endothelin-1 and Heart-Defects--Congenital

Topics: Antihypertensive Agents; Combined Modality Therapy; Endothelin-1; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Survival; Tomography, X-Ray Computed

Congenital heart disease can predispose individuals to pulmonary vascular remodeling as a result of the abnormality in pulmonary blood flow and pressure that accompanies the specific congenital defect being considered. Pulmonary arterial hypertension associated with congenital heart defects is an important determinant of functional capacity and survival, especially when the Eisenmenger's state of reversed shunt is present. The likelihood of right ventricular dysfunction and failure increases with the degree of pulmonary artery pressure. Thus, the aim of disease management in this patient population should be to prevent or improve right heart failure. Current therapies that modify the progression of pulmonary vascular disease-including endothelin-1 receptor antagonists, phosphodiesterase-5 inhibitors, and prostanoids-should be considered carefully in patients with congenital heart disease-associated pulmonary hypertension. The risks and benefits of altering the balance of pulmonary vascular resistance to systemic vascular resistance must be weighed for each patient.

Topics: Antihypertensive Agents; Endothelin-1; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Randomized Controlled Trials as Topic; Survival; Ventricular Dysfunction, Right

In this review, the role of wall shear stress in the chicken embryonic heart is analyzed to determine its effect on cardiac development through regulating gene expression. Therefore, background information is provided for fluid dynamics, normal chicken and human heart development, cardiac malformations, cardiac and vitelline blood flow, and a chicken model to induce cardiovascular anomalies. A set of endothelial shear stress-responsive genes coding for endothelin-1 (ET-1), lung Krüppel-like factor (LKLF/KLF2), and endothelial nitric oxide synthase (eNOS/NOS-3) are active in development and are specifically addressed.

Topics: Animals; Chick Embryo; Disease Models, Animal; Endothelin-1; Gene Expression Regulation, Developmental; Heart; Heart Defects, Congenital; Hemodynamics; Humans; Kruppel-Like Transcription Factors; Ligation; Myocardium; Nitric Oxide Synthase Type III; Pulsatile Flow; Stress, Mechanical; Veins

Secondary erythrocytosis results in increased shear stress in cyanotic congenital heart disease (CCHD), which may modify the balance between vasodilators and vasoconstrictors and affect systemic endothelial function. Because no data are available on systemic vasomotion, systemic endothelial function and nitric oxide (NO) availability were investigated in CCHD patients.. Responses to arterial endothelium-dependent (acetylcholine [Ach]) and -independent (sodium nitroprusside [SNP]) vasodilation, NO synthase blockade (NG-monomethyl-L-arginine [L-NMMA]), endothelin-1 (ET-1), and ET-1 receptor blockade by BQ-123 in 11 CCHD patients (O2 saturation <90%; mean+/-SD, 79+/-1%; mean+/-SD age, 39+/-2 years) were compared with those in 10 age-matched healthy referents by using forearm venous occlusion plethysmography. Resting forearm blood flow (FBF) was lower in CCHD patients than in referents (2.4+/-0.2 versus 3.5+/-0.4 mL.min(-1).100 mL(-1) of forearm volume [FAV], P<0.05). Although the response to SNP was similar in both groups (CCHD, 2.0+/-0.3 to 8.3+/-1.0; referents, 3.6+/-0.7 to 11.9+/-1.2 mL.min(-1).100 mL(-1) of FAV; P>0.1), the response to Ach was markedly reduced in CCHD (maximal increase in FBF, 2.8+/-0.8 versus 37.5+/-4.4 mL.min(-1).100 mL(-1) of FAV; P<0.0001). l-NMMA was less effective in CCHD (decrease in FBF, 25+/-6% versus 40+/-4%; P<0.05). ET-1 caused less vasoconstriction in the CCHD group (-25+/-9% versus -51+/-7%, P<0.05), but the response to BQ-123 was similar in both groups (32+/-9% versus 27+/-9%).. Systemic endothelial dysfunction is evident in CCHD patients as shown by strikingly reduced endothelial vasodilation to Ach. The response to exogenous ET-1 is reduced, possibly because of elevated endogenous ET-1 levels, but the effects of endogenous ET-1 on arterial tone are not enhanced, as indicated by the similar response to ET-1 blockade.

