ResearchPad - vascular-diseases https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[A three-dimensional phase-field model for multiscale modeling of thrombus biomechanics in blood vessels]]> https://www.researchpad.co/article/elastic_article_14644 Thromboembolism is associated with detachment of small thrombus pieces from the bulk in the blood vessel. These detached pieces, also known as emboli, travel through the blood flow and may block other vessels downstream, e.g., they may plug the deep veins of the leg, groin or arm, leading to venous thromboembolism (VTE). VTE is a significant cause of morbidity and mortality and it affects more than 900,000 people in the United States and result in approximately 100,000 deaths every year. Mechanical interaction between flowing blood and a thrombus is crucial in determining the deformation of the thrombus and the possibility of releasing emboli. In this study, we develop a phase-field model that is capable of describing the structural properties of a thrombus and its biomechanical properties under different blood flow conditions. Moreover, we combine this thrombus model with a particle-based model which simulates the initiation of the thrombus. This combined framework is the first computational study to simulate the development of a thrombus from platelet aggregation to its subsequent viscoelastic responses to various shear flows. Informed by clinical data, this framework can be used to predict the risk of diverse thromboembolic events under physiological and pathological conditions.

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<![CDATA[Proenkephalin A Adds No Incremental Prognostic Value After Acute Ischemic Stroke]]> https://www.researchpad.co/article/Nb42a9d58-70ec-4363-8ab0-eda7cb7c696a

Objective:

The aim of this study was to confirm previous observations that proenkephalin A (PENK-A) may serve as prognostic marker in the setting of acute ischemic stroke in a large stroke cohort.

Methods:

The plasma concentration of PENK-A was measured within 72 hours of symptom onset in 320 consecutively enrolled patients with stroke. The primary outcome measures were unfavorable functional outcome (modified Rankin Scale score 0-2 vs 3-6) and mortality within 90 days. Logistic and cox proportional regression analyses were fitted to estimate odds ratios (ORs), hazard ratios (HRs) and 95% confidence intervals (CIs), respectively, for the association between PENK-A and the primary outcome measures.

Results:

After adjusting for demographic and vascular risk factors, PENK-A was neither independently associated with functional outcome (OR: 1.29, 95% CI: 0.16-10.35) nor mortality (HR: 1.02, 95% CI: 0.14-7.33).

Conclusion:

Among patients with acute stroke, PENK-A does not serve as an independent prognostic marker in this external validation cohort.

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<![CDATA[Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios Predict All-Cause Mortality in Acute Pulmonary Embolism]]> https://www.researchpad.co/article/N7351fb3a-ec25-48dc-bcb8-e0d04a90c0cb

The aim of this study was to investigate the utility of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) to predict all-cause mortality in patients presenting with acute pulmonary embolism (PE). Three hundred consecutive patients with acute PE between March 2016 and December 2018 were retrospectively analyzed. We identified 191 patients who met the study inclusion criteria. Twenty-eight patients died during the study period. There was a significant difference in PLR, but not NLR, between patients with low risk, submassive, and massive risk PE (P = .02 and P = .58, respectively, by the Kruskal-Wallis test). Elevated NLR and PLR were associated with all-cause mortality (P < .01 and P < .01, respectively). Neutrophil-to-lymphocyte ratio of 5.46 was associated with all-cause mortality with sensitivity of 75.0% and specificity of 66.9% (area under the curve [AUC]: 0.692 [95% confidence interval, CI]: 0.568-0.816); P < .01). Platelet-to-lymphocyte ratio of 256.6 was associated with all-cause mortality with sensitivity of 53.6% and specificity of 82.2% (AUC: 0.693 [95% CI: 0.580-0.805]; P < .01). Neutrophil-to-lymphocyte ratio and PLR are simple biomarkers that are readily available from routine laboratory values and may be useful components of PE risk prediction models.

