylin Eosin (HE) staining, the efficacy of AST IV was verified using quantitative reverse transcription polymerase chain reaction (qRT-PCR). The mRNA expression levels of inflammatory factors and endothelial dysfunction-related biomarkers in rat aortic root tissues were appraised. The changes in the composition of intestinal flora in rats after AST IV treatment were appraised using Image J (Multi-point Tool). Western blot was used to evaluate phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway-related protein levels in rat aortic root tissues. AST IV administration alleviated the pathological symptoms of AS rats. AST IV administration reduced serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), endothelin-1 (ET-1) and angiotensin (Ang)-II (Ang-II) levels, and augmented serum high-density lipoprotein cholesterol (HDL-C) and nitric oxide (NO) levels. At the same time, AST IV administration inhibited the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, vascular cell adhesion molecule-1 (VCAM-1), matrix metalloproteinase-2 (MMP-2), macrophage inflammatory protein-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) in the aortic root tissue of AS rats. In addition, the intestinal flora changed significantly after AST IV administration. The number of Bifidobacterium, Lactobacillus, and Bacteroides augmented significantly, and Enterobacter, Enterococcus, Fusobacterium, and Clostridium significantly decreased. Mechanistically, AST IV administration inhibited the phosphorylation of PI3K, Akt, and mTOR in AS rats. When combined with Dactolisib (BEZ235) (a PI3K/Akt/mTOR pathway inhibitor), AST IV could further inhibit phosphorylation and reduce inflammation. AST IV has a potential anti-AS effect, which can improve the pathological changes of the aorta in ApoE-/- rats fed with a high-fat diet, reduce the level of inflammatory factors, and modulate the composition of intestinal flora via the PI3K/Akt/mTOR pathway.

Effect of Yoga-Based Cardiac Rehabilitation Program on Endothelial Function, Oxidative Stress, and Inflammatory Markers in Acute Myocardial Infarction: A Randomized Controlled Trial.

The aim of this study was to evaluate the effects of yoga-based cardiac rehabilitation (Yoga-CaRe) on the endothelial system, oxidative stress, and inflammatory markers in patients with acute myocardial infarction (MI). A sub-study was conducted in two clinical sites of the Yoga-CaRe trial (a multicenter randomized controlled trial). Participants with acute MI were randomized and allocated to either the Yoga-CaRe program (13 sessions with encouragement to home practice) or enhanced standard care (three educational sessions). Endothelial function, oxidative stress, and inflammatory biomarkers were assessed using biomarkers such as asymmetric dimethylarginine (ADMA), endothelial nitric oxide synthase (eNOS), endothelin-1 (ET-1), E-selectin, P-selectin, vascular cell adhesion molecule (VCAM), intercellular cell-adhesion molecule-1, total nitric oxide concentration (NOx), oxidized low-density lipoprotein (Oxd-LDL), superoxide dismutase, total antioxidant capacity (TAOC), tumor necrosis factor-alpha (TNFα), and C-reactive protein (CRP) at baseline and 12 weeks. Laboratory and statistical analysis were done by staff blinded to group allocation. Eighty-two patients (of the 110 patients recruited) completed the study. The mean age was 53.1 ± 10.6 and 51.9 ± 10.7 years in enhanced standard care and Yoga-CaRe group, respectively. At 12 weeks, Yoga-CaRe significantly reduced ADMA, ET-1, and ICMA-1 than the enhanced standard care group. Although E-selectin and VCAM at 12 weeks were reduced in both groups, enhanced standard care had a significantly higher reduction than the Yoga-CaRe group. Among markers of oxidative stress, TAOC increased in the Yoga-CaRe group. We found no difference in eNOS, NOx, P-selectin, TNFα, CRP, and Oxd-LDL between the two groups. Yoga-CaRe improved the endothelial function (through a reduction in ET-1 and modulating adhesion molecules) and enhanced antioxidant capacity.

Increased Levels of VCAM-1 in Patients with High Cardiovascular Risk and Obstructive Sleep Apnea Syndrome.

(1) Background: Although obstructive sleep apnea (OSA) is associated with increased cardiovascular morbidity, the link between OSA and cardiovascular disease (CVD) is not completely elucidated. Thus, we aim to assess cardiovascular risk (CVR) using SCORE 2 and SCORE 2 for older persons (SCORE 2OP), and to evaluate the association between the endothelial biomarkers VCAM-1, ICAM-1, epicardial fat, and sleep study parameters in order to improve current clinical practices and better understand the short-and long-term CVRs in OSA patients. (2) Methods: 80 OSA patients and 37 healthy volunteers were enrolled in the study. SCORE2 and SCORE 2 OP regional risk charts (validated algorithms to predict the 10-year risk of first-onset CVD) were used for the analysis of CVR. Two-dimensional echocardiography was performed on all patients and epicardial fat thickness was measured. VCAM-1 and ICAM-1 serum levels were assessed in all patients. (3) Results: OSA patients were classified as being at high CVR, regardless of the type of score achieved. Increased EFT was observed in the OSA group. VCAM-1 was associated with a high CVR in OSA patients, but no significant correlation was observed between adhesion molecules and epicardial fat thickness. (4) Conclusions: OSA patients have a high CVR according to the SCORE 2 and SCORE 2OP risk scores. VCAM-1 may be associated with a high CVR in OSA patients. Extending conventional risk stratification scores by adding other potential biomarkers improves the risk stratification and guide treatment eligibility for CVD prevention in the OSA population.