Topics: Acetylcholine; Adult; Antihypertensive Agents; Cyanosis; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Heart Defects, Congenital; Hemoglobins; Humans; Microcirculation; Nitroprusside; omega-N-Methylarginine; Oxygen; Peptides, Cyclic; Polycythemia; Vasoconstriction; Vasodilation; Vasodilator Agents

Topics: Adolescent; Adult; Blood Pressure; Cardiopulmonary Bypass; Child; Child, Preschool; Endothelin-1; Female; Heart Defects, Congenital; Hemofiltration; Humans; Hypertension, Pulmonary; Infant; Male

The endothelium-derived vasoconstrictor endothelin-1 is increased after cardiopulmonary bypass in children with congenital heart defects. This study determines whether antioxidant therapy with Salvia miltiorrhiza injection, an herb extract containing phenolic compounds, prevents the postoperative increase of endothelin-1. The relationship between endothelin-1 and the endothelium-derived prostacyclin (prostaglandin I2) and thromboxane A2 postoperatively is also investigated.. Twenty children with congenital heart defects and pulmonary hypertension were randomly assigned to group A (placebo control, n=10) or B (200 mg/kg Salvia miltiorrhiza intravenously after anesthesia induction and at the time of rewarming, respectively; n =10) before cardiac surgery. Central venous blood samples were taken before operation (T(0)), 10 (T(1)) and 30 minutes (T(2)) after starting cardiopulmonary bypass, 10 (T(3)) and 30 minutes (T(4)) after aortic declamping, and 30 minutes (T(5)) and 24 hours (T(6)) after termination of cardiopulmonary bypass. Plasma lipid peroxidation product malondialdehyde, myocardial specific creatine kinase-MB activity, thromboxane B2, and 6-keto-prostaglandin F(1 alpha) (stable metabolites of thromboxane A2 and prostaglandin I2) were measured.. Malondialdehyde increased significantly at T(1) in group A and remained significantly higher than in group B thereafter (P <.05). Malondialdehyde in group B did not significantly increase over time. At T(5), plasma creatine kinase-MB, thromboxane B2, and endothelin-1 in group B were lower than in group A (P <.05); malondialdehyde correlated significantly with creatine kinase-MB (r = 0.71, P =.0005). At T(6), endothelin-1 negatively correlated with the 6-keto-prostaglandin F(1 alpha)/thromboxane B2 ratio (r = -0.64, P =.0025).. Antioxidant therapy reduces myocardial damage and attenuates postoperative vasoactive mediator imbalance.

Topics: Adolescent; Antioxidants; Biological Assay; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Chemotherapy, Adjuvant; Child; Child, Preschool; Confidence Intervals; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Endothelin-1; Female; Heart Defects, Congenital; Humans; Infusions, Intravenous; Intraoperative Period; Male; Multivariate Analysis; Phytotherapy; Postoperative Complications; Probability; Prognosis; Salvia miltiorrhiza; Sensitivity and Specificity; Severity of Illness Index; Thromboxane B2; Treatment Outcome

A prospective randomized study was performed to test whether removal of endothelin-1, by ultrafiltration techniques, will reduce pulmonary hypertension after operations for congenital heart disease.. Twenty-four patients with pulmonary hypertension (systolic pulmonary/systemic arterial pressure ratio > 60%) undergoing cardiac operations were randomized into a control group (n = 12) having conventional ultrafiltration and an experimental group (n = 12) undergoing dilutional ultrafiltration during and modified ultrafiltration after cardiopulmonary bypass. Plasma endothelin-1, nitric oxide metabolites, and cyclic guanosine monophosphate were assayed before bypass, 10 minutes into bypass, after bypass, and 0, 3, 6, and 12 hours after the operation in both groups, as well as in the ultrafiltrates and after modified ultrafiltration in the experimental group. Both groups received alpha-blockers (chlorpromazine and/or prazosin) postoperatively using the same guidelines.. The ultrafiltrates contained significant amounts of endothelin-1 (1.81 +/- 0.86 pg/ml, dilutional, and 6.44 +/- 1.82 pg/ml, modified ultrafiltrate). Endothelin-1 and the pulmonary/systemic pressure ratio were significantly lower in experimental compared with control patients. Nitric oxide metabolites and cyclic guanosine monophosphate increased similarly in both groups for 12 hours after the operation (p = not significant). Three of 12 control patients (25%) but no experimental patients had pulmonary hypertensive crises (p = 0.07). The experimental patients required significantly less ventilatory support (67 +/- 47 hours vs 178 +/- 139 hours for control patients, p = 0.048).. Dilutional and modified ultrafiltration reduce endothelin-1 and the pulmonary/systemic pressure ratio postoperatively and may become an important adjunct for preventing pulmonary hypertension after operations for congenital heart disease in high-risk patients.

