endothelin-1 and Coronary-Artery-Disease

The saphenous vein is the most commonly used bypass graft in patients with coronary artery disease. During routine coronary artery bypass, grafting the vascular damage inflicted on the vein is likely to stimulate the release of endothelin-1, a potent endothelium-derived vasoconstrictor that also possesses cell proliferation and inflammatory properties, conditions associated with vein graft failure. In both in vitro and in vivo studies, endothelin receptor antagonists reduce neointimal thickening. The mechanisms underlying these observations are multifactorial and include an effect on cell proliferation and cell/tissue damage. Much of the data supporting the beneficial action of endothelin-1 receptor antagonism at reducing intimal thickening and occlusion in experimental vein grafts were published over 20 years ago. The theme of the recent ET-16 conference in Kobe was "Visiting Old and Learning New". This short review article provides an overview of studies showing the potential of endothelin receptor antagonists to offer an adjuvant therapeutic approach for reducing saphenous vein graft failure and poses the question why this important area of research has not been translated from bench to bedside given the potential benefit for coronary artery bypass patients.

Topics: Animals; Cell Proliferation; Coronary Artery Bypass; Coronary Artery Disease; Disease Models, Animal; Drug Repositioning; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Graft Occlusion, Vascular; Graft Rejection; Humans; Saphenous Vein; Vascular Patency

Since its identification in 1988 and the recognition of its primary role as a potent vasoconstrictor, endothelin has been extensively studied and is now considered as a ubiquitous protein, involved in important aspects of human homeostasis as well as in several pathophysiological pathways, mostly associated with cardiovascular disease. From an evolutionary point of view, endothelin consists a primitive molecule with the rare characteristic of being exactly the same in all mammals, thus permitting scientists to perform experiments in animals and doing predictions for humans. The understanding of its contribution to the genesis, evolution and maintenance of disease through activation of special receptor subtypes has led to the development of both selective and unselective receptor antagonists. Despite the disappointing results of these antagonists in the field of heart failure, almost from the initial animal trials of bosentan, a dual endothelin receptor antagonist, in pulmonary arterial hypertension, it has been demonstrated that the drug leads at least to hemodynamic and clinical improvement of the patients, thus receiving official approval for the management of this rare but eventually lethal disease. Resistant hypertension is another area where endothelin receptor blockers might potentially play a role, while the pathophysiological role of endothelin in atherosclerotic coronary artery disease is well-established and the relative research goes on. The main goal of this review is to describe the endothelin system and mostly to enlighten its role in pathophysiologic pathways, as well to state the relative research in the various fields of cardiovascular disease and also highlight its prognostic significance wherever there exists one.

Topics: Animals; Atherosclerosis; Atrial Fibrillation; Bosentan; Cardiovascular Diseases; Coronary Artery Disease; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Humans; Hypertension, Pulmonary; Phenylpropionates; Predictive Value of Tests; Pyridazines; Receptors, Endothelin; Sulfonamides

The biomarkers associated with coronary artery lesions (CAL) secondary to Kawasaki disease (KD) in Chinese children were investigated by using Meta-analysis. We searched documents published from January 1997 to December 2009 from medical electronic databases. According to inclusion and exclusion criteria, eligible full-text papers were identified. We conducted a comprehensive quantitative analysis by using Stata10.0 statistical software package to assess the heterogeneity among the documents, calculated the summary effect and analyze publication bias and sensitivity. A total of 92 documents and 16 biomarkers were identified. All documents were case-control studies, and included 2398 patients in CAL group and 5932 patients in non-CAL (NCAL) group. The Meta-analysis showed that the levels of platelet count, platelet hematocrit (PCT), neutrophils count, platelet distribution width (PDW), mean platelet volume (MPV), erythrocyte sedimentation rate (ESR), cardiac troponin I (cTnI), and endothelin-1 (ET-1) in CAL group were significantly higher than those in NCAL group, and serum albumin (Alb) and hemoglobin (Hb) levels were significantly lower in CAL group (all P<0.05). White blood cell (WBC) count, serum sodium, matrix metalloproteinase 9 (MMP-9), total cholesterol (TC), hematocrit (HCT) and CD3+T lymphocytes percentage had no statistically significant difference between the two groups. In conclusion, our results indicated that the 10 biomarkers including platelet count, neutrophils count, PCT, PDW, MPV, ESR, cTnI, ET-1, Alb and Hb were associated with CAL, and may be involved in the pathogenesis of CAL. The biomarkers of WBC count, serum sodium, MMP-9, TC, HCT, and CD3+T lymphocytes percentage bore no relationship with the development of CAL among Chinese children with KD.

Topics: Asian People; Biomarkers; Blood Sedimentation; Child; Coronary Artery Disease; Coronary Vessels; Endothelin-1; Female; Humans; Male; Mucocutaneous Lymph Node Syndrome; Platelet Count

Endogenous endothelin-1-dependent (ET-1) tone in coronary arteries depends on the balance between ET(A) and ET(B) receptor-mediated effects and on parameters such as receptor distribution and endothelial integrity. Numerous studies highlight the striking functional interactions that exist between nitric oxide (NO) and ET-1 in the regulation of vascular tone. Many of the cardiovascular complications associated with cardiovascular risk factors and aging are initially attributable, at least in part, to endothelial dysfunction characterized by a dysregulation between NO and ET-1. The contribution of the imbalance between smooth muscle ET(A/B) and endothelial ET(B) receptors to this process is poorly understood. An increased contribution of ET-1 that is associated with a proportional decrease in that of NO accompanies the development of coronary endothelial dysfunction, coronary vasospasm, and atherosclerosis. These data form the basis for the rationale of testing therapeutic approaches counteracting ET-1-induced cardiovascular dysfunction. It remains to be determined whether the beneficial role of endothelial ET(B) receptors declines with age and risk factors for cardiovascular diseases, revealing smooth muscle ET(B) receptors with proconstricting and proinflammatory activities.

Topics: Animals; Blood Pressure; Coronary Artery Disease; Coronary Circulation; Coronary Vessels; Endothelin-1; Humans; Receptors, Endothelin; Risk Factors; Stress, Mechanical; Vasculitis

Topics: Coronary Artery Disease; Endothelin Receptor Antagonists; Endothelin-1; Humans; Vasoconstrictor Agents

Endothelins (ETs) are the peptides made up of 21 amino acids synthesized and released by variety of cells. Following studies revealed three isoforms of ETs-ET-1, ET-2 and ET-3. Endothelin ET-1 is known as the most potent endothelium-derived vasoconstrictor peptide identified so far. Endothelin ET-1 acts in a paracrine manner on the two types of receptors ET-A and ET-B. The former is responsible for the vascular smooth muscle constriction and the latter for vasodilation or vasoconstriction depending on the subtype of this receptor (ET-B1 or ET-B2 respectively). Endothelin receptor subtypes have been demonstrated and pharmacologically characterized in the coronary vascular bed. A good deal of experimental and clinical data has been accumulated to support an important role of endothelin-1 in ischemic heart disease. In experimental animals, exogenous ET-1 was found to cause coronary vasoconstriction and, at higher doses, ventricular fibrillation and death. The plasma levels of immunoreactive endothelin-1 were found to be increased in patients with coronary arteriosclerosis, acute myocardial infarction, and angina. The purpose of this study was to critically review the experimental and clinical data supporting the involvement of ET-1 in ischemic heart disease.

Topics: Animals; Coronary Artery Disease; Coronary Vessels; Endothelin-1; Humans; Myocardial Ischemia; Receptors, Endothelin

Atherosclerosis, a chronic systemic disease of the vasculature with an inflammatory component, is the primary cause of cardiovascular morbidity and mortality in industrialized countries. It is associated with the impairment of endothelium-dependent relaxation in the coronary, systemic circulation due to decreased bioavailability of nitric oxide, and increased release oxygen-derived free radicals, thus promoting vasoconstriction, leukocyte adhesion, thrombosis, inflammation, and cell proliferation. Expression of endothelin (ET)-1, a 21-amino acid peptide and major isoform of the endothelin peptide family, is produced by endothelial, vascular smooth muscle cells, and macrophages and acts through Gi-protein-coupled ET(A) and ET(B) receptors. Endothelin-1 increases in hypercholesterolemia and atherosclerosis in humans and experimental animals. This paper reviews current experimental and clinical evidence for the involvement of ET-1 in atherogenesis. Furthermore, the effects of ET receptor blockade on experimental hypercholesterolemia and atherosclerosis will be discussed. As chronic endothelin blockade inhibits fatty streak formation and improves vascular function in experimental hypercholesterolemia, hypertension, and heart failure, and as it restores nitric oxide (NO)-mediated endothelial function and reduces atheroma formation in animals with atherosclerosis, endothelin receptor blockade may therefore offer a novel approach for the treatment of atherosclerosis and its vascular complications.

Topics: Coronary Artery Disease; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Humans; Nitric Oxide; Receptors, Endothelin; Risk Factors

Endothelins are 21 amino acid peptides that are produced ubiquitously by vascular endothelial cells, smooth muscle cells, and other cells in different organs. Endothelins are secreted as big-endothelins that are converted to active proteins by the endothelin-converting enzyme. These peptides possess many biological activities, such as vasoconstriction and mitogenesis, and are involved in numerous physiological and pathophysiological processes in humans. Elevated plasma levels of endothelin have been associated with heart failure, and increased immunoreactivity for endothelin is observed in transplant coronary artery disease. In this brief review, we will discuss the regulation of endothelin in cardiac transplantation and the pathological role this peptide plays in renal impairment, systemic hypertension, graft rejection and arteriosclerosis after heart transplantation.

Topics: Acute Disease; Animals; Aspartic Acid Endopeptidases; Cells, Cultured; Coronary Artery Disease; Endothelin-1; Endothelin-Converting Enzymes; Endothelium, Vascular; Graft Rejection; Heart Transplantation; Humans; Metalloendopeptidases; Muscle, Smooth, Vascular; Transplantation, Homologous; Up-Regulation

We have conducted this study to seek and observe visual clues through immunohistochemical staining for differences in Et-1/2/3 expression and the free-flow capacity measuring the blood flow through grafts, in the left internal mammary artery grafts prepared either with clipped or nonclipped techniques.. A total of 40 consecutive patients with a diagnosis of coronary artery disease who would benefit from elective coronary artery bypass graft surgery were randomised into two groups consisting 20 patients each. Left internal mammary artery was harvested by a traditional clipped (control group) and a modified nonclipped (study group) technique in each of the groups. All harvested arterial segments were evaluated for luminal endothelial integrity through hematoxylin&eosin and immunohistochemical staining.. The free-flow capacity of left internal mammary artery grafts were significantly higher in nonclipped arteries when compared with that of clipped ones (P=0.001). The arterial lumen of the nonclipped segments were visibly more dilated than the clipped ones. Nonclipped segments presented a lighter immunostaining for Et-1/2/3 when compared with the clipped ones (P<0.001).. We believe that lesser endothelial damage caused by the lower intraluminal pressure in modifiedly harvested left internal mammary artery segments has positive implications on intraoperative and postoperative cardiac events related to graft vasospasm, especially related with endothelins. We recommend modified left internal mammary artery harvesting in patients going under coronary artery bypass graft operation.

Topics: Aged; Blood Flow Velocity; Coronary Artery Bypass; Coronary Artery Disease; Endothelin-1; Endothelin-2; Endothelin-3; Female; Humans; Immunohistochemistry; Male; Mammary Arteries; Middle Aged; Regional Blood Flow; Tissue and Organ Harvesting; Turkey

To investigate the usefulness of the plasma big endothelin-1 (big ET-1) level in predicting the severity of new-onset stable angiography-proven coronary artery disease (CAD).. A total of 963 consecutive stable CAD patients with more than 50% stenosis in at least one main vessel were enrolled. The patients were classified into the three groups according to the tertile of the Gensini score (GS, low GS ＜20, n=300; intermediate GS 20-40, n=356 and high GS ＞40, n=307), and the relationship between the big ET-1 level and GS was evaluated.. The plasma levels of big ET-1 increased significantly in association with increases in the GS tertile (p=0.007). A multivariate analysis suggested that the plasma big ET-1 level was an independent predictor for a high GS (OR=2.26, 95%CI: 1.23-4.15, p=0.009), and there was a positive correlation between the big ET-1 level and the GS (r=0.20, p=0.000). The area under the receiver operating characteristic curve (AUC) for the big ET-1 level in predicting a high GS was 0.64 (95% CI 0.60-0.68, p=0.000), and the optimal cutoff value for the plasma big ET-1 level for predicting a high GS was 0.34 fmol/mL, with a sensitivity of 62.6% and specificity of 60.3%. In the high-big ET-1 level group (≥0.34 fmol/mL), there were significantly increased rates of three-vessel disease (43.6% vs. 35.4%, p=0.017) and a high GS [31 (17-54) vs. 24 (16-44), p=0.001] compared with that observed in the low-big ET-1 level group.. The present findings indicate that the plasma big ET-1 level is a useful predictor of the severity of new-onset stable CAD associated with significant stenosis.

Topics: Age of Onset; Biomarkers; China; Cohort Studies; Coronary Angiography; Coronary Artery Disease; Coronary Stenosis; Endothelin-1; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prognosis; ROC Curve; Severity of Illness Index

Endothelial microparticles (EMPs) are vehicles released from activated or apoptotic endothelium. The aim of this study was to establish a new cytometric bead assay for EMPs and investigate the prognostic value of EMPs in chest pain patients.. We invented and verified the cytometric bead assay to quantify EMP level in vitro. A total of 80 healthy volunteers and 350 chest pain patients were recruited and the EMPs measured. The major adverse cardiovascular events (MACE) of documented coronary artery disease patients were recorded in the follow-up period. The level of EMPs statistically correlated with those of endothelin-1 (ET-1) and intercellular adhesion molecule-1 (ICAM-1) in vitro. The EMP level in healthy subjects was <300.10. The patients had a remarkably higher EMP level than healthy subjects. Diabetes mellitus, EMP, and ET-1 levels were significantly associated with future cardiovascular events in chest pain patients. There was a significantly higher event incidence in the top tertile EMP level than in the lower tertile in the acute coronary syndrome (ACS) patient group.. A novel EMP quantification assay has been successfully established. The EMPs in vitro and in patients were significantly correlated with ET-1 and ICAM-1 level. The patients with a higher EMP level had a higher risk of MACE. EMP level is a predictor for MACE in ACS patients.

Topics: Aged; Cell-Derived Microparticles; Chest Pain; Coronary Artery Disease; Diabetes Mellitus; Endothelial Cells; Endothelin-1; Female; Flow Cytometry; Follow-Up Studies; Humans; Intercellular Adhesion Molecule-1; Male; Middle Aged; Prognosis

The objective of this study was to evaluate the influence of cardiopulmonary bypass (CPB) on endothelin-1 (ET-1) expression in various circulation compartments in patients undergoing myocardial revascularization.. A total of 30 patients were randomized to undergo myocardial revascularization with (CABG, n = 15) or without (OPCAB, n = 15) CPB. Samples were taken preoperatively, after establishing CPB and after CPB (CABG group), prior to and after revascularization (OPCAB group), and 6 and 24 h postoperatively. Values of ET-1 were compared between groups at all time points and correlated with postoperative cardioselective enzyme values and clinical parameters.. In OPCAB group, ET-1 levels did not significantly vary between time points. In CABG group, ET-1 levels were significantly elevated vs. baseline in arterial: ART-T2 vs. ART-T0 (1.83 ± 1.81 vs. 0.76 ± 1.07 fmol/mL, p = 0.05), pulmonary: SG-T2 vs. SG-T0 (2.70 ± 2.75 vs. 0.39 ± 0.28 fmol/mL, p < 0.001) and SG-T3 vs. SG-T0 (1.56 ± 0.28 vs. 0.39 ± 0.28 fmol/mL, p < 0.001), and coronary circulation CS-T2 vs. CS-T1 (1.12 ± 0.49 vs. 0.27 ± 0.09 fmol/mL, p = 0.01). ET-1 levels were significantly higher in CABG group in all vascular compartments: ART-T2 (1.83 ± 1.81 vs. 0.17 ± 0.16 fmol/mL, p = 0.02), ART-T4 (0.99 ± 0.56 vs. 0.24 ± 0.12 fmol/mL, p = 0.01), SG-T1 (0.59 ± 0.15 vs. 0.25 ± 0.13 fmol/mL, p = 0.01), SG-T2 (2.70 ± 2.75 vs. 0.30 ± 0.24 fmol/mL, p = 0.004), SG-T3 (1.56 ± 0.28 vs. 0.35 ± 0.31 fmol/mL, p < 0.001), SG-T4 (1.34 ± 0.11 vs. 0.34 ± 0.16 fmol/mL, p < 0.001), and CS-T2 (1.12 ± 0.49 vs. 0.12 ± 0.12 fmol/mL, p = 0.004). Coronary sinus ET-1 level after CPB (CS-T2) in CABG group correlated positively with troponin-I level 24 h postoperatively (r(2) = 0.802, p = 0.02) CONCLUSION: Off-pump myocardial revascularization attenuates ET-1 expression in all investigated vascular compartments. Elevated coronary ET-1 levels after CPB in CABG group correlate with troponin-I levels 24 h postoperatively.

Topics: Biomarkers; Coronary Artery Bypass, Off-Pump; Coronary Artery Disease; Coronary Circulation; Coronary Vessels; Endothelin-1; Female; Humans; Male; Middle Aged; Myocardial Revascularization; Pulmonary Artery; Pulmonary Circulation; Treatment Outcome; Troponin I

Extracts from pine tree bark containing a variety of flavonoids have been used in traditional medicine. Pycnogenol is a proprietary bark extract of the French maritime pine tree (Pinus pinaster ssp. atlantica) that exerts antioxidative, anti-inflammatory, and anti-platelet effects. However, the effects of Pycnogenol on endothelial dysfunction, a precursor of atherosclerosis and cardiovascular events, remain still elusive.. Twenty-three patients with coronary artery disease (CAD) completed this randomized, double-blind, placebo-controlled cross-over study. Patients received Pycnogenol (200 mg/day) for 8 weeks followed by placebo or vice versa on top of standard cardiovascular therapy. Between the two treatment periods, a 2-week washout period was scheduled. At baseline and after each treatment period, endothelial function, non-invasively assessed by flow-mediated dilatation (FMD) of the brachial artery using high-resolution ultrasound, biomarkers of oxidative stress and inflammation, platelet adhesion, and 24 h blood pressure monitoring were evaluated. In CAD patients, Pycnogenol treatment was associated with an improvement of FMD from 5.3 ± 2.6 to 7.0 ± 3.1 (P < 0.0001), while no change was observed with placebo (5.4 ± 2.4 to 4.7 ± 2.0; P = 0.051). This difference between study groups was significant [estimated treatment effect 2.75; 95% confidence interval (CI): 1.75, 3.75, P < 0.0001]. 15-F(2t)-Isoprostane, an index of oxidative stress, significantly decreased from 0.71 ± 0.09 to 0.66 ± 0.13 after Pycnogenol treatment, while no change was observed in the placebo group (mean difference 0.06 pg/mL with an associated 95% CI (0.01, 0.11), P = 0.012]. Inflammation markers, platelet adhesion, and blood pressure did not change after treatment with Pycnogenol or placebo.. This study provides the first evidence that the antioxidant Pycnogenol improves endothelial function in patients with CAD by reducing oxidative stress.

Topics: Adult; Aged; Anti-Inflammatory Agents; Antihypertensive Agents; Antioxidants; Arginine; Biomarkers; Blood Platelets; Blood Pressure; C-Reactive Protein; Coronary Artery Disease; Cross-Over Studies; Double-Blind Method; Endothelin-1; Endothelium, Vascular; Female; Flavonoids; Humans; Male; Middle Aged; Oxidative Stress; Plant Extracts; Prospective Studies; Shear Strength; Treatment Outcome; Vasodilation; Vasodilator Agents

Endothelin (ET-1) is a potent vasoconstrictor. We compared patterns of ET-1 in percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) and correlated it with markers of inflammation. Patients with multivessel disease were enrolled in a prospective randomized study of PCI vs. on-pump CABG. Procedural myocardial injury was assessed biochemically (CK-MB) and with new late gadolinium enhancement (LGE) on magnetic resonance imaging (MRI) one week postprocedure. ET-1 was measured at baseline, 1 h, 6 h, 12 h, 24 h and one week postprocedure. Log ET-1 values were compared between PCI and CABG and between patients without significant myocardial injury. Measurement of ET-1 values was performed in 36 PCI and 31 CABG patients. Baseline ET-1 values were similar between PCI and CABG patients (0.91 ± 0.36 vs. 1.0 ± 49 pg/ml, P = 0.38). Peak values were reached at 1 h in PCI and at 24 h in CABG patients and patients undergoing CABG had significantly higher log ET-1 values at 6 h, 12 h and 24 h. ET-1 did not correlate with biochemical or morphological markers of myocardial injury or change of left ventricular ejection fraction (LV-EF) but good linear correlation between max logET-1 and max logCRP was found (r = 0.44, P = 0.0002). ET-1 rise is more pronounced in on-pump CABG and ET-1 production could be driven by periprocedural inflammatory reaction.

Topics: Aged; Analysis of Variance; Angioplasty, Balloon, Coronary; Biomarkers; Cardiopulmonary Bypass; Chi-Square Distribution; Contrast Media; Coronary Artery Bypass; Coronary Artery Disease; Creatine Kinase, MB Form; Endothelin-1; England; Female; Humans; Inflammation; Inflammation Mediators; Magnetic Resonance Imaging; Male; Middle Aged; Myocardial Infarction; Myocardium; Predictive Value of Tests; Prospective Studies; Stroke Volume; Time Factors; Treatment Outcome; Troponin I; Up-Regulation; Ventricular Function, Left

Endothelin (ET-1) is one of the most potent vasoconstrictors and plays a seminal role in the pathogenesis of atherosclerosis. The present study was designed to test the hypothesis that long-term treatment with an endothelin-A (ET(A)) receptor antagonist improves coronary endothelial function in patients with early coronary atherosclerosis.. Forty-seven patients with multiple cardiovascular risk factors, nonobstructive coronary artery disease, and coronary endothelial dysfunction were randomized in a double-blind manner to either the ET(A) receptor antagonist atrasentan (10 mg) or placebo for 6 months. Coronary endothelium-dependent vasodilation was examined by infusing acetylcholine (10(-6) to 10(-4) mol/L) in the left anterior descending coronary artery. N(G)-monomethyl-l-arginine was administered to a subgroup of patients. Endothelium-independent coronary flow reserve was examined by use of intracoronary adenosine and nitroglycerin. Baseline characteristics and incidence of adverse effects were similar between the 2 groups. There was a significant improvement in percent change of coronary blood flow in response to acetylcholine at 6 months from baseline in the atrasentan group compared with the placebo group (39.67%, 95% confidence interval 23.23% to 68.21%, versus -2.22%, 95% confidence interval -27.37% to 15.28%; P<0.001). No significant difference in the percent change of coronary artery diameter or change in coronary flow reserve was demonstrated. Coronary blood flow, coronary artery diameter, and the effect of N(G)-monomethyl-l-arginine were similar between the groups at baseline and at 6 months.. This study demonstrates that 6-month treatment with atrasentan improves coronary microvascular endothelial function and supports the role of the endogenous endothelin system in the regulation of endothelial function in early atherosclerosis in humans. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00271492.