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<![CDATA[Whole exome sequencing identifies MRVI1 as a susceptibility gene for moyamoya syndrome in neurofibromatosis type 1]]> https://www.researchpad.co/article/5b5c0709463d7e28a3e55d74

Background and purpose

Moyamoya angiopathy is a progressive cerebral vasculopathy. The p.R4810K substitution in RNF213 has previously been linked to moyamoya disease in Asian populations. When associated with other medical conditions, such as neurofibromatosis type 1, this vasculopathy is frequently reported as moyamoya syndrome. Intriguingly, most cases of moyamoya-complicated neurofibromatosis type 1 have been described in Caucasians, inverting the population ratio observed in Asians, although prevalence of neurofibromatosis type 1 is constant worldwide. Our aim was to investigate whether, among Caucasians, additive genetic factors may contribute to the occurrence of moyamoya in neurofibromatosis type 1.

Methods

Whole exome sequencing was carried out on an Italian family with moyamoya-complicated neurofibromatosis type 1 to identify putative genetic modifiers independent of the NF1 locus and potentially involved in moyamoya pathogenesis. Results were validated in an unrelated family of German ancestry.

Results

We identified the p.P186S substitution (rs35857561) in MRVI1 that segregated with moyamoya syndrome in both the Italian and German family.

Conclusions

The rs35857561 polymorphism in MRVI1 may be a genetic susceptibility factor for moyamoya in European patients with neurofibromatosis type 1. MRVI1 is a functional partner of ITPR1, PRKG1 and GUCY1A3, which are involved in response to nitric oxide. Mutations in GUCY1A3 have been recently linked to a recessive syndromic form of moyamoya with esophageal achalasia.

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<![CDATA[The Redox State of Transglutaminase 2 Controls Arterial Remodeling]]> https://www.researchpad.co/article/5989db05ab0ee8fa60bc8226

While inward remodeling of small arteries in response to low blood flow, hypertension, and chronic vasoconstriction depends on type 2 transglutaminase (TG2), the mechanisms of action have remained unresolved. We studied the regulation of TG2 activity, its (sub) cellular localization, substrates, and its specific mode of action during small artery inward remodeling. We found that inward remodeling of isolated mouse mesenteric arteries by exogenous TG2 required the presence of a reducing agent. The effect of TG2 depended on its cross-linking activity, as indicated by the lack of effect of mutant TG2. The cell-permeable reducing agent DTT, but not the cell-impermeable reducing agent TCEP, induced translocation of endogenous TG2 and high membrane-bound transglutaminase activity. This coincided with inward remodeling, characterized by a stiffening of the artery. The remodeling could be inhibited by a TG2 inhibitor and by the nitric oxide donor, SNAP. Using a pull-down assay and mass spectrometry, 21 proteins were identified as TG2 cross-linking substrates, including fibronectin, collagen and nidogen. Inward remodeling induced by low blood flow was associated with the upregulation of several anti-oxidant proteins, notably glutathione-S-transferase, and selenoprotein P. In conclusion, these results show that a reduced state induces smooth muscle membrane-bound TG2 activity. Inward remodeling results from the cross-linking of vicinal matrix proteins, causing a stiffening of the arterial wall.

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<![CDATA[PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance]]> https://www.researchpad.co/article/5989db41ab0ee8fa60bd6d33

Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, dissection and aneurysm affecting mainly the renal and cerebrovascular arteries. FMD is often an underdiagnosed cause of hypertension and stroke, has higher prevalence in females (~80%) but its pathophysiology is unclear. We analyzed ~26K common variants (MAF>0.05) generated by exome-chip arrays in 249 FMD patients and 689 controls. We replicated 13 loci (P<10−4) in 402 cases and 2,537 controls and confirmed an association between FMD and a variant in the phosphatase and actin regulator 1 gene (PHACTR1). Three additional case control cohorts including 512 cases and 669 replicated this result and overall reached the genomic level of significance (OR = 1.39, P = 7.4×10−10, 1,154 cases and 3,895 controls). The top variant, rs9349379, is intronic to PHACTR1, a risk locus for coronary artery disease, migraine, and cervical artery dissection. The analyses of geometrical parameters of carotids from ~2,500 healthy volunteers indicate higher intima media thickness (P = 1.97×10−4) and wall to lumen ratio (P = 0.002) in rs9349379-A carriers, suggesting indices of carotid hypertrophy previously described in carotids of FMD patients. Immunohistochemistry detected PHACTR1 in endothelium and smooth muscle cells of FMD and normal human carotids. The expression of PHACTR1 by genotypes in primary human fibroblasts showed higher expression in rs9349379-A carriers (N = 86, P = 0.003). Phactr1 knockdown in zebrafish resulted in dilated vessels indicating subtle impaired vascular development.