Topics: Cardiopulmonary Bypass; Cyclic GMP; Endothelin-1; Female; Heart Defects, Congenital; Hemofiltration; Humans; Hypertension, Pulmonary; Infant; Male; Nitric Oxide; Postoperative Complications; Prospective Studies

We have reported that the plasma endothelin-1 (ET-1) level is significantly increased by exercise in healthy athletes and that it is elevated in the circulation of the non-working leg but not the working leg, suggesting that ET-1 plays an important role in redistribution of blood during exercise. This study was designed to compare alterations of neurohumoral substances by exercise in normal subjects and patients with heart disease. Study patients comprised three groups: eight patients with congestive heart failure (CHF) due to Ebstein's anomaly or single-ventricle heart after Fontan operation; six patients with complete transposition of the great arteries (TGA) after an anatomic surgical correction who may be candidates for ischemic heart disease; and five age-matched normal subjects. All patients were in New York Heart Association functional class I. All subjects performed symptom-limited treadmill exercise. It is suggested that patients with CHF or TGA have a manifest or latent exercise intolerance, respectively. In failed to increase plasma ET-1 level, although it caused a greater increase in norepinephrine, angiotensin II, and arginine vasopressin than in the controls. Exercise also caused a delay in the increased response of plasma ET-1 levels in patients with TGA after an anatomic surgical repair. On the other hand, plasma brain natriuretic peptide (BNP) level was augmented by exercise in patients with CHF and patients with TGA but not in the controls. The present results suggest that an increase in ET-1 production during exercise is absent in patients with heart disease. The mechanisms of inhibition of ET-1 production during exercise in patients with heart disease remain to be elucidated. However, the present study suggests that ET-1 plays an important role in redistribution of blood during exercise, and proposes the possibility that failure of an increase in ET-1 production results in exercise intolerance in patients with heart disease.

Topics: Child; Endothelin-1; Exercise; Heart Defects, Congenital; Heart Failure; Heart Rate; Humans; Neurotransmitter Agents; Pulmonary Gas Exchange; Transposition of Great Vessels

Topics: Biomarkers; Cardiac Catheterization; Child, Preschool; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; Nitric Oxide; Radioimmunoassay; Sensitivity and Specificity

Topics: Child; Endothelin-1; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Nitric Oxide; rho-Associated Kinases

This study aims to explore the changes in endothelin-1 (ET-1), plasma neuropeptide Y, and calcitonin gene-related peptide (CGRP) in child patients before and after operation. A total of 80 child patients with congenital heart disease (CHD) complicated with pulmonary hypertension (PH) were enrolled and divided into control group (n = 40, conservative treatment for various reasons) and observation group (n = 40, active preoperative preparation and timely operative intervention) according to different treatments. There were positive correlations between systolic pulmonary arterial pressure (sPAP) and ET-1, plasma neuropeptide Y, while negative correlation between sPAP and CGRP. In conclusion, our data demonstrate that the levels of ET-1, plasma neuropeptide Y, and CGRP in PH-CHD were significantly changed after interventions, which provides new leads as alternative biomarkers to assess the efficacy of treatments against PH-CHD.

Topics: Calcitonin Gene-Related Peptide; Child; Child, Preschool; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Male; Neuropeptide Y; Postoperative Period; Preoperative Period

Our goal was to evaluate whether endothlin-1 (ET-1) plays an important role in the Fontan circulation.. Thirteen patients with single-ventricle physiology (Glenn circulation, n = 7; Fontan circulation, n = 6) were evaluated using lung histopathological and immunohistochemical studies and then compared with the normal autopsied controls without congenital heart disease (n = 13). We evaluated the medial thickness of the small pulmonary arteries. For 10 of these patients, quantitative real-time polymerase chain reaction analyses of ET-1, endothelin receptors Type A and Type B, endothelin-converting enzyme-1 and endothelial nitric oxide synthase were performed.. The medial thickness of the small pulmonary arteries in patients with single-ventricle physiology was greater than that of those in the control group (P = 0.0341). Severe medial hypertrophy of the pulmonary arteries was observed in patients who had poor outcomes. Immunohistochemical studies revealed that the marked expression of ET-1 was observed in the endothelium and media of their pulmonary arteries. In these patients, the messenger RNA expression of ET-1 was also increased. Two patients showed high levels of expression of ETAR and ETBR, although these 2 cases maintain good Fontan circulation.. Medial hypertrophy and the overexpression of ET-1 in the pulmonary arteries were observed in some patients in whom the Fontan circulation failed. Our data suggest that ET-1 may play an important role in maintaining the Fontan circulation.

Topics: Adolescent; Adult; Child; Child, Preschool; Endothelin-1; Female; Fontan Procedure; Heart Defects, Congenital; Humans; Infant; Lung; Male; Nitric Oxide Synthase Type III; Pulmonary Artery; Pulmonary Circulation; Young Adult

Breathlessness is the most common symptom in people with pulmonary arterial hypertension and congenital heart disease (CHD-APAH), previously thought to be caused by worsening PAH, but perhaps also by inflammation and abnormalities of lung function. We studied lung function and airway inflammation in patients with CHD-APAH and compared the results with controls.. Raised biomarkers for inflammation were found in CHD-APAH. Significant abnormalities in airway physiology may contribute to the dyspnea but are not driven by inflammation as assessed by circulating and sputum cytokines. A relationship between increased serum endothelin-1 and airway dysfunction may relate to its bronchoconstrictive properties.