Whole blood transcriptomics identifies subclasses of pediatric septic shock

BackgroundSepsis is a highly heterogeneous syndrome, which has hindered the development of effective therapies. This has prompted investigators to develop a precision medicine approach aimed at identifying biologically homogenous subgroups of patients with septic shock and critical illnesses. Transcriptomic analysis can identify subclasses derived from differences in underlying pathophysiological processes that may provide the basis for new targeted therapies. The goal of this study was to elucidate pathophysiological pathways and identify pediatric septic shock subclasses based on whole blood RNA expression profiles.MethodsThe subjects were critically ill children with cardiopulmonary failure who were a part of a prospective randomized insulin titration trial to treat hyperglycemia. Genome-wide expression profiling was conducted using RNA sequencing from whole blood samples obtained from 46 children with septic shock and 52 mechanically ventilated noninfected controls without shock. Patients with septic shock were allocated to subclasses based on hierarchical clustering of gene expression profiles, and we then compared clinical characteristics, plasma inflammatory markers, cell compositions using GEDIT, and immune repertoires using Imrep between the two subclasses.ResultsPatients with septic shock depicted alterations in innate and adaptive immune pathways. Among patients with septic shock, we identified two subtypes based on gene expression patterns. Compared with Subclass 2, Subclass 1 was characterized by upregulation of innate immunity pathways and downregulation of adaptive immunity pathways. Subclass 1 had significantly worse clinical outcomes despite the two classes having similar illness severity on initial clinical presentation. Subclass 1 had elevated levels of plasma inflammatory cytokines and endothelial injury biomarkers and demonstrated decreased percentages of CD4 T cells and B cells and less diverse T cell receptor repertoires.ConclusionsTwo subclasses of pediatric septic shock patients were discovered through genome-wide expression profiling based on whole blood RNA sequencing with major biological and clinical differences.Trial Registration This is a secondary analysis of data generated as part of the observational CAF-PINT ancillary of the HALF-PINT study (NCT01565941). Registered March 29, 2012.

Development of a Multi-Organ Radiation Injury Model with Precise Dosimetry with Focus on GI-ARS.

The goal of this study was to establish a model of partial-body irradiation (PBI) sparing 2.5% of the bone marrow (BM2.5-PBI) that accurately recapitulates radiological/nuclear exposure scenarios. Here we have reported a model which produces gastrointestinal (GI) damage utilizing a clinical linear accelerator (LINAC) with precise dosimetry, which can be used to develop medical countermeasures (MCM) for GI acute radiation syndrome (ARS) under the FDA animal rule. The PBI model (1 hind leg spared) was developed in male and female C57BL/6 mice that received radiation doses ranging from 12-17 Gy with no supportive care. GI pathophysiology was assessed by crypt cell loss and correlated with peak lethality between days 4 and 10 after PBI. The radiation dose resulting in 50% mortality in 30 days (LD50/30) was determined by probit analysis. Differential blood cell counts in peripheral blood, colony forming units (CFU) in bone marrow, and sternal megakaryocytes were analyzed between days 1-30, to assess the extent of hematopoietic ARS (H-ARS) injury. Radiation-induced GI damage was also assessed by measuring: 1. bacterial load (16S rRNA) by RT-PCR on days 4 and 7 after PBI in liver, spleen and jejunum, 2. liposaccharide binding protein (LBP) levels in liver, and 3. fluorescein isothiocyanate (FITC)-dextran, E-selectin, sP-selectin, VEGF, FGF-2, MMP-9, citrulline, and serum amyloid A (SAA) levels in serum. The LD50/30 of male mice was 14.3 Gy (95% confidence interval 14.1-14.7 Gy) and of female mice was 14.5 Gy (95% confidence interval 14.3-14.7 Gy). Secondary endpoints included loss of viable crypts, higher bacterial loads in spleen and liver, higher LBP in liver, increased FITC-dextran and SAA levels, and decreased levels of citrulline and endothelial biomarkers in serum. The BM2.5-PBI model, developed for the first time with precise dosimetry, showed acute radiation-induced GI damage that is correlated with lethality, as well as a response to various markers of inflammation and vascular damage. Sex-specific differences were observed with respect to radiation dose response. Currently, no MCM is available as a mitigator for GI-ARS. This BM2.5-PBI mouse model can be regarded as the first high-throughput PBI model with precise dosimetry for developing MCMs for GI-ARS under the FDA animal rule.

Endothelial Biomarkers in Critically Ill COVID-19 Patients: Potential Predictors of the Need for Dialysis

Plain Language SummaryThis study reports the use of endothelial biomarkers as useful tools to predict the first dialysis requirement during the ICU stay in patients with severe COVID-19. Endothelial dysfunction is an important mechanism to explain the pathophysiology of acute kidney injury caused by severe acute respiratory syndrome coronavirus 2 infection.