We report the first susceptibility locus for FMD and provide evidence for a complex genetic pattern of inheritance and indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.

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<![CDATA[Requirements for Membrane Attack Complex Formation and Anaphylatoxins Binding to Collagen-Activated Platelets]]> https://www.researchpad.co/article/5989d9e2ab0ee8fa60b6a053

Background

The activation of complement during platelet activation is incompletely understood. Objectives: We sought to explore the formation of C5b-9 and anaphylatoxins binding to collagen-activated platelets.

Methods

C5b-9, anaphylatoxins C3a, C4a and C5a, and anaphylatoxin receptors C3aR1 and C5aR were measured by flow cytometry and/or confocal microscopy. Platelet microparticles were quantified by flow cytometry, and their C5b-9 content was determined by western blot analyses. In all experiments, sodium citrate was used for blood anticoagulation.

Results

C5b-9 rapidly formed on the platelet surface following activation with collagen, TRAP, ADP or A23187, but was surprisingly restricted to a subset of platelets (1 to 15%) independently of P-selectin or phosphatidylserine exposure. Following collagen activation, C5b-9-positive platelets in thrombi were found associated with collagen fibres. C5b-9 formation was obliterated by Mg2+-EGTA and significantly reduced by the thrombin inhibitor hirudin (−37%, p<0.05), but was unaffected by chondroitinase, compstatin, SCH79797 (PAR-1 inhibitor), or in the PRP of a MBL-deficient donor. Compstatin and Mg2+-EGTA, but not hirudin, SCH79797 or chondroitinase, inhibited the formation of collagen-induced microparticles (−71% and −44%, respectively, p<0.04). These microparticles contained greater amounts of C5b-9 compared with the other agonists. Platelet activation by collagen or convulxin resulted in the strong binding of anaphylatoxins and the exposure of receptors C3aR1 and C5aR (CD88) on their surface.

Conclusions

C5b-9 formation on collagen-activated platelets is i) partially controlled by thrombin, ii) restricted to a subset of platelets, and iii) can occur without P-selectin expression or phosphatidylserine exposure. Activated platelets bind anaphylatoxins on their surface and express C3a and C5a receptors, which may contribute to the localization of inflammatory processes during thrombosis.

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<![CDATA[Abnormally Low and High Ankle-Brachial Indices Are Independently Associated with Increased Left Ventricular Mass Index in Chronic Kidney Disease]]> https://www.researchpad.co/article/5989da0aab0ee8fa60b773a8

Abnormally low and high ankle-brachial indices (ABIs) are associated with high cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD), but the mechanisms responsible for the association are not fully known. This study is designed to assess whether there is a significant correlation between abnormal ABI and echocariographic parameters in patients with CKD stages 3–5. A total of 684 pre-dialysis CKD patients were included in the study. The ABI was measured using an ABI-form device. Patients were classified into ABI <0.9, ≥0.9 to <1.3, and ≥1.3. Clinical and echocariographic parameters were compared and analyzed. Compared with patients with ABI of ≥0.9 to <1.3, the values of left ventricular mass index (LVMI) were higher in patients with ABI <0.9 and ABI ≥1.3 (P≤0.004). After the multivariate analysis, patients with ABI <0.9 (β = 0.099, P = 0.004) and ABI ≥1.3 (β = 0.143, P<0.001) were independently associated with increased LVMI. Besides, increased LVMI (odds ratio, 1.017; 95% confidence interval, 1.002 to 1.033; P = 0.031) was also significantly associated with ABI <0.9 or ABI ≥1.3. Our study in patients of CKD stages 3–5 demonstrated abnormally low and high ABIs were positively associated with LVMI. Future studies are required to determine whether increased LVMI is a causal intermediary between abnormal ABI and adverse cardiovascular outcomes in CKD.

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<![CDATA[Incidence, Mortality and Positive Predictive Value of Type 1 Cardiorenal Syndrome in Acute Coronary Syndrome]]> https://www.researchpad.co/article/5989db42ab0ee8fa60bd73b2

Objectives

To determine whether the risk of cardiovascular mortality associated with cardiorenal syndrome subtype 1 (CRS1) in patients who were hospitalized for acute coronary syndrome (ACS) was greater than the expected risk based on the sum of its components, to estimate the predictive value of CRS1, and to determine whether the severity of CRS1 worsens the prognosis.

Methods

Follow-up study of 1912 incident cases of ACS for 1 year after discharge. Cox regression models were estimated with time to event (in-hospital death, and readmission or death during the first year after discharge) as the dependent variable.

Results

The incidence of CRS1 was 9.2/1000 person-days of hospitalization (95% CI = 8.1–10.5), but these patients accounted for 56.6% (95% CI = 47.4–65.) of all mortality. The positive predictive value of CRS1 was 29.6% (95% CI = 23.9–36.0) for in-hospital death, and 51.4% (95% CI = 44.8–58.0) for readmission or death after discharge. The risk of in-hospital death from CRS1 (RR = 18.3; 95% CI = 6.3–53.2) was greater than the sum of risks associated with either acute heart failure (RR = 7.6; 95% CI = 1.8–31.8) or acute kidney injury (RR = 2.8; 95% CI = 0.9–8.8). The risk of events associated with CRS1 also increased with syndrome severity, reaching a RR of 10.6 (95% CI = 6.2–18.1) for in-hospital death at the highest severity level.

Conclusions

The effect of CRS1 on in-hospital mortality is greater than the sum of the effects associated with each of its components, and it increases with the severity of the syndrome. CRS1 accounted for more than half of all mortality, and its positive predictive value approached 30% in-hospital and 50% after discharge.

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<![CDATA[β2-Adrenergic Receptor-Dependent Attenuation of Hypoxic Pulmonary Vasoconstriction Prevents Progression of Pulmonary Arterial Hypertension in Intermittent Hypoxic Rats]]> https://www.researchpad.co/article/5989daeeab0ee8fa60bc0345

In sleep apnea syndrome (SAS), intermittent hypoxia (IH) induces repeated episodes of hypoxic pulmonary vasoconstriction (HPV) during sleep, which presumably contribute to pulmonary arterial hypertension (PAH). However, the prevalence of PAH was low and severity is mostly mild in SAS patients, and mild or no right ventricular hypertrophy (RVH) was reported in IH-exposed animals. The question then arises as to why PAH is not a universal finding in SAS if repeated hypoxia of sufficient duration causes cycling HPV. In the present study, rats underwent IH at a rate of 3 min cycles of 4–21% O2 for 8 h/d for 6w. Assessment of diameter changes in small pulmonary arteries in response to acute hypoxia and drugs were performed using synchrotron radiation microangiography on anesthetized rats. In IH-rats, neither PAH nor RVH was observed and HPV was strongly reversed. Nadolol (a hydrophilic β1, 2-blocker) augmented the attenuated HPV to almost the same level as that in N-rats, but atenolol (a hydrophilic β1-blocker) had no effect on the HPV in IH. These β-blockers had almost no effect on the HPV in N-rats. Chronic administration of nadolol during 6 weeks of IH exposure induced PAH and RVH in IH-rats, but did not in N-rats. Meanwhile, atenolol had no effect on morphometric and hemodynamic changes in N and IH-rats. Protein expression of the β1-adrenergic receptor (AR) was down-regulated while that of β2AR was preserved in pulmonary arteries of IH-rats. Phosphorylation of p85 (chief component of phosphoinositide 3-kinase (PI3K)), protein kinase B (Akt), and endothelial nitric oxide synthase (eNOS) were abrogated by chronic administration of nadolol in the lung tissue of IH-rats. We conclude that IH-derived activation of β2AR in the pulmonary arteries attenuates the HPV, thereby preventing progression of IH-induced PAH. This protective effect may depend on the β2AR-Gi mediated PI3K/Akt/eNOS signaling pathway.