Topics: Adult; Biomarkers; Bronchoconstriction; Case-Control Studies; Databases, Factual; Dyspnea; Endothelin-1; Exercise Tolerance; Female; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Inflammation Mediators; Lung; Male; Middle Aged; Plethysmography, Whole Body; Pneumonia; Risk Factors; Spirometry; Sputum; Up-Regulation; Walk Test

Aim of this study was to investigate the potential effects of sildenafil on the function of endothelial cells from patients with congenital heart disease with pulmonary hypertension (CHDPH). Patients who are diagnosed as CHD with PH (n=30) or without PH (n=30), and 30 healthy persons (control) were enrolled in this study. The 30 CHDPH cases were separated into two groups, one was given aspirin while the other received aspirin and sildenafil. An ELISA assay was used to detect the biological indexes for endothelial cells. Furthermore, 24 male New Zealand white rabbits were used to construct the CHDPH model. The signal pathway-related protein expression was analyzed using RT-PCR and western blotting. Compared to that in healthy people, levels for flowmediated dilatation (FDM), NO, and adiponectin (APN) were significantly decreased while endothelin (ET-1) was significantly increased in CHD patients, while their levels were drastically changed in CHDPH patients (P<0.01). Besides, no significant differences for expression levels including FDM, APN, NO, and ET-1 was observed in CHDPH patients receiving aspirin. But the levels for FDM, APN, NO, and ET-1 were significantly changed in CHDPH patients after treatment with sildenafil for 3 months (P<0.01). The mRNA and protein levels for JNK1/2, MAPK, and NF-κB were significantly increased in CHDPH rabbits compared to the control (P<0.01), but their levels were significantly suppressed by the sildenafil application compared to the CHDPH group (P<0.01). Taken together, our study suggested that sildenafil may play a protective role on endothelial function via suppressing the JNK and NF-κB signal pathways in CHDPH patients.

Topics: Adiponectin; Animals; Aspirin; Endothelial Cells; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Healthy Volunteers; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; NF-kappa B; Nitric Oxide; Platelet Aggregation Inhibitors; Rabbits; Signal Transduction; Sildenafil Citrate; Vasodilation; Vasodilator Agents

In Taiwan, the average prevalence of congenital heart disease (CHD) is 13.08/1000 live births. Most children with CHD die before the age of 5 years; therefore, identifying treatment methods to extend the life of CHD patients is an important issue in clinical practice. The objective of this study is to evaluate the roles of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS), endothelin-1 (ET-1), and CD34 in CHD autopsy cases in comparison with autopsy cases without CHD. The study included 19 autopsy cases, which were divided into the following four groups: acyanotic CHD (n = 11), cyanotic CHD (n = 3), CHD associated with chromosomal abnormalities (n = 3), and complex CHD (n = 2). Heart specimens obtained from 10 autopsy cases without CHD were included as controls. Our results indicated that high percentages of HIF-1α (100%), VEGF (89.5%), iNOS (78.9%), and ET-1 (84.2%) expressions were observed in CHD autopsy cases and this was found to be significant. HIF-1α induced by hypoxia could play a potential role in relating downstream gene expressions in CHD patients. Upregulation of VEGF by HIF-1α could play an important role in triggering angiogenesis to protect myocardial cell survival in a hypoxic microenvironment. Therefore, HIF-1α could be a significant prognosis marker in CHD and be a prospective candidate in the development of target therapy in cardiovascular diseases.

Topics: Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Infant; Infant, Newborn; Male; Microvessels; Neovascularization, Physiologic; Nitric Oxide Synthase Type II; Vascular Endothelial Growth Factor A

Cyanotic congenital heart disease is associated with functional limitation and vascular events. The nature and extent of endothelial dysfunction in cyanotic adults is poorly understood. We sought to characterise endothelial function in this setting.. A total of fourteen adults with cyanotic congenital heart disease (40±3 years) together with age- and sex-matched healthy controls underwent assessment of nitric oxide-dependent vascular responses, including flow-mediated dilatation of the brachial artery and dynamic vessel analysis of the retina in response to flickering light. Plasma levels of the endothelium-derived vasoconstrictor endothelin-1 and the nitric oxide antagonist, asymmetric dimethylarginine, were measured. Circulating endothelial progenitor cells were assessed by flow cytometry.. Flow-mediated dilatation was significantly lower in cyanosed adults than controls (4.0±0.8 versus 7.2±1.0%, p=0.019, n=11 per group). Retinal arterial and venous dilatory responses were also impaired (2.9±0.8 versus 5.0±0.6%, p=0.05 and 3.4±0.3 versus 5.2±0.7%, p=0.04, n=13). Serum levels of endothelin-1 and asymmetric dimethylarginine were higher in cyanosed adults (3.0±0.6 versus 1.1±0.1 pg/ml, p=0.004 and 0.68±0.05 versus 0.52±0.02 μmol/L, p=0.03, n=11). Endothelial progenitor cells (CD34+CD45dimCD133+KDR+) were reduced in those with chronic cyanosis (17±4 versus 40±6 per million white blood cells, p=0.005, n=11).. Endothelial function is impaired in the systemic arteries and retinal vessels in adults with cyanotic congenital heart disease, suggesting a widespread endotheliopathy. Diminished numbers of endothelial progenitor cells might potentially contribute to these observations.