Topics: Adult; Atrasentan; Blood Glucose; Blood Pressure; Coronary Artery Disease; Coronary Circulation; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Female; Follow-Up Studies; Heart Rate; Humans; Kidney; Lipoprotein(a); Male; Microcirculation; Middle Aged; Nitric Oxide; omega-N-Methylarginine; Pyrrolidines; Receptor, Endothelin A; Triglycerides; Uric Acid

To explore the morphological and functional effect of selective and non-selective endothelin (ET)-receptor blockade in coronary artery disease (CAD).. Prospective randomised controlled trial.. University hospital.. 26 patients with stable CAD.. Intracoronary infusion (30 minutes) of the ET-A receptor blocker BQ-123 (40 nmol/min, group A, n = 13) alone or with the ET-B receptor blocker BQ-788 (10 nmol/min, group AB, n = 13) as well.. Fractional flow reserve (FFR), coronary flow reserve (CFR) and intramyocardial resistance (IMR) by PressureWire, mean arterial blood pressure (MAP), minimal lumen diameter (MLD) and average angiographic lumen diameter (mean LD) of the target vessel before and after intracoronary infusion of ET antagonists. Concentrations of C-terminal pro-endothelin-1 (CT-proET1) in arterial blood were determined before and after infusion.. Mean MLD, mean LD, FFR, CFR, IMR and MAP remained unaffected by ET-receptor blockade in both groups; their changes were comparable. Concentrations of CT-proET-1 increased by 6.2 (SD 5.9) pmol/l (95% CI 1.2 to 11.1 pmol/l; p = 0.022) in group A and by 4.1 (SD 4.3) pmol/l (95% CI 1.1 to 7.2 pmol/l; p = 0.014) in group AB.. We found a broad variety of individual haemodynamic responses to ET-receptor antagonists with an overall neutral effect after an infusion period of 30 minutes despite an overall effective blockade of ET-receptors. Prolonged infusion time may be needed to cause a more distinct vasomotor response.. NCT00427232.

Topics: Adult; Aged; Angina Pectoris; Antihypertensive Agents; Coronary Angiography; Coronary Artery Disease; Endothelin Receptor Antagonists; Endothelin-1; Female; Fractional Flow Reserve, Myocardial; Humans; Male; Middle Aged; Myocardial Ischemia; Oligopeptides; Peptides, Cyclic; Piperidines; Prospective Studies; Protein Precursors; Young Adult

Endothelin plays an important role in the pathogenesis of atherosclerosis. The aim of the study was to evaluate the safety and hemodynamic and metabolic responses to 6 months treatment with atrasentan, the selective endothelin-A receptor antagonist. Seventy-two patients with multiple cardiovascular risk factors and nonobstructive coronary artery disease on coronary angiogram were randomly assigned in a double-blind manner to atrasentan or placebo. Mean aortic blood pressure decreased from 92+/-10 to 80+/-10 mm Hg (P<0.001) in the atrasentan group and did not change in the placebo group (93+/-10 and 92+/-11 mm Hg; P=0.84). The difference between the groups was significant (P<0.001). No effect on heart rate was observed. In a subgroup of patients not treated with angiotensin-converting enzyme inhibitor, creatinine level decreased in the atrasentan versus the placebo group (P=0.011). Fasting glucose (P=0.026), glycosylated hemoglobin level (P=0.041), triglyceride l (P=0.013), lipoprotein-A (P=0.046), and uric acid levels (P=0.048) decreased significantly in the atrasentan group compared with the placebo group. No progression of angiographic coronary disease was observed. The most common adverse effects with atrasentan were nasal stuffiness, headache, and edema. In conclusion, 6 months of treatment with atrasentan results in a reduction of blood pressure and improvement in glucose and lipid metabolism. These findings suggest the beneficial role of atrasentan in the treatment of hypertension and metabolic syndrome.

Topics: Adult; Antihypertensive Agents; Atrasentan; Blood Glucose; Blood Pressure; Coronary Artery Disease; Edema; Endothelin A Receptor Antagonists; Endothelin-1; Female; Follow-Up Studies; Humans; Hypertension; Kidney; Lipid Metabolism; Male; Metabolic Syndrome; Middle Aged; Pyrrolidines; Receptor, Endothelin A; Risk Factors; Treatment Outcome

Endothelin-1 is a potent vasoconstrictor in the body. Previous studies have identified associations between the coding polymorphism K198N and hypertension, systolic blood pressure and HDL levels. We sought to examine the evidence for these associations and, additionally, the association between K198N, insulin resistance, metabolic syndrome and coronary artery disease (CAD). We used generalised linear modelling to test K198N for association with hypertension and systolic blood pressure, lipid levels, insulin resistance scores and metabolic syndrome in a general cross-sectional community sample. Mean carotid intima media thickness and risk of carotid plaque were examined in the general population sample, and Gensini score was examined in a sample of patients with CAD. A case/control sample was used to examine the association of K198N with risk of CAD. There was no significant evidence for association between K198N and hypertension, systolic blood pressure, lipid levels, insulin resistance or metabolic syndrome in either population. The minor allele was marginally associated with increased mean IMT levels (P = 0.02) in the general population sample, although not with CAD in the case/control study or with the severity of disease in patients with CAD. In conclusion, we found no robust evidence for the associations between K198N and hypertension, systolic blood pressure or HDL levels seen in previous studies.

Topics: Adult; Aged; Blood Pressure; Case-Control Studies; Cholesterol, HDL; Coronary Artery Disease; Cross-Sectional Studies; Endothelin-1; Female; Glucose; Humans; Hypertension; Insulin Resistance; Lipoproteins; Male; Metabolic Syndrome; Middle Aged; Polymorphism, Genetic; Surveys and Questionnaires

In patients with coronary artery disease (CAD), coronary blood flow is usually impaired due to imbalanced vasoactive substances such as nitric oxide (NO) and endothelin-1 (ET-1). The study was designed to test the effects of Ginkgo biloba extract (GBE) on the distal left anterior descending coronary artery (LAD) blood flow and plasma NO and ET-1 levels. Eighty CAD patients were randomly assigned to GBE (n = 42) and control (n = 38) groups. The LAD blood flow was assessed non-invasively using Doppler echocardiography at baseline and after 2 weeks. GBE treatment demonstrated a significant improvement in maximal diastolic peak velocity (MDPV), maximal systolic peak velocity (MSPV) and diastolic time velocity integral (DTVI) compared with controls (14.61 +/- 4.51% vs 0.67 +/- 2.66%, 9.03 +/- 4.81% vs 0.34 +/- 2.67% and 14.69 +/- 5.08% vs 0.68 +/- 3.00%, respectively, p < 0.01). NO was increased by 12.42% (p < 0.01), whereas ET-1 was decreased by 5.82% (p < 0.01). The NO/ET-1 ratio was increased by 19.47% (p < 0.01). A linear correlation was confirmed between the percentage change in LAD blood flow and in NO, ET-1 or NO/ET-1 ratio following GBE treatment. The results suggest that GBE treatment in CAD patients led to an increase of LAD blood flow, which might at least be related partly to the restoration of the delicate equilibrium between NO and ET-1.

Topics: Aged; Coronary Artery Disease; Coronary Circulation; Echocardiography; Endothelin-1; Female; Ginkgo biloba; Humans; Male; Middle Aged; Nitric Oxide; Plant Extracts; Treatment Outcome

Acute vigorous exercise, associated with increased release of plasma catecholamines, transiently increases the risk of primary cardiac arrest. We tested the effect of acute submaximal exercise on vasoactive substances and their combined result on platelet function.. Healthy volunteers, hypertensive patients and patients with coronary artery disease (CAD) performed a modified treadmill exercise test. We determined plasma catecholamines, thromboxane A2, prostacyclin, endothelin-1 and platelet aggregation induced by adenosine diphosphate (ADP) and collagen at rest and during exercise.. Our results during exercise showed a) platelet activation (increased thromboxane B2, TXB2), b) increased prostacyclin release from endothelium and c) decreased platelet aggregation in all groups, significantly more in healthy volunteers than in patients with CAD (with hypertensives lying in between these two groups).. Despite the pronounced activation of Sympathetic Nervous System (SNS) and increased TXB2 levels during acute exercise platelet aggregation decreases, possibly to counterbalance the prothrombotic state. Since this effect seems to be mediated by the normal endothelium (through prostacyclin and nitric oxide), in conditions characterized by endothelial dysfunction (hypertension, CAD) reduced platelet aggregation is attenuated, thus posing such patients in increased risk for thrombotic complications.

Topics: Adult; Catecholamines; Coronary Artery Disease; Endothelin-1; Endothelium, Vascular; Epoprostenol; Exercise; Female; Humans; Hypertension; Male; Platelet Activation; Platelet Aggregation; Thromboxane A2

To observe the levels of serum C-reactive protein (CRP), endothelin-1 (ET-1), nitric oxide (NO), and superoxide dismutase (SOD) in patients after intracoronary stenting (ICS), and the effects of Erigeron Injection (EI) on them.. Seventy-two patients, who received ICS and had symptoms of chest stuffiness, palpitation and chest pain, were randomly divided into two groups, with 36 patients in the control group treated with Plavix alone for anti-platelet aggregation, and the other 36 patients in the treated group treated with Plavix and EI in combination. CRP, ET-1, NO and SOD were determined and compared before and 1, 2 and 3 weeks after treatment.. As compared with those in the control group, improvement of symptoms in the treated group was significantly better, with the levels of CRP and ET-1 lower and levels of SOD and NO higher or approaching to normal ranges and significant difference was shown between the two groups (P < 0.01).. EI could alleviate uncomfortable feelings such as chest stuffiness in patients after ICS, and improve the function of vascular endothelium.

Topics: C-Reactive Protein; Clopidogrel; Coronary Artery Disease; Drug Therapy, Combination; Endothelin-1; Endothelium, Vascular; Erigeron; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Nitric Oxide; Phytotherapy; Plant Preparations; Platelet Aggregation Inhibitors; Stents; Superoxide Dismutase; Ticlopidine

We sought to assess the effects of raloxifene, a selective estrogen receptor modulator, on arterial physiology and biology in postmenopausal women with coronary artery disease (CAD).. Raloxifene improves endothelial function and markers of vascular health in vitro in experimental animals and in healthy postmenopausal women. In women whose arteries are affected by advanced atherosclerosis, however, the vascular effects of estrogen receptor modulation are unknown.. We conducted a prospective, randomized, double-blinded, placebo-controlled, crossover trial of raloxifene, 60 mg/day for 8 weeks, in 33 consecutively eligible and consenting postmenopausal women age 50 to 75 years with known CAD. Parameters measured at the beginning and end of each treatment period included brachial artery flow-mediated dilation (FMD), the primary end point, as well as nitroglycerin-induced dilation, peripheral artery tonometry, serum lipoprotein levels, and markers of vascular function, including urinary prostaglandin, serum endothelin-1, and fibrinogen levels.. Baseline FMD was impaired in these women, as expected (2.84 +/- 0.60%), but there was no significant difference between the effect of raloxifene (0.26 +/- 0.66% increase) and placebo (0.01 +/- 0.63% decrease) on this marker of endothelial function (p = 0.82). No significant raloxifene-related effects were observed on derived aortic pressure, pulse pressure, augmentation index, total cholesterol or low- and high-density lipoprotein subfractions, markers of thrombosis, or vasoconstrictor or vasodilator substances.. In postmenopausal women with treated CAD, selective estrogen receptor modulation with raloxifene does not improve a comprehensive set of parameters examining vascular function and serum lipoprotein levels.

Topics: Aged; Biomarkers; Coronary Artery Disease; Coronary Vessels; Cross-Over Studies; Double-Blind Method; Endothelin-1; Endothelium, Vascular; Female; Fibrinogen; Humans; Lipoproteins; Middle Aged; Postmenopause; Prospective Studies; Prostaglandins; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Vasodilation

We sought to assess the effects of heparin and the potential protective effects of trimetazidine (TMZ) on exercise performance, plasma nitric oxide (NO), endothelin-1 (ET-1) and free fatty acid (FFA) release in patients with stable coronary artery disease (CAD).. Heparin has been shown to reduce the ischemic threshold in patients with CAD. Trimetazidine may affect myocardial substrate utilization by shifting energy production from FFA to glucose oxidation.. In four consecutive days, nine patients with CAD each received one of the following four regimens: 1) one tablet of placebo the evening before and at 8 AM and 4 PM on the day of the study, 10 ml of saline in a bolus 10 min before exercise, followed by an infusion of the same preparation; 2) placebo at the same times as in the first regimen, 5,000 IU of heparin 10 min before exercise, followed by 1,000 IU/h; 3) 20 mg TMZ at the same times as in the first regimen, 5,000 IU of heparin 10 min before exercise, followed by 1,000 IU/h; or 4) TMZ at the same times as in the first regimen, 10 ml of saline 10 min before exercise, followed by an infusion of the same preparation.. During placebo (test 2), heparin reduced the time to 1-mm ST-segment depression and prolonged the recovery time, as compared with the results of test 1. When heparin was administered after TMZ (test 3), the time to 1-mm ST-segment depression and the recovery time were similar to those recorded during saline (test 1). Finally, compared with all study phases, TMZ during saline (test 4) prolonged the time to 1 mm. No changes in NO release were found, whereas ET-1 was decreased at peak exercise and during recovery, when the patients were receiving TMZ (tests 3 and 4). Free fatty acids increased after heparin, both with placebo and TMZ.. In patients with CAD, heparin reduces the ischemic threshold. Trimetazidine reduces the effects of heparin, probably by inhibiting FFA oxidation and enhancing glucose metabolism. The concomitant novel observation of reduced ET-1 release is likely to be also dependent on TMZ-induced improvement of endothelial metabolism or reduction of myocardial ischemia.

Topics: Aged; Analysis of Variance; Anticoagulants; Biomarkers; Blood Pressure; Coronary Artery Disease; Double-Blind Method; Electrocardiography; Endothelin-1; Exercise Test; Fatty Acids, Nonesterified; Heart Rate; Heparin; Humans; Lactic Acid; Male; Middle Aged; Nitric Oxide; Sensory Thresholds; Treatment Outcome; Trimetazidine; Vasodilator Agents

There were controversies as to whether endothelin-1 is released after coronary angioplasty. We sought to determine whether endothelin-1 is released after coronary angioplasty and whether oestrogen administration can affect coronary vasomotor tone by reducing endothelin-1 concentrations.. The study was designed to prospectively investigate 24 consecutive patients scheduled for elective coronary angioplasty. Patients were randomized into two groups according to whether they did not (group 1, n = 12) or did (group 2, n = 12) have intracoronary treatment with oestrogen. Quantitative coronary angiography was monitored at baseline, immediately after successful angioplasty, and 15 min after the last deflation. Blood samples for measuring the levels of endothelin-1 were drawn from the ascending aorta and the coronary sinus simultaneously before angioplasty and 15 min after balloon dilatation.. The diameters of the coronary artery at the dilated segments were significantly reduced 15 min after dilation compared with those immediately after dilation in group 1 from 3.20 +/- 0.22 to 2.30 +/- 0.23 mm (P < 0.001), respectively. The vasoconstriction was significantly blunted in group 2. The endothelin-1 levels from the coronary sinus rose significantly, by 29%, 15 min after angioplasty in group 1, which was attenuated after administering oestrogen. Significant correlation was found between the changes of coronary vasomotion of the dilated segment and endothelin-1 levels (r = 0.70, P = 0.01).. Endothelin-1 is released into the coronary circulation after angioplasty, and this vasoactive substance may contribute to the occurrence of vasoconstriction. The vasoconstriction is attenuated by oestrogen by reducing the endothelin-1 levels. This finding provided a new strategy to treat coronary vasoconstriction after angioplasty.

Topics: Angioplasty, Balloon, Coronary; Aorta; Blood Pressure; Coronary Artery Disease; Coronary Vessels; Electrocardiography; Endothelin-1; Estrogens; Female; Humans; Lactates; Male; Middle Aged; Myocardial Ischemia; Prospective Studies; Sinus of Valsalva; Vasoconstriction

a large body of evidence has been accumulated suggesting that impairment of vascular endothelial function is an initial step in the development of atherosclerosis. Recent studies have shown that estrogen replacement therapy in postmenopausal women (PMW) improves endothelium-dependent, flow-mediated dilatation (FMD) while the cyclical adjunct of a progestin may reverse this effect.. the purpose of this study was to evaluate endothelium-dependent, FMD in the brachial artery and the plasma levels of Endothelin-1 in menopausal females treated with estradiol valerate with and without cyclical cyproterone acetate in 20 PMW (mean age 64+/-6 years) with more than one risk factor for coronary artery disease. After a baseline evaluation, PMW entered a double-blinded, placebo controlled single cross-over study and were randomized to receive either estradiol valerate (2 mg) for 21 days or estradiol valerate (2 mg) for 11 days and estradiol valerate (2 mg) and cyproterone acetate (1 mg) for 10 days. Patients were crossed-over the complementary treatment 7 days after completing the first treatment phase. The study of forearm blood flow was repeated at the end of each treatment period.. estradiol valerate significantly increased FMD as compared with baseline (12+/-3 vs. 7+/-4%, P<0.01) the adjunct of cyproterone acetate did not affect the effect of estradiol valerate upon FMD (12+/-3 vs. 11+/-4%, P=NS). Similarly reactive hyperemic flow increased after estradiol valerate alone (24%) or in association with cyproterone acetate (24%) compared with baseline. Plasma levels of Endothelin-1 were significantly reduced by estradiol valerate alone or in association with cyproterone acetate.. in conclusion hormone replacement therapy with estradiol valerate and cyproterone acetate improves endothelial function and reduces plasma levels of Endothelin-1 in PMW at risk of coronary artery disease. These effects may be relevant for cardioprotection.

Topics: Brachial Artery; Coronary Artery Disease; Cross-Over Studies; Cyproterone Acetate; Double-Blind Method; Drug Administration Schedule; Endothelin-1; Endothelium, Vascular; Estradiol; Estrogens, Conjugated (USP); Female; Forearm; Hormone Replacement Therapy; Humans; Middle Aged; Postmenopause; Progesterone Congeners; Regional Blood Flow; Treatment Outcome

Topics: Adult; Angina, Unstable; Coronary Artery Disease; Endothelial Cells; Endothelin-1; Humans; Myocardial Infarction; Peptides; Plasma; Tissue Plasminogen Activator; von Willebrand Factor

Early risk stratification with simple biomarkers is essential in patients with non-ST segment-elevation myocardial infarction (NSTEMI).. This study aimed to evaluate the association between plasma big endothelin-1 (ET-1) level and the SYNTAX score (SS) in patients with NSTEMI.. A total of 766 patients with NSTEMI undergoing coronary angiography were recruited. Patients were divided into three groups: low SS (≤22), intermediate SS (23-32), and high SS (>32). Spearman correlation, smooth curve fitting, logistic regression, and receiver operating characteristic (ROC) curve analysis were performed to evaluate the association between plasma big ET-1 level and the SS. A p-value <0.05 was considered statistically significant.. There was a significant correlation between the big ET-1 and the SS (r=0.378, p<0.001). The smoothing curve indicated a positive correlation between the plasma big ET-1 level and the SS. The ROC curve analysis showed that the area under the curve was 0.695 (0.661-0.727) and the optimal cutoff of plasma big ET-1 level was 0.35pmol/l. Logistic regression showed that elevated big ET-1 was an independent predictor of intermediate-high SS in patients with NSTEMI, whether entered as a continuous variable [OR (95% CI): 1.110 (1.053-1.170), p<0.001] or as a categorical variable [OR (95% CI): 2.962 (2.073-4.233), p<0.001].. In patients with NSTEMI, the plasma big ET-1 level was significantly correlated with the SS. Elevated plasma big ET-1 level was an independent predictor for intermediate-high SS.. A estratificação de risco precoce com biomarcadores simples é essencial em pacientes com infarto do miocárdio sem supradesnivelamento do segmento ST (IAMSSST).. Este estudo tem o objetivo de avaliar a associação entre nível de big endotelina-1 plasmática (ET-1) e o escore SYNTAX (SS) em pacientes com IAMSSST.. Foram recrutados 766 pacientes com IAMSSST que passaram por angiografia coronária. Os pacientes foram divididos em três grupos: SS baixo (≤22), SS intermediário (23-32), e SS alto (>32). A correlação de Spearman, o ajuste de curva suave, a regressão logística, e a análise de curva característica de operação do receptor (ROC) foram realizados para avaliar a associação entre o nível de big ET-1 plasmática e o SS. Um p-valor <0.05 foi considerado estatisticamente significativo.. Foi identificada uma correlação significativa entre a big ET-1 e o SS (r=0,378, p<0,001). A curva suavizada indicou uma correlação positiva entre o nível de big ET-1 plasmática e o SS. A análise de curva ROC demonstrou que a área sob a curva foi de 0,695 (0,661-0,727) e o ponto de corte ideal do nível de big ET-1 plasmática foi de 0,35 pmol/l. A regressão logística demonstrou que a big ET-1 elevada era um preditor independente de SS intermediário a alto em pacientes com IAMSSST, seja como variável contínua [RC (IC 95%: 1,110 (1,053-1,170), p<0,001] ou como variável categórica [RC (IC 95%: 2,962 (2,073-4,233), p<0,001].. Em pacientes com IAMSSST, o nível de big ET-1 plasmática estava significativamente correlacionado ao SS. O nível de big ET-1 plasmática elevado foi um preditor independente para SS intermediário a alto.

Topics: Coronary Angiography; Coronary Artery Disease; Endothelin-1; Humans; Non-ST Elevated Myocardial Infarction; Predictive Value of Tests; Severity of Illness Index; ST Elevation Myocardial Infarction

In this study, we investigated whether increased renin angiotensin aldosterone system (RAAS) activation and endothelin-1 levels are related to coronary artery calcium (CAC) score, total plaque volume (TPV), high risk plaque, hyperemic myocardial blood flow (MBF) and coronary microvascular dysfunction (CMD).. After correction for baseline characteristics, including RAAS inhibiting therapy, renin associated positively with CAC score and TPV, but not with hyperemic MBF (p < 0.01; p = 0.02 and p = 0.23). Patients with high risk plaque displayed higher levels of renin (mean logarithmic renin 1.25 ± 0.43 vs. 1.12 ± 0.35 pg/ml; p = 0.04), but not endothelin-1. Compared to no or non-obstructive CAD patients, renin was significantly elevated in obstructive CAD patients but not in CMD patients (mean logarithmic renin 1.06 ± 0.34 vs. 1.23 ± 0.36; p < 0.01 and 1.06 ± 0.34 vs. 1.16 ± 0.41 pg/ml; p = 0.65). Endothelin-1 did not differ between the three patient groups.. Our report provides evidence that RAAS activity measured by renin concentration is elevated in patients with coronary atherosclerosis and high risk plaque but not in patients with CMD, whereas endothelin-1 is not related to either.