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<![CDATA[Morphological and Hemodynamic Discriminators for Rupture Status in Posterior Communicating Artery Aneurysms]]> https://www.researchpad.co/article/5989db3aab0ee8fa60bd4ab7

Background and Purpose

The conflicting findings of previous morphological and hemodynamic studies on intracranial aneurysm rupture may be caused by the relatively small sample sizes and the variation in location of the patient-specific aneurysm models. We aimed to determine the discriminators for aneurysm rupture status by focusing on only posterior communicating artery (PCoA) aneurysms.

Materials and Methods

In 129 PCoA aneurysms (85 ruptured, 44 unruptured), clinical, morphological and hemodynamic characteristics were compared between the ruptured and unruptured cases. Multivariate logistic regression analysis was performed to determine the discriminators for rupture status of PCoA aneurysms.

Results

While univariate analyses showed that the size of aneurysm dome, aspect ratio (AR), size ratio (SR), dome-to-neck ratio (DN), inflow angle (IA), normalized wall shear stress (NWSS) and percentage of low wall shear stress area (LSA) were significantly associated with PCoA aneurysm rupture status. With multivariate analyses, significance was only retained for higher IA (OR = 1.539, p < 0.001) and LSA (OR = 1.393, p = 0.041).

Conclusions

Hemodynamics and morphology were related to rupture status of intracranial aneurysms. Higher IA and LSA were identified as discriminators for rupture status of PCoA aneurysms.

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<![CDATA[Temporal Network Based Analysis of Cell Specific Vein Graft Transcriptome Defines Key Pathways and Hub Genes in Implantation Injury]]> https://www.researchpad.co/article/5989d9d9ab0ee8fa60b67127

Vein graft failure occurs between 1 and 6 months after implantation due to obstructive intimal hyperplasia, related in part to implantation injury. The cell-specific and temporal response of the transcriptome to vein graft implantation injury was determined by transcriptional profiling of laser capture microdissected endothelial cells (EC) and medial smooth muscle cells (SMC) from canine vein grafts, 2 hours (H) to 30 days (D) following surgery. Our results demonstrate a robust genomic response beginning at 2 H, peaking at 12–24 H, declining by 7 D, and resolving by 30 D. Gene ontology and pathway analyses of differentially expressed genes indicated that implantation injury affects inflammatory and immune responses, apoptosis, mitosis, and extracellular matrix reorganization in both cell types. Through backpropagation an integrated network was built, starting with genes differentially expressed at 30 D, followed by adding upstream interactive genes from each prior time-point. This identified significant enrichment of IL-6, IL-8, NF-κB, dendritic cell maturation, glucocorticoid receptor, and Triggering Receptor Expressed on Myeloid Cells (TREM-1) signaling, as well as PPARα activation pathways in graft EC and SMC. Interactive network-based analyses identified IL-6, IL-8, IL-1α, and Insulin Receptor (INSR) as focus hub genes within these pathways. Real-time PCR was used for the validation of two of these genes: IL-6 and IL-8, in addition to Collagen 11A1 (COL11A1), a cornerstone of the backpropagation. In conclusion, these results establish causality relationships clarifying the pathogenesis of vein graft implantation injury, and identifying novel targets for its prevention.

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<![CDATA[Divergent Cardiopulmonary Actions of Heme Oxygenase Enzymatic Products in Chronic Hypoxia]]> https://www.researchpad.co/article/5989dad9ab0ee8fa60bb9061

Background

Hypoxia and pressure-overload induce heme oxygenase-1 (HO-1) in cardiomyocytes and vascular smooth muscle cells (VSMCs). HO-1−/− mice exposed to chronic hypoxia develop pulmonary arterial hypertension (PAH) with exaggerated right ventricular (RV) injury consisting of dilation, fibrosis, and mural thrombi. Our objective was to indentify the HO-1 product(s) mediating RV protection from hypoxic injury in HO-1−/− mice.

Methodology/Principal Findings

HO-1−/− mice were exposed to seven weeks of hypoxia and treated with inhaled CO or biliverdin injections. CO reduced right ventricular systolic pressure (RVSP) and prevented hypoxic pulmonary arteriolar remodeling in both HO-1−/− and control mice. Biliverdin had no significant effect on arteriolar remodeling or RVSP in either genotype. Despite this, biliverdin prevented RV failure in the hypoxic HO-1−/− mice (0/14 manifested RV wall fibrosis or thrombus), while CO-treated HO-1−/− mice developed RV insults similar to untreated controls. In vitro, CO inhibited hypoxic VSMC proliferation and migration but did not prevent cardiomyocyte death from anoxia-reoxygenation (A-R). In contrast, bilirubin limited A-R-induced cardiomyocyte death but did not inhibit VSMC proliferation and migration.

Conclusions/Significance

CO and bilirubin have distinct protective actions in the heart and pulmonary vasculature during chronic hypoxia. Moreover, reducing pulmonary vascular resistance may not prevent RV injury in hypoxia-induced PAH; supporting RV adaptation to hypoxia and preventing RV failure must be a therapeutic goal.

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<![CDATA[Response of Various Conduit Arteries in Tachycardia- and Volume Overload-Induced Heart Failure]]> https://www.researchpad.co/article/5989dac1ab0ee8fa60bb0a3f

Although hemodynamics changes occur in heart failure (HF) and generally influence vascular function, it is not clear whether various HF models will affect the conduit vessels differentially or whether local hemodynamic forces or systemic factors are more important determinants of vascular response in HF. Here, we studied the hemodynamic changes in tachycardia or volume-overload HF swine model (created by either high rate pacing or distal abdominal aortic-vena cava fistula, respectively) on carotid, femoral, and renal arteries function and molecular expression. The ejection fraction was reduced by 50% or 30% in tachycardia or volume-overload model in four weeks, respectively. The LV end diastolic volume was increased from 65±22 to 115±78 ml in tachycardia and 67±19 to 148±68 ml in volume-overload model. Flow reversal was observed in diastolic phase in carotid artery of both models and femoral artery in volume-overload model. The endothelial function was also significantly impaired in carotid and renal arteries of tachycardia and volume-overload animals. The endothelial dysfunction was observed in femoral artery of volume-overload animals but not tachycardia animals. The adrenergic receptor-dependent contractility decreased in carotid and femoral arteries of tachycardia animals. The protein expressions of NADPH oxidase subunits increased in the three arteries and both animal models while expression of MnSOD decreased in carotid artery of tachycardia and volume-overload model. In conclusion, different HF models lead to variable arterial hemodynamic changes but similar vascular and molecular expression changes that reflect the role of both local hemodynamics as well as systemic changes in HF.

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<![CDATA[Intravenous S-Ketamine Does Not Inhibit Alveolar Fluid Clearance in a Septic Rat Model]]> https://www.researchpad.co/article/5989daecab0ee8fa60bbfaa1

We previously demonstrated that intratracheally administered S-ketamine inhibits alveolar fluid clearance (AFC), whereas an intravenous (IV) bolus injection had no effect. The aim of the present study was to characterize whether continuous IV infusion of S-ketamine, yielding clinically relevant plasma concentrations, inhibits AFC and whether its effect is enhanced in acute lung injury (ALI) which might favor the appearance of IV S-ketamine at the alveolar surface. AFC was measured in fluid-instilled rat lungs. S-ketamine was administered IV over 6 h (loading dose: 20 mg/kg, followed by 20 mg/kg/h), or intratracheally by addition to the instillate (75 µg/ml). ALI was induced by IV lipopolysaccharide (LPS; 7 mg/kg). Interleukin (IL)-6 and cytokine-induced neutrophil chemoattractant (CINC)-3 were measured by ELISA in plasma and bronchoalveolar lavage fluid. Isolated rat alveolar type-II cells were exposed to S-ketamine (75 µg/ml) and/or LPS (1 mg/ml) for 6 h, and transepithelial ion transport was measured as short circuit current (ISC). AFC was 27±5% (mean±SD) over 60 min in control rats and was unaffected by IV S-ketamine. Tracheal S-ketamine reduced AFC to 18±9%. In LPS-treated rats, AFC decreased to 16±6%. This effect was not enhanced by IV S-ketamine. LPS increased IL-6 and CINC-3 in plasma and bronchoalveolar lavage fluid. In alveolar type-II cells, S-ketamine reduced ISC by 37% via a decrease in amiloride-inhibitable sodium transport. Continuous administration of IV S-ketamine does not affect rat AFC even in endotoxin-induced ALI. Tracheal application with direct exposure of alveolar epithelial cells to S-ketamine decreases AFC by inhibition of amiloride-inhibitable sodium transport.

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<![CDATA[Association of Interarm Systolic Blood Pressure Difference with Atherosclerosis and Left Ventricular Hypertrophy]]> https://www.researchpad.co/article/5989da8dab0ee8fa60b9eb38

An interarm systolic blood pressure (SBP) difference of 10 mmHg or more have been associated with peripheral artery disease and adverse cardiovascular outcomes. We investigated whether an association exists between this difference and ankle-brachial index (ABI), brachial-ankle pulse wave velocity (baPWV), and echocardiographic parameters. A total of 1120 patients were included in the study. The bilateral arm blood pressures were measured simultaneously by an ABI-form device. The values of ABI and baPWV were also obtained from the same device. Clinical data, ABI<0.9, baPWV, echocariographic parameters, and an interarm SBP difference ≥10 mmHg were compared and analyzed. We performed two multivariate forward analyses for determining the factors associated with an interarm SBP difference ≥10 mmHg [model 1: significant variables in univariate analysis except left ventricular mass index (LVMI); model 2: significant variables in univariate analysis except ABI<0.9 and baPWV]. The ABI<0.9 and high baPWV in model 1 and high LVMI in model 2 were independently associated with an interarm SBP difference ≥10 mmHg. Female, hypertension, and high body mass index were also associated with an interarm SBP difference ≥10 mmHg. Our study demonstrated that ABI<0.9, high baPWV, and high LVMI were independently associated with an interarm SBP difference of 10 mmHg or more. Detection of an interarm SBP difference may provide a simple method of detecting patients at increased risk of atherosclerosis and left ventricular hypertrophy.

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<![CDATA[Viscolin Inhibits In Vitro Smooth Muscle Cell Proliferation and Migration and Neointimal Hyperplasia In Vivo]]> https://www.researchpad.co/article/5989d9e4ab0ee8fa60b6ab97

Viscolin, an extract of Viscum coloratum, has anti-inflammatory and anti-proliferative properties against harmful stimuli. The aim of the study was to examine the anti-proliferative effects of viscolin on platelet derived growth factor-BB (PDGF)-treated human aortic smooth muscle cells (HASMCs) and identify the underlying mechanism responsible for these effects. Viscolin reduced the PDGF-BB-induced HASMC proliferation and migration in vitro; it also arrested HASMCs in the G0/G1 phase by decreasing the protein expression of Cyclin D1, CDK2, Cyclin E, CDK4, and p21Cip1 as detected by Western blot analysis. These effects may be mediated by reduced PDGF-induced phosphorylation of ERK1/2, JNK, and P38, but not AKT as well as inhibition of PDGF-mediated nuclear factor (NF)-κB p65 and activator protein 1 (AP-1)/c-fos activation. Furthermore, viscolin pre-treatment significantly reduced neointimal hyperplasia of an endothelial-denuded femoral artery in vivo. Taken together, viscolin attenuated PDGF–BB-induced HASMC proliferation in vitro and reduced neointimal hyperplasia in vivo. Thus, viscolin may represent a therapeutic candidate for the prevention and treatment of vascular proliferative diseases.

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<![CDATA[The Association of Mid-Regional Pro-Adrenomedullin and Mid-Regional Pro-Atrial Natriuretic Peptide with Mortality in an Incident Dialysis Cohort]]> https://www.researchpad.co/article/5989daa1ab0ee8fa60ba5bd7

High levels of the plasma peptides mid-regional pro-adrenomedullin (MR-proADM) and mid-regional pro-atrial natriuretic peptide (MR-proANP) are associated with clinical outcomes in the general population. Data in patients with chronic kidney disease are sparse. We therefore investigated the association of MR-proANP and MR-proADM levels with all-cause and cardiovascular (CV) mortality, CV events and peripheral arterial disease in 201 incident dialysis patients of the INVOR-Study prospectively followed for a period of up to more than 7 years. The overall mortality rate was 43%, thereof 43% due to CV events. Both baseline MR-proANP and MR-proADM were associated with higher risk of all-cause (HR = 1.44, p = 0.001 and HR = 1.32, p = 0.002, respectively) and CV mortality (HR = 1.75, p<0.001 and HR = 1.41, p = 0.007, respectively) after adjustment for age, sex, previous CV events, diabetes mellitus and time-dependent type of renal replacement therapy. We then stratified patients in high risk (both peptides in the upper tertile), intermediate risk (only one of the two peptides in the upper tertile) and low risk (none in the upper tertile). Although demographic, clinical and laboratory variables were similar among the intermediate and high risk group, to be with both parameters in the upper tertile was associated with a 3-fold higher risk for all-cause (HR = 2.87, p<0.001) and CV mortality (HR = 3.58, p = 0.001). In summary, among incident dialysis patients MR-proANP and MR-proADM were shown to be associated with all-cause and CV mortality, with the highest risk when both parameters were in the upper tertiles.

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<![CDATA[A mathematical model of aortic aneurysm formation]]> https://www.researchpad.co/article/5989db53ab0ee8fa60bdca9d

Abdominal aortic aneurysm (AAA) is a localized enlargement of the abdominal aorta, such that the diameter exceeds 3 cm. The natural history of AAA is progressive growth leading to rupture, an event that carries up to 90% risk of mortality. Hence there is a need to predict the growth of the diameter of the aorta based on the diameter of a patient’s aneurysm at initial screening and aided by non-invasive biomarkers. IL-6 is overexpressed in AAA and was suggested as a prognostic marker for the risk in AAA. The present paper develops a mathematical model which relates the growth of the abdominal aorta to the serum concentration of IL-6. Given the initial diameter of the aorta and the serum concentration of IL-6, the model predicts the growth of the diameter at subsequent times. Such a prediction can provide guidance to how closely the patient’s abdominal aorta should be monitored. The mathematical model is represented by a system of partial differential equations taking place in the aortic wall, where the media is assumed to have the constituency of an hyperelastic material.

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<![CDATA[Hydrogen Peroxide Elicits Constriction of Skeletal Muscle Arterioles by Activating the Arachidonic Acid Pathway]]> https://www.researchpad.co/article/5989db19ab0ee8fa60bcdae4

Aims

The molecular mechanisms of the vasoconstrictor responses evoked by hydrogen peroxide (H2O2) have not been clearly elucidated in skeletal muscle arterioles.

Methods and Results

Changes in diameter of isolated, cannulated and pressurized gracilis muscle arterioles (GAs) of Wistar-Kyoto rats were determined under various test conditions. H2O2 (10–100 µM) evoked concentration-dependent constrictions in the GAs, which were inhibited by endothelium removal, or by antagonists of phospholipase A (PLA; 100 µM 7,7-dimethyl-(5Z,8Z)-eicosadienoic acid), protein kinase C (PKC; 10 µM chelerythrine), phospholipase C (PLC; 10 µM U-73122), or Src family tyrosine kinase (Src kinase; 1 µM Src Inhibitor-1). Antagonists of thromboxane A2 (TXA2; 1 µM SQ-29548) or the non-specific cyclooxygenase (COX) inhibitor indomethacin (10 µM) converted constrictions to dilations. The COX-1 inhibitor (SC-560, 1 µM) demonstrated a greater reduction in constriction and conversion to dilation than that of COX-2 (celecoxib, 3 µM). H2O2 did not elicit significant changes in arteriolar Ca2+ levels measured with Fura-2.

Conclusions

These data suggest that H2O2 activates the endothelial Src kinase/PLC/PKC/PLA pathway, ultimately leading to the synthesis and release of TXA2 by COX-1, thereby increasing the Ca2+ sensitivity of the vascular smooth muscle cells and eliciting constriction in rat skeletal muscle arterioles.

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