Topics: Adult; Arginine; Brachial Artery; Case-Control Studies; Cell Count; Cyanosis; Endothelial Cells; Endothelial Progenitor Cells; Endothelin-1; Female; Flow Cytometry; Heart Defects, Congenital; Humans; Male; Middle Aged; Nitric Oxide; Retinal Artery; Retinal Vein; Risk Factors

This study aims to estimate plasma levels of acylated ghrelin in children with pulmonary hypertension (PH) associated with congenital heart disease (CHD) and to correlate the levels of acylated ghrelin with endothelin-1 (ET-1), nitric oxide (NO), and clinical hemodynamic parameters. We investigated the plasma concentration of acylated ghrelin, ET-1, NO, and the hemodynamic parameters in 20 children with CHD, 20 children with PH-CHD, and 20 normal children. Plasma-acylated ghrelin and NO levels were significantly higher in CHD group than in control subjects (P < 0.001). Moreover, plasma-acylated ghrelin, ET-1, and NO levels were significantly elevated in PH-CHD group compared with the CHD group (P < 0.05). In PH-CHD children, plasma-acylated ghrelin levels correlated positively with pulmonary artery systolic pressure (PASP; r = 0.740, P < 0.001), pulmonary artery diastolic pressure (PADP; r = 0.613, P = 0.004), right ventricular systolic pressure (RVSP; r = 0.642, P = 0.002), mean pulmonary arterial hypertension (mPAP; r = 0.685, P = 0.001), right ventricle diameter (RVD; r = 0.473, P = 0.035), pulmonary artery trunk diameter (PAD; r = 0.613, P = 0.004), NO (r = 0.463, P = 0.04), and ET-1 (r = 0.524, P = 0.018). Plasma-acylated ghrelin levels were elevated both in CHD and in PH-CHD. Increased acylated ghrelin levels correlated positively with ET-1, NO, PASP, PADP, RVSP, mPAP, RVD, and PAD. Acylated ghrelin may be a new biomarker of PH-CHD.

Topics: Biomarkers; Cardiac Catheterization; Case-Control Studies; Child, Preschool; Echocardiography; Endothelin-1; Female; Ghrelin; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Infant; Male; Nitric Oxide; Pulmonary Artery

To investigate changes in the level of circulating endothelial cells (CECs) and endothelin-1 (ET-1) in peripheral venous blood of the patients with congenital heart disease (CHD) complicated with pulmonary artery hypertension (PAH), and research on their effects in the onset and progress of CHD complicated with PAH.. A case-control study including 30 cases of healthy controls, 15 cases of left-to-right shunt CHD without PAH, 26 cases of CHD complicated with mild PAH, and 17 cases of CHD complicated with moderate-severe PAH was performed. We used flow cytometry to measure the percentage of CECs accounting for nucleated cells in whole blood, and enzyme linked immunosorbent assay (ELISA) to measure the level of ET-1 in serum. The differences of above-mentioned biomarkers between different groups were compared.. (1) The level of CECs and ET-1in the group of moderate-severe PAH was significantly higher than those in the group of mild PAH and the group of CHD without PAH. Significantly difference was also observed between the level of CECs and ET-1 in the group of mild PAH and those in the group of CHD without PAH and the control group. Meanwhile, the level of CECs and ET-1 in the group of large shunt was significantly higher than those in the group few shunt and few-medium shunt. (2) Strong positive correlations were observed between pulmonary artery systolic pressure and percentage of CECs as well as ET-1 production. Mean pulmonary artery pressure also positively correlated with percentage of CECs as well as ET-1 production. (3) Arterial partial pressure of oxygen as well as arterial oxygen saturation negatively correlated with the level of CECs, whereas the volume of left-to-right shunt positively correlated with the level of ET-1. (4) The level of CECs and ET-1 were positively correlated as well in CHD patients.. CHD complicated with PAH is associated with increased CEC counts and ET-1 production. This study suggests that CECs and ET-1 could be used as clinical biomarkers to define medical strategies for control of PAH.

Topics: Adolescent; Adult; Aged; Arterial Pressure; Biomarkers; Case-Control Studies; Cell Count; Child; Child, Preschool; Endothelial Cells; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Linear Models; Male; Middle Aged; Oxygen; Partial Pressure; Pulmonary Artery; Pulmonary Circulation; Severity of Illness Index; Up-Regulation; Young Adult

In mammals, seven proprotein convertases (PCs) cleave secretory proteins after basic residues, and four of them are called furin-like PCs: furin, PC5, PACE4, and PC7. In vitro, they share many substrates. However, furin is essential during development since deficient embryos die at embryonic day 11 and exhibit multiple developmental defects, particularly defects related to the function of endothelial cells. To define the role of furin in endothelial cells, an endothelial cell-specific knockout (ecKO) of the Furin gene was generated. Newborns die shortly after birth, indicating that furin is essential in these cells. Magnetic resonance imaging revealed that ecKO embryos exhibit ventricular septal defects (VSD) and/or valve malformations. In addition, primary cultures of wild-type and ecKO lung endothelial cells revealed that ecKO cells are unable to grow. Growth was efficiently rescued by extracellular soluble furin. Analysis of the processing of precursors of endothelin-1 (ET-1), adrenomedullin (Adm), transforming growth factor β1 (TGF-β1), and bone morphogenetic protein 4 (BMP4) confirmed that ET-1, Adm, and TGF-β1 are in vivo substrates of endothelial furin. Mature ET-1 and BMP4 forms were reduced by ~90% in ecKO purified endothelial cells from lungs.

Topics: Adrenomedullin; Animals; Animals, Newborn; Bone Morphogenetic Protein 4; Cell Proliferation; Cells, Cultured; Embryo, Mammalian; Endothelial Cells; Endothelin-1; Female; Furin; Gene Knockout Techniques; Heart Defects, Congenital; Humans; Lung; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Transforming Growth Factor beta1

We focused on neurohumoral activity and its clinical correlates early and late after fenestrated, lateral intra-atrial total cavopulmonary connection (TCPC). Between 2007 and 2010, we prospectively studied 28 early and 48 late postoperative TCPC patients. Plasma concentrations of vasopressin, endothelin-1, proBNP, proANP were determined. We reviewed clinical data to determine relationship between neurohumoral activation and clinical status after TCPC. There was a significant influence of preoperative ventricular end-diastolic pressure (VEDP) (P=0.008) and vasopressin concentration (P=0.02) on the appearance of prolonged pleural effusions. A significant correlation between a combined predictor (a product of preoperative vasopressin concentration and VEDP) and time of effusions (r=0.59, P=0.006) was found. The mean respiratory equivalent of carbon dioxide at peak exercise (VE/VCO(2peak)) was significantly lower in patients operated before the second year of life compared to patients operated after two years of age (27.5±1.39 vs. 48.6±3.86; P=0.039). There was a significant correlation of endothelin-1 (r=0.84; P=0.008) and proBNP (r=0.88; P=0.02) concentrations with VE/VCO(2peak). The prolonged postoperative pleural effusions can be predicted based on the product of preoperative vasopressin concentration and VEDP. Exercise performance is related to the age at TCPC. Endothelin-1 and proBNP can be useful for identification of high-risk Fontan patients.

Topics: Analysis of Variance; Atrial Natriuretic Factor; Biomarkers; Child, Preschool; Endothelin-1; Exercise Tolerance; Female; Fontan Procedure; Heart Defects, Congenital; Humans; Infant; Length of Stay; Logistic Models; Male; Natriuretic Peptide, Brain; Pleural Effusion; Poland; Prospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Vasopressins; Ventricular Pressure

It is unclear why some patients, who undergo complete repair or palliative surgery for congenital heart disease (CHD), still develop irreversible pulmonary artery hypertension (PAH). There is no consensus to preoperationally assess the reversible and irreversible pulmonary vasculopathy seen in PAH.. The peri-operative pulmonary hemodynamic data of 16 CHD patients (reversible PAH, n = 6; irreversible PAH, n = 10) were analyzed. The lung biopsies were also performed during surgery for defining histopathological characteristics as well as immunohistochemical expression of endothelin-1 (ET-1), endothelin-1 receptors (ETR), and its downstream signaling markers in the small pulmonary arteries and arterioles. Neointimal formation and neoangiogenesis was characterized by increased intimal layer immunoreactivity for α-SMA, Factor VIII, CD34, and VEGF. Neointimal formation was found in 90% of patients and neoangiogenesis was found in 80% of patients with irreversible PAH. Neither was present in the reversible PAH group and the control group. Expression of ET-1 and ETR in the neointimal layer of the pulmonary arterioles was upregulated in irreversible PAH, and immunoreactivity of phospho-Akt, phospho-ERK1/2, and phospho-mTOR was also increased in irreversible PAH.. Increased expression of ET-1, ETR, and activation of signaling pathways were observed in the pulmonary arteries and arterioles of irreversible PAH patients associated with CHD. Activation of these pathways might in turn lead to neointimal formation and neoangiogenesis and thus might contribute to irreversible pulmonary vascular abnormalities.

Topics: Actins; Adolescent; Adult; Antigens, CD34; Biopsy; Cell Proliferation; China; Endothelin-1; Factor VIII; Familial Primary Pulmonary Hypertension; Female; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Immunohistochemistry; Male; Middle Aged; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neovascularization, Pathologic; Phosphorylation; Proto-Oncogene Proteins c-akt; Pulmonary Artery; Receptor, Endothelin A; Receptor, Endothelin B; Retrospective Studies; Signal Transduction; TOR Serine-Threonine Kinases; Tunica Intima; Up-Regulation; Vascular Endothelial Growth Factor A; Young Adult

Patients with 1-ventricle (1V) physiology may be at risk for peripheral arterial dysfunction at a young age. To determine whether infants and young children with 1V physiology and hypoxemia have peripheral arterial dysfunction before undergoing the Fontan operation, we measured (1) flow-mediated vasodilation (FMD) in the brachial artery, (2) serum levels of vasoactive mediators endothelin-1 (ET-1) and metabolites of nitric oxide, and (3) arterial stiffness with pulse-wave velocity (PWV) in the aorta. Eighteen patients with 1V physiology before the Fontan procedure and hypoxemia and 19 patients with normoxemia and 2-ventricle (2V) physiology were studied. Measurements were collected during cardiac catheterization. FMD in the brachial artery was the diameter gain after 4.5 minutes of forearm occlusion measured with high-resolution ultrasound and edge-detection software. Nitric oxide and ET-1 levels were measured in venous blood. PWV between the left carotid and femoral arteries was measured using pulse Doppler ultrasound. FMD was lower (2.4 +/- 3.7% vs 11.3 +/- 6%, p <0.0005) and ET-1 levels were higher (35.5 +/- 11.3% vs 24.1 +/- 9.7%, p = 0.003) in subjects with 1V physiology versus those with 2V physiology, respectively. There were no differences in nitric oxide levels or PWV. In conclusion, infants and young children with 1V physiology and hypoxemia have blunted FMD and higher ET-1 levels before undergoing the Fontan operation compared with normoxemic subjects with 2V physiology. A further understanding of pathophysiologic mechanisms underlying peripheral arterial dysfunction, including the roles of hypoxemia, low cardiac index, and ET-1, may lead to targeted therapies and improve the long-term survival of patients with 1V physiology.

Topics: Blood Flow Velocity; Brachial Artery; Child, Preschool; Endothelin-1; Female; Heart Defects, Congenital; Heart Ventricles; Humans; Hypoxia; Infant; Male

Topics: Animals; Blood Flow Velocity; Chick Embryo; Cilia; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Heart; Heart Defects, Congenital; Hemodynamics; Image Processing, Computer-Assisted; Imaging, Three-Dimensional; Mechanoreceptors; Mice; Vascular Resistance

The present study aimed to elucidate the pathophysiological roles of endothelin (ET)-1 in patients with pulmonary hypertension and pulmonary vascular obstructive disease secondary to congenital heart disease and compare the plasma levels of ET-1 between children with and without Down syndrome.. Subjects comprised 32 children with congenital heart disease aged 0.5-14 months. Patients were classified into two groups: those with Down syndrome (Group D, n = 16); and those with nonDown syndrome (Group ND, n = 16). Heparinized blood samples were taken from a radial arterial line and plasma ET-1 levels were measured preoperatively, during cardiopulmonary bypass (CPB), a few minutes after termination of CPB, and 2, 6 and 24 h after discontinuation of CPB.. Plasma ET-1 levels were significantly higher in Group D than in Group ND at all times except for a few minutes after termination of CPB. In both groups, peak ET-1 values were obtained at 6 h after CPB. At 24 h after CPB, ET-1 concentrations returned to baseline levels before CPB in Group ND, but not in Group D. A correlation was identified between preoperative pulmonary to systemic pressure ratio and ET-1 concentration before and after CPB in both groups.. Pre- and postoperative plasma ET-1 concentrations reflect pre- and postoperative pulmonary artery conditions in both groups. Specific features in Down syndrome could be associated with ET injury and might cause persistent increases in ET concentration and prolong artificial respiration.

Topics: Cardiac Catheterization; Cardiopulmonary Bypass; Down Syndrome; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Linear Models; Lung Diseases, Obstructive; Male; Monitoring, Intraoperative; Time Factors

Topics: Adrenomedullin; Child; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension; Hypertension, Pulmonary; Male; Nitric Oxide

Hemodynamics play an important role in cardiovascular development, and changes in blood flow can cause congenital heart malformations. The endothelium and endocardium are subjected to mechanical forces, of which fluid shear stress is correlated to blood flow velocity. The shear stress responsive genes lung Krüppel-like factor (KLF2), endothelin-1 (ET-1), and endothelial nitric oxide synthase (NOS-3) display specific expression patterns in vivo during chicken cardiovascular development. Nonoverlapping patterns of these genes were demonstrated in the endocardium at structural lumen constrictions that are subjected to high blood flow velocities. Previously, we described in chicken embryos a dynamic flow model (the venous clip) in which the venous return to the heart is altered and cardiac blood flow patterns are disturbed, causing the formation of congenital cardiac malformations. In the present study we test the hypothesis that disturbed blood flow can induce altered gene expression. In situ hybridizations indeed show a change in gene expression after venous clip. The level of expression of ET-1 in the heart is locally decreased, whereas KLF2 and NOS-3 are both upregulated. We conclude that venous obstruction results in altered expression patterns of KLF2, ET-1, and NOS-3, suggestive for increased cardiac shear stress.

Topics: Animals; Blood Circulation; Chick Embryo; DNA-Binding Proteins; Endothelin-1; Gene Expression Regulation; Heart Defects, Congenital; In Situ Hybridization; Kruppel-Like Transcription Factors; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Repressor Proteins; RNA, Messenger; Stress, Mechanical; Transcription Factors

To study the expression and pathological implication of transforming growth factor-1 (TGF-1) and endothelin-1 (ET-1) in intraacinar pulmonary arterioles of children with congenital heart disease and pulmonary hypertension (HP).. Forty-one children with left-to-right shunt congenital heart disease were studied including 25 cases of HP (group A), 16 cases without HP (group B) and 10 children without congenital heart disease as the contols (group C). Expression of TGF-beta1 mRNA and ET-1 mRNA in intraacinar pulmonary arteriolar (IAPA) was studied using in-situ hybridization and image pattern analysis of their absorption values (A value). Changes of the intraacinar arterioles and lung tissue were studied by elastic fiber staining and electronic microscopy respectively.. (1) There was a significant difference in the amount of intraacinar pulmonary arterioles (partial-muscular and muscular) counted in either group A or B in comparing with that of group C (F values 149.96 and 142.01 respectively, P < 0.01); (2) Electronic microscopy demonstrated endothelial proliferation of the small arteries, thickening of arteriolar wall, increased density of collagen fibers at adventitia and increased thickness of the capillary basal membrane; (3) The A value of TGF-beta1 mRNA expressed in the pulmonary arterioles of groups A and B by in-situ hybridization were 0.1988 +/- 0.0498 and 0.1098 +/- 0.0428 respectively, however, the expression was weak in group C (A value: 0.0578 +/- 0.0096). There were all significant between each two groups (F = 45.95, P < 0.01). The expression of ET-1 mRNA was markedly increased as well in the endothelial cells of pulmonary arterioles in both groups A and B, with A values of 0.1692 +/- 0.0205 and 0.1004 +/- 0.0140 respectively, whereas the expression was weak in group C (A value of 0.0746 +/- 0.0119). There were all significant between each two groups (F = 139.996, P < 0.01).. The number of intraacinar pulmonary partial-muscular and muscular arterioles in patients with left-to-right shunt congenital heart defect is drastically increased, along with marked restructuring of the pulmonary vasculatures. In addition, there seems a correlation present between the overexpression of TGF-beta1 mRNA and ET-1 mRNA in intraacinar pulmonary arterioles and the occurrence of pulmonary hypertension in patients with congenital heart disease.

Topics: Child; Child, Preschool; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Lung; Male; Pulmonary Artery; RNA, Messenger; Transforming Growth Factor beta1

In order to characterize the changes of five neurohormones in pediatric patients with varying degrees of congestive heart failure (CHF) secondary to congenital heart disease (CHD), we measured plasma neurohormone levels by using radioimmunoassay or high-performance liquid chromatography in 81 subjects including 13 normal children and 68 pediatric patients with CHD. Patients with CHF (n=27) had elevated levels of big endothelin-1 (big ET-1) (29.5+/-1.6 vs. 18.1+/-2.1 pg/ml, p<0.001), endothelin-1 (ET-1) (17.9+/-1.7 vs. 7.8+/-1.7 pg/ml, p<0.001) and norepinephrine (505.6+/-65.6 vs. 219.6+/-23.3 pg/ml, p<0.01) as compared with healthy control subjects (n=13). Plasma norepinephrine levels (505.6+/-65.6 vs. 230.0+/-8.0 pg/ml, p<0.001) and atrial natriuretic peptide (35.5+/-4.2 vs. 7.6+/-0.6 pg/ml, p<0.001) in the 27 patients with CHF were significantly higher than in the 41 patients without CHF. There was also a highly significant stepwise increase in big ET-1, atrial natriuretic peptide and norepinephrine according to the severity of heart failure. Our results suggest that increased circulating neurohormonal activity in CHD relates to the presence and clinical severity of heart failure in children. Plasma levels of big ET-1 and ET-1 were not only significant markers of CHF but also correlated well with the severity of CHF in CHD with left-to-right shunt.

Topics: Adolescent; Atrial Natriuretic Factor; Biomarkers; Child; Child, Preschool; Chromatography, High Pressure Liquid; Endothelin-1; Female; Heart Defects, Congenital; Heart Failure; Humans; Infant; Male; Norepinephrine; