endothelin-1 and Angina-Pectoris

Mechanisms responsible for anti-ischemic benefits of enhanced external counterpulsation (EECP) remain unknown. This was the first randomized sham-controlled study to investigate the extracardiac effects of EECP on peripheral artery flow-mediated dilation.. Forty-two symptomatic patients with coronary artery disease were randomized (2:1 ratio) to thirty-five 1-hour sessions of either EECP (n=28) or sham EECP (n=14). Flow-mediated dilation of the brachial and femoral arteries was performed with the use of ultrasound. Plasma levels of nitrate and nitrite, 6-keto-prostaglandin F(1α), endothelin-1, asymmetrical dimethylarginine, tumor necrosis factor-α, monocyte chemoattractant protein-1, soluble vascular cell adhesion molecule, high-sensitivity C-reactive protein, and 8-isoprostane were measured. EECP increased brachial (+51% versus +2%) and femoral (+30% versus +3%) artery flow-mediated dilation, the nitric oxide turnover/production markers nitrate and nitrite (+36% versus +2%), and 6-keto-prostaglandin F(1α) (+71% versus +1%), whereas it decreased endothelin-1 (-25% versus +5%) and the nitric oxide synthase inhibitor asymmetrical dimethylarginine (-28% versus +0.2%) in treatment versus sham groups, respectively (all P<0.05). EECP decreased the proinflammatory cytokines tumor necrosis factor-α (-16% versus +12%), monocyte chemoattractant protein-1 (-13% versus +0.2%), soluble vascular cell adhesion molecule-1 (-6% versus +1%), high-sensitivity C-reactive protein (-32% versus +5%), and the lipid peroxidation marker 8-isoprostane (-21% versus +1.3%) in treatment versus sham groups, respectively (all P<0.05). EECP reduced angina classification (-62% versus 0%; P<0.001) in treatment versus sham groups, respectively.. Our findings provide novel mechanistic evidence that EECP has a beneficial effect on peripheral artery flow-mediated dilation and endothelial-derived vasoactive agents in patients with symptomatic coronary artery disease.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Angina Pectoris; Blood Pressure; Brachial Artery; C-Reactive Protein; Chronic Disease; Counterpulsation; Cytokines; Endothelin-1; Exercise Tolerance; Femoral Artery; Humans; Middle Aged; Nitric Oxide; Oxygen Consumption; Regional Blood Flow; Tumor Necrosis Factor-alpha; Vasodilation

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

We tested the hypothesis that asymmetric dimethylarginine (ADMA) levels could be elevated and influence endothelin-1 and nitric oxide release and action in patients with cardiac syndrome X (CSX). In addition, we evaluated whether an intravenous infusion of L-arginine would improve endothelial function in these subjects.. Nine patients with CSX and 14 control subjects underwent a continuous infusion of L-arginine (0.125 g/min) or saline for 120 minutes. Sixty minutes after L-arginine or saline infusions, an intravenous insulin bolus (0.1 U/kg) combined with a euglycemic clamp was performed. Basal ADMA and endothelin-1 levels were higher in patients with CSX than in controls. At the end of the first hour of infusion, compared with saline, L-arginine infusion increased basal forearm blood flow, nitrite and nitrate (NOx), and forearm cGMP release and decreased endothelin-1. After insulin bolus, during saline, insulin-induced NOx, endothelin-1, and forearm cGMP release was almost abolished. Conversely, L-arginine restored a physiological profile of all endothelial variables compared with control subjects. In control subjects, compared with saline infusion, L-arginine infusion did not modify any parameter. ADMA levels were positively correlated with basal endothelin-1 levels and negatively correlated with insulin-induced incremental levels of NOx and forearm cGMP release.. Plasma ADMA levels are increased in patients with CSX, and they are correlated with increases in endothelin-1 and reductions in insulin-induced increments in plasma NOx and cGMP, effects that are reversed by intravenous L-arginine. These data suggest that increased ADMA levels play a role in the abnormal vascular reactivity that is observed in patients with CSX.

Topics: Angina Pectoris; Arginine; Blood Pressure; Coronary Angiography; Cyclic GMP; Endothelin-1; Endothelium, Vascular; Female; Forearm; Humans; Infusions, Intravenous; Insulin; Male; Middle Aged; Nitric Oxide; Regional Blood Flow; Syndrome

To explore the protective effect and the mechanism of Puerarin Injection (PI) on myocardial ischemia reperfusion in patients with coronary heart disease (CHD) and angina pectoris (AP).. Seventy-eight patients with AP planned to receive the PTCA and stenting treatment were randomly divided and single-blindedly into the conventional group and the PI group. Based on the conventional treatment and pre-operational preparation, the PI group was given 200 ml of PI by intravenous dripping once a day, beginning from one week before operation, but to the conventional group, normal saline was given for instead. The condition of AP attack in balloon dilatatory stage of PTCA was observed and change of ST segment of ECG detected by a 12-lead ECG monitor. The blood levels of von Willebrand factor (vWF:Ag), nitric oxide (NO) and endothelin-1 (ET-1) were also observed before and after treatment.. As compared with those in the conventional group, number of patients having AP attack and ST segment change in PTCA process was lessened in the PI group, with blood levels of vWF:Ag and ET-1 obviously lower, and NO content obviously higher than those in the conventional group,. PI could protect the myocardium in 2-3 days after ischemia reperfusion, one of the possible reasons is that PI can simulate the late phase of ischemic preconditioning, which may be related to its effect in lowering plasma vWF:Ag and ET-1, and increasing the serum NO content.

