endothelin-1 and Aortic-Aneurysm--Abdominal

Endothelin-1 (ET-1) is the most potent known vasoconstrictor. Elevated plasma levels have been demonstrated in patients with myocardial infarction, cardiogenic and septic shock, and respiratory, heart, and kidney failure, as well as in those undergoing elective abdominal aortic aneurysm (AAA) repair. However, endothelin levels have not previously been examined in patients undergoing repair of ruptured AAA. We hypothesized that hemorrhagic shock, lower torso ischemia, and reperfusion associated with ruptured AAA repair lead to increased synthesis and secretion of ET-1, which, in turn, predispose to organ failure, one of the principal causes of death in this condition.. Fourteen patients were studied. Plasma levels of big ET-1 and ET-1 were measured immediately before operation and immediately before, 5 minutes, and 6 hours after aortic clamp release.. All patients survived for at least 24 hours after operation. Big ET-1 levels were above the normal range at one or more sample points in all patients, and the ET-1 levels were above the normal range in all survivors and four of five nonsurvivors. Five patients who died of organ failure had significantly lower big ET-1 levels at all sample points and significantly lower ET-1 levels after 5 minutes of reperfusion when compared with survivors. Preoperative ET-1 levels were significantly lower in eight patients who subsequently developed kidney failure than in six patients who did not.. Contrary to our original hypothesis, these novel data demonstrate that patients with ruptured AAA in whom fatal postoperative organ failure develops have significantly lower perioperative endothelin levels than survivors.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Aneurysm, Ruptured; Aortic Aneurysm, Abdominal; Endothelin-1; Female; Follow-Up Studies; Humans; Male; Multiple Organ Failure; Postoperative Complications; Postoperative Period; Preoperative Care; Probability; Prospective Studies; Risk Assessment; Sensitivity and Specificity; Statistics, Nonparametric; Survival Rate; Treatment Outcome

To investigate whether ECC may produce regional liberation of inflammatory mediators capable of inducing vascular effects and organ damage.. Comparative study [corrected].. Cardiac surgery department in a University hospital.. Fifteen patients undergoing coronary artery bypass grafting (CABG, group A) and ten patients operated for infrarenal abdominal aortic aneurysm (controls, group B) have been studied.. Levels of Interleukin 1beta (IL1), Tumor Necrosis Factor alpha (TNF), Interleukin 6 (IL6), and Endothelin 1 (ET1) were measured in pulmonary capillary, arterial, and venous blood and in bronchoalveolar lavages (BAL) before, during and after extracorporeal circulation (ECC) or surgical intervention.. TNF-alpha (never >35 pg/ml) and IL1beta (range 20-300 pg/ml) values did not change over time for both groups. IL6 concentrations in all samples of group A increased between five and twenty fold, during and after ECC (from 3-5 pg/ml up to 240 pg/ml, p<0.001). This trend was similar in controls after surgical stress. Endothelin 1 was always undetectable in the BAL fluid, with a modest, but significant increase in pulmonary capillary blood of group A, after ECC, (from 11+/-4 pg/ml to 18+/-5 pg/ml, p<0.001). This increment correlated well with the PVR increase, but was transient and after 24 hours, ET1 values returned to baseline levels. Mean values of ET1 increased also in controls, but not significantly.. ECC may induce ET1 liberation in pulmonary circulation with transient pulmonary vasoconstriction, but wihout intra-alveolar release, or lung damage. Augmented concentrations of IL6 probably express a response to surgical procedure rather than an effect exclusively related to ECC.

Topics: Adult; Aged; Aged, 80 and over; Aortic Aneurysm, Abdominal; Bronchoalveolar Lavage Fluid; Coronary Artery Bypass; Coronary Disease; Endothelin-1; Endothelium, Vascular; Extracorporeal Circulation; Female; Humans; Interleukin-1; Male; Middle Aged; Pulmonary Alveoli; Pulmonary Circulation; Reference Values; Tumor Necrosis Factor-alpha

Endothelin (ET)-1 plays a role in vascular reactive oxygen species production and inflammation. ET-1 has been implicated in human atherosclerosis and abdominal aortic aneurysm (AAA) development. ET-1 overexpression exacerbates high-fat diet-induced atherosclerosis in apolipoprotein E(-/-) (Apoe(-/-)) mice. ET-1-induced reactive oxygen species and inflammation may contribute to atherosclerosis progression and AAA development.. Eight-week-old male wild-type mice, transgenic mice overexpressing ET-1 selectively in endothelium (eET-1), Apoe(-/-) mice, and eET-1/Apoe(-/-) mice were fed high-fat diet for 8 weeks. eET-1/Apoe(-/-) had a 45% reduction in plasma high-density lipoprotein (P<0.05) and presented ≥ 2-fold more aortic atherosclerotic lesions compared with Apoe(-/-) (P<0.01). AAAs were detected only in eET-1/Apoe(-/-) (8/21; P<0.05). Reactive oxygen species production was increased ≥ 2-fold in perivascular fat, media, or atherosclerotic lesions in the ascending aorta and AAAs of eET-1/Apoe(-/-) compared with Apoe(-/-) (P<0.05). Monocyte/macrophage infiltration was enhanced ≥ 2.5-fold in perivascular fat of ascending aorta and AAAs in eET-1/Apoe(-/-) compared with Apoe(-/-) (P<0.05). CD4(+) T cells were detected almost exclusively in perivascular fat (3/6) and atherosclerotic lesions (5/6) in ascending aorta of eET-1/Apoe(-/-) (P<0.05). The percentage of spleen proinflammatory Ly-6C(hi) monocytes was enhanced 26% by ET-1 overexpression in Apoe(-/-) (P<0.05), and matrix metalloproteinase-2 was increased 2-fold in plaques of eET-1/Apoe(-/-) (P<0.05) compared with Apoe(-/-).. ET-1 plays a role in progression of atherosclerosis and AAA formation by decreasing high-density lipoprotein, and increasing oxidative stress, inflammatory cell infiltration, and matrix metalloproteinase-2 in perivascular fat, vascular wall, and atherosclerotic lesions.

Topics: Adipose Tissue; Animals; Antigens, Ly; Aorta; Aortic Aneurysm, Abdominal; Apolipoproteins E; Atherosclerosis; Diet, High-Fat; Disease Models, Animal; Endothelin-1; Humans; Lipoproteins, HDL; Macrophages; Male; Matrix Metalloproteinase 2; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Monocytes; Plaque, Atherosclerotic; Reactive Oxygen Species; Up-Regulation

The etiology of abdominal aortic aneurysm (AAA) includes inflammation and endothelial dysfunction. To evaluate relations between these mechanisms and AAA growth, endothelin (ET)-1, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and CD40 ligand were related to yearly AAA growth for 2.9 +/- 1.6 years (mean +/- SD) in 178 patients with conservatively followed AAA. Total number of follow-up years was 491. Abdominal aortic aneurysm diameter increased by 3.3 +/- 4.0 mm during the first year and by 4.9 +/- 4.4 mm during the first 2 years. Median (range) growth was 2.5 (-1.0 to 30.6) mm/year. When patients with AAA growth above or below median were compared, initial AAA diameter (46.1 +/- 5.8 vs 42.0 +/- 8.3 mm; P < .0001), age (75 +/- 7 vs 72 +/- 8 years; P < .029), and initial ET-1 levels (1.31 +/- 0.50 vs 1.13 +/- 0.49 pg/mL; P < .0177) were higher in patients with growth above median. Endothelin 1 (P = .0230) and initial AAA diameter (P = .0019) predicted AAA growth above median in logistic regression. In conclusion, higher initial levels of ET-1 and initial AAA diameter independently predict AAA growth.

Topics: Age Factors; Aged; Aged, 80 and over; Aortic Aneurysm, Abdominal; Aortic Rupture; CD40 Ligand; Endothelin-1; Female; Follow-Up Studies; Humans; Interleukin-6; Logistic Models; Male; Risk Factors; Tumor Necrosis Factor-alpha

Resistin belongs to a family of cysteine-rich secreted polypeptides that are mainly produced by monocytes/macrophages in humans. Recently, high concentrations of resistin were shown to induce vascular endothelial dysfunction and vascular smooth muscle cell proliferation. We examined if resistin was secreted from macrophages locally in atheromas and if it affected vascular cell function in human.. Immunohistochemical staining of human vessels showed that aortic aneurysms exhibited resistin-positive staining areas along macrophage infiltration, while normal arteries and veins did not. Co-localization of resistin and CD68 (a marker for macrophages) was observed in immunofluorescent double staining of aneurysms. Resistin mRNA was expressed much higher in cultured monocytes/macrophages than in human vascular smooth muscle cells (VSMCs) and human umbilical venous endothelial cells (HUVECs). This suggested that the resistin in aneurysms originates from macrophages within the vessels. To determine the effects of resistin on atherosclerosis, HUVECs and human VSMCs were incubated with resistin (10-100 ng/mL for 4 approximately 24 h). In HUVECs, plasminogen activator inhibitor (PAI)-1 release was assayed by ELISA, while the PAI-1 and endothelin (ET)-1 mRNA levels were analyzed by Northern blotting. Both were increased significantly with resistin treatment by factors of 1.3-2.5 (p<0.05). Migratory activity of VSMCs measured by scratched wound assay also increased significantly (1.6 times, p<0.05). In summary, macrophages infiltrating atherosclerotic aneurysms secrete resistin, and resistin affects endothelial function and VSMC migration.. Resistin secreted from macrophages may contribute to atherogenesis by virtue of its effects on vascular endothelial cells and smooth muscle cells in humans.

Topics: Actins; Aged; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Aortic Aneurysm, Abdominal; Atherosclerosis; Cells, Cultured; Endothelial Cells; Endothelin-1; Fluorescent Antibody Technique; Humans; Immunohistochemistry; Macrophages; Male; Middle Aged; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Plasminogen Activator Inhibitor 1; Platelet Endothelial Cell Adhesion Molecule-1; Resistin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

We previously found that human chymase cleaves big endothelins at the Tyr31-Gly32 bond and produces 31-amino-acid endothelins, endothelins(1-31). Endothelin-1(1-31) has been isolated from a number of human organs, including the heart and lungs. As endothelin-1 has been shown to play a significant role in the paracrine regulation of cardiovascular functions in humans, it is possible that endothelin-1(1-31) may also exhibit biological activity on human tissues. We previously reported that synthetic endothelin-1(1-31) exhibits a number of physiological actions on cultured cells in vitro. In the present study, we investigated the plasma concentrations of endothelin-1(1-31) and endothelin-1 in healthy subjects and compared them with those in patients with cardiovascular diseases. Endothelin-1(1-31) and endothelin-1 in human plasma was measured using a sandwich-enzyme-immunoassay system, which was recently described for measurement of endothelin-1(1-31). The plasma concentrations of endothelin-1(1-31) and endothelin-1 in healthy volunteers were 19.24 +/- 5.70 and 15.54 +/- 4.45 pg/ml (n = 5), respectively. We also measured plasma concentrations of endothelin-1(1-31) and endothelin-1 before and after surgery in patients with abdominal aortic aneurysms. Before surgery, plasma concentrations of endothelin-1(1-31) and endothelin-1 in these patients were higher than those in healthy individuals. After surgery, both endothelin-1(1-31) and endothelin-1 in plasma decreased to levels similar to those of healthy subjects. This suggests that endothelin-1(1-31) may have similar physiological significance to endothelin-1 in patients with atherosclerosis.

Topics: Adult; Aged; Aortic Aneurysm, Abdominal; Arteriosclerosis; Endothelin-1; Humans; Male; Middle Aged; Peptide Fragments

We investigated the plasma levels of endothelin 1/2 in patients with acute symptoms relating to a known or newly diagnosed aortic aneurysm in order to investigate the possible role of peptides in the development of the disease.. Endothelin 1/2 plasma levels were determined in patients admitted to the emergency unit with suspected acute aortic disease. The history, type of aneurysm, outcome and laboratory findings were determined and compared to endothelin 1/2 levels collected on admission.. In patients with ruptured aneurysm (n=27) or acute aortic dissection (n=18) the endothelin 1/2 median levels were higher 1.1 (25th and 75th quartile 0.7, 1.7) fmol/ml than in patients (n=20) with pre-existing aneurysm 0.7 (0.4, 1.1) fmol/ml (P=0.013). Patients who died had significantly higher endothelin levels 1.3 (0.8, 1.9) fmol/ml than the survivors 0.8 (0.5, 1.4) fmol/ml (P=0.04). In a logistic regression analysis, only a higher blood pressure on admission was an independent predictor of survival.. Endothelin 1/2 levels are elevated in patients with acute dissection or ruptured aneurysm, but they are not an independent predictor of survival.

Topics: Adult; Aged; Aged, 80 and over; Aortic Aneurysm, Abdominal; Endothelin-1; Endothelin-2; Female; Humans; Male; Middle Aged; Prognosis; Survival Analysis

ischaemia of the colon is an important complication of abdominal aortic aneurysm (AAA) repair. The aim of this animal study was to investigate the effect of sequential ischaemia and reperfusion on sigmoid mucosal pO2 and its association with local ET-1 release.. twelve pigs underwent colonic ischaemia followed by complete reperfusion. Six other animals were sham controls. A Clark-type microcatheter was used for continuous mucosal pO2 measurements. Serial systemic and inferior mesenteric vein blood samples were obtained for determination of ET-1 concentration. Neutrophil extravasation was assessed by tissue myeloperoxidase (MPO) activity.. arterial occlusion was associated with a gradual decrease of mucosal pO2 and local release of ET-1. After restoration of blood flow, mucosal pO2 returned to near baseline values, whereas ET-1 reached its maximum concentration during the reperfusion period. MPO activity was significantly increased.. colonic ischaemia and reperfusion causes neutrophil extravasation and local ET-1.

Topics: Animals; Aortic Aneurysm, Abdominal; Colon; Endothelin-1; Female; Intestinal Mucosa; Ischemia; Male; Oxygen Consumption; Reperfusion Injury; Swine

endothelin 1,2 plays a significant role in the process of atherogenesis and vascular wall injury. The aim of this study was to assess whether plasma endothelin 1,2 levels were elevated in patients with large or symptomatic abdominal aortic aneurysms (AAAs).. a prospective open study.. plasma endothelin 1,2 levels were measured in 65 consecutive patients with infrarenal aortic aneurysms and compared with the levels in 44 healthy volunteer controls. The data for abdominal aneurysm patients was analysed in four subgroups: (i) small aneurysms (<5 cm), (ii) large aneurysms (>/=5 cm), (iii) asymptomatic aneurysms and (iv) symptomatic aneurysms. Comparisons were made between endothelin 1,2 levels in aneurysm patients and controls and between the different aneurysm subgroups.. a highly significant difference (p<0.0001) was found between aneurysm patients and controls. Patients with large aneurysms had significantly higher levels than patients with small aneurysms (p<0.01). There was no statistical difference in endothelin 1,2 levels between symptomatic and asymptomatic patients; however, the highest levels were found in large, symptomatic aneurysms and the lowest in small, asymptomatic aneurysms.. plasma endothelin 1,2 is an endogenous marker of aneurysm diameter. Further studies are required to determine whether it relates to the rate of growth of aneurysms.

Topics: Aged; Aged, 80 and over; Aortic Aneurysm, Abdominal; Biomarkers; Endothelin-1; Endothelin-2; Female; Humans; Male; Middle Aged; Prospective Studies; Reference Values; Risk Factors; Sensitivity and Specificity; Statistics, Nonparametric; Veins