Topics: Aged; Chest Pain; Coronary Angiography; Coronary Artery Disease; Cross-Sectional Studies; Endothelin-1; Female; Fractional Flow Reserve, Myocardial; Humans; Male; Middle Aged; Myocardial Ischemia; Myocardial Perfusion Imaging; Plaque, Atherosclerotic; Predictive Value of Tests; Prospective Studies; Renin; Renin-Angiotensin System

To develop a general framework to assess temporal changes in lesion morphology on radiological images beyond volumetric changes and to test whether cocaine abstinence changes coronary plaque structure on serial coronary CT angiography (CTA).. Chronic cocaine users with human immunodeficiency virus (HIV) infection were prospectively enrolled to undergo cash-based contingency management to achieve cocaine abstinence. Participants underwent coronary CTA at baseline and 6 and 12 months following recruitment. We segmented all coronary plaques and extracted 1103 radiomic features. We implemented weighted correlation network analysis to derive consensus eigen radiomic features (named as different colors) and used linear mixed models and mediation analysis to assess whether cocaine abstinence affects plaque morphology correcting for clinical variables and plaque volumes and whether serum biomarkers causally mediate these changes. Furthermore, we used Bayesian hidden Markov network changepoint analysis to assess the potential rewiring of the radiomic network.. Sixty-nine PLWH (median age 55 IQR: 52-59 years, 19% female) completed the study, of whom 26 achieved total abstinence. Twenty consensus eigen radiomic features were derived. Cocaine abstinence significantly affected the pink and cyan eigen features (-0.04 CI: [-0.06; -0.02], p = 0.0009; 0.03 CI: [0.001; 0.04], p = 0.0017, respectively). These effects were mediated through changes in endothelin-1 levels. In abstinent individuals, we observed significant rewiring of the latent radiomic signature network.. Using our proposed framework, we found 1 year of cocaine abstinence to significantly change specific latent coronary plaque morphological features and rewire the latent morphologic network above and beyond changes in plaque volumes and clinical characteristics.. • We propose a general methodology to decompose the latent morphology of lesions on radiological images using a radiomics-based systems biology approach. • As a proof-of-principle, we show that 1 year of cocaine abstinence results in significant changes in specific latent coronary plaque morphologic features and rewiring of the latent morphologic network above and beyond changes in plaque volumes and clinical characteristics. • We found endothelin-1 levels to mediate these structural changes providing potential pathological pathways warranting further investigation.

Topics: Bayes Theorem; Cocaine; Computed Tomography Angiography; Coronary Angiography; Coronary Artery Disease; Endothelin-1; Female; Humans; Male; Middle Aged; Plaque, Atherosclerotic; Predictive Value of Tests

The present study aimed to examine the association between big endothelin-1 (big ET-1) and long-term all-cause death in patients with coronary artery disease (CAD) and different glucose metabolism status.. We consecutively enrolled 8550 patients from January 2013 to December 2013. Patients were categorized according to both status of glucose metabolism status [Diabetes Mellitus (DM), Pre-Diabetes (Pre-DM), Normoglycemia (NG)] and big ET-1 levels. Primary endpoint was all-cause death. During a median of 5.1-year follow-up periods, 301 all-cause deaths occurred. Elevated big ET-1 was significantly associated with long-term all-cause death (adjusted HR: 2.230, 95%CI 1.629-3.051; p < 0.001). Similarly, patients with DM, but not Pre-DM, had increased risk of all-cause death compared with NG group (p < 0.05). When patients were categorized by both status of glucose metabolism and big ET-1 levels, high big ET-1 were associated with significantly higher risk of all-cause death in Pre-DM (adjusted HR: 2.442, 95% CI 1.039-5.740; p = 0.041) and DM (adjusted HR: 3.162, 95% CI 1.376-7.269; p = 0.007). The Kaplan-Meier curve indicated that DM patients with the highest big ET-1 levels were associated with the greatest risk of all-cause death (p < 0.05).. The present data indicate that baseline big ET-1 levels were independently associated with the long-term all-cause death in DM and Pre-DM patients with CAD undergoing PCI, suggesting that big ET-1 may be a valuable marker in patients with impaired glucose metabolism.

Topics: Blood Glucose; Coronary Artery Disease; Diabetes Mellitus; Endothelin-1; Humans; Percutaneous Coronary Intervention; Prediabetic State; Risk Factors; Time Factors; Treatment Outcome

The changes in testosterone level and its correlation with the endothelial nitric oxide systems balance in patients with coronary artery disease (CAD) remains uncertain. Therefore, in our study, we aimed to evaluate the levels of testosterone, endothelin-1 (ET-1), nitric oxide (NO), and endothelial NOS (eNOS) in CAD patients, and control group to find the relationship between these parameters and disease severity.. Forty-four patients as CAD group with significant (≥50%) stenosis confirmed by angiography was included in the study, and 40 healthy men were included as the control group. According to the number of vessels obstruction, CAD severity was determined. The serum indicated parameters were assessed to discriminate between patients and controls.. It was found that testosterone levels in the CDA group were significantly lower than those of the control group (p<0.05). In addition, the level of ET-1 in the CAD group was higher than that in the control group, but levels of NO and eNOS in observation were significantly lower than those in the control group (p<0.05). The correlation analysis revealed that testosterone was passivity correlated with serum NO levels (r=0.550, p=0.001).. The current study reports that serum levels of testosterone are closely related to endothelial NO levels and might be of relevance to the pathogenesis of endothelial dysfunction and disease severity in CAD patients.

Topics: Coronary Artery Disease; Endothelin-1; Humans; Male; Nitric Oxide; Nitric Oxide Synthase Type III; Severity of Illness Index; Testosterone

Central obesity is associated with increased level and activity of endothelin-1. The waist and hip circumferences are simple indicators of central obesity. Waist circumference correlates with visceral adiposity, whereas hip circumference associates with gluteofemoral peripheral adiposity. Both measurements have independent and opposite correlation with coronary artery disease (CAD) risk factors. The relation between serum endothelin-1 in stable CAD and both parameters of central obesityneeds to be investigated. This study aims to examine the correlation between serum endothelin-1 level and waist and hip circumferences as parameters of central obesity in patients with stable CAD. This was a cross-sectional study. Consecutive subjects were enrolled among those who underwent elective coronary angiography with significant CAD. Serum endothelin-1 was measured from peripheral blood samples taken before coronary angiography procedure. The measurement of waist circumference, hip circumference, and ratio derived from them, was performed. Central obesity was determined by waist circumference cut-off for Indonesian population. The correlation analysis was performed with Pearson test. The multivariate analysis was performed with multiple linear regression test. The comparison of serum endothelin-1 level between groups was performed with Student T test. We enrolled 50 subjects. The majority of subjects was male (80.0%), hypertensive (86.0%), dyslipidemic (68%) and smoker (52%). Most subjects had history of acute coronary syndrome (64%). Mean waist circumference was 87.6 +/- SD cm, hip circumference was 95.3 cm +/- SD, mean waist-to-hip ratio was 0.92 +/- SD and mean waist-to-height ratio was 0.54 +/- SD. Central obesity occurred in 32% of subjects. Mean serum endothelin-1 level was 2.2 ± 0.7 pg/mL. Serum endothelin-1 level tended to be higher in subjects with central obesity as compared to those without. Serum endothelin-1 level was significantly correlated with age, hemoglobin level, waist circumference (coefficient of 0.311,

Topics: Body Mass Index; Coronary Artery Disease; Cross-Sectional Studies; Endothelin-1; Female; Humans; Male; Risk Factors; Waist Circumference

Topics: Aged; Biomarkers; Coronary Angiography; Coronary Artery Disease; Coronary Circulation; Coronary Vessels; Endothelin-1; Female; Follow-Up Studies; Humans; Male; Microcirculation; Positron Emission Tomography Computed Tomography; Prognosis; Retrospective Studies

Coronary slow flow (CSF) refers to coronary arteries with no obvious stenosis but have slow coronary flow without effective treatment. The main cause of CSF is endothelial dysfunction. The long non-coding RNA (lncRNA) MALAT1 is involved in regulating endothelial dysfunction, but its role in CSF endothelial dysfunction is still unclear.. We included 41 CSF patients and 37 controls in the study, who all underwent coronary angiography, echocardiography, and brachial artery flow-mediated dilatation (FMD) examination. Human umbilical vein endothelial cells (HUVECs) stimulated by oxygen-glucose deprivation were used as CSF-induced HUVECs. Plasma endothelin-1 (ET-1) concentrations were determined by enzyme-linked immunosorbent assay (ELISA). The expression levels of MALAT1, miR-181b-5p, myocyte enhancer factor 2A (MEF2A), and ET-1 were measured by qRT-PCR or western blotting. Cell proliferation was determined by 5-ethynyl-2'-deoxyuridine (EdU) and Cell Counting Kit-8 (CCK-8) assays. Apoptosis was examined by flow cytometry. The relationship between miR-181b-5p and MALAT1 or MEF2A was verified by dual-luciferase reporter assay. MEF2A binding directly to the ET-1 promoter region was verified via chromatin immunoprecipitation (ChIP) assay.. MALAT1 and ET-1 were increased, and miR-181b-5p was decreased in the peripheral blood of the CSF patients, and could be used as predictors of CSF. In the CSF-induced HUVECs, MALAT1 was highly expressed, and MALAT1 knockdown improved endothelial function. In contrast, miR-181b-5p was downregulated in the CSF-induced HUVECs, and miR-181b-5p overexpression improved endothelial function. While MEF2A was highly enriched in CSF-induced HUVECs, MEF2A knockdown reduced ET-1 and increased the endothelial function of CSF-induced HUVECs as a transcriptional regulator of ET-1. MALAT1 modulated MEF2A expression positively by sponging miR-181b-5p.. Endothelial function is reduced in CSF. MALAT1 participates in regulating CSF endothelial dysfunction through the miR-181b-5p-MEF2A-ET-1 axis, and could provide a new target for CSF treatment.

Topics: Aged; Blood Flow Velocity; Case-Control Studies; Cells, Cultured; Coronary Artery Disease; Coronary Circulation; Coronary Vessels; Endothelin-1; Female; Human Umbilical Vein Endothelial Cells; Humans; Male; MEF2 Transcription Factors; MicroRNAs; Middle Aged; RNA, Long Noncoding; Signal Transduction

Restenosis remains the main complication after percutaneous coronary interventions in patients with coronary heart disease. The causes of its development include, in particular, genetic factors. We studied polymorphic loci of genes encoding endothelin-1 (EDN1 rs5370), endothelin-1 receptor (EDNRA rs5333), endothelin-converting enzyme (ECE1 rs1076669), and endothelial NO synthase (eNOS rs1549758, eNOS rs1799983, and eNOS rs2070244) in the context of in-stent restenosis development. It was found that the analyzed polymorphisms of the endothelin system genes were more significant for patients aged ≥ 65 years, while the polymorphic loci of the endothelial NO synthase gene (eNOS rs1799983 and eNOS rs1549758) were predominantly associated with time of in-stent restenosis. The obtained results can be useful for comprehensive assessment of the restenosis risk factors and the choice of optimal treatment for patients with coronary heart disease before elective surgical intervention.

Topics: Aged; Aged, 80 and over; Case-Control Studies; Coronary Artery Disease; Coronary Vessels; Endothelin-1; Endothelin-Converting Enzymes; Endothelium, Vascular; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Graft Occlusion, Vascular; Humans; Male; Neovascularization, Pathologic; Nitric Oxide Synthase Type III; Percutaneous Coronary Intervention; Polymorphism, Single Nucleotide; Postoperative Complications; Receptor, Endothelin A; Stents

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide linked to vascular diseases through a common intronic gene enhancer [(rs9349379-G allele), chromosome 6 (PHACTR1/EDN1)]. We performed a multimodality investigation into the role of ET-1 and this gene variant in the pathogenesis of coronary microvascular dysfunction (CMD) in patients with symptoms and/or signs of ischaemia but no obstructive coronary artery disease (CAD).. Three hundred and ninety-one patients with angina were enrolled. Of these, 206 (53%) with obstructive CAD were excluded leaving 185 (47%) eligible. One hundred and nine (72%) of 151 subjects who underwent invasive testing had objective evidence of CMD (COVADIS criteria). rs9349379-G allele frequency was greater than in contemporary reference genome bank control subjects [allele frequency 46% (129/280 alleles) vs. 39% (5551/14380); P = 0.013]. The G allele was associated with higher plasma serum ET-1 [least squares mean 1.59 pg/mL vs. 1.28 pg/mL; 95% confidence interval (CI) 0.10-0.53; P = 0.005]. Patients with rs9349379-G allele had over double the odds of CMD [odds ratio (OR) 2.33, 95% CI 1.10-4.96; P = 0.027]. Multimodality non-invasive testing confirmed the G allele was associated with linked impairments in myocardial perfusion on stress cardiac magnetic resonance imaging at 1.5 T (N = 107; GG 56%, AG 43%, AA 31%, P = 0.042) and exercise testing (N = 87; -3.0 units in Duke Exercise Treadmill Score; -5.8 to -0.1; P = 0.045). Endothelin-1 related vascular mechanisms were assessed ex vivo using wire myography with endothelin A receptor (ETA) antagonists including zibotentan. Subjects with rs9349379-G allele had preserved peripheral small vessel reactivity to ET-1 with high affinity of ETA antagonists. Zibotentan reversed ET-1-induced vasoconstriction independently of G allele status.. We identify a novel genetic risk locus for CMD. These findings implicate ET-1 dysregulation and support the possibility of precision medicine using genetics to target oral ETA antagonist therapy in patients with microvascular angina.. ClinicalTrials.gov: NCT03193294.

Topics: Coronary Artery Disease; Endothelin-1; Humans; Microvascular Angina; Myocardial Ischemia; Vasoconstriction

C-type Natriuretic Peptide (CNP) and Endothelin-1 (ET-1) have reciprocal roles in maintaining vascular homeostasis and are acutely modulated by statins in human cultured endothelial cells. Whether these actions of statins in vitro are reflected in studies in vivo is unknown. In a prospective study of 66 subjects with or without post- acute coronary syndrome (ACS), plasma concentrations of bioactive CNP and bio-inactive aminoterminal proCNP (NTproCNP), ET-1, B-type Natriuretic Peptide (BNP) and high sensitivity C Reactive Protein (hsCRP) were measured together with lipids before and at intervals of 1, 2 and 7 days after commencing atorvastatin 40 mg/day - and for a further period of 6months in those with ACS. Plasma lipids fell significantly in all subjects but plasma CNP, NTproCNP and ET-1 were unchanged by atorvastatin. In ACS, baseline hsCRP, BNP and CNP but not NTproCNP or ET-1 were significantly raised compared to values in age-matched controls. The ratio of NTproCNP to CNP was significantly lower in ACS throughout the study and was unaffected by statin therapy. We conclude that conventional doses of atorvastatin do not affect plasma CNP products or ET-1. Elevated CNP after cardiac injury likely results from regulated changes in clearance, not enhanced production.

Topics: Adult; Biomarkers; C-Reactive Protein; Coronary Artery Disease; Endothelin-1; Heart Function Tests; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Natriuretic Peptide, C-Type; Sex Factors; Treatment Outcome; Young Adult

BACKGROUND Human endothelin-1 (ET-1) gene polymorphism is closely associated with coronary artery disease (CAD). This study aimed to investigate the association of 2 single-nucleotide polymorphisms (SNPs), +138 I/D and Lys198Asn) of the ET-1 gene,with early onset of CAD in Han Chinese patients. We investigated the effects of Lys198Asn polymorphism on ET-1 protein expression upon stimulation with pro-inflammatory factors. MATERIAL AND METHODS Genotyping of the 2 SNPs +138 I/D and Lys198Asn was performed in 88 early-onset CAD patients (≤55 years for males; ≤60 years for females) and 52 healthy control participants using a polymerase chain reaction direct sequencing method. The association of the 2 SNPs was analyzed with SPSS 17.0 software. Western blotting was performed to assess the effects of ET-1 polymorphisms on ET-1 protein expression upon tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and lipopolysaccharide (LPS) stimulation in HEK-293T cells. RESULTS Fisher's exact test showed that the T allele (odds ratio [OR]=3.38, P=0.02) and GT/TT genotype (OR=3.76, P=0.02) of the ET-1 gene Lys198Asn were associated with increased early-onset CAD risk. Multivariate logistic regression analysis showed smoking was the single independent variable related to early-onset CAD (P<0.05). An increase of ET-1 protein levels in cells transfected with Asn198 plasmid was seen upon TNF-alpha or IL-6 stimulation. CONCLUSIONS T allele frequency in Lys198Asn loci might be associated with the pathogenesis of early-onset CAD. T-variant might contribute to early-onset CAD by upregulating ET-1 expression upon inflammatory cytokines stimulation, and smokers who have the T allele might be vulnerable to CAD in the Chinese population.

Topics: Adult; Aged; Asian People; Case-Control Studies; China; Coronary Artery Disease; Endothelin-1; Ethnicity; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Odds Ratio; Polymorphism, Single Nucleotide; Risk Factors

BACKGROUND The aim of this study was to investigate the effects of puerarin on vascular endothelial function and inflammatory factors in coronary artery disease (CAD) patients with stable angina pectoris (SAP). MATERIAL AND METHODS To evaluate the effects of angina pectoris, the differences of scores of the Seattle angina questionnaire (SAQ), vascular endothelial function [endothelial progenitor cells (EPCs), nitric oxide (NO) and endothelin 1 (ET-1)], and inflammatory factors [tumor necrosis factor a (TNF-α), hypersensitive C-reactive protein (hs-CRP), interleukin-6 (IL-6)] in 2 groups were assessed before and after treatment. RESULTS Regarding the curative effect of angina pectoris, the total effective rate of the treatment group was significantly superior to that of the control group (89% vs. 65%, P<0.05). The duration of angina pectoris, the number of abnormal leads, the improvement of the ST segment depression of electrocardiogram, and the scores of SAQ life quality indexes in the treatment group were better than those of the control group (P<0.05). In the 2 groups, EPCs and NO were both elevated, while ET-1 was decreased, and the improvements of the treatment group were superior to those of the control group (P<0.05). After treatment, the average levels of serum TNF-α, hs-CRP and IL-6 in the 2 groups were all decreased, which the treatment group showed a much sharper decrease than in the control group (P<0.05). CONCLUSIONS Puerarin effectively improves clinical symptoms and vascular endothelial function and reduces the levels of inflammatory factors in patients with CAD.

Topics: Aged; Angina Pectoris; Angina, Stable; C-Reactive Protein; China; Coronary Artery Disease; Endothelial Cells; Endothelial Progenitor Cells; Endothelin-1; Female; Humans; Inflammation; Interleukin-6; Isoflavones; Male; Middle Aged; Nitric Oxide; Treatment Outcome; Tumor Necrosis Factor-alpha

To evaluate the prognostic value of plasma big endothelin-1 level in the context of three-vessel disease (TVD) with heavy atherosclerotic burden.. A total of 6,150 patients with TVD and available big endothelin-1 data were included in the study. Participants were divided into two groups according to the optimal cutoff value of big endothelin-1 for mortality prediction. The primary endpoint was all-cause death. C-index, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were calculated to evaluate the added prognostic value of plasma big endothelin-1 level beyond the SYNTAX score Ⅱ.. On the basis of the optimal cutoff value of 0.79 pmol/L, 1,984 patients were assigned to the high big endothelin-1 group. During a median follow-up of 6.8 years, 818 patients experienced all-cause death. Plasma big endothelin-1 level was significantly higher in patients who died than in patients who survived. Multivariable analysis found that high big endothelin-1 level was independently associated with an increased risk of mortality (hazard ratio: 1.36, 95% confidence interval: 1.18-1.57, P＜0.001). The association of big endothelin-1 with all-cause death was relatively consistent across subgroups with no significant interactions. The predictive ability of the SYNTAX score Ⅱ was significantly enhanced by addition of plasma big endothelin-1 level (C-index: 0.723 vs.0.715, P =0.029; NRI: 0.304, P＜0.001; IDI: 0.009, P＜0.001).. Plasma big endothelin-1 level is an independent predictor of long-term mortality in patients with TVD. It can improve the discrimination and reclassification of the SYNTAX score Ⅱ for mortality prediction.

Topics: Aged; Biomarkers; Case-Control Studies; Cause of Death; China; Coronary Artery Disease; Endothelin-1; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prevalence; Prognosis; Prospective Studies; Survival Rate

Endothelin-1 (ET-1) is a vasoconstrictor associated with cardiovascular disease, whereas adrenomedullin (ADM) is a vasorelaxant with cardioprotective properties. We sought to determine the relationship between plasma ET-1 and ADM with coronary circulatory function and long-term major adverse cardiovascular events (MACE).. Thirty-two patients undergoing coronary angiography for chest pain were recruited. Baseline plasma ET-1 and ADM levels were measured. The index of microcirculatory resistance (IMR), coronary flow mediated dilatation (cFMD) and coronary flow reserve (CFR) were measured in a non-obstructed coronary artery. Patients were assessed for MACE over a median period of 8.8 years.. Plasma ET-1 levels correlated with IMR (r = 0.57; p < 0.01) and ADM levels correlated with CFR (r = 0.50; p = 0.04) and cFMD (r = 0.62; p = 0.01). After adjustment for age, gender and cardiovascular risk factors, the association between ADM and cFMD (β = 0.79; p < 0.01) and between ET-1 and IMR (β = 5.7; p = 0.01) remained significant. IMR was higher, although not statistically significant, in patients with long-term MACE (17.9 ± 5.3 vs. 13.1 ± 6.0 units; p = 0.14). In patients free of MACE, cFMD (9.3 ± 7.6 vs. 2.8 ± 5.0%; p = 0.01) and plasma ADM levels (7.6 ± 5.3 vs. 4.0 ± 1.9 pmol/L; p = 0.07) were higher.. Plasma ET-1 and ADM were associated with measures of coronary microvascular and coronary conduit vessel function, respectively. Increased cFMD and elevated plasma ADM were associated with a cardioprotective effect.

Topics: Adrenomedullin; Aged; Biomarkers; Chest Pain; Cohort Studies; Coronary Angiography; Coronary Artery Disease; Coronary Circulation; Endothelin-1; Female; Follow-Up Studies; Fractional Flow Reserve, Myocardial; Humans; Male; Middle Aged

Noncalcified plaques (NCPs) and mixed plaques (MPs) are considered as the high-risk coronary plaques. Endothelin-1 (ET-1) is a vasoactive peptide and shows a high expression in vulnerable plaque. The aim of this study is to investigate the relationship between the bigET-1, the precursor of ET-1, and NCPs/MPs in a Chinese population.. A total of 513 patients with chest pain and suspected coronary artery disease were collected and divided into three groups with no plaques, calcified plaques, or NCPs/MPs according to the characteristics of all the plaques. It demonstrated that NCPs/MPs were associated with elevated bigET-1 (P < 0.001). Moreover, the proportion of NCPs/MPs was significantly increased from 43.3% in bigET-1 tertile 1 to 61.0% in tertile 3 group (P = 0.001). Multiple logistic regression analysis further showed that bigET-1 was an independent predictor for the presence of NCPs/MPs (odds ratio = 1.858; 95% confidence interval: 1.017-3.394; P = 0.044).. The bigET-1 could be an independent predictor for the presence of NCPs/MPs.

Topics: Adult; Aged; Biomarkers; Coronary Artery Disease; Cross-Sectional Studies; Endothelin-1; Female; Humans; Male; Middle Aged; Plaque, Atherosclerotic; Retrospective Studies; Risk Assessment; Risk Factors; Vascular Calcification

Topics: Adult; Carbon Monoxide; Case-Control Studies; CD4 Lymphocyte Count; Comorbidity; Coronary Artery Disease; Coronary Vessels; Endothelin-1; Female; Forced Expiratory Volume; HIV Infections; Humans; Intercellular Adhesion Molecule-1; Lung; Male; Middle Aged; Mortality; Odds Ratio; Pulmonary Diffusing Capacity; Pulmonary Emphysema; Smoking; Spirometry; Tomography, X-Ray Computed; United States; Vascular Calcification; Viral Load

Subject of Review: Gupta et al. [Cell 2017; 170: 522-533] have shown that a genetic variant associated with the 5 vascular diseases is a distal regulator of endothelin (ET)-1 gene (EDN1) expression. A common single nucleotide polymorphism (SNP) in the third intron of the PHACTR1 gene, rs9349379, is the potential variant responsible for increased risk of coronary artery disease, and lower risk of migraine, carotid dissection, fibromuscular dysplasia, and hypertension. Since ET-1 acts through ET type B receptors (ETBR) on endothelial cells to stimulate the production of nitric oxide and prostacyclin and induce vasodilation, this may contribute to these findings. Second Opinion: However, ET-1 has been demonstrated to play a role in experimental and human hypertension. How can enhanced transcription of EDN1 and translation leading to increased production of ET-1 by endothelial cells play a role in hypertension despite the availability of data that suggest a hypotensive action of ET-1? This could depend on the genetic background of individuals. In some humans, the increased ET-1 vasoconstrictor action on ETAR and ETBR in vascular smooth muscle might predominate over the vasodilator effects exerted via endothelial ETBR, thus resulting in elevated blood pressure.. Alternatively, hypertension could be attributed to renal actions of ET-1. Either of these pathophysiological actions may explain a hypertensive role of ET-1 despite a lower risk of hypertension associated with the G allele at rs9349379, the common SNP in the PHACTR1 gene that is a distal regulator of EDN1 and leads to an increased expression of ET-1.

Topics: Blood Pressure; Coronary Artery Disease; Endothelin-1; Humans; Hypertension; Muscle, Smooth, Vascular

Progression of coronary artery calcification (CAC) was significantly associated with all-cause mortality, and high coronary artery calcium score (CACS) portends a particularly high risk of cardiovascular events. But how often one should rescan is still an unanswered question. Preliminary screening by testing circulating biomarker may be an alternative before repeat computed tomography (CT) scan. The aim of this study was to investigate the value of big endothelin-1 (bigET-1), the precursor of endothelin-1 (ET-1), in predicting the severity of CAC. A total of 428 consecutively patients who performed coronary computed tomography angiography (CCTA) due to chest pain in Fuwai Hospital were included in the study. The clinical characteristics, CACS, and laboratory data were collected, and plasma bigET-1 was detected by enzyme-linked immunosorbent assay (ELISA). The bigET-1 was positively correlated with the CACS ( r = .232, P < .001), and the prevalence of CACS >400 increased significantly in the highest bigET-1 tertile than the lowest tertile. Multivariate analysis showed that bigET-1was the independent predictor of the presence of CACS >400 (odds ratio [OR] = 1.721, 95% confidence interval [CI], 1.002-2.956, P = .049). The receiver operating characteristic (ROC) curve analysis showed that the optimal cutoff value of bigET-1 for predicting CACS >400 was 0.38 pmol/L, with a sensitivity of 59% and specificity of 68% (area under curve [AUC] = 0.65, 95% CI, 0.58-0.72, P < .001). The present study demonstrated that the circulating bigET-1 was valuable in the assessment of the severity of CAC.

Topics: Atherosclerosis; Coronary Artery Disease; Coronary Vessels; Endothelin-1; Female; Humans; Male; Middle Aged; Risk Factors; Vascular Calcification

Endothelin-1 (ET-1) plays important roles in endothelial dysfunction, vascular physiology, inflammation, and atherosclerosis. Nonetheless, the role of ET-1 (

Topics: Aged; Asian People; Case-Control Studies; Coronary Artery Disease; Endothelin-1; Female; Genetic Predisposition to Disease; Haplotypes; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide

Endothelin-1 (ET-1) is associated with endothelial dysfunction and vasoconstriction. Increased circulating ET-1 levels are associated with long-term cardiovascular mortality. Renalase, released from kidney, metabolizes catecholamines and regulates blood pressure. An increase in circulating renalase levels has been reported in patients with chronic kidney disease (CKD) and is associated with coronary artery disease (CAD). We hypothesized the existence of a synergistic effect of serum renalase levels and CKD on ET-1 levels in patients with CAD. We evaluated 342 non-diabetic patients with established CAD. ET-1 and renalase levels were measured in all patients after an overnight fast. Patients with CKD had higher ET-1 (1.95 ± 0.77 vs. 1.62 ± 0.76 pg/ml, P < 0.001) and renalase levels (46.8 ± 17.1 vs. 33.9 ± 9.9 ng/ml, P < 0.001) than patients without CKD. Patients with both CKD and high renalase levels (>the median of 36.2 ng/ml) exhibited the highest serum ET-1 (P value for the trend <0.001). According to multivariate linear regression analysis, the combination of high serum renalase levels with CKD was a significant risk factor for increased serum ET-1 levels (regression coefficient = 0.297, 95% confidence interval = 0.063‒0.531, P = 0.013). In conclusion, our data suggest a synergistic effect of high serum renalase levels and CKD on increases in ET-1 levels in patients with established CAD.

Topics: Aged; Catecholamines; Coronary Artery Disease; Cross-Sectional Studies; Endothelin-1; Female; Humans; Kidney; Male; Middle Aged; Monoamine Oxidase; Renal Insufficiency, Chronic

Genome-wide association studies (GWASs) implicate the PHACTR1 locus (6p24) in risk for five vascular diseases, including coronary artery disease, migraine headache, cervical artery dissection, fibromuscular dysplasia, and hypertension. Through genetic fine mapping, we prioritized rs9349379, a common SNP in the third intron of the PHACTR1 gene, as the putative causal variant. Epigenomic data from human tissue revealed an enhancer signature at rs9349379 exclusively in aorta, suggesting a regulatory function for this SNP in the vasculature. CRISPR-edited stem cell-derived endothelial cells demonstrate rs9349379 regulates expression of endothelin 1 (EDN1), a gene located 600 kb upstream of PHACTR1. The known physiologic effects of EDN1 on the vasculature may explain the pattern of risk for the five associated diseases. Overall, these data illustrate the integration of genetic, phenotypic, and epigenetic analysis to identify the biologic mechanism by which a common, non-coding variant can distally regulate a gene and contribute to the pathogenesis of multiple vascular diseases.

Topics: Acetylation; Cells, Cultured; Chromatin; Chromosome Mapping; Chromosomes, Human, Pair 6; Coronary Artery Disease; Endothelial Cells; Endothelin-1; Epigenomics; Gene Editing; Gene Expression; Genetic Predisposition to Disease; Genome-Wide Association Study; Histones; Humans; Muscle, Smooth, Vascular; Polymorphism, Single Nucleotide; Vascular Diseases

Big endothelin-1 (ET-1) has been proposed as a novel prognostic indicator of acute coronary syndrome, while its predicting role of cardiovascular outcomes in patients with stable coronary artery disease (CAD) is unclear.. A total of 3154 consecutive patients with stable CAD were enrolled and followed up for 24months. The outcomes included all-cause death, non-fatal myocardial infarction, stroke and unplanned revascularization (percutaneous coronary intervention and coronary artery bypass grafting). Baseline big ET-1 was measured using sandwich enzyme immunoassay method. Cox proportional hazard regression analysis and Kaplan-Meier analysis were used to evaluate the prognostic value of big ET-1 on cardiovascular outcomes. One hundred and eighty-nine (5.99%) events occurred during follow-up. Patients were divided into two groups: events group (n=189) and non-events group (n=2965). The results indicated that the events group had higher levels of big ET-1 compared to non-events group. Multivariable Cox proportional hazard regression analysis showed that big ET-1 was positively and statistically correlated with clinical outcomes (Hazard Ratio: 1.656, 95% confidence interval: 1.099-2.496, p=0.016). Additionally, the Kaplan-Meier analysis revealed that patients with higher big ET-1 presented lower event-free survival (p=0.016).. The present study firstly suggests that big ET-1 is an independent risk marker of cardiovascular outcomes in patients with stable CAD. And more studies are needed to confirm our findings.

Topics: Aged; Cohort Studies; Coronary Artery Disease; Endothelin-1; Female; Hospitalization; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Proportional Hazards Models; Risk Factors

Identification of biomarkers that assess posttransplant risk is needed to improve long-term outcomes following heart transplantation. The Clinical Trials in Organ Transplantation (CTOT)-05 protocol was an observational, multicenter, cohort study of 200 heart transplant recipients followed for the first posttransplant year. The primary endpoint was a composite of death, graft loss/retransplantation, biopsy-proven acute rejection (BPAR), and cardiac allograft vasculopathy (CAV) as defined by intravascular ultrasound (IVUS). We serially measured anti-HLA- and auto-antibodies, angiogenic proteins, peripheral blood allo-reactivity, and peripheral blood gene expression patterns. We correlated assay results and clinical characteristics with the composite endpoint and its components. The composite endpoint was associated with older donor allografts (p < 0.03) and with recipient anti-HLA antibody (p < 0.04). Recipient CMV-negativity (regardless of donor status) was associated with BPAR (p < 0.001), and increases in plasma vascular endothelial growth factor-C (OR 20; 95%CI:1.9-218) combined with decreases in endothelin-1 (OR 0.14; 95%CI:0.02-0.97) associated with CAV. The remaining biomarkers showed no relationships with the study endpoints. While suboptimal endpoint definitions and lower than anticipated event rates were identified as potential study limitations, the results of this multicenter study do not yet support routine use of the selected assays as noninvasive approaches to detect BPAR and/or CAV following heart transplantation.

Topics: Adult; Biomarkers; Blotting, Western; Case-Control Studies; Clinical Trials as Topic; Coronary Artery Disease; Endothelin-1; Female; Gene Expression Profiling; Graft Rejection; Heart Diseases; Heart Transplantation; Humans; Male; Middle Aged; Prospective Studies; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vascular Endothelial Growth Factor A

Topics: Coronary Artery Disease; Endothelin-1; Humans; MicroRNAs

The correct understanding of the biochemical and metabolic interactions between coronary risk factors contribute to the exploration of cardiovascular pathophysiology and improves therapeutic care. The aim of this study was to explore the endothelin-1 (ET-1) concentration and the angiotensin converting enzyme (ACE) activity among Tunisian patients with coronary heart disease, and to investigate the metabolic relationships between these two markers,… and to assess the possible relationship between them and the different risk factors. In this present study, ET-1 concentration was determined by an analytical method (High Performance Chromatography, coupled by Mass Spectrometry), ACE activity was measured by a kinetic method for patients and healthy controls. These subjects (157 patients and 142 controls) beneficed also by a biochemical exploration (lipid, apolipoproteins and glucose profiles) to quantify cardiovascular risk.. A statistically significant increase of the ET-1 concentration was found among patients compared to healthy controls (15.2 ± 5.3 nM vs 7.1 ± 2.7 nM, p < 0,00001). For the ACE activity, in spite the treatment of the majority of patients (97%) with ACE inhibitors, this activity was statistically elevated in patients compared to healthy subjects (86.7 ± 25.4 IU/L vs 42.8 ± 12.1 IU/L, p < 0.00001). Furthermore, a statistically positive correlation was identified between these two cardiac markers (r = 0.68 p < 0.00001).. The study of the metabolic relationship between the ET-1 and ACE among coronary patients reveals other therapeutics targets.

Topics: Biomarkers; Chromatography, High Pressure Liquid; Coronary Artery Disease; Endothelin-1; Female; Follow-Up Studies; Humans; Male; Mass Spectrometry; Middle Aged; Peptidyl-Dipeptidase A; Prospective Studies; Risk Factors; Tunisia

Type 2 diabetes (DMT2) combined with ischemic heart disease (IHD) promotes the occurrence and development of coronary atherosclerosis. We aimed to provide a theoretical basis for improving patient prognosis through analyzing expression of plasma brain natriuretic peptide (BNP), endothelin-1 (ET 1), and matrix metalloproteinase 9 (MMP-9).. Enzyme-linked immunosorbent assay (ELISA) was used to detect BNP, ET-1, and MMP-9 levels in 50 patients with DMT2 only (group A), 47 patients with IHD only (group B), 43 patients with comorbid (both) IHD and DMT2 (group C), and 50 health controls (group D). Group C was further divided into single-branch lesion group, double-branch lesions group, and triple-branch lesion group according to coronary angiography, or cardiac function grade II, III, and IV group according to cardiac function, and their BNP, ET-1, and MMP-9 levels were compared.. Compared with group D, TG, diastolic, and systolic blood pressure were all significantly elevated in groups A, B, and C. Group C exhibited obviously higher glycosylated hemoglobin than group A. Gensini score in group C was markedly higher than in group B. Compared with group D, BNP, ET-1, and MMP-9 levels were all increased in groups A, B, and C. Group C showed higher levels of BNP, ET-1, and MMP-9 than group A and B. BNP, ET-1, and MMP-9 levels in the triple-branch lesions group were higher than in the single-branch lesions group and double-branch lesions group. The cardiac function grade IV group presented higher levels of BNP, ET-1, and MMP-9 than did the grade II and III groups. BNP, ET-1, and MMP-9 showed a positive correlation to each other.. BNP, ET-1, and MMP-9 may participate in the occurrence and development of comorbid DMT2 and IHD. They are important objective indicators for evaluating severity and prognosis of patients with comorbid DMA2 and IHD.

Topics: Adult; Aged; Biomarkers; Coronary Artery Disease; Diabetes Mellitus, Type 2; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Heart Function Tests; Humans; Male; Matrix Metalloproteinase 9; Middle Aged; Myocardial Ischemia; Natriuretic Peptide, Brain; Prognosis

The role of endothelin-1 (ET-1) in the neurobiology of anxiety is unknown, therefore, we assessed in the observational multicenter DIAST-CHF study whether the C-terminal ET-1 precursor fragment (CT-proET-1) is linked to anxiety.. Plasma concentrations of CT-proET-1 were measured in a total of 1,410 patients presenting with cardiovascular risk factors (mean age 66.91±8.2 years, 49.3% males, mean left ventricular ejection fraction 60.0±8.2%) who had completed the Hospital Anxiety and Depression Scale (HADS) questionnaire.. Among the total study cohort (n = 1,410), there were 118 subjects (8.4%) with an HADS anxiety score above the cut-off level of 11 suggestive of clinically relevant anxiety. Plasma CT-proET-1 levels were significantly lower in the group of anxious patients as compared to non-anxious patients (p = 0.013). In regression models adjusted for sex, age, systolic blood pressure, and diameters of left atrium and ventricle, plasma CT-proET-1 was again linked to anxiety (Exp(β) = 0.247, 95%-confidence interval [95%-CI] = 0.067-0.914, p = 0.036). Given the high prevalence of depressive disorders in anxious patients, we additionally included the HADS depression score as an independent variable in the models and found that CT-proET-1 remained a significant predictor of anxiety, independent of comorbid depression (Exp(β) = 0.114, 95%-CI = 0.023-0.566, p = 0.008).. Our data from a population-based study in outpatients with cardiovascular risk factors revealed that circulating CT-proET-1 levels are negatively associated with anxiety. Further investigations are required to clarify the putative anxiolytic effect of ET-1 or its precursor molecules in humans and to decipher its mechanistic pathways.

Topics: Aged; Aged, 80 and over; Anxiety; Coronary Artery Disease; Depression; Endothelin-1; Female; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptides; Peptide Fragments; Risk Factors; Signal Transduction; Stroke Volume; Surveys and Questionnaires

Recently, several vasoactive molecules have been found in pericardial fluid (PF). Thus, we hypothesized that in coronary artery disease due to ischemia or ischemia-reperfusion, the level of vasoconstrictors, mainly endothelin-1 (ET-1), increases in PF, which can increase the vasomotor tone of arteries. Experiments were performed using an isometric myograph. Vasomotor effects of PF from patients undergoing coronary artery bypass graft (PFCABG, n = 14) or valve replacement (PFVR, n = 7) surgery were examined in isolated rat carotid arteries (N = 14; n = 26). Vasomotor responses to KCl (40 or 60 mmol/L) were also tested. The selective endothelin A receptor antagonist BQ123 (10(-6) mol/L) was used to elucidate the role of ET-1. Both the first and the second additions of KCl elicited increases in the isometric force of the isolated arteries (KCl1, 6.1 ± 0.2 mN; KCl2, 6.5 ± 0.9 mN). PFCABG and PFVR elicited substantial increases in the isometric force of arteries (PFCABG, 3.1 ± 0.7 mN; PFVR, 3.0 ± 0.9 mN; p > 0.05). The presence of the selective endothelin A receptor blocker significantly reduced arterial contractions to PFCABG (before BQ123, 2.6 ± 0.5 mN vs. after BQ123, 0.8 ± 0.1 mN; p < 0.05). This study is the first to demonstrate that PFs of patients elicit substantial arterial constrictions, which is mediated primarily by ET-1. Interfering with the vasoconstrictor action of PF could be a potential therapeutic target to improve coronary blood flow in cardiac patients.

Topics: Animals; Carotid Arteries; Coronary Artery Disease; Endothelin Receptor Antagonists; Endothelin-1; Humans; In Vitro Techniques; Male; Peptides, Cyclic; Pericardial Fluid; Potassium Chloride; Rats; Vasoconstriction

Endothelial microparticle (EMP) is a biomarker for endothelial dysfunction. The aim of this study is to investigate the utility of EMP in evaluating coronary intermediate lesions. Participants included 49 patients with coronary intermediate lesions and 24 subjects with normal coronary arteries. Among these subjects, 28 patients accepted fractional flow reserve (FFR). Results showed that level of EMP was significantly higher in the intermediate lesion group. No correlation was found between EMP and FFR value, suggesting that circulating EMP is a systemic marker rather than a focal one.

Topics: Aged; Biomarkers; Cell-Derived Microparticles; Chi-Square Distribution; Coronary Artery Disease; Endothelin-1; Endothelium, Vascular; Female; Fractional Flow Reserve, Myocardial; Humans; Male; Middle Aged; Nitric Oxide; Nitric Oxide Synthase Type III

The coronary artery calcification (CAC) is clinically considered as one of the important predictors of atherosclerosis. Several studies have confirmed that endothelin-1(ET-1) plays an important role in the process of atherosclerosis formation. The aim of this study was to investigate whether big ET-1 is associated with CAC.. A total of 510 consecutively admitted patients from February 2011 to May 2012 in Fu Wai Hospital were analyzed. All patients had received coronary computed tomography angiography and then divided into two groups based on the results of coronary artery calcium score (CACS). The clinical characteristics including traditional and calcification-related risk factors were collected and plasma big ET-1 level was measured by ELISA. Patients with CAC had significantly elevated big ET-1 level compared with those without CAC (0.5 ± 0.4 vs. 0.2 ± 0.2, P<0.001). In the multivariate analysis, big ET-1 (Tertile 2, HR = 3.09, 95% CI 1.66-5.74, P <0.001, Tertile3 HR = 10.42, 95% CI 3.62-29.99, P<0.001) appeared as an independent predictive factor of the presence of CAC. There was a positive correlation of the big ET-1 level with CACS (r = 0.567, p<0.001). The 10-year Framingham risk (%) was higher in the group with CACS>0 and the highest tertile of big ET-1 (P<0.01). The area under the receiver operating characteristic curve for the big ET-1 level in predicting CAC was 0.83 (95% CI 0.79-0.87, p<0.001), with a sensitivity of 70.6% and specificity of 87.7%.. The data firstly demonstrated that the plasma big ET-1 level was a valuable independent predictor for CAC in our study.

Topics: Adult; Aged; Calcinosis; Calcium; Coronary Angiography; Coronary Artery Disease; Coronary Vessels; Endothelin-1; Female; Humans; Male; Middle Aged; Multivariate Analysis

Endothelin-1 (ET-1), a potent vasoconstrictor, IL-6, and catecholamines are increased and heart rate variability [SD of normal to normal R-R intervals (SDNN)] decreased during emotional excitement, but individual responses vary. We tested the hypothesis that exercise capacity is associated with physiological responses caused by real-life emotional excitement. We measured the plasma levels of ET-1, IL-6, catecholamines, heart rate, and SDNN in enthusiastic male ice hockey spectators (n = 51; age, 59 ± 9 years) with stable coronary artery disease (CAD) at baseline and during the Finnish National Ice Hockey League's final play-off matches. Maximal exercise capacity (METs) by bicycle exercise test and left ventricular ejection fraction (LVEF) were measured on a separate day. ET-1 response from baseline to emotional excitement correlated with maximal METs (r = -0.30; P = 0.040). In a linear stepwise regression analysis age, body mass index (BMI), METs, LVEF, basal ET-1, and subjective experience of excitement were entered the model as independent variables to explain ET-1 response. This model explained 27% of ET-1 response (P = 0.003). Maximal METs were most strongly correlated with ET-1 response (β = -0.45; partial correlation r = -0.43; P = 0.002), followed by BMI (β = -0.31; partial correlation r = -0.31; P = 0.033) and LVEF (β = -0.30; partial correlation r = -0.33; P = 0.023). Exercise capacity may protect against further cardiovascular events in CAD patients, because it is associated with reduced ET-1 release during emotional excitement.