Topics: Angina Pectoris; Angioplasty, Balloon, Coronary; Antigens; Endothelin-1; Female; Humans; Infusions, Intravenous; Isoflavones; Male; Middle Aged; Myocardial Reperfusion Injury; Nitric Oxide; Stents; von Willebrand Factor

Recent studies showed that coronary artery spasm may be due to disturbances of secretory and excretory endothelial activity in atherosclerotic coronary artery. However, this theory does not explain the reasons of coronary artery spasm when endothelium is not damaged. There must be other patomechanisms of coronary artery spasm. The aim of our study was examination of calcium efflux through the lymphocytic cell membrane and determination of endothelin-1 plasma levels in patients with variant angina in order to define the participation of these factors in pathogenesis of coronary artery spasm. The survey was made in 76 patients with ischaemic heart disease. All patients were divided into 2 groups. The first group consisted of 48 patients with variant angina (d.b.s.), the other consisted of 28 patients with stable angina (d.b.w.). The control group (g.k.) was composed of 25 healthy people. Patients were administered 100 ml of trometamol (TRIS, pH = 10.5) intravenously for 5 minutes. After stopping the infusion the examined patient was breathing deeply for 5 minutes at a rate of 40/min. The endothelin-1 (ET-1) plasma levels and transmembrane calcium transport in lymphocytes were determined before and just after the hyperventilation test, as well as 10 minutes after the test. ET-1 plasma concentrations were estimated with a radioimmunologic assay. The method of estimation of transmembrane calcium transport was elaborated in Laboratory of Department of Cardiology of Medical University of Wrocław. We showed that ET-1 plasma levels and transmembrane calcium transport in patients with d.b.s. before the test were normal. There was an increase in transmembrane calcium efflux in patients with d.b.s. during coronary artery spasm that had been caused by ET-1. ET-1 plasma levels were still high 10 min. after the coronary artery spasm. Disturbances of transmembrane calcium transport and increased endothelin-1 plasma level may be the primary factors responsible for coronary artery spasm.

Topics: Adult; Aged; Angina Pectoris; Angina Pectoris, Variant; Calcium; Endothelin-1; Female; Humans; Ion Transport; Lymphocytes; Male; Middle Aged; Tromethamine

The pathophysiologic meaning of elevated circulating endothelin-1 (ET-1) levels in various cardiovascular diseases is not understood. The aim of this study was to measure ET-1 and big ET-1 levels in patients with unstable angina pectoris (UAP) and within 5 days after stabilization. These values were compared to those of patients with stable angina pectoris (SAP) and to healthy controls (Co). In addition, a venous occlusion test was performed as an endothelial provocation test to characterize endothelial function. Big ET-1 levels were increased to 2.6 +/- 1.5 fmol/ml during unstable angina pectoris compared to normal values of 0.52 +/- 0.07 fmol/ml (p < 0.03; n = 14). After stabilization, big ET-1 decreased to 1.5 +/- 0.4 fmol/ml within 5 days (n.s.). ET-1 levels were not increased during UAP and after stabilization. ET-1 and big ET-1 levels from patients with SAP did not differ from those of healthy controls. The venous occlusion test resulted in an increase of ET-1 levels (0.3 +/- 0.02 to 0.46 +/- 0.02 fmol/mg, p = 0.008; SAP 0.3 +/- 0.04 to 0.39 +/- 0.05 fmol/ml, p = 0.009) in healthy controls and in patients with SAP. In contrast, patients with UAP showed no significant increase in ET-1 with this test. After stabilization for 5 days, the provocation test induced an increase in circulating ET-1 in patients with UAP comparable to that of controls (0.62 +/- 0.18 fmol/mg vs. 0.95 +/- 0.25 fmol/mg; p < 0.02). In summary, during UAP big ET-1 values are significantly increased and ET-1 values tend to be elevated. In an endothelial provocation test, ET-1 values did not increase. This might reflect a general activation of the endothelium in UAP during the acute stage, because the normal response is recovered 5 days later.

Topics: Adult; Angina Pectoris; Angina, Unstable; Endothelin-1; Endothelins; Humans; Protein Precursors; Reference Values

To study the effect of purified Xuefu Capsule (PXFC) in treating angina pectoris (AP).. Fifty-seven patients with AP were randomly divided into two groups. Group A (30 cases) was treated with PXFC and western medicine, and group B(27 cases) with western medicine (isosorbide dinitrate, diltiazem or atenolol) alone.. The total effective rates and ECG ST-T changes of AP were 93.3% and 63.3% respectively in group A. These results were all superior to those of group B (P < 0.05). Moreover, in group A the level of plasma endothelin (ET-1) decreased from 85.09 +/- 37.56 ng/L to 61.19 +/- 4.02 ng/L, and that of calcitonin gene related peptide (CGRP) increased from 58.64 +/- 19.30 ng/L to 88.87 +/- 20.41 ng/L. Comparing with group B, these changes were statistically different (P < 0.01).. The effects of adding PXFC on conventional treatment with western medicine were better than those of western medicine.

Topics: Aged; Angina Pectoris; Calcitonin Gene-Related Peptide; Capsules; Drug Therapy, Combination; Drugs, Chinese Herbal; Endothelin-1; Female; Humans; Male; Middle Aged; Nifedipine; Single-Blind Method

To investigates the outcomes of enhanced external counterpulsation (EECP) among coronary microvascular disease (CMD) patients.. Coronary microvascular disease patients were separated into the EECP (n=41) and control cohorts (n=42). Prior to and following the 4-week EECP program, coronary flow reserve (CFR) was recorded using transthoracic Doppler echocardiography. The serum endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) contents were analyzed by ELISA. Quality of life (QoL) was assessed by the Seattle Angina Questionnaire (SAQ) and the Canadian Cardiovascular Society (CCS) angina class.. After four weeks, CFR was substantially enhanced in the EECP versus control cohort (. Enhanced external counterpulsation may improve CFR and enhance the CMD patient QoL.

Topics: Angina Pectoris; Canada; Counterpulsation; Endothelin-1; Humans; Quality of Life; Treatment Outcome

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

Endothelin-1 and angiotensin II are strong vasoconstrictors. Patients with ischemic heart disease have elevated plasma levels of endothelin-1 and angiotensin II and show increased vascular tone. The aim of the present study was to examine the endothelin and angiotensin II receptor expression in subcutaneous arteries from patients with different degrees of ischemic heart disease.. Subcutaneous arteries were obtained, by biopsy from the abdomen, from patients undergoing coronary artery bypass graft (CABG) surgery because of ischemic heart disease (n = 15), patients with angina pectoris without established myocardial infarction (n = 15) and matched cardiovascular healthy controls (n = 15). Endothelin type A (ETA) and type B (ETB), and angiotensin type 1 (AT1) and type 2 (AT2) receptors expression and function were examined using immunohistochemistry, Western blot and in vitro pharmacology.. ETA and, to a lesser extent, ETB receptor staining was observed in the healthy vascular smooth muscle cells. The level of ETB receptor expression was higher in patients undergoing CABG surgery (250% +/- 23%; P < 0.05) and in the patients with angina pectoris (199% +/- 6%; P < 0.05), than in the healthy controls (100% +/- 28%). The data was confirmed by Western blotting. Arteries from CABG patients showed increased vasoconstriction upon administration of the selective ETB receptor agonist sarafotoxin S6c, compared to healthy controls (P < 0.05). No such difference was found for the ETA receptors. AT1 and, to a lesser extent, AT2 receptor immunostaining was seen in the vascular smooth muscle cells. The level of AT1 receptor expression was higher in both the angina pectoris (128% +/- 25%; P < 0.05) and in the CABG patients (203% +/- 41%; P < 0.05), as compared to the healthy controls (100% +/- 25%). The increased AT1 receptor expression was confirmed by Western blotting. Myograph experiment did however not show any change in vasoconstriction to angiotensin II in CABG patients compared to healthy controls (P = n.s).. The results demonstrate, for the first time, upregulation of ETB and AT1 receptors in vascular smooth muscle cells in ischemic heart disease. These receptors may play a role in the pathophysiology of ischemic heart disease and could provide important targets for pharmaceutical interventions.

Topics: Aged; Angina Pectoris; Angiotensin II; Angiotensin II Type 2 Receptor Blockers; Arteries; Blotting, Western; Case-Control Studies; Coronary Artery Bypass; Dose-Response Relationship, Drug; Endothelin-1; Humans; Imidazoles; Immunohistochemistry; Middle Aged; Muscle, Smooth, Vascular; Myocardial Ischemia; Myography; Pyridines; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptor, Endothelin A; Receptor, Endothelin B; Subcutaneous Tissue; Up-Regulation; Vasoconstriction; Vasoconstrictor Agents; Viper Venoms

Ischemic preconditioning may provide a systemic organ protection, evident as the phenomenon known as remote preconditioning. Unstable angina may be a clinical analogue to ischemic preconditioning. Vein graft harvesting induces inflammation of the graft wall. We hypothesized that preoperative unstable angina preconditions vein grafts and reduces the inflammatory response to graft harvesting. Consecutive patients with stable or unstable angina undergoing open heart surgery (n = 12 in each group) were studied. Saphenous vein biopsies were collected at the start of graft harvesting, and when the last proximal anastomosis to the aorta was finished (average 112 minutes later). Gene expression of inflammatory mediators (tumor necrosis factor alpha, interleukin-1beta (IL-1beta), E-selectin (CD62E), intercellular leukocyte adhesion molecule 1, inducible nitric oxide synthase, endothelin-1) increased after surgical handling (semiquantitative RT-PCR). In vein grafts from unstable patients the increase was attenuated for Il-1beta (p < 0.004) and CD62E (p < 0.001). In stable patients the protein expression of IkappaBalpha and heat shock protein72 was reduced by surgical handling (p < 0.04), but was not influenced in unstable patients (immunoblotting). In vitro relaxation to acetylcholine was enhanced, and contractions to phenylephrine and endothelin-1 were attenuated in veins rings from unstable patients (p < 0.003). In conclusion, surgical handling of vein grafts induces inflammation of the vessel wall. This response was reduced in grafts from patients with unstable angina, indicating a possible systemic preconditioning-like effect of acute coronary syndromes.

Topics: Aged; Angina Pectoris; Angina, Unstable; Cell Adhesion Molecules; E-Selectin; Endothelin-1; Female; Gene Expression; Gene Expression Regulation; HSP72 Heat-Shock Proteins; Humans; I-kappa B Proteins; Inflammation; Interleukin-1beta; Ischemic Preconditioning; Male; Middle Aged; Nitric Oxide Synthase; Reverse Transcriptase Polymerase Chain Reaction; Saphenous Vein; Tumor Necrosis Factor-alpha; Ventricular Remodeling

Topics: Angina Pectoris; Endothelin-1; Exercise; Humans; Myocardial Ischemia; Placebos; Simvastatin

Elevations in endothelin-1 (ET-1) and inflammatory cytokines may impair myocardial reperfusion through the induction of microvascular constriction or obstruction; however, the generation of these factors close to the site of lesion rupture is unknown.. Coronary sinus (CS) and aortic blood was sampled during angioplasty for acute myocardial infarction (AMI) or stable angina to assess the local release of ET-1, interleukin-1beta, interleukin-6, tumor necrosis factor-alpha and C-reactive protein following atherosclerotic plaque rupture. Transthoracic echocardiography documented left ventricular function in AMI. ET-1 levels were higher in CS than in aortic blood in AMI (3.0 +/- 0.3 pmol/L vs 2.6 +/- 0.3 pmol/L, P =.04), but not in stable angina (1.7 +/- 0.2 pmol/L vs 1.5 +/- 0.3 pmol/L, P = NS). CS ET-1 levels were also higher in AMI than in stable angina (3.0 +/- 0.3 pmol/L vs 1.7 +/- 0.2 pmol/L, P =.002), and correlated with left ventricular dysfunction (R(2) = 0.51, P =.02). In contrast, C-reactive protein levels were higher in CS than in aortic blood only in stable angina (2.3 +/- 0.4 mg/L vs 1.8 +/- 0.3 mg/L, P =.01). Similarly, CS tumor necrosis factor-alpha was higher in stable angina than in AMI (6.0 +/- 1.4 pg/mL vs 2.5 +/- 0.9 pg/mL, P =.02).. Local myocardial release of ET-1 is highest in AMI, where it relates to the extent of myocardial dysfunction. Although local inflammation is a component of stable coronary artery disease, it does not appear acutely enhanced in AMI.

Topics: Angina Pectoris; Angioplasty, Balloon, Coronary; C-Reactive Protein; Cytokines; Endothelin-1; Female; Humans; Inflammation; Male; Middle Aged; Myocardial Infarction; Myocardium; Ventricular Function, Left

In this study, the endothelin-1 (ET-1) and nitric oxide (NO) concentrations in slow coronary flow (SCF) patients were assessed before and at the peak of the exercise stress test and compared with the values from healthy controls. The study population was 25 patients who underwent coronary angiography and were diagnosed as SCF (11 females (44%), aged 56.7+/-9.8 years), and 20 normal subjects (9 females (45%), aged 54.3+/-9.2 years). Mean TIMI frame count in the patients was 54.1+/-13.4. Blood samples were drawn at rest and immediately at the end of exercise testing. The baseline ET-1 concentrations of the control subjects were lower than those of the patients (7.0+/-4.5 pg/ml vs 11.1+/-5.9 pg/ml p<0.0001) and this difference increased after exercise (6.2+/-4.3 pg/ml vs 20.1 +/-10.4 pg/ml, p<0.0001). Post-exercise ET-1 concentrations were significantly higher than baseline in patients with SCF (p<0.0001) and a reduction in the ET-1 concentrations was observed in control subjects (p<0.05). Baseline NO concentrations of the patients were lower than those of the control subjects (27 +/-5.1 micromol/L vs 31.2+/-4.9 micromol/L, p=0.0001). Although the NO concentrations in both groups were significantly increased after exercise (29.4 +/-5.9 micromol/L vs 33.3+/-5.6 micromol/L, p<0.05 for both), the difference was not significant. A significant negative correlation among post-exercise ET-1 concentrations and maximal heart rate, exercise duration and exercise rate - pressure product, and a significant positive correlation among post-exercise NO concentrations and maximal heart rate and exercise duration were observed in both groups. The results of this study show that endothelial function (assessed by ET-1 and NO concentrations) and its response to exercise were abnormal in SCF patients compared with healthy subjects, and this may play some pathophysiologic role.