Topics: Aged; Biomarkers; Catecholamines; Coronary Artery Disease; Echocardiography, Stress; Electrocardiography; Emotions; Endothelin-1; Exercise Test; Exercise Tolerance; Finland; Heart Rate; Hockey; Humans; Interleukin-6; Linear Models; Male; Middle Aged; Stroke Volume; Time Factors; Ventricular Function, Left

To explore the effects of allitridi capsules on endothelial function and clinical prognosis in coronary artery disease (CAD) patients with obstructive sleep apnea hypopnea syndrome (OSAHS).. A total of 80 CAD patients with OSAHS were randomly assigned to receive conventional treatment (control, n = 40) and additional allitridi treatment (120 mg/day, n = 40) for 6 months. Another 40 CAD patients without OSAHS and 30 healthy individuals were chosen as controls. Endothelial function was assessed by endothelium dependent flow-mediated dilation (FMD) with high-definition color Doppler ultrasound. Serum nitric oxide (NO) and plasma endothelin-1 (ET-1) levels were determined by enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay. The duration of follow-up was 1 year.. The baseline clinical characteristics were not different between control and allitridi groups (P > 0.05). Compared with CAD patients without OSAHS, FMD and serum NO level were significantly lower ((7.9 ± 1.5)% vs (11.2 ± 2.9)%, P = 0.011 and (71.11 ± 10.62) vs (86.28 ± 11.03) µmol/L, P = 0.007), plasma ET-1 level was markedly higher ((112.34 ± 17.22) vs (89.87 ± 11.56) ng/L, P = 0.025) in CAD patients with OSAHS. At Month 6 post-treatment, FMD and serum NO level were significantly higher ((12.1 ± 3.1)% vs (9.1 ± 1.6)%, P = 0.020 and (105.24 ± 17.01) vs (82.39 ± 11.12) µmol/L, P = 0.001) and plasma ET-1 level in the allitridi group was lower ((77.12 ± 9.65) vs (97.77 ± 11.04) ng/L, P = 0.001) than that in the control group. At Month 12 post-treatment, the incidence of MACE was lower in the allitridi group than that in the control group (8.3% vs 15.8%, P = 0.016).. Allitridi capsules significantly improved endothelial function in CAD patients with OSAHS.

Topics: Allyl Compounds; Capsules; Coronary Artery Disease; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Humans; Nitric Oxide; Prognosis; Sleep Apnea, Obstructive; Sulfides

This study was to investigate the utility of platelet-derived microparticles (PMPs) to detect coronary intermediate lesions. Fifty-two patients with coronary intermediate lesions and 24 subjects with normal coronary arteries were enrolled. In the former group, 31 patients accepted both intravenous ultrasound (IVUS) and fractional flow reserve (FFR). Results showed that the level of PMPs was significantly higher in the intermediate lesion group and PMPs titer was positively correlated with thromboxane B2, platelet activating factor, endothelin-1, and neutrophil to lymphocyte ratio. The level of PMPs also increased after IVUS/FFR, suggesting platelet activation and endothelial dysfunction.

Topics: Aged; Biomarkers; Blood Platelets; Coronary Artery Disease; Endothelin-1; Female; Humans; Lymphocyte Count; Male; Middle Aged; Neutrophils; Platelet Activating Factor; Platelet Activation; Thromboxane B2

We studied the impact of diabetes mellitus (DM) on the radial artery (RA) in 30 patients with DM and 30 non-diabetic patients undergoing coronary artery bypass grafting with autologous RA. RAs were recorded as normal if there was no cellular or stromal tissue between the endothelium and the internal elastic lamina. The RA was normal in 26.7% of diabetic and 76.7% of non-diabetic patients (p = 0.000298). Intimal thickness index and intima:media ratio were higher in the former than in the latter (p < 0.05; p < 0.05), with no significant difference in luminal narrowing (p > 0.05). Electron microscopy scores were lower in the non-diabetic group (p < 0.001); endothelial nitric oxide synthase (eNOS) protein expression and optical density were higher (p < 0.001). Von Willebrand factor and endothelin-1 messenger RNA (mRNA) levels were higher in the DM patients (p < 0.001). The quality of the RA in patients with DM was thus inferior to that in non-diabetic patients. Care should be taken when selecting RA as a conduit in patients with DM.

Topics: Aged; Carotid Intima-Media Thickness; Carotid Stenosis; Coronary Artery Bypass; Coronary Artery Disease; Diabetic Angiopathies; Endothelin-1; Endothelium, Vascular; Female; Humans; Hyperplasia; Male; Microscopy, Electron, Transmission; Middle Aged; Nitric Oxide Synthase Type III; Radial Artery; RNA, Messenger; Transplantation, Autologous; Up-Regulation; von Willebrand Factor

Topics: Adult; Anthropometry; Asian People; Blood Flow Velocity; Brachial Artery; China; Cholesterol; Coronary Artery Disease; Endothelin-1; Endothelium, Vascular; Humans; Male; Occupations; Regional Blood Flow; Tibet

Detailed evaluation of coronary function early in diabetes mellitus (DM)-associated coronary artery disease (CAD) development is difficult in patients. Therefore, we investigated coronary conduit and small artery function in a preatherosclerotic DM porcine model with type 2 characteristics. Streptozotocin-induced DM pigs on a saturated fat/cholesterol (SFC) diet (SFC + DM) were compared with control pigs on SFC and standard (control) diets. SFC + DM pigs showed DM-associated metabolic alterations and early atherosclerosis development in the aorta. Endothelium-dependent vasodilation to bradykinin (BK), with or without blockade of nitric oxide (NO) synthase, endothelium-independent vasodilation to an exogenous NO-donor (S-nitroso-N-acetylpenicillamine), and vasoconstriction to endothelin (ET)-1 with blockade of receptor subtypes, were assessed in vitro. Small coronary arteries, but not conduit vessels, showed functional alterations including impaired BK-induced vasodilatation due to loss of NO (P < 0.01 vs. SFC and control) and reduced vasoconstriction to ET-1 (P < 0.01 vs. SFC and control), due to a decreased ET(A) receptor dominance. Other vasomotor responses were unaltered. In conclusion, this model demonstrates specific coronary microvascular alterations with regard to NO and ET-1 systems in the process of early atherosclerosis in DM. In particular, the altered ET-1 system correlated with hyperglycemia in atherogenic conditions, emphasizing the importance of this system in DM-associated CAD development.

Topics: Animals; Blood Glucose; Bradykinin; Coronary Artery Disease; Coronary Vessels; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Disease Progression; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Male; Nitric Oxide; Nitric Oxide Donors; Receptors, Endothelin; S-Nitroso-N-Acetylpenicillamine; Swine; Time Factors; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

OBJECTIVES. Emotional excitement may trigger serious cardiovascular (CV) events. Our objective was to compare the changes in potential surrogate markers of CV events in patients with coronary artery disease (CAD) during emotional excitement and exercise. DESIGN. Fifty-three enthusiastic ice-hockey spectators with stable CAD attended the Finnish national ice-hockey play-off matches and a maximal bicycle exercise. Plasma catecholamines, endothelin-1, interleukin-6, and markers of platelet activation and blood coagulation were determined before and during the match and before and after the exercise. RESULTS. Plasma endothelin-1 (2.82 ± 0.21 vs. 2.94 ± 0.25 pg/mL, p < 0.0001), noradrenaline (4.38 ± 1.79 vs. 4.77 ± 1.75 nmol/L, p = 0.009) and interleukin-6 (2.04 ± 1.98 vs. 2.90 ± 2.41 pg/mL, p < 0.0001) increased during the match, but markers of platelet activation and coagulation remained unchanged. Endothelin-1 did not change during exercise (2.73 ± 0.17 vs. 2.72 ± 0.19 pg/mL, p = 0.593) but noradrenaline (2.70 ± 1.08 vs.10.6 ± 5.5 nmol/L), adrenaline (0.23 ± 0.13 vs. 0.52 ± 0.37 nmol/L), interleukin-6 (1.77 ± 1.59 vs. 2.43 ± 1.78 pg/mL) and markers of platelet activation and blood coagulation increased significantly (p < 0.0001 for all). CONCLUSIONS. The responses of surrogate markers of acute CV events to emotional excitement and physical exercise are partly different. Emotional excitement causes concomitant increases in markers reflecting vulnerability to atherosclerotic plaque complications while physical exercise causes more prominent changes in markers of coagulation.

Topics: Aged; Biomarkers; Blood Coagulation; Catecholamines; Coronary Artery Disease; Emotions; Endothelin-1; Epinephrine; Exercise; Exercise Test; Humans; Interleukin-6; Leisure Activities; Male; Middle Aged; Norepinephrine; Platelet Activation

Endothelin-1 (ET-1) has been shown to increase endothelial superoxide (O(2)(-)) production in experimental animal models. It is unclear whether ET-1 increases O(2)(-) production in humans. We sought to elucidate whether ET-1 increases O(2)(-) production in human vessels and to identify the mechanism behind this effect.. Segments of internal mammary artery (IMA) and human saphenous vein (HSV) were harvested from 90 patients undergoing elective coronary artery bypass graft surgery. Paired vessel rings were incubated in the presence and absence of ET-1 (10(-10)M), the ET(A) receptor antagonist BQ123 alone, or in combination with the ET(B) receptor antagonist BQ788 (dual BQ) and known inhibitors of sources of O(2)(-) and further analysed for O(2)(-) production using lucigenin-enhanced chemiluminescence and DHE fluorescence.. ET-1 increased O(2)(-) production in both IMA (2.6 ± 1.5 vs. 1.4 ± 0.8 relative light units/s/mg tissue (RLU); n=33; p < 0.0001) and HSV (1.4 ± 0.8 vs. 1.1 ± 0.6 RLU; n=24; p<0.05). The increase in O(2)(-)production induced by ET-1 in IMA was inhibited by co-incubation with dual BQ (p < 0.05; n=15) and BQ123 (p<0.05; n = 17). Of known O(2)(-) inhibitors, only incubation with Tiron and diphenyleneiodonium resulted in a significant reduction in ET-mediated O(2)(-) production.. ET-1 increases O(2)(-) production especially in human arteries and less so in veins from patients with coronary artery disease via a receptor-dependent pathway involving a flavin dependent enzyme which is likely to be NADPH oxidase. Production of O(2)(-) may be an important factor underlying the negative effects of ET-1 on vascular function such as impairment of endothelium-dependent vasodilatation and pro-inflammatory effects.

Topics: 1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; Aged; Coronary Artery Bypass; Coronary Artery Disease; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Female; Humans; Luminescent Measurements; Male; Mammary Arteries; Middle Aged; Oligopeptides; Onium Compounds; Peptides, Cyclic; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; Saphenous Vein; Superoxides

The endothelial dysfunction has been implicated as a major event in the pathogenesis of atherosclerosis. Therefore, this study was planned to determine (a) role of endothelium-derived nitric oxide (NO) and endothelin as coronary artery disease (CAD) risk markers and (b) intergenotypic variation of endothelial nitric oxide synthase (eNOS) Glu298Asp polymorphism in CAD.The endothelin, NO and eNOS genotypes were determined in 60 patients with documented history of CAD. These were compared with 50 age- and sex- matched healthy controls. The genotype frequencies for eNOS gene polymorphism were determined by PCR and RFLP. The plasma endothelin in CAD patients was significantly higher (p< 0.001) whereas, the NO level in CAD group was significantly lower (p< 0.001) than the control group. The genotype frequencies for Glu298/Asp (Glu/Glu and Glu/Asp) genotypes were 75% and 25% in CAD subjects and 88% and 12% in control subjects, respectively. No Asp/Asp was found in any of the groups. The genotype frequencies differed significantly (p< 0.05) between the controls and cases. In conclusion, endothelin and NO may be used as markers of endothelial dysfunction in CAD. Asp allele might be a risk factor for CAD in the North Indian population.

Topics: Aged; Amino Acid Substitution; Biomarkers; Case-Control Studies; Coronary Artery Disease; Endothelin-1; Endothelium; Female; Genetic Association Studies; Genotype; Humans; India; Male; Middle Aged; Nitric Oxide; Nitric Oxide Synthase Type III; Polymorphism, Single Nucleotide; Sequence Analysis, DNA

Topics: Angioplasty, Balloon, Coronary; Cardiopulmonary Bypass; Coronary Artery Bypass; Coronary Artery Disease; Endothelin-1; Female; Humans; Inflammation; Inflammation Mediators; Male; Myocardial Infarction; Ventricular Function, Left

1. The aim of the present study was to determine the relationship between plasma concentrations of nitrite/nitrate (NO(x)) and endothelin (ET)-1 and non-invasive measures of peripheral vasodilator function in patients with coronary artery disease (CAD). 2. Twenty-two patients with angiographic CAD underwent non-invasive measurement of peripheral vasodilator function in the brachial conduit artery (flow-mediated dilation (FMD) testing via ultrasound) and in the forearm resistance arteries (via venous occlusion plethysmography) during reactive hyperaemia after 5 min ischaemia. In addition, plasma NO(x) and ET-1 concentrations were determined. 3. The plasma concentration of NO(x) was related to the peak brachial FMD response when expressed as either the relative (%) or absolute (mm) change in diameter (r = 0.73, P < 0.001; and r = 0.64, P < 0.01, respectively). Moreover, plasma concentrations of NO(x) demonstrated a relationship with forearm vasodilation estimated by total forearm blood flow following 5 min ischaemia (r = 0.63, P < 0.01) and the flow debt repayment of the forearm (r = 0.54, P < 0.01). Finally, ET-1 concentrations were inversely related to FMD% (r = -0.45, P < 0.05). 4. The findings of the present study demonstrate a relationship between the plasma concentrations of NO(x) and measures of vascular reactivity in conduit and resistance arteries in patients with CAD. Therefore, measurement of plasma NO(x) may serve as a reliable marker for peripheral vasodilator dysfunction in patients with CAD.

Topics: Brachial Artery; Coronary Artery Disease; Endothelin-1; Female; Forearm; Humans; Hyperemia; Male; Middle Aged; Nitric Acid; Nitric Oxide; Reactive Nitrogen Species; Ultrasonography; Vasodilation

Endothelial dysfunction plays an important role in the pathogenesis of hypertension. Other risk factors of atherosclerosis also affect its development. The aim of the study was to assess nitric oxide metabolites concentration (nitrites and nitrates No(x)) and endothelin (ET-1) in plasma and cyclic 3,5-guanosine monophosphate (cGMP) in 24 h-urine collection in patients with noncomplicated hypertension without risk factors of atherosclerosis and in hypertensive patients with coronary artery disease (CAD). Sixty-eight subjects were included in the study (44 men, 24 women), aged 47 +/- 76 years, allotted into four groups: I - controls (18 clinically healthy subjects); II - 12 subjects with hypertension without risk factors of atherosclerosis; III - 16 subjects with hypertension and risk factors of atherosclerosis; and IV - 22 subjects with hypertension and CAD. Plasma NO(x) concentration was determined using the Greiss method, plasma ET-1 by ELISA, and urine cGMP using the immunoenzymatic method. Plasma NO(x) concentration was 14.00 +/- 6.88 micromol/L in group I, in group II - 18.62 +/- 5.84 micromol, in group III - 9.96 +/- 4.72 micromol/L, and in group IV - 8.78 +/- 3.72 micromol/L. Statistically significant differences were between groups I and III (p < 0.05) and I and IV (p < 0.04) and groups II and III (p < 0.01) and II and IV (p < 0.01). The concentration of cGMP in 24 h urine collection was in group I - 40 +/- 24 pmol/L; in group II - 54 +/- 41 pmol/L; in group III - 38 +/- 32 pmol/L; and in group IV - 42 +/- 36 pmol/L. There were no significant differences between the groups. Plasma ET-1 concentration was 3.86 +/- 0.52 pg/mL in group I, in group II - 4.05 +/- 0.71 pg/mL, in group III - 4.22 +/- 0.79 pg/mL and in group IV - 4.38 +/- 0.75 pg/mL. Statistically significant differences were between group I and III (p < 0.05), I and IV (p < 0.03), and between group II and IV (p < 0.04). Endothelial dysfunction was not found in hypertensive patients without a family history of cardiovascular diseases and without other risk factors of atherosclerosis. Deterioration of endothelial function was observed in patients with hypertension with risk factors of atherosclerosis. It was most pronounced in those with CAD.

Topics: Aged; Atherosclerosis; Case-Control Studies; Coronary Artery Disease; Cyclic GMP; Endothelin-1; Endothelium, Vascular; Female; Humans; Hypertension; Male; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Risk Factors; Vasodilation

Endothelin (ET) A receptor antagonism causes decreased vasodilation in hypertensive coronary arteries and decreased effects on coronary artery compliance in diabetic patients.. We investigate the mRNA expression of ET-1, ET(A) and ET(B) receptors, using real time RT-PCR, in biopsies from the internal mammary artery obtained from 49 patients, 18 diabetics and 34 hypertensives, all undergoing coronary artery bypass grafting.. Hypertensive patients had higher ET-1 mRNA expression (16438 [8417, 23917]), than normotensive patients (2974 [2283, 18055], p=0.008). Diabetic patients had significantly lower ET(A) receptor levels than non-diabetic patients (455 [167, 1496] vs. 1660 [700, 3190], respectively, p = 0.003).. Multivariate analysis demonstrated that the presence of systemic hypertension was the only independent predictor of log ET(A) receptor expression and log ET-1 expression, while insulin-dependent diabetes was negatively correlated with ET(A) receptor expression. ETB receptor expression was not correlated with any predictor. Systemic hypertension is associated with increased ET-1 and ET(A) receptor mRNA expression, whereas insulin-dependent diabetes down-regulates ET(A) receptor mRNA expression in the internal mammary artery in patients with coronary artery disease undergoing bypass grafting.

Topics: Aged; Coronary Artery Bypass; Coronary Artery Disease; Diabetes Mellitus, Type 1; Down-Regulation; Endothelin-1; Female; Gene Expression; Humans; Hypertension; Male; Mammary Arteries; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Receptor, Endothelin A; Receptor, Endothelin B; RNA, Messenger; Vasodilation

Transplant coronary arteriosclerosis (TCA) is the principal long-term complication in cardiac transplant recipients. The mediators responsible for vascular proliferation and vasoconstriction typical of TCA remain largely unknown. We tested whether endothelin-1 (ET-1), a potent vasoconstrictor and mitogen, contributes to the pathogenesis and manifestations of TCA.. BQ-123, an ET-1 receptor-A antagonist, was infused into a coronary artery (40 nmol/min for 60 minutes) of 18 subjects, 6 + or - 4 years after transplantation. Vasomotor responses were measured in the infused artery and in a noninfused control artery in patients with (n=10) and without (n=8) advanced TCA (108 total coronary segments). Changes in diameters were compared at 15-minute intervals up to 60 minutes. Contribution of ET-1 to coronary constrictor tone was assessed by comparing vasodilation from BQ-123 with that of the maximal vasodilator nitroglycerin (200-microg intracoronary bolus). BQ-123 dilated coronary arteries of transplanted patients (8.4% at 60 minutes versus -0.4% in noninfused arteries, P<0.001). Dilation was greater for arteries with advanced TCA defined as diameter stenosis > or = 15% (dilation 15.2% with versus 0.6% without advanced TCA, P=0.004). Judged against the response to nitroglycerin, ET-1 accounted for 53.2% of coronary tone in advanced TCA but only 12.9% without advanced TCA.. This study shows for the first time in humans that ET-1 is an important mediator of coronary vasoconstriction in TCA and accounts for >50% of the increased vasomotor tone. Therapeutic targeting of ET-1 may retard the development of TCA.

Topics: Adult; Aged; Blood Flow Velocity; Case-Control Studies; Coronary Artery Disease; Coronary Circulation; Endothelin A Receptor Antagonists; Endothelin-1; Female; Heart Transplantation; Humans; Infusions, Intravenous; Male; Microcirculation; Middle Aged; Peptides, Cyclic; Receptor, Endothelin A; Severity of Illness Index; Time Factors; Vascular Resistance; Vasoconstriction; Vasodilator Agents

Endothelin is the most potent endogenous vasoconstrictor and is involved in several vascular disorders such as arterial hypertension. Its intense interaction with other vasoactive hormone systems revealed the consideration about the endothelin gene as an interesting candidate for influencing the development of essential hypertension and hypertensive endorgan damage. The purpose of this study was to investigate the role of endothelin-1 Lys198Asn polymorphism in patients with severe arterial hypertension as well as associated endorgan damages.. In 400 hypertensive patients and 150 normotensive controls we examined the endothelin-1 Lys198Asn polymorphism by DNA sequencing and patients were divided according to their genotype (GG, GT, and TT). Moreover, the frequency of endothelin-1 Lys198Asn polymorphism was investigated with respect to the prevalence of several actual or historical endorgan damages (renal disorder, coronary artery disease, vascular events, vascular damage, and congestive heart failure) in hypertensive patients.. Genotype distribution for endothelin-1 Lys198Asn polymorphism was 57.3% (GG), 41.3% (GT), and 1.43% (TT) in normotensive individuals; and in hypertensive individuals was 54.75% (GG), 43% (GT) and 2.25% (TT). Genotype distribution was unaffected in patients with severe hypertension, renal disorder, vascular events, vascular damage, and congestive heart failure. We, however, found a significant difference in hypertensive individuals with coronary artery disease and TT genotype (P=0.004).. Homozygous TT carrier contributes to a higher prevalence of coronary artery disease, especially for three-vessel disease in hypertensive individuals. Thus, the polymorphism at position 198 could serve as a possibility to differentiate high-risk subgroups in the heterogeneous population of hypertensive patients.

Topics: Adult; Aged; Atherosclerosis; Case-Control Studies; Coronary Artery Disease; Endothelin-1; Female; Gene Frequency; Genetic Predisposition to Disease; Heart Failure; Homozygote; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Polymorphism, Genetic; Risk Factors; Severity of Illness Index

Endothelin (ET)-1 receptor blockade improves endothelial function in the forearm of patients with atherosclerosis. The aim was to investigate whether intracoronary ET receptor blockade improves coronary endothelial function and increases blood flow in patients with coronary artery disease. Ten patients received a 60-minute infusion of either the selective ETA receptor antagonist BQ123 (40 nmol/min, n = 6) or BQ123 + the ETB receptor antagonist BQ788 (40 nmol/min, n = 4). In all patients, substance P, an endothelium-dependent vasodilator, did not increase baseline coronary flow reserve with thermodilution (CFRThermo) (0.71 +/- 0.14 s during NaCl versus 0.59 +/- 0.14 s during substance P) or baseline quantitative coronary angiography (QCA) (2.74 +/- 0.16 mm versus 2.83 +/- 0.20 mm). After ET receptor blockade, however, the response to substance P was significantly improved as determined both by CFRThermo (0.62 +/- 0.14 s during NaCl versus 0.48 +/- 0.10 s during substance P, p < 0.05) and by QCA (2.70 +/- 0.18 mm versus 2.85 +/- 0.19 mm, p < 0.05). In addition, ET blockade increased blood flow in all patients by 16% +/- 10% (n = 10, p < 0.05) and in the BQ123 group by 22% +/- 16% (n = 6, p < 0.05). Furthermore, ETA blockade increased blood flow significantly more than did dual ETA/ETB blockade (p < 0.05). These findings indicate that ET receptor blockade may be a new therapeutic strategy to improve coronary vascular function in patients with coronary artery disease.

Topics: Aged; Aorta, Thoracic; Atherosclerosis; Blood Pressure; C-Reactive Protein; Capillaries; Cardiac Catheterization; Coronary Angiography; Coronary Artery Disease; Coronary Circulation; Coronary Vessels; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Female; Humans; Lipids; Male; Oligopeptides; Peptides, Cyclic; Piperidines

Several inflammatory biomarkers are linked to cardiovascular risk. In order to investigate their coexistence and relative responses, several established and two novel markers (lactoferrin and the terminal complement complex), representing infection and central components of inflammation, were measured simultaneously in patients undergoing first-time coronary angiography.. Blood samples from patients with (n=131) or without (n=103) significant coronary artery stenosis were analyzed for plasma markers representing endothelium, platelets, neutrophils, monocytes, and complement, C-reactive protein, and antibodies against the infectious agents Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus. In multivariate logistic regression analysis, hypercholesterolemia (p<0.001), increased concentrations of the neutrophil activation marker lactoferrin (p<0.001) and the monocyte activation marker neopterin (p=0.012), lower concentrations of the terminal complement complex (p<0.001), and antibodies against C. pneumoniae (p=0.023) were variables linked to coronary artery stenosis. In univariate analysis additional relationships were found to current smoking (p<0.001), increased plasma concentrations of vascular cell adhesion molecule-1 (p=0.015), E-selectin (p<0.01), myeloperoxidase (p=0.051) and endothelin-1 (p=0.053), as well as diabetes (p=0.039).. Activation of multiple inflammatory pathways and C. pneumoniae infection may influence the inflammatory response in atherosclerosis. These pilot data provide an indication of the relative usefulness of various inflammatory biomarkers, indicating that the novel markers lactoferrin and the terminal complement complex warrant further investigation.

Topics: Analysis of Variance; C-Reactive Protein; Chi-Square Distribution; Complement Membrane Attack Complex; Coronary Angiography; Coronary Artery Disease; E-Selectin; Endothelin-1; Female; Humans; Inflammation; Intercellular Adhesion Molecule-1; Lactoferrin; Logistic Models; Male; Middle Aged; Neopterin; Peroxidase; Risk Factors; Vascular Cell Adhesion Molecule-1

Inflammation is a major contributor to atherosclerotic vascular disease. Inflammatory parameters such as C-reactive protein (CRP) and Interleukin-6 (IL-6) have been shown to be strong predictors of cardiovascular events. The association between preoperative inflammatory parameters and early graft occlusion as well as cardiovascular events after coronary artery bypass grafting (CABG) has not, however, been fully elucidated. The aims of the present study were to prospectively investigate the prognostic value of the inflammatory parameters IL-6, CRP, and endothelin (ET-1) to predict early graft occlusion as well as late cardiovascular events after CABG.. In the present study 99 patients undergoing CABG because of stable angina pectoris due to significant coronary artery disease were prospectively included. Coronary angiography was repeated 3 months after CABG in 81 patients in order to evaluate early graft occlusion. Blood samples were collected before CABG in all patients. Patients were followed up for a median of 5 (3-7) years after CABG.. Twenty-five patients (31%) had one or more occluded grafts at the 3-month control coronary angiography. The patients with occluded grafts had higher preoperative CRP and IL-6 levels in plasma [CRP 2.22 (1.11-4.47) mg/L vs. 1.23 (0.71-2.27) mg/L P=0.03] and [IL-6 2.88 (1.91-5.94) pg/mL vs. 2.15 (1.54-3.14) pg/mL P=0.006]. There were 23 late cardiovascular events among the 99 patients during the follow-up. Patients experiencing late cardiovascular events had higher preoperative IL-6 levels than those without late cardiovascular events [4.13 (1.83-5.87) pg/mL vs. 2.08 (1.53-2.29) pg/mL, P=0.002] whereas CRP levels did not differ significantly between the two groups [1.5 (0.79-4.41) mg/L vs. 1.33 (0.74-2.48) mg/L, P=0.41]. Looking at IL-6, a cut off value more than 3.8 pg/ml was associated with a significant higher risk for an early graft occlusion (P=0.04) and late cardiovascular events (P=0.00003). Preoperative endothelin-1 did not predict early graft occlusions or late cardiovascular events.. Raised preoperative IL-6 levels are predictors of both early graft occlusion and late cardiovascular events after CABG. Elevated preoperative CRP levels can predict early graft occlusion after CABG. Endothelin did not differ between the two groups.

Topics: Aged; C-Reactive Protein; Cardiovascular Diseases; Cohort Studies; Coronary Artery Bypass; Coronary Artery Disease; Endothelin-1; Female; Graft Occlusion, Vascular; Humans; Interleukin-6; Male; Middle Aged; Predictive Value of Tests; Time Factors; Treatment Outcome

Increased concentrations of serum C-reactive protein (CRP) have been reported to predict major cardiovascular events in patients with coronary artery disease (CAD). Increased concentrations of endothelin-1 (ET-1) are also associated with poor prognosis after myocardial infarction.. We tested the hypothesis that ET-1 might contribute to CRP in prediction of adverse outcome in CAD.. Serum high sensitive CRP and plasma ET-1 levels of 40 patients who have stable CAD and 25 control subjects were measured, and correlation analysis between these molecules was performed.. Mean high sensitive CRP was 8.64 +/- 12.73 mg/l, and mean ET-1 was 8.24 +/- 7.06 pg/ml in the CAD group. We found that there was no statistically significant correlation between high sensitive CRP and ET-1 in either CAD group (p = 0.82), or the control group (p = 0.85). In a subgroup of 13 patients who were not under statin treatment, we found a strong correlation between the levels of these molecules (p = 0.01).. Our study does not clearly support or exclude a link between CRP and ET-1 in patients who have stable CAD.

Topics: Biomarkers; C-Reactive Protein; Coronary Artery Disease; Cross-Sectional Studies; Endothelin-1; Female; Humans; Male; Predictive Value of Tests; Prospective Studies

Endothelin 1 mediates coronary vasoconstriction and endothelial dysfunction via endothelin receptor type A (ET(A)) activation. However, the effects of selective endothelin receptor type B (ET(B)) and combined ET(A+B) receptor blockade on coronary vasomotion are unknown. We measured coronary vascular tone and endothelium-dependent and -independent vasomotor function before and after selective infusion of BQ-788 (an ET(B) receptor antagonist) or combined infusion of BQ-788+BQ-123 (an ET(A) antagonist) into unobstructed coronary arteries of 39 patients with coronary atherosclerosis or risk factors undergoing cardiac catheterization. BQ-788 did not affect epicardial diameter but constricted the microcirculation (P<0.0001), increased coronary sinus endothelin, and reduced nitrogen oxide levels. In contrast, BQ-123+BQ-788 dilated epicardial (P<0.0001) and resistance (P=0.022) arteries. Responses to acetylcholine and sodium nitroprusside were unaffected by BQ-788 alone. Epicardial endothelial dysfunction improved after BQ-123+BQ-788 (P=0.007). Coronary microvascular responses to acetylcholine and sodium nitroprusside were unaffected by BQ-123+BQ-788. We conclude that selective ET(B) receptor antagonism causes coronary microvascular constriction, without affecting epicardial tone or endothelial function, via reduced endothelin clearance and NO availability. Combined ET(A+B) blockade dilates coronary conduit and resistance vessels and improves endothelial dysfunction of the epicardial coronary arteries. Thus, endogenous endothelin, predominantly via ET(A) receptor stimulation, contributes to basal constrictor tone and endothelial dysfunction, whereas ET(B) activation mediates vasodilation in human coronaries. Our data suggest that selective ET(A) blockade may have greater therapeutic potential than nonselective agents, particularly for treatment of endothelial dysfunction in atherosclerosis.

Topics: Coronary Artery Disease; Coronary Circulation; Coronary Vessels; Drug Combinations; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Humans; Microcirculation; Nitrogen Oxides; Oligopeptides; Peptides, Cyclic; Pericardium; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; Vasoconstriction; Vasodilation; Vasomotor System

Coronary artery disease (CAD) is a major health concern in both developed and developing countries. With a heritability estimated at ~50%, there is a strong rationale to better define the genetic contribution to CAD. This project involves the analysis of 884 individuals from 142 families (with average sibships of 5.7) as well as 558 case and control subjects from the Saguenay Lac St-Jean region of northeastern Quebec, with the use of 1,536 single-nucleotide polymorphisms (SNPs) in 103 candidate genes for CAD. By use of clusters of SNPs to generate multiallelic haplotypes at candidate loci for segregation studies within families, suggestive linkage for high-density lipoprotein (HDL) cholesterol is observed on chromosome 1p36.22. Furthermore, several associations that remain significant after Bonferroni correction are observed with lipoprotein-related traits as well as plasma concentrations of adiponectin. Of note, HDL cholesterol levels are associated with an amino acid substitution (lysine/asparagine) at codon 198 (rs5370) of endothelin-1 (EDN1) in a sex-specific manner, as well as with a SNP (rs2292318) located 7.7 kb upstream of lecithin cholesterol acyl-transferase (LCAT). Whereas the other observed associations are described in the current literature, these two are new. Using an independent validation sample of 806 individuals, we confirm the EDN1 association (P<.005), whereas the LCAT association was nonsignificant (P=.12).

Topics: Adiponectin; Aged; Cholesterol, HDL; Chromosome Mapping; Chromosomes, Human, Pair 1; Coronary Artery Disease; DNA Primers; Endothelin-1; Female; Founder Effect; Genetic Predisposition to Disease; Genotype; Humans; Linkage Disequilibrium; Male; Middle Aged; Polymorphism, Single Nucleotide; Quebec; Sex Factors

The aim of this study was to evaluate traditional risk factors for coronary artery disease (CAD), homocysteine, anti-oxidized low-density lipoprotein (anti-oxLDL), anti-lipoprotein lipase (anti-LPL) and endothelin-1 (ET-1) in patients with primary anti-phospholipid syndrome (APS), furthermore verify possible association among these variables and arterial thrombosis. Thirty-eight women with primary APS and 30 age-and-sex-matched controls were evaluated. Patients presented higher-LDL and triglycerides levels and lower-HDL levels than controls. Anti-LPL antibodies were not detected in both groups. The mean number of risk factors was higher in patients than in controls (P = 0.030). Anti-oxLDL antibodies, homocysteine and ET-1 mean levels were similar between groups, but abnormal homocysteine levels were found only among primary APS patients (P = 0.031). Hypertension and the presence of at least one risk factor for CAD were more prevalent in patients with arterial involvement than those without. Homocysteine levels and mean number of risk factors for CAD were significantly higher in patients with arterial thrombosis than controls. In a multivariate analysis hypertension was the only independently associated with arterial thrombosis (OR 14.8, 95% CI = 2.1-100.0, P = 0.006). This study showed that in primary APS patients other risk factors besides anti-phospholipid antibodies contribute for the occurrence of arterial events and the most important factor was hypertension.

Topics: Adult; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Autoantibodies; Case-Control Studies; Coronary Artery Disease; Endothelin-1; Female; Homocysteine; Humans; Hyperhomocysteinemia; Hypertension; Lipoprotein Lipase; Lipoproteins, LDL; Middle Aged; Risk Factors; Thrombosis

The vasoconstricting peptide endothelin-1 (ET-1) has been associated with atherosclerotic cardiovascular disease, vascular smooth muscle cell (VSMC) growth stimulation, and intimal thickening. ET-1 binds 2 receptor subtypes, endothelin A and B, and the ETA receptor mediates vasoconstriction and VSMC growth. This study aims to quantitatively assess arterial remodeling variables and compare them with changes in ET-1, ETA, and ETB expression in the internal mammary artery (IMA).. Specimens from 55 coronary artery disease (CAD) patients (45 men, 10 women; mean age 65 years) and 14 control IMA specimens (from 7 men and 7 women; mean age 45 years) were collected. IMA cross sections were assessed by histochemical and immunohistochemical staining methods to quantify the levels of medionecrosis, fibrosis, VSMC growth, ET-1, ETA, ETB, and macrophage infiltration. The percentage area of medionecrosis in the patients was almost double that in the controls (31.85+/-14.52% versus 17.10+/-9.96%, P=0.0006). Total and type 1 collagen was significantly increased compared with controls (65.8+/-18.3% versus 33.7+/-13.7%, P=0.07, and 14.2+/-10.0% versus 4.8+/-2.8%, P=0.01, respectively). Despite ACE and/or statin therapy, ET-1 expression and cell cycling were significantly elevated in the patient IMAs relative to the controls (46.27+/-18.46 versus 8.56+/-8.42, P=0.0001, and 37.29+/-12.88 versus 11.06+/-8.18, P=0.0001, respectively). ETA and ETB staining was elevated in the patient vessels (46.88+/-11.52% versus 18.58+/-7.65%, P=0.0001, and 42.98+/-7.08% versus 34.73+/-5.20%, P=0.0067, respectively). A mild presence of macrophages was noted in all sections.. Elevated distribution of collagen indicative of fibrosis coupled with increased cell cycling and high levels of ET-1 and ETA expression in the absence of chronic inflammation suggests altered IMA VSMC regulation is fundamental to the remodeling process.

Topics: Aged; Case-Control Studies; Cell Proliferation; Coronary Artery Disease; Endothelin-1; Female; Fibrosis; Humans; Macrophages; Male; Mammary Arteries; Middle Aged; Muscle, Smooth, Vascular; Necrosis; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin

Enhanced external counterpulsation (EECP) significantly augments diastolic blood flow and has been postulated to improve endothelial function by increased shear stress. We examined the effects of EECP on plasma nitric oxide and endothelin-1 (ET-1) levels. Plasma nitrate and nitrite (NOx) and ET-1 levels were measured serially in 13 patients with coronary artery disease who received 1-hour daily treatments of EECP over 6 weeks. During the course of EECP therapy, plasma NOx progressively increased and plasma ET-1 progressively decreased. After 36 hours of EECP, there was a 62 +/- 17% increase in plasma NOx compared with baseline (43.6 +/- 4.3 vs 27.1 +/- 2.6 micromol/L, p <0.0001) and a 36 +/- 8% decrease in plasma ET-1 (76.7 +/- 9.5 vs 119.5 +/- 8.5 pg/L, p <0.0001). At 3 months after completion of EECP, NOx remained 12 +/- 11% above baseline (p = 0.002), and ET-1 remained 11 +/- 10% below baseline (p = 0.0068). Our data provides neurohormonal evidence to support the hypothesis that EECP improves endothelial function.

Topics: Adult; Coronary Artery Disease; Coronary Circulation; Coronary Vessels; Counterpulsation; Endothelin-1; Female; Humans; Male; Myocardial Ischemia; Nitric Oxide; Oxygen; Treatment Outcome

Topics: Animals; Blood Pressure; Coronary Artery Bypass, Off-Pump; Coronary Artery Disease; Coronary Circulation; Creatine Kinase; Creatine Kinase, MB Form; Endothelin-1; Humans; Isoenzymes; Myocardial Contraction; Myocardial Reperfusion; Nitric Oxide; Postoperative Complications; Stroke Volume; Treatment Outcome

To investigate the relationship between vascular endothelial dysfunction and serum homocysteine (HCY) level in patients with coronary lesions.. Serum HCY, serum nitric oxide (NO), plasma endothelin-1 (ET-1), and circulation endothelial cell (CEC) were measured in 76 patients who received coronary angiography. Fifty-four patients with a stenosis of 50% or more at least in one coronary atery were as coronary artery disease (CAD) group. Other 22 cases with no recognizable plaque and/or stenosis were as control group. HCY level was detected using an enzyme immunoassay kit. NO concentration was measured using a nitrate reductase kit. Radio-immunoassay was applied to analyse the ET-1 level, and CEC was measured by flow cytometry.. The levels of HCY, ET-1, and CEC in patients with coronary lesions were significantly increased in comparison with control group (P < 0.01), while NO level in CAD group was significantly lower compared with that in control (P < 0.01). Using a multivariate stepwise regression analysis, HCY level had a positive correlation with ET-1 level (r = 0.420, P < 0.05) and CECs number (r = 0.423, P < 0.05); and had a negative correlation with NO/ET-1 (r = -0.403, P < 0.05). But there was no significant correlation between HCY and NO levels.. HCY might lead to endothelial cell injury, which would provide a plausible mechanism for the relationship between hyperhomocysteinemia and development of coronary artery disease. HCY can be considered as a predictor for preliminary or active coronary lesion.

Topics: Aged; Biomarkers; Cell Count; Coronary Artery Disease; Endothelial Cells; Endothelin-1; Female; Homocysteine; Humans; Male; Middle Aged; Nitric Oxide

Topics: Adult; Arrhythmias, Cardiac; Cardiovascular Diseases; Child; Comorbidity; Coronary Artery Disease; Endothelin-1; Endothelium, Vascular; Epidemiologic Studies; Genetic Predisposition to Disease; Heart Failure; Humans; Hypertension; Male; Obesity; Risk Factors; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Thrombophilia

We evaluated the protective effects of retrograde coronary sinus perfusion to offset potential systolic and diastolic dysfunction (myocardial stunning) after temporary regional ischemia needed for off-pump coronary artery bypass grafting.. Twenty Yorkshire-Duroc pigs (31.8 +/- 3.9 kg) underwent 15 minutes of mid-left anterior descending coronary artery ischemia in the beating heart. In 8 pigs, no protective measures were used. In 12 pigs, an aorta-coronary sinus shunt (with conventional cannulas) allowed retrograde perfusion during temporary ischemia; in 6 of these pigs, no leakage to the right atrium was ensured. Regional endocardial contraction was measured with sonomicrometer crystals. Systolic dysfunction (impaired regional shortening), diastolic dysfunction (contraction extending into early diastole), and coronary sinus nitric oxide and endothelin-1 levels were recorded.. Before ischemia, contraction did not extend into the diastolic interval. During ischemia, paradoxic bulging occurred in all hearts except in the occlusive coronary sinus shunt group (16% +/- 6% of baseline, P <.01). Sixty minutes after ischemia, systolic segment shortening recovered 36% +/- 24% without retrograde perfusion versus 56% +/- 20% and 61% +/- 14% with coronary sinus shunting (P <.05). Diastolic dysfunction (as percentage of diastolic time in contraction) was 38% +/- 16% in the nontreated group versus 22% +/- 22% and 9% +/- 9% (P <.05) after shunting and occlusive shunting, respectively. This correlated with a left ventricular end-diastolic pressure increase of 4 mm Hg in the ischemic group versus no change in the retrograde perfusion groups. Nitric oxide decreased 15% without shunting and increased 8% after occlusive coronary sinus shunting (P <.05).. Retrograde coronary sinus perfusion during simulated off-pump coronary revascularization diminishes systolic and diastolic dysfunction. An aortic-coronary sinus shunt is a rapid, recognized approach that can improve myocardial muscle and endothelial safety during off-pump coronary artery bypass grafting.

Topics: Animals; Biomarkers; Blood Pressure; Coronary Artery Bypass; Coronary Artery Disease; Coronary Circulation; Creatine Kinase; Creatine Kinase, MB Form; Disease Models, Animal; Endothelin-1; Female; Infusion Pumps, Implantable; Isoenzymes; Male; Models, Cardiovascular; Myocardial Contraction; Myocardial Reperfusion; Nitric Oxide; Postoperative Complications; Stroke Volume; Swine; Ventricular Fibrillation

The plasma levels of brain natriuretic peptide, tumor necrosis factor-alpha, big endothelin-1 and cardiac troponins have been reported to correlate with the severity of heart failure.. In a single population of 80 outpatients with mild to moderate chronic heart failure the correlation between the patient's functional capacity, as evaluated at a 6-min walk test, the clinical parameters and plasma levels of brain natriuretic peptide, tumor necrosis factor-alpha, big endothelin-1 and cardiac troponins was evaluated.. A significant inverse correlation was found with the patient's age (p < 0.0001), NYHA functional class (p < 0.0001), left ventricular dysfunction etiology (ischemic vs dilated cardiomyopathy, p < 0.0005), heart rate (p < 0.05), plasma levels of brain natriuretic peptide (p < 0.05) and of tumor necrosis factor-alpha (p < 0.0005). At multiple regression analysis a correlation was found between the 6-min walk test results and the patient's age (p < 0.05), NYHA functional class (p < 0.01), left ventricular dysfunction etiology (ischemic vs dilated cardiomyopathy, p < 0.05) and tumor necrosis factor-alpha plasma levels (p < 0.05).. In our patients with mild to moderate heart failure, a significant correlation was found between the results of the 6-min walk test and only the plasma concentrations of tumor necrosis factor-alpha among the laboratory parameters analyzed in this study.

Topics: Adult; Aged; Biomarkers; Cardiomyopathy, Dilated; Coronary Artery Disease; Endothelin-1; Exercise Tolerance; Female; Heart Failure; Humans; Male; Middle Aged; Mitral Valve Insufficiency; Multivariate Analysis; Natriuretic Peptide, Brain; Severity of Illness Index; Statistics as Topic; Troponin; Tumor Necrosis Factor-alpha; Ventricular Dysfunction, Left; Walking

Smoking is one of the most important risk factors of atherosclerosis and ischaemic heart disease. Endothelial dysfunction is a pathological result of smoking. The aim of the study was to examine the influence of cigarette smoking on biochemical parameters of endothelial function in persons with angiographically confirmed coronary arteries atherosclerosis. The study group included 117 men: 55 patients (mean age 58.8 +/- 10.4) with ischaemic heart disease and 62 healthy subjects (mean age 47.1 +/- 9.3) of control group. In all patients blood lipid concentrations, biochemical parameters of endothelial function (nitric oxide, endothelin-1, sICAM, selectin-E), and inflammation parameters (interleukin-1 beta, interleukin-6) were measured. In a group of smoking patients both: with atherosclerosis and in control subjects nitric oxide (NO) concentrations in serum were decreased in comparison to nonsmokers. In patients with diagnosed coronary arteries atherosclerosis interleukin-6 and sICAM concentrations were increased in comparison to non-smokers. It is concluded that cigarette smoking activates or maintains inflammatory reaction in vessels with atherosclerotic changes.

Topics: Adult; Aged; Analysis of Variance; Biomarkers; Case-Control Studies; Coronary Artery Disease; E-Selectin; Endothelin-1; Endothelium, Vascular; Humans; Intercellular Adhesion Molecule-1; Interleukin-1; Interleukin-6; Male; Middle Aged; Nitric Oxide; Risk Factors; Smoking

The aim of the study was to evaluate whether there was an imbalance between endothelin-1 (ET-1) and nitric oxide (NOx) release and diffuse atherosclerotic changes existed in patients with slow coronary flow (SCF). Baseline and post-atrial pacing coronary sinus ET-1 and NOx levels were measured in 19 patients with SCF (11 female, 56 +/- 9 years) and in 14 control subjects (nine female, 54 +/- 7 years). All patients underwent subsequent intravascular ultrasound (IVUS) investigation at the same setting with right atrial pacing. Baseline arterial (12.4 +/- 9.9 vs. 6.3 +/- 5.1 pg/ml, P<0.005) and coronary sinus (12.2 +/- 11.1 vs. 6.4 +/- 6.9 pg/ml, P<0.005) ET-1 plasma levels were higher in patients than in controls. After atrial pacing, concentration of ET-1 level from coronary sinus (24.7 +/- 14.6) significantly increased as compared to baseline (12.4 +/- 9.9, P<0.0001) and control levels (5.3 +/- 6.3, P<0.0001). Additionally, coronary sinus ET-1 level increased significantly with atrial pacing compared to femoral artery ET-1 level (16.3 +/- 8.5, P<0.005) in patients with SCF. After atrial pacing, the femoral artery ET-1 level also increased in patients compared to control level (P<0.0001). No significant differences in arterial and coronary sinus NOx plasma levels were found between the two groups, both at baseline and after pacing. Upon IVUS investigation, the common finding was longitudinally extended massive calcification throughout the epicardial arteries in patients with SCF. Mean intimal thickness was 0.59 +/- 0.18 mm. The data of this study suggest that increased ET-1 levels and insufficient NOx response, as well as the pathological data of IVUS may be associated with coronary microvascular dysfunction and may be the manifestation of early diffuse epicardial atherosclerosis in these patients with SCF.

Topics: Coronary Artery Disease; Coronary Circulation; Coronary Vessels; Endothelin-1; Female; Humans; Male; Middle Aged; Nitric Oxide; Time Factors; Ultrasonography

Topics: Coronary Artery Bypass; Coronary Artery Disease; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Graft Occlusion, Vascular; Humans; Muscle, Smooth, Vascular; Vasoconstriction

Endothelial dysfunction is a pathology resulting from smoking and occupational exposure to lead. The aim of the study was to examine the influence of cigarette smoking on biochemical parameters of endothelial function in people occupationally exposed to lead.. The study covered 105 men, including 43 lead exposed copper-smelters (mean age 49.9 +/- 4.1) and 62 non-exposed men (mean age 47.3 +/- 9.3) formed the control group. In all subjects, peripheral blood lipid concentrations, biochemical parameters of endothelial function (nitric oxide, endothelin-1, sICAM-1, selectin-E) and inflammation parameters (interleukin-1beta, interleukin-6) were measured.. In the group of smokers, including both copper-smelters and control subjects, serum nitric oxide concentrations were lower than in non-smokers. In the serum of men occupationally exposed to lead, sICAM-1 concentrations were higher than in the control group. The lack of physiological correlation between serum concentration of nitric oxide and endothelin-1 resulted from interactions of tobacco smoking with lead exposure.. Workers occupationally exposed to lead should be informed about adverse effects of tobacco smoking in terms of the interaction between nicotine and lead, two combined toxic agents affecting the circulatory system.

Topics: Adult; Analysis of Variance; Biomarkers; Case-Control Studies; Coronary Artery Disease; E-Selectin; Endothelin-1; Endothelium, Vascular; Humans; Intercellular Adhesion Molecule-1; Interleukin-1; Interleukin-6; Lead Poisoning; Male; Middle Aged; Nitric Oxide; Occupational Diseases; Occupational Exposure; Poland; Risk Factors; Smoking

Endothelial injury is the main stimulus for endothelin-1 (ET-1) secretion - a strong vasoconstricting agent. The role of endothelial dysfunction in the pathogenesis of hypertension and atherosclerosis which already develops in childhood, has been recently underlined.. To asses plasma ET-1 concentration in children and adolescents with such atherogenic risk factors as hypertension, obesity or diabetes.. The study group consisted of 105 children and adolescents in the mean age of 15.3+/-2.4 years who were divided into 5 groups: (1) hypertension, (2) obesity and hypertension, (3) obesity, (4) diabetes and (5) diabetes with hypertension. The control group was composed of 32 healthy subjects of appropriate weight, aged 14.7+/-2.9 years. Plasma concentration of ET-1 was measured using the enzymatic method ELISA (R and D Systems).. ET-1 plasma concentration was significantly higher in the whole study group than in controls (0.71 vs 0.40 pg/mL; p<0.05) as well as in each studied subgroup compared with healthy subjects (0.63 pg/mL, p<0.05; 0.88 pg/mL p<0.05; 0.96 pg/mL, p<0.05, 0.60 pg/mL, p<0.05, and 0.63, p<0.05, respectively). There was a significant correlation between ET-1 concentration and body mass index in the whole study group (p=0.001) as well as cholesterol (p=0.018) and triglyceride (p=0.001) levels. In the group of patients with hypertension, ET-1 correlated with body mass index (p=0.023) and systolic blood pressure (p=0.02).. Children and adolescents with hypertension, obesity or diabetes have higher ET-1 plasma concentration than healthy subjects. ET-1 level correlates with body mass index, lipid parameters and systolic blood pressure.

Topics: Adolescent; Adult; Child; Coronary Artery Disease; Diabetes Mellitus, Type 1; Endothelin-1; Female; Humans; Hypertension; Male; Obesity; Risk Factors

The objective was to investigate whether the renin-angiotensin (RA) system and related peptides endothelin-1 (ET-1) and vasopressin (VP) influence the development of coronary artery disease (CAD). Angiotensin I-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism has been associated with the risk of CAD. The ACE I/D polymorphism determines ACE activity, but plasma levels of other RA system components remain unchanged. However, ET-1 and VP production could be increased by RA system-dependent stimulation, continually promoted by paracrine stimulation and sustained by neointimal growth. ET-1 and VP have not been associated with the ACE I/D polymorphism so far. The present study investigated the association of the ACE I/D polymorphism with plasma concentrations of ET-1 and VP, as well as with renin, angiotensin-II (AT-II) and ACE activity in 98 Caucasian individuals with CAD. ACE I/D polymorphism showed no association with plasma levels of VP, ET-1, AT-II or renin. These parameters were also not associated taking into consideration different patient variables, such as diabetes mellitus, hypertension or severity of CAD. Only plasma ACE activity was associated with the D allele. In conclusion, the ACE I/D polymorphism could not be related to plasma concentrations of VP, ET-1, renin or AT-II, but as previously demonstrated, it could only be related to ACE activity in patients with CAD. Differences in ACE activity between ACE I/D genotype subgroups are probably compensated within the RA system itself or within non-ACE pathways, so that plasma concentrations of the related peptides ET-1 and VP remain unaffected.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin II; Coronary Artery Disease; Endothelin-1; Female; Gene Deletion; Humans; Male; Middle Aged; Mutagenesis, Insertional; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Renin; Vasoconstrictor Agents; Vasopressins

Topics: Coronary Artery Disease; Endothelin Receptor Antagonists; Endothelin-1; Humans; Myocardial Infarction; Ventricular Remodeling

Coronary endothelial dysfunction is associated with an increase in cardiac events. Hypercholesterolemia (HC) and hypertension (HT) are both associated with endothelial dysfunction, and their coexistence is associated with an increased incidence of cardiac events in epidemiological studies. However, pathogenic mechanisms are poorly understood. Here we studied the effects of coexisting HC and HT on coronary endothelial function.. Four groups of pigs were studied after 12 weeks of a normal diet (n=9), a 2% HC diet (n=9), HT (achieved by unilateral renal artery stenosis, n=8), or HC+HT (n=6). Coronary endothelial function was tested, in epicardial arteries and arterioles, by using organ chamber techniques. Oxidative stress was measured in coronary artery tissue. Vasodilatory response to bradykinin and calcium ionophore was significantly impaired in animals with HC+HT compared with each risk factor alone (P<0.05 for both). In animals with coexistent HC and HT, the increase in oxidative stress was more pronounced compared with each risk factor alone (P<0.05). Furthermore, chronic antioxidant supplementation significantly improved coronary artery vasoreactivity.. These results suggest that HC and HT have a synergistic deleterious effect on coronary endothelial function, associated with increased oxidative stress. This interaction may contribute to the increased incidence of coronary heart disease and cardiac events seen when HC and HT coexist.

Topics: Animals; Antioxidants; Ascorbic Acid; Bradykinin; Calcimycin; Coronary Artery Disease; Coronary Vessels; Cyclic GMP; Diet, Atherogenic; Endothelin-1; Endothelium, Vascular; Female; Hemodynamics; Hypercholesterolemia; Hypertension, Renovascular; Lipids; Nitric Oxide; Nitroprusside; Oxidative Stress; Renal Artery Obstruction; Renin; Substance P; Swine; Vasodilator Agents; Vitamin E

Endothelin-1 (ET-1) signaling mechanisms have been implicated in the pathogenesis of excess coronary artery disease in diabetic dyslipidemia. We hypothesized that in diabetic dyslipidemia ET-1-induced coronary smooth muscle calcium (Ca2+m) and tyrosine phosphorylation would be increased, and the lipid lowering agent, atorvastatin, would inhibit these increases. Male Yucatan miniature swine groups were treated for 20 weeks: normal low-fat fed control, high-fat/cholesterol fed (hyperlipidemic), hyperlipidemic made diabetic with alloxan (diabetic dyslipidemic), and diabetic dyslipidemic treated with atorvastatin (atorvastatin-treated). Blood glucose values were 5-fold greater in diabetic dyslipidemic and atorvastatin-treated versus control and hyperlipidemic. Total and low-density lipoprotein (LDL) plasma cholesterol in hyperlipidemic, diabetic dyslipidemic, and atorvastatin-treated were approximately 5-fold greater than control. Intravascular ultrasound detectable coronary disease and hypertriglyceridemia were only observed in diabetic dyslipidemic and were abolished by atorvastatin. In freshly isolated cells, the Ca2+m response to ET-1 in diabetic dyslipidemic was greater than in control, hyperlipidemic, and atorvastatin-treated groups. Selective ET-1 receptor antagonists showed in the control group that the ETB subtype inhibits ETA regulation of Ca2+m. There was almost a complete switch of receptor subtype regulation of Ca2+m from largely ETA in control to an increased inhibitory interaction between ETA and ETB in hyperlipidemic and diabetic dyslipidemic groups, such that neither ETA nor ETB antagonist alone could block the ET-1-induced Ca2+m response. The inhibitory interaction was attenuated in the atorvastatin-treated group. In single cells, basal and ET-1-induced tyrosine phosphorylation in diabetic dyslipidemic were more than 3- and 6-fold greater, respectively, than in control, hyperlipidemic, and atorvastatin-treated. Attenuation by atorvastatin of coronary disease and ET-1-induced Ca2+m and tyrosine phosphorylation signaling with no change in cholesterol provides strong evidence for direct actions of atorvastatin and/or triglycerides on the vascular wall.

Topics: Animals; Anticholesteremic Agents; Atorvastatin; Calcium; Calcium Signaling; Coronary Artery Disease; Diabetes Complications; Diet; Disease Models, Animal; Endothelin-1; Endothelins; Heptanoic Acids; Hyperlipidemias; Male; Phosphorylation; Pyrroles; Receptor, Endothelin A; Receptors, Endothelin; Swine; Tyrosine

The aim of this study was to investigate the known risk factors, such as lipids, homocysteine and endothelin, for the development of coronary artery disease (CAD) in phenylketonuria (PKU) patients, depending on their diet. The PKU patients (n = 74) were divided into two groups. Group A (n = 34; mean age 6.78 +/- 1.5 y) adhered strictly to a diet and group B (n = 40; mean age 8.0 +/- 3.2 y) did not comply with the diet. The control group comprised 50 healthy non-PKU children. All groups were evaluated for blood levels of homocysteine and vitamin B6 by high-performance liquid chromatography, vitamin B12 and folate in serum by a radioassay, lipids by a routine method, and lipoprotein(a) and endothelin-1 with an immunoassay. Homocysteine levels (28.65 +/- 3.3 micromol l(-1)) were increased in group A compared with group B (6.86 +/- 1.6 micromol l(-1)) and the controls (6.9 +/- 2.0 micromol l(-1)) (p < 0.001). Vitamin B6 (10.7 +/- 10.9 nmol l(-1)), vitamin B12 (98.5 +/- 22.3 pmol l(-1)), folate (2.35 +/- 1.3 nmol l(-1)) and lipids were decreased in group A. The other vascular risk factors, which were not dependent on diet [lipoprotein(a) and endothelin-1], did not differ among the three groups.. PKU patients on a strict diet had low vitamin B6, vitamin B12 and folate levels resulting in moderate hyperhomocysteinaemia. The evaluation of these vitamins at short intervals and their supplementation could be an early measure in the prevention of CAD.

Topics: Child; Child, Preschool; Coronary Artery Disease; Diet, Protein-Restricted; Endothelin-1; Folic Acid; Homocysteine; Humans; Lipids; Nutrition Assessment; Phenylalanine; Phenylketonurias; Risk Factors; Vitamin B 12; Vitamin B 6

In this study, we investigated the crosstalk of endothelin-1 (ET-1) and platelet-derived growth factor (PDGF) in coronary artery smooth muscle cell (SMC) proliferation in the rat cardiac allograft model.. Previous studies have suggested an independent role of ET-1 and PDGF in the development of cardiac allograft arteriosclerosis (i.e., chronic rejection).. Heterotopic heart transplantations were performed from Dark Agouti to Wistar Furth rats. Grafts were harvested after five days in an acute rejection model and after 60 days in a chronic rejection model. In the in vitro part of the study, SMC proliferation and migration were quantitated, as well as messenger ribonucleic acid (mRNA) levels of ET-1 and PDGF ligands and receptors after growth factor stimulation.. Acute rejection induced both ET-1 receptors in the arterial wall. On linear regression analysis of chronically rejecting cardiac allografts, a strong correlation between intimal thickening and immunoreactivity of ET-1 and ET receptors A and B (ET(A) and ET(B)) in the arterial walls was observed. Treatment with Bosentan, a mixed ET-1 receptor antagonist, significantly reduced the incidence and intensity of arteriosclerotic lesions in rat cardiac allografts, as well as total intragraft ET(A) and ET(B) mRNA expression and intimal cell ET-1 and receptor immunoreactivity. This was associated with significantly reduced intragraft PDGF beta-receptor (PDGF-Rbeta) mRNA expression. In contrast, CGP 53716, a protein tyrosine kinase inhibitor selective for the PDGF receptor, did not reduce intragraft ET-1, ET(A) or ET(B) mRNA expression. In rat coronary artery SMC cultures, ET-1 stimulation significantly upregulated PDGF-Ralpha and -Rbeta mRNA expression and augmented PDGF-BB-mediated SMC proliferation as well as PDGF-AB- and PDGF-BB-mediated SMC migration.. Our results suggest that the ET-1/PDGF-Rbeta/PDGF-BB axis may operate in SMC migration and proliferation in cardiac allograft arteriosclerosis, thus explaining the marked beneficial effects of blocking the signaling downstream of ET-1 receptors.

Topics: Animals; Cell Culture Techniques; Coronary Artery Disease; Coronary Vessels; Disease Models, Animal; Endothelin-1; Graft Rejection; Heart Transplantation; Muscle, Smooth, Vascular; Platelet-Derived Growth Factor; Rats; Rats, Inbred Strains; Rats, Inbred WF; Receptor Cross-Talk; Transplantation, Homologous

We sought to demonstrate, in an appropriate animal model, that co-medication with a transcription factor-blocking agent limits restenosis after percutaneous transluminal coronary angioplasty (PTCA).. Enhanced synthesis in the vessel wall of endothelin-1 (ET-1), a powerful co-mitogen for vascular smooth muscle cells, appears to be one mechanism that promotes restenosis after PTCA. Deformation-induced expression of prepro-ET-1 is governed by the transcription factor, activator protein-1 (AP-1).. An anti-AP-1 decoy oligodeoxynucleotide (dODN) strategy was devised in which the dODN-containing solution (20 nmol) was administered locally through a Dispatch catheter into the coronary arteries of hypercholesterolemic minipigs at the time of PTCA (AVE-GFX stent).. Treatment with an AP-1 dODN, mimicking the consensus binding site of the transcription factor, significantly reduced neointimal formation in the coronary arteries of hypercholesterolemic minipigs (n = 10 to 12), compared with vehicle-treated coronary arteries, after four weeks of follow-up (neointimal area 2.64 +/- 0.33 vs. 4.81 +/- 1.04 mm(2) [mean +/- SEM]; p < 0.05). This effect was maintained after eight weeks (neointimal area 2.04 +/- 0.22 mm(2); n = 3) and correlated with a reduction in both nuclear translocation of AP-1 and ET-1 synthesis in the vessel wall 48 h after PTCA (n = 4). In contrast, an AP-1 mutant dODN, to which the transcription factor does not bind, showed no effect on neointimal formation at either time point (n = 3 to 7). Moreover, a consensus dODN directed against CCAAT/enhancer binding protein (C/EBP), another deformation-sensitive transcription factor, did not significantly affect neointimal formation after four weeks (n = 3).. These findings demonstrate the feasibility, efficacy and specificity of the anti-AP-1 dODN approach to the treatment of restenosis, which principally but not exclusively targets deformation-induced ET-1 synthesis in the vessel wall. Provided that these findings can be extrapolated to the situation of patients with coronary artery disease, the observed extent of the inhibitory effect of the AP-1 dODN treatment suggests that this co-medication may greatly reduce the incidence of in-stent restenosis.

Topics: Angioplasty, Balloon, Coronary; Animals; Cardiac Catheterization; Coronary Artery Disease; Coronary Restenosis; Coronary Vessels; Disease Models, Animal; Endothelin-1; Feasibility Studies; Hypercholesterolemia; Oligonucleotides; Swine, Miniature; Transcription Factor AP-1; Transcription Factors; Tunica Intima

Topics: Atrial Natriuretic Factor; Biomarkers; Coronary Artery Disease; Endothelin-1; Heart Failure; Humans; Natriuretic Peptide, Brain; Neurotransmitter Agents; Rest; Supine Position

Graft coronary artery disease (GCAD) is characterized by vascular narrowing resulting from intimal hyperplasia. Endothelin (ET)-1, derived from the vascular endothelium and macrophages, stimulates vascular smooth muscle cells (SMCs), which leads to neointimal formation in donor graft coronary arteries. In this study, we hypothesized that antisense (AS) oligodeoxynucleotides (ODN) for preproendothelin-1 (ppET-1) delivered to rat cardiac allografts by means of hyperbaric pressure would reduce the incidence of GCAD.. PVG donor hearts were infused with ppET-1 AS ODN (80 micromol/liter), sense ODN, scrambled ODN or saline alone and incubated in a pressure chamber at 75 psi or ambient pressure for 45 minutes. Cardiac allografts were heterotopically transplanted into ACI rats treated with cyclosporine (7.5 mg/kg, Days 0 to 9). Allografts were procured at post-operative days (POD) 7 or 90. Reverse transcription-polymerase chain reaction (RT-PCR) assay for ET-1 mRNA and ET01 immunohistochemistry (IHC) were performed at PODs 7 and 90. Elastic staining and IHC with anti-macrophage and alpha-SMC actin antibodies were performed to assess GCAD at POD 90.. Treatment with AS ODN and pressure significantly reduced ET-1 mRNA and protein expression. A significant reduction in GCAD was achieved with inhibition of ET-1 and was associated with attenuation of macrophages and SMCs in the neointima.. Peri-operative ex vivo inhibition of ET-1 expression results in a reduction of GCAD. This highly targeted therapy may be a clinically viable strategy for the prevention of ET-1-induced GCAD following cardiac transplantation.

Topics: Animals; Coronary Artery Disease; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Heart Transplantation; Immunohistochemistry; Male; Models, Cardiovascular; Muscle, Smooth, Vascular; Postoperative Complications; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

VasoCare therapy, which involves the administration of autologous blood following the ex vivo exposure to physico-chemical stressors, has been shown to modulate immune responses. Since immune mechanisms have been recognized to be pivotal in the pathogenesis of atherosclerosis, we hypothesized that VasoCare treatment would inhibit atherosclerosis in LDL-R (-/-) mice. Three groups of LDL-R (-/-) mice were studied: a control group that was fed normal chow (Group I) and no other treatment; a control group that received a high cholesterol (HC) diet for 8 weeks (group II) with sham saline injections; and a third group (III) that received HC diet for 8 weeks and VasoCare treatment initiated after four weeks of HC feeding. Atherosclerotic area (AA), relative to total aortic area (TA), was assessed after 8 weeks of HC feeding by oil red O staining, and cross sectional plaque area at the level of the aortic valve leaflets was determined by quantitative morphometry. HC mice exhibited substantial aortic lipid deposition which was profoundly reduced in the VasoCare treated animals (AA/TA ratios in group II: 0.32+/-0.15 vs. group III: 0.17+/-0.06; P<0.05). This was associated with a significant decrease in cross sectional area of plaque in the aortic sinuses. VasoCare therapy also reduced the xanthoma formation and limb swelling characteristic of this animal model. However, cholesterol levels, measured by an enzymatic assay, showed similar marked increases in total serum cholesterol (CHO) in the animals receiving HC diet alone and those receiving the HC diet and VasoCare treatment [group I: 5.4+/-0.8 mM, group II: 46.7+/-3.6 mM, and group III: 44.7+/-2.8 mM (P<0.01 vs. group I)]. We conclude that VasoCare treatment inhibits progression of atherosclerotic lesions in a murine model of human familial hypercholesterolemia by a mechanism independent of cholesterol lowering.

Topics: Actins; Animals; Antibody Specificity; Aortic Valve; Cholesterol, Dietary; Cholesterol, LDL; Coronary Artery Disease; Disease Models, Animal; Disease Progression; Endothelin-1; Hyperlipidemias; Immunohistochemistry; Immunotherapy; Lipid Metabolism; Macrophages; Male; Mice; Mice, Inbred C57BL; Models, Cardiovascular; Muscle, Smooth, Vascular; Pilot Projects; Receptors, LDL; T-Lymphocytes; Treatment Outcome; Xanthomatosis

The purpose of this study was to test the hypothesis that endothelin (ET) receptor antagonism reduces coronary vasa vasorum neovascularization in experimental hypercholesterolemia.. Experimental hypercholesterolemia is associated with increased expression of ET-1, an endothelium-derived peptide with vasoconstricting, mitogenic and angiogenic properties, in the coronary arterial wall as well as with vasa vasorum neovascularization. A pathomechanistic role of the endogenous ET system in vasa vasorum neovascularization in hypercholesterolemia has, however, remained uncertain so far.. Female domestic pigs were placed on a normal diet (N; n = 7) or on a hypercholesterolemic diet without (HC; n = 6) or with ET-A receptor antagonism (ABT-627, 4 mg/kg/day; HC + ET-A; n = 6). After 12 weeks, coronary vasa vasorum structure was assessed by three-dimensional microscopic computed tomography, expression of vascular endothelial growth factor (VEGF) within the coronary arterial wall by Western blotting and immunostaining.. Compared with the N group, plasma concentrations of low-density lipoprotein cholesterol were higher in both the HC and HC + ET-A groups (36 +/- 3 mg/dl vs. 312 +/- 153 mg/dl and 303 +/- 113 mg/dl, p < 0.01). Vasa vasorum density was higher in the HC group compared with the N group (4.7 +/- 1.8 per mm(2) vs. 2.5 +/- 1.5 per mm(2); p < 0.05) and was preserved in the HC + ET-A group (3.2 +/- 0.7 per mm(2)). In parallel, increase in VEGF expression in the coronary arterial wall in the HC group was preserved in the HC + ET-A group.. The current study demonstrates that chronic endothelin receptor antagonism prevents the increase in VEGF expression and vasa vasorum density of coronary arteries in experimental hypercholesterolemia. These findings support a role for the endogenous ET system in vasa vasorum neovascularization in early coronary atherosclerosis.

Topics: Animals; Blotting, Western; Cholesterol, Dietary; Coronary Artery Disease; Coronary Vessels; Disease Models, Animal; Endothelial Growth Factors; Endothelin Receptor Antagonists; Endothelin-1; Female; Hypercholesterolemia; Immunohistochemistry; Lymphokines; Neovascularization, Pathologic; Swine; Tomography, X-Ray Computed; Vasa Vasorum; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

The relationship between alterations in the immunohistochemical expression of three vasoactive agents [endothelial nitric oxide synthase (eNOS), endothelin-1 (ET-1), and angiotensin-converting enzyme (ACE)] and the occurrence human atherosclerosis was investigated in relation to the myocardial bridge (MB) of the left anterior descending coronary artery (LAD), an anatomical site that experiences increased shear stress. Five millimetre cross-sections of LADs with MB from 22 autopsied cases were taken from the left coronary ostium to the cardiac apex and were immunohistochemically stained with antibodies against eNOS, ET-1, and ACE. The extent of atherosclerosis in each section was calculated using the atherosclerosis ratio (intimal cross-sectional area/medial cross-sectional area) determined by histomorphometry. The results were analysed according to their anatomical location relative to the MB, either proximal, beneath, or distal. The extent of atherosclerosis was significantly lower beneath the MB, compared with proximal and distal segments. The expression of eNOS, ET-1, and ACE was also significantly lower beneath the MB. The expression of these agents correlated significantly with the extent of atherosclerosis. Because nitric oxide, after its production by eNOS, is believed to be degraded by superoxide radicals, the effect of eNOS expression on atherosclerosis remains controversial. However, the present findings clearly indicate that the expression of ET-1 and ACE is directly related to the development of human coronary atherosclerosis in vivo through shear stress.

Topics: Adult; Aged; Aged, 80 and over; Cardiovascular Agents; Coronary Artery Disease; Coronary Vessel Anomalies; Endothelin-1; Female; Humans; Immunoenzyme Techniques; Male; Middle Aged; Nitric Oxide Synthase; Peptidyl-Dipeptidase A; Stress, Mechanical

Endothelium takes part in the regulation of vascular tone through the production of endothelium-derived relaxing factor, nitric oxide (NO), and the contracting factor endothelin-(ET-1). Induction of ET-1 and NO is influenced by many stimuli including hypoxia and shear stress. Some of these stimuli may arise during coronary angiography (CAG). In this study, the authors aimed to show endothelial response in patients undergoing CAG by evaluating plasma ET-1 and NO end-products including nitrite and nitrate concentrations. Twenty-four male patients with a mean age of 54.3 years (age range: 37-70) were included in the study. The patients had no coronary atherosclerotic lesions established by CAG. The mean time of the CAG procedures was 24.8 minutes, with a range of 19-33 minutes. Immediately before blood sampling, systolic and diastolic blood pressures were recorded. The mean blood pressures before and after CAG were 140/90 and 150/95, respectively. End products of NO radical, nitrite and nitrate (NOx), in plasma were used as a marker for the production of NO radical. ET-1 concentrations were measured by ELISA method. Significant increases in ET-1 concentrations were observed during CAG while no change observed in NOx concentrations. Duration of the CAG procedure was found to be correlated with the percent increase of the plasma ET-1 concentrations during CAG (r = 0.45, p<0.05, Figure 1), but not with NOx concentrations. Plasma ET-1 concentrations in patients who were cigarette smoking were found higher than those of patients who were nonsmokers (1.26 +/- 0.38 and 2.97 +/- 0.87 fmol/L, respectively). It was concluded that endothelial cells show increased ET-1 production as a response of some mechanical or emotional stimuli during CAG procedure that may play an important role in the regulation of vascular tonicity and some pathological processes. The authors suggest that duration and manipulation of CAG may be an important factor in plasma ET-1 concentrations.

Topics: Adult; Aged; Biomarkers; Coronary Angiography; Coronary Artery Disease; Coronary Vessels; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Humans; Male; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Vascular Resistance

The aim of the study was to assess the plasma levels of endothelial injury markers in children from families with high risk of premature coronary heart disease (CHD) without other common CHD risk factors (hyperlipidaemia, obesity, hypertension, low physical activity). The study comprised 48 children, including 24 children from high-risk families (HR), according to the NCEP (National Cholesterol Education Programme) criteria: one or two parents had clinical manifestation of cardiovascular disease before the age of 65 years (mother) or 55 years (father). The control group included 24 healthy children with no familial history of cardiovascular disease. All the children were normolipidaemic according to the NCEP and the European Atherosclerosis Society criteria for children aged 2-19 years. In the HR group, the concentration of vWf was significantly elevated in comparison to that in the control group (p<0.0001). Plasma concentrations of ET-1 and TxB2 did not differ significantly between the HR group and the controls. Plasma concentrations of the 6-ketoPGF1alpha in the HR group and in the respective age and gender HR subgroups were significantly lower compared with those of the control group (p<0.00005). Concentration of vWf in the HR group was negatively correlated with the concentration of 6-ketoPGF1alpha (r = -0.47; p<0.05) and positively correlated with TxB2 (r=0.39; p<0.01). In a logistic regression analysis, we found that the 6-ketoPGF1alpha concentration in the lower quartile (< 16.1 pmol/L) was associated with a 3.4-fold odds of inclusion in the high-risk group versus the upper quartile (>23.0 pmol/L).

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Child; Child, Preschool; Coronary Artery Disease; Endothelin-1; Endothelium, Vascular; Epoprostenol; Family Health; Female; Humans; Male; Risk Factors; Thromboxane B2; von Willebrand Factor

Atherosclerotic coronary arteries are prone to constriction but the underlying causes are incompletely understood. We tested the hypothesis that endothelin-1 (ET-1), a potent vasoconstrictor, contributes to the heightened tone of atherosclerotic human coronary arteries.. In 8 patients with coronary artery disease (CAD) and 8 patients with angiographically smooth coronary arteries (normal), we infused BQ-123, an antagonist of the ET(A) receptor, into a major coronary artery (infused artery) at 40 nmol/min for 60 minutes. The infused artery in the CAD patients contained a >50% stenosis. Using quantitative angiography, we compared the dilation of the infused artery with another, noninfused coronary artery. To estimate the magnitude of the contribution of ET-1 to coronary tone, we compared the dilation to BQ-123 with that elicited by intracoronary nitroglycerin (200 microgram). BQ-123 induced significant dilation in the normal arteries (7.3% at 60 minutes, P<0.001 versus noninfused arteries) and a greater dilation in the CAD arteries (16.3% at 60 minutes, P<0.001 versus infused normal arteries). The dilation at stenoses was particularly pronounced (21.6% at 60 minutes, P<0.001 versus infused CAD arteries). Compared with the dilation from nitroglycerin, ET-1 contributed to 39% of the coronary tone in normal arteries, 74% of tone in CAD arteries, and 106% of tone at stenoses (P<0.01).. ET-1 accounts for nearly all the resting tone in atherosclerotic coronary arteries, especially at stenoses. Inhibitors of ET-1, by relieving constriction, may significantly lessen the hemodynamic significance of coronary stenoses and thereby reduce myocardial ischemia.

Topics: Coronary Artery Disease; Coronary Circulation; Coronary Vessels; Endothelin Receptor Antagonists; Endothelin-1; Humans; Middle Aged; Multivariate Analysis; Nitroglycerin; Peptides, Cyclic; Receptor, Endothelin A; Vasoconstriction; Vasodilator Agents

The endothelium-derived peptide endothelin-1 (ET-1) causes vasoconstriction predominantly via smooth muscle ET(A) receptor activation. We hypothesized that ET(A) receptor inhibition would improve human coronary vascular function. We studied unobstructed coronary arteries of 44 patients with atherosclerosis or its risk factors. Epicardial diameter (D) and Doppler flow velocity were measured, and coronary vascular resistance (CVR) was calculated during intracoronary infusions of acetylcholine (ACH) and sodium nitroprusside (SNP), and during cold pressor testing, before and after a 60-minute intracoronary infusion of the ET(A) receptor antagonist BQ-123. BQ-123 dilated the coronary circulation; D increased by 5.6+/-1.0% (P<0.0001), and CVR fell by 12+/-3% (P<0.01). The D response to ACH, corrected for the SNP response, improved in segments that constricted with ACH at baseline (P=0.03), whereas segments that initially dilated with ACH did not change with BQ-123 (P=NS). Improvement in D and CVR responses to ACH with BQ-123 inversely correlated with baseline ACH responses (r=-0.44 [P=0.006] and r=-0.78 [P=0.001], respectively), indicating greater improvement in those with endothelial dysfunction. Similarly, cold pressor testing-mediated epicardial vasoconstriction (-2.0+/-1.1%) was reversed after BQ-123 (+1.0+/-0.7%), especially in dysfunctional segments (from -5.6+/-0.9% to +2.2+/-0.9%, P<0.001). There was no correlation between any risk factor and the response to BQ-123. An arteriovenous difference in ET-1 levels developed after BQ-123, which was consistent with enhanced cardiac clearance of ET-1, probably via ET(B) receptors. Thus, ET-1 acting via the ET(A) receptor contributes to basal human coronary vasoconstrictor tone and endothelial dysfunction. This suggests that ET(A) receptor antagonism may have therapeutic potential in the treatment of endothelial dysfunction and atherosclerosis.

Topics: Acetylcholine; Cold Temperature; Coronary Artery Disease; Coronary Circulation; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Endothelium, Vascular; Female; Heart; Hemodynamics; Humans; Male; Middle Aged; Myocardium; Nitroprusside; Peptides, Cyclic; Protein Precursors; Receptor, Endothelin A; Vasoconstriction; Vasodilation

Atherosclerosis, a chronic systemic disease of the vasculature with an inflammatory component, is the primary cause of cardiovascular morbidity and mortality in industrialized countries. Impairment of vascular endothelial cell function in atherosclerosis and in conditions associated with increased cardiovascular risk are important determinants of disease progression. Reduced endothelium-dependent relaxation in the coronary and systemic circulation due to decreased bioavailability of nitric oxide (NO) and increased release of oxygen-derived free radicals promotes the adhesion of leukocytes, thrombosis, inflammation, cell proliferation, and increases in vascular tone. In addition to decreases in bioactive NO, enhanced production of the 21-amino acid peptide endothelin-1 contributes to the progression of atherosclerosis. This paper discusses mechanisms and therapeutic approaches to improving endothelial pathways in atherosclerosis. Restoration of endothelium-derived NO bioactivity through inhibition of the renin-angiotensin system, the endothelin system, or statin therapy improves vascular function in experimental hypercholesterolemia, hypertension and heart failure. These treatments may also have therapeutic benefit for patients at risk or with overt atherosclerosis, and are likely to reduce vascular and myocardial complications of this disease.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Coronary Artery Disease; Endothelin-1; Endothelium, Vascular; Folic Acid; Macrophages; Muscle Relaxation; Muscle, Smooth, Vascular; Nitric Oxide; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk Factors

The aim of the present study was to test whether oral dosing of an endothelin (ET) receptor antagonist was able to reduce restenosis in the model of stent-induced restenosis. After pigs underwent coronary artery catheterization they were randomly allocated either to controls or to treatment with the ET receptor antagonist BSF 208075. Thirty-seven pigs underwent percutaneous transluminal coronary angioplasty plus stent implantation; seven animals died of ventricular fibrillation due to procedure-related myocardial ischaemia. From the 30 surviving animals coronary arteries were sampled after 6 weeks of oral treatment with 10 mg/kg/day BSF 208075 or vehicle and histologically evaluated. Stent implantation had no effect on total coronary artery diameter, and media thickness was virtually identical in the two groups. However, neointimal thickness in the group treated with the ET receptor antagonist was significantly reduced, resulting in a significantly larger total coronary artery lumen in the treated group. As in the setting of stent implantation neither 'recoil' nor scar-related vascular remodelling can occur, this result allows the conclusion of a significant antiproliferative effect of ET receptor antagonism in pig coronary arteries.

Topics: Angioplasty, Balloon; Angioplasty, Balloon, Coronary; Animals; Coronary Artery Disease; Coronary Restenosis; Endothelin Receptor Antagonists; Endothelin-1; Male; Models, Animal; Myocardial Ischemia; Propionates; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Stents; Swine

Low-density lipoproteins (LDL) are known to cause endothelial injury and to promote the development of atherosclerotic lesions. This study demonstrates a significant concentration-dependent stimulatory effect of LDL on hepatocyte growth factor (HGF) synthesis (maximum release: 423 +/- 16% of control) and HGF receptor mRNA expression in cultured human coronary artery endothelial cells (HCAEC). HGF is a potent mitogen for endothelial cells but does not affect smooth muscle cell proliferation. In contrast, endothelin-1 (ET-1) acts as a mitogen on vascular smooth muscle cells and seems to be upregulated in coronary atherosclerosis. In this study, the basal ET-1 synthesis in HCAEC was concentration-dependently reduced by HGF (minimum: 54 +/- 3% of control). This inhibitory effect seems to be mediated via the tyrosine kinase activity of the HGF receptor c-met, since it was antagonized by the tyrosine kinase inhibitor lavendustin A. In addition, HGF also significantly reduced the LDL-stimulated ET-1 release. The LDL-induced upregulation of HGF synthesis in HCAEC and the inhibitory effect of HGF on ET-1 synthesis suggest a protective role of HGF in coronary atherosclerosis.

Topics: Cells, Cultured; Coronary Artery Disease; Coronary Vessels; Endothelin-1; Endothelium, Vascular; Gene Expression; Hepatocyte Growth Factor; Humans; Lipoproteins, LDL; Proto-Oncogene Proteins c-met; RNA, Messenger

To assess the effects of percutaneous transluminal coronary angioplasty on endothelin-1 (ET-1) release, we assessed ET-1 concentrations at different sites of the coronary circulation in patients submitted to elective procedures. ET-1 levels immediately downstream from the plaque and ET-1 aortocoronary gradient increased significantly after the procedure, which was related to mechanical wall stress in patients only receiving balloons, but not in those undergoing stent percutaneous transluminal coronary angioplasty. No changes were found in the coronary sinus; these results suggest ET-1 release from the plaque rather than an ischemia/reperfusion-related production from the distal myocardium.

Topics: Aged; Angina Pectoris; Angioplasty, Balloon, Coronary; Coronary Artery Disease; Endothelin-1; Female; Humans; Male; Middle Aged; Reference Values; Stents

The "American Heart Association Committee on Vascular Lesions" suggests the following morphologic classification of atherosclerotic plaques: the classification is based on large autopsy studies facilitating the assessment of the natural course of atherosclerotic lesions at precisely defined progression prone areas of the coronary tree from their clinically silent beginning to the stage where they produce symptoms. Lesion evolution is divided in 5 phases reflecting the possible time course of plaque development. Each phase is characterized by plaques with a distinctive morphology. The classification offers a framework of typical morphologies which the results of clinical investigations may be related to. Looking at the plaque composition, it is readily conceivable that atherosclerosis shares many characteristics with the general pathology of chronic inflammation and wound healing. Clinical symptoms e.g. acute coronary syndromes, arise from inflammation-mediated endothelial erosion and/or plaque rupture with ensuring coronary thrombosis. Advanced or complicated plaques are composed of different kinds of constituents in varying proportions. However, plaques at risk display a large lipid core occupying more than 40% of the plaque's volume, increased numbers of macrophages, reduced numbers of smooth muscle cells, an increased expression of tissue factor, and a thin plaque cap. Functionally, active plaques are characterized by a locally enhanced vasoreactivity with evidence coming from our own recent investigations that localised chronic inflammatory processes within the atherosclerotic plaque are responsible not only for the plaque rupture itself, but also for the hyperreactivity of these vessels to vasoconstrictor stimuli. In this context endothelin 1 (ET-1), a very potent vasoconstrictor peptide, may play an important role. ET-1 was originally reported to be produced by endothelial cells and to act locally in a paracrine fashion to regulate vascular tone. However, further studies have clarified that ET-1 is not only produced by endothelial cells but also by human inflammatory cells suggesting a role for ET-1 in inflammatory processes. Additionally, ET-1 displays a potent mitogenic activity. We examined immunohistochemically the presence of ET-1 in coronary plaque tissue obtained by directional coronary atherectomy. ET-1 immunoreactivity preferentially localized in plaque components indicative of a chronic inflammatory process. In addition, semiquantitative a

Topics: Adult; Coronary Artery Disease; Endothelin-1; Endothelium, Vascular; Femoral Artery; Humans; Immunohistochemistry; Inflammation

The purpose of this study was to determine whether endothelin-1 (ET-1) contributes to the development of graft arteriosclerosis and whether the orally active nonpeptide endothelin receptor antagonist bosentan, which blocks both ETA and ETB receptors, can protect against this pathologic damage.. Recipient male Lewis rats were divided into three groups; group 1 received heterotopic heart transplantations from Lewis donors and groups 2 and 3 received transplantations from Brown-Norway donors; group 3 recipients also received bosentan orally at the dose of 20 mg/kg per day for 120 days. All recipients were given cyclosporine and were euthanized at examination 120 days after transplantation. Plasma ET-1 levels were significantly higher in group 2 than in group 1 (6.99+/-0.91 and 4.15+/-.83 pg/mL, respectively). Strong ET-1 immunoreactivity was seen in both the thickened neointima and the media of the coronary arteries in group 2 but not in group 1. The mean ratio of the coronary luminal area to the total vascular area in group 2 (19.0+/-11.7%) was significantly lower than that in group 1 (34.2+/-9.9%) and was significantly increased in group 3 (33.2+/-9.2%).. These results show that local upregulation of ET-1, mainly in the thickened neointima and the media of the coronary arteries, may play an important role in the pathogenesis of graft arteriosclerosis by stimulating ETA receptors, ETB receptors, or both. Orally active bosentan might be a useful agent for the clinical prevention of graft arteriosclerosis.

Topics: Actins; Animals; Antihypertensive Agents; Bosentan; Coronary Artery Disease; Endothelin-1; Endothelium, Vascular; Graft Survival; Heart Transplantation; Male; Rats; Rats, Inbred Lew; Staining and Labeling; Sulfonamides; Transplantation, Homologous

Overproduction of the potent vasoconstrictor peptide endothelin-1 (ET-1) is implicated in the pathogenesis of coronary artery disease. In endothelium-denuded human coronary arteries the response to big ET-1 was significantly enhanced in atherosclerotic arteries (coronary artery disease, CAD; n=7) with an EC50 value of 96 nM (57- 161 nM, 95% C.I.) compared to 274 nM (205-365 nM) in non-diseased arteries (dilated cardiomyopathy, DCM; n=10) (Mann-Whitney U-test, P<0.05). Higher levels of immunoreactive endothelin (ET) could be detected by radioimmunoassay in bathing medium taken from CAD arteries than from DCM arteries (2.8+/-0.5 nM, n=5 vs 1.1+/-0.2 nM, n=7) (Student's two-tailed t-test, P<0.05). There were no differences in responses of arteries from either group to ET-1 (EC50 10 nM, CAD vs 14 nM, DCM). The enhanced response of atherosclerotic human coronary arteries to big ET-1 appears to be due to up-regulation of endothelin-converting enzyme (ECE) activity rather than to an augmented response of the arteries to ET-1. This non-endothelial ECE may therefore be an important therapeutic target in coronary artery disease.

Topics: Adult; Aspartic Acid Endopeptidases; Cardiomyopathy, Dilated; Coronary Artery Disease; Coronary Vessels; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Endothelium, Vascular; Enzyme Activation; Female; Humans; Male; Metalloendopeptidases; Middle Aged; Protein Precursors; Up-Regulation

Endothelin-1 is a potent vasoconstrictor peptide and mitogen for vascular smooth muscle cells. Increased plasma or tissue levels of endothelin-1 have been described after myocardial infarction and in atherosclerosis, suggesting that this peptide may play a pathophysiological role in various coronary syndromes. Here, we have studied regional variations in ET-1 and its receptors in control and atherosclerotic human coronary vasculature using standard immunohistochemistry and in vitro autoradiography. ET-1 immunoreactivity was associated with luminal endothelial cells and smooth muscle cells at regions of atherosclerosis. ET(A) receptors were present on smooth muscle cells of coronary arteries and on cardiac myocytes. Medial ET(B) receptor binding at the proximal region of coronary arteries was weak, but increased significantly towards distal regions of this vessel (p<0.005 in control and p<0.0005 in ischaemic heart disease). Microvascular endothelial cells in the adventitia of coronary arteries, myocardial microvessels and the endocardial endothelium expressed the ET(B) receptor exclusively. The receptor variations revealed in this study provide supporting evidence that ET-1 is associated with (1) vascular smooth muscle and endothelial cell proliferation, including areas of intimal hyperplasia and regions of neovascularization (2) increased ET-1-induced reactivity of distal portions of the human coronary artery, (3) ET-1-mediated constriction of myocardial microvessels. These results provide new insights into different potential roles for this peptide in healthy and diseased human coronary vasculature.

Topics: Autoradiography; Coronary Artery Disease; Coronary Vessels; Endothelin-1; Humans; Immunohistochemistry; Receptor, Endothelin A; Receptors, Endothelin

The pathogenesis of transplant coronary artery disease (TCAD) is unknown, but it is thought to derive from an interaction between immune and nonimmune factors, leading to smooth muscle cell proliferation and accumulation in the expanded neointima. Endothelin-1 (ET-1), a potent vasoconstrictor with mitogenic properties for vascular smooth muscle cells, has recently been demonstrated in native vessel atherosclerosis. The present study used immunohistochemistry to investigate the role of ET-1 in TCAD.. ET-1 immunoreactivity and cellular localization were assessed in human coronary arteries with TCAD (n = 13) and in normal coronary arteries (n = 10) with single- and double-label immunohistochemistry. The intensity of immunostaining was determined by a semiquantitative method. Diffuse and intense ET-1 immunoreactivity was found in 11 of 13 patients with TCAD (85%), mainly in myointimal cells and, in lesser amounts, in macrophages and endothelial cells. In contrast, normal coronary arteries had only faint immunostaining localized to the endothelial layer. Mean semiquantitative grade was significantly higher in TCAD than in normal arteries (1.8 versus 0.7; P < .05). ET-1 was more frequently present in lipid-rich, atheromatous lesions than in lipid-poor, proliferative ones. Intimal neovessels consistently immunostained for ET-1.. Immunoreactivity for ET-1 is significantly increased in TCAD, possibly as a result of stimulatory cytokines and growth factors that are upregulated in the posttransplant state. The results suggest a role for this mitogenic peptide in the pathogenesis of graft arteriosclerosis.

Topics: Adult; Coronary Artery Disease; Coronary Disease; Coronary Vessels; Endothelin-1; Female; Heart Transplantation; Humans; Immunohistochemistry; Male; Middle Aged; Transplantation, Homologous