Topics: Angina Pectoris; Biomarkers; Blood Flow Velocity; Blood Pressure; Coronary Disease; Endothelin-1; Exercise Test; Female; Heart Rate; Humans; Male; Middle Aged; Nitric Oxide; Reference Values; Regression Analysis

The aim of this study was to determine the plasma and pericardial levels of endothelin-1 (ET-1) and its precursor big endothelin-1 (Big ET-1) in patients with unstable and stable angina prior to and following coronary bypass surgery. To further investigate the content of ET-1, tissue levels were studied in the internal mammary artery (IMA) in patients with stable and unstable angina pectoris. Finally, the difference in reactivity of the IMA to ET-1 and Big ET-1 in stable and unstable patients was evaluated.. Plasma and pericardial levels of ET-1 and Big ET-1 were determined with radioimmunoassay in 81 patients (33 unstable) immediately before coronary bypass surgery, and at 6, 14, 40 and 64 h following the procedure. Specimens of the distal IMA from 12 patients (six unstable) were collected at the beginning of surgery for determination of tissue levels of ET-1. Additionally, distal internal mammary arteries were obtained from another 24 patients (12 unstable). These vessels were mounted in organ baths for functional studies on vascular reactivity to ET-1 and Big ET-1.. The peripheral plasma levels of ET-1 in unstable patients were significantly lower in patients with unstable angina compared with patients with stable angina pectoris at all points of measurement. The levels of Big ET-1 were significantly higher pre-operatively in the unstable group, but decreased to similar levels to those of stable patients following coronary bypass grafting. There was no difference in ET-1 tissue content in the IMA between the patients. ET-1 and Big ET-1 caused an endothelin(A) (ET(A))-receptor blocker sensitive, concentration-dependent contraction of the IMA obtained from stable as well as unstable patients.. It is concluded that unstable angina pectoris is associated with an increased ET-1 turnover. This increased turnover may participate in the local regulation of coronary vascular tone with subsequent influence of the condition of the patients. The present investigation also implies that ET(A)-blockade may be useful as an additional pharmacological principal in the treatment of unstable angina pectoris prior to revascularization, as well as to prevent post-operative arterial graft spasm.

Topics: Adult; Aged; Aged, 80 and over; Angina Pectoris; Angina, Unstable; Biomarkers; Coronary Artery Bypass; Endothelin-1; Endothelins; Female; Follow-Up Studies; Humans; Male; Mammary Arteries; Middle Aged; Myocardium; Postoperative Period; Preoperative Care; Probability; Prospective Studies; Protein Precursors; Sensitivity and Specificity; Statistics, Nonparametric; Treatment Outcome

This paper aims to demonstrate that there is currently sufficient evidence to suggest that endothelin-1 (ET-1) may play a role in angina and be associated with myocardial ischaemia. In order to demonstrate the potential role of ET-1 in angina, this paper examines three main factors: (i) that endothelin-1 can cause the pathophysiological states associated with myocardial ischaemia and angina; (ii) that ET-1 is over-expressed in humans and in animal models of myocardial ischaemia, which is associated with angina; and (iii) that modification of the ET-1 system is associated with an improvement in myocardial ischaemia and angina.

Topics: Angina Pectoris; Animals; Cardiovascular Diseases; Cyclic GMP; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Humans; Myocardial Ischemia

Neurohormones may influence vascular tone both during and after exercise. Neuropeptide Y (NPY), which is costored and released with norepinephrine (NE) during sympathetic activity, is a potent vasoconstrictor with a relatively long half-life. We therefore examined its possible association with the ischemic response to exercise in patients with coronary artery disease.. Twenty-nine male patients with effort-induced angina pectoris underwent a symptom-limited exercise test. In addition to conventional ST-segment analysis, we examined ischemia on the basis of heart rate (HR)-adjusted ST-segment changes through calculation of the ST/HR slope during the final 4 minutes of exercise and of the ST/HR recovery loop after exercise. Blood samples were taken before, during, and after exercise for an analysis of several neurohormones. Mean ST-segment depression was -223+/-20.2 microV (P:<0.0001) just before the termination of exercise, followed by a gradual normalization, but it remained significant after 10 minutes (-49+/-8.9 microV, P:<0.0001). At the end of exercise, the ST/HR slope, which reflects myocardial ischemia, was -6.0+/-0.77 microV/HR. In most patients, ST-segment levels at a given HR were lower during recovery than during exercise, here referred to as ST "deficit." Exercise increased the plasma levels of NPY, NE, epinephrine, and N-terminal proatrial natriuretic peptide, but big endothelin remained unchanged. Although NE and epinephrine peaked at maximal exercise, the highest levels of NPY and N-terminal proatrial natriuretic peptide were observed 4 minutes after exercise. The maximal increase in the NPY correlated significantly with ST-segment depression at 3 minutes after exercise (r=-0.61, P:= 0.0005), the ST deficit at the corresponding time point (r=-0.66, P:= 0.0001), and the duration of ST-segment depression after exercise (r= 0.42, P:=0.02). In contrast, no such correlations were found for NE.. The present study has for the first time demonstrated a correlation between plasma NPY levels and the degree and duration of ST-segment depression after exercise in patients with coronary artery disease, which suggests that NPY may contribute to myocardial ischemia in these patients.

Topics: Analysis of Variance; Angina Pectoris; Atrial Natriuretic Factor; Coronary Disease; Electrocardiography; Endothelin-1; Endothelins; Epinephrine; Exercise Test; Heart Rate; Humans; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Protein Precursors; Time Factors

Plasma atrial natriuretic peptide (ANP) concentration increases during ventricular arrhythmias and rapid ventricular pacing but less is known about plasma brain natriuretic peptide (BNP) and endothelin (ET-1). In the present study concentrations of ANP, the amino terminal part of the proANP (NT-proANP), BNP, and ET-1 were measured in the coronary sinus and femoral artery before and at the end of rapid ventricular pacing in 15 patients with coronary arterial disease. The changes were compared with the changes in mean arterial blood pressure, pulmonary capillary wedge pressure (PCWP), transcardiac differences in pH, pCO2, lactate, and norepinephrine. There was an increase in PCWP and a transient decrease in blood pressure after initiation of pacing. Pacing caused a decrease in ST-segment, transcardiac difference of norepinephrine, lactate extraction, pCO2 difference, and an increase in pH difference. Concentration of ANP in the coronary sinus and femoral artery and its transcardiac difference increased during pacing (P < 0.001), whereas changes in NT-proANP were small and BNP and ET-1 levels remained unchanged. The change in transcardiac ANP difference correlated with the change in lactate (r = 0.53, P < 0.05) but not that of norepinephrine, PCWP, or blood pressure. The results show that the plasma concentration of ANP increases more than that of NT-proANP during rapid ventricular pacing. Ischemia-induced release of ANP and its diminished elimination may contribute to the increased plasma ANP level.

Topics: Aged; Angina Pectoris; Atrial Natriuretic Factor; Cardiac Pacing, Artificial; Coronary Disease; Endothelin-1; Energy Metabolism; Female; Heart Rate; Heart Ventricles; Hemodynamics; Humans; Lactic Acid; Male; Middle Aged; Myocardium; Natriuretic Peptide, Brain

Endothelin has both vasoconstrictor and mitogenic properties and might, therefore, play a role in the pathogenesis of acute coronary syndromes and coronary atherosclerosis. The aim of the study was to characterize the mechanisms and kinetics of cardiac endothelin-1 (ET-1) release following a local endothelial injury during PTCA (group A) and after sustained myocardial ischemia (group B). Additionally, the precision of agreement between measurements in coronary sinus and peripheral venous samples should be analyzed. In group A, elective PTCA was performed in 20 patients with stable angina pectoris and a > 70% type A stenosis. Simultaneous determinations of ET-1 from coronary venous and peripheral venous blood were done before balloon inflation and during the several hours following the last dilatation procedure. A coronary sinus study with high rate atrial pacing was performed in 20 group B patients with coronary multivessel disease. ET-1 was determined from coronary sinus and peripheral venous blood samples prior to stimulation and during several hours after cessation of pacing. Control groups were provided for both groups. The control group consisted of 10 patients with coronary angiography without PTCA for group A and 10 patients with angiographic normal coronary arteries for group B.PTCA induced an instantaneous increase of coronary sinus ET levels from 4.1 +/- 1.1 pg/ml to 13.7 +/- 2.3 pg/ml (peripheral venous 7.9 +/- 2.5 pg/ml), which was more pronounced if the target vessel was the left anterior descending artery. This peak was followed by a gradual decrease of ET-1 to the limit of normal within 6 hours. The concentrations of ET, furthermore, remained higher in the coronary sinus compared with the peripheral vein indicating a persisting cardiac release of ET. In group B, incremental atrial pacing resulted in myocardial ischemia, and a significant increase in ET-1 from 4.6 +/- 0.6 pg/ml to 13.1 +/- 2.8 pg/ml was detected in the coronary sinus samples. A persistent cardiac release of ET-1, as reflected by sustained elevated coronary sinus concentrations, was observed for up to one hour after cessation of pacing. The analysis of measurement agreement between coronary venous and peripheral venous samples revealed considerable variations of the differences between the two sampling sites indicating wide limits of agreement. Despite a significant positive correlation, our date reflecting a remarkable lack of agreement.. 1) An enhanced release of ET-1 following PTCA is mainly due to the localized endothelial injury, and the ET-1 levels remain elevated for up to hours after the mechanical stimulus. 2) A short-lasting myocardial ischemia is associated with a significant ET-1 increase. 3) For refined evaluations of release kinetics of cardiac ET-1, blood sampling from the coronary sinus seems to be essential.

Topics: Aged; Angina Pectoris; Angioplasty, Balloon, Coronary; Cardiac Pacing, Artificial; Coronary Disease; Endothelin-1; Endothelium, Vascular; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Reference Values; Sensitivity and Specificity

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

Some patients with typical angina and electrocardiographic evidence of ischemia have normal coronary angiograms. These patients have a reduced coronary flow reserve and abnormal endothelium-dependent vasodilator responses; this syndrome is known as microvascular angina. Among endothelium-derived peptides, endothelin-1 (ET-1) is a potent vasoconstrictor and an important modulator of microvascular function.. Plasma ET-1 was measured in 13 patients with typical angina, instrumental evidence of ischemia, and normal arteriograms and in 20 normal control subjects.. Mean concentration of ET-1 was 2.89+/-1.24 pmol/L in patients with angina and normal angiograms and 1.99+/-0.81 pmol/L in normal control subjects (p < 0.02). Plasma levels of ET-1 values were significantly higher in patients with angina, positive exercise test results for ischemia, and normal coronary arteriograms compared with the group of patients with no clinical or instrumental evidence of ischemia.. This is consistent with the hypothesis that in patients with microvascular angina, an endothelial dysfunction in the coronary vascular area caused by impaired endothelium-derived ET-1 could play an active role in the disease process.

Topics: Adult; Angina Pectoris; Blood Pressure; Coronary Angiography; Electrocardiography; Endothelin-1; Exercise Test; Female; Humans; Male; Middle Aged; Radioimmunoassay; Retrospective Studies; Stroke Volume; Vasoconstriction

At peak exercise, plasma endothelin-1 concentration increases in patients with effort angina as well as thallium-201 radionuclide perfusion defects; the opposite occurs in patients with normal scans and in healthy volunteers. It is concluded that exercise-induced ischemia correlates with enhanced endothelin-1 production.

Topics: Angina Pectoris; Case-Control Studies; Endothelin-1; Exercise Test; Female; Heart; Humans; Male; Middle Aged; Myocardial Ischemia; Radionuclide Imaging; Thallium Radioisotopes

The endothelium-derived peptide endothelin-1 (ET-1) was evaluated in 14 male patients [mean age 52.74 years (SEM 1.10)] affected by coronary artery disease during a bicycle electrocardiographic stress test and dipyridamole echocardiogram. Both tests were performed before and after coronary revascularization. Fourteen healthy male subjects served as controls [mean age 53.21 years (SEM 1.63)]. Baseline plasma endothelin-1 levels were higher (P < 0.0001) in ischaemic patients [1.81 pg mL-1 (0.15, n = 14)] than in control subjects [0.61 pg mL-1 (0.03, n = 14)], but did not increase with exercise in both groups. Similar results were obtained with dipyridamole infusion. Endothelin-1 levels significantly decreased after coronary revascularization [before: mean 1.81 pg mL-1 (SEM 0.15, n = 14); after: mean 1.16 pg mL-1 (SEM 0.11), P < 0.002], without changes in the peptide response to both tests. In conclusion, elevated plasma endothelin-1 concentrations were found in patients with stable angina compared with non-ischaemic subjects. No changes were observed during exercise or dipyridamole infusion in both groups. Coronary revascularization was followed by a significant decrease in plasma endothelin-1 levels.

Topics: Adult; Angina Pectoris; Case-Control Studies; Dipyridamole; Echocardiography; Endothelin-1; Exercise Test; Humans; Male; Middle Aged; Myocardial Ischemia; Myocardial Revascularization

To investigate whether circulating endothelin-1 (Et-1) may be related to the increased incidence and severity of ischaemic heart disease in type 2 diabetes mellitus, we compared the concentrations in type 2 diabetic patients and in non-diabetic patients with coronary artery disease (CAD) angiographically documented. Plasma levels of Et-1 were determined in 34 type 2 diabetic patients with CAD (16 with stable angina, 6 with unstable angina, 12 with previous myocardial infarction) and in 19 nondiabetic patients with CAD (4 with stable angina, 5 with unstable angina, 10 with previous myocardial infarction). Fifteen diabetic patients without CAD and 9 healthy volunteers served as control subjects. In the type 2 diabetic patients, the mean Et-1 levels were 3.19 +/- 1.61 pmol/l in those with stable angina, 3.58 +/- 1.92 pmol/l in those with unstable angina, 4.24 +/- 2.53 pmol/l in those with myocardial infarction. These values were not significantly different one another, nor from the values obtained from type 2 diabetic controls (3.64 +/- 2.13 pmol/l). In the non-diabetic patients, the mean Et-1 levels were 3.92 +/- 0.73 pmol/l in those with stable angina, 4.35 +/- 1.67 pmol/l in those with unstable angina, 4.33 +/- 1.66 pmol/l in those with myocardial infarction. These values were not significantly different one another, but significantly higher than those obtained from healthy controls (2.07 +/- 0.67 pmol/l; P < 0.001). No significant differences were found in Et-1 levels between diabetic and non-diabetic patients with stable, unstable angina and previous myocardial infarction. In contrast, a statistically significant difference was found in Et-1 levels between diabetic and non-diabetic control subjects (P < 0.05). In conclusion, similar raised concentrations of Et-1 in diabetic and non-diabetic patients with stable, unstable angina and previous myocardial infarction do not support the hypothesis that higher levels of Et-1 in diabetic patients are responsible for the increased incidence of CAD in diabetes mellitus. However, the raised Et-1 levels found in diabetic patients in the absence of CAD strongly suggest that a generalised endothelial dysfunction, documented in our study by increased levels of Et-1, most probably precedes subsequent cardiovascular diseases.

Topics: Aged; Analysis of Variance; Angina Pectoris; Blood Pressure; Diabetes Mellitus, Type 2; Endothelin-1; Female; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Reference Values

Cardiopulmonary bypass is thought to injure all endothelial cells, mainly by cell-to-cell interaction with activated granulocytes which, augmented by endothelin-1 (ET-1), enhance the generation of superoxide radicals. These radicals on the other hand, may sustain and prolong endothelial injury. In the present study, by means of a magnetic separation radioimmunoassay procedure, ET-1 levels were measured in 10 adult patients undergoing coronary artery bypass surgery, in 10 perioperative phases, in order to reconfirm and further elucidate the effect of cardiopulmonary bypass on endothelial secretion of ET-1. ET-1 levels before cardiopulmonary bypass showed a definite rising trend, especially after median sternotomy. After induction of cardiopulmonary bypass, ET-1 levels increased significantly compared with preoperative values (P < 0.01). ET-1 levels in stable angina patients during and after aortic cross-clamping were strongly and positively correlated with preoperative mean pulmonary artery pressure (r = 0.79, n = 7, P < 0.05 and r = 0.92, n = 7, P = 0.05) respectively. After the first hour in the intensive care unit, ET-1 levels in three patients with unstable angina were considerably higher than in those with stable angina, a fact that deserves further consideration and study.

Topics: Aged; Angina Pectoris; Cardiopulmonary Bypass; Coronary Artery Bypass; Endothelin-1; Endothelium, Vascular; Humans; Intraoperative Period; Middle Aged; Postoperative Period; Radioimmunoassay

Endothelin (ET), the most potent endogenous vasoconstrictor with mitogenic potency, is generated from its precursor big-endothelin (BET) in a proteolytic process and discussed as a pathogenetic factor in coronary artery disease and in the acute coronary syndromes. Several studies documented elevated plasma endothelin concentrations in acute myocardial infarction, but conflicting results were reported in patients with stable and unstable angina. Only few studies determined big endothelin, although it half-life and plasma concentrations are higher in comparison to endothelin. ET and BET levels (Radioimmunoassay, Biomedica GmbH, Vienna) were determined in patients with stable angina (SAP, n = 20), unstable angina (IAP, n = 12), acute myocardial infarction (AMI, n = 12) and healthy subjects (NP, n = 11). The concentrations of ET and BET (median (minimum-maximum) in fmol/ml) of the patients with stable angina (SAP: ET 0.7 (0.3-1.1); BET 1.7 (0.7-2.9)), unstable angina (IAP: ET 1.0(0.5-1.7); BET 2.5 (1.3-4.1)) and acute myocardial infarction (AMI: ET 1.2 (0.6-2.3); BET 3.6 (3.2-5.3)) showed a significant difference compared to controls (NP: ET 0.5 (0.4-0.7); BET 1.4 (1.1-1.7)) (SAP vs. NP: ET p < 0.01; BET p < 0.05; IAP and AMI vs. NP: ET and BET p < 0.001). Also, the concentrations of the peptides differed significantly dependent on the clinical severity of coronary artery disease (AMI vs. SAP: ET and BET p < 0.001; AMI vs. IAP: BET p < 0.05; IAP vs. SAP: ET p < 0.05; BET p < 0.01). Twelve of 15 patients with big endothelin concentrations over 3 fmol/ml suffered acute myocardial infarction. Seven of 12 patients with AMI showed elevated ET and BET concentrations before the increase of creatinecinase. There was no correlation between number of risk factors per patient, cholesterin and subfractions, severity of CAD classified in one-two-three-vessel disease or coronary score according to modified criteria of the American Heart Association (AHA). We conclude that in patients with coronary artery disease endothelin and big endothelin levels are elevated and related to the clinical and not to the morphological severity of coronary artery disease. Big endothelin is the more sensitive parameter in comparison to endothelin and indicates a severe course of myocardial ischemia in patients with unstable angina. The development of assays with the possibility of a quick determination of the peptides may be valuable for risk stratification of acute coronary events.

Topics: Adult; Aged; Aged, 80 and over; Angina Pectoris; Angina, Unstable; Coronary Disease; Endothelin-1; Endothelin-2; Endothelins; Humans; Male; Middle Aged; Myocardial Infarction; Prognosis; Protein Precursors; Radioimmunoassay; Reference Values; Risk Factors

To elucidate the pathophysiologic significance of the family of endothelin (ET) peptides, we have investigated plasma and urinary immunoreactive (ir-) ET levels and its molecular forms in normal and pathological conditions. Plasma and urine ET were extracted with an Amprep C2 column. The molecular form of ET was determined by a combination of radioimmunoassay and reverse-phase high-performance liquid chromatography. Although plasma ir-ET was composed mainly of big ET and endothelin-1 (ET-1) in normal subjects, that in acute myocardial infarction, chronic renal failure (CRF), essential hypertension, and vasospastic angina pectoris was characterized by an increase of high molecular ir-ET in addition to increases in big ET and ET-1. Urinary ir-ET in both normal subjects and patients with CRF was composed mainly of a high molecular form in addition to big ET and ET-1. These results suggest that the biosynthetic and/or degradation process of ET under pathological conditions appears to be different from that under normal conditions.

Topics: Angina Pectoris; Cardiovascular Diseases; Endothelin-1; Endothelins; Humans; Hypertension; Kidney Diseases; Myocardial Infarction; Protein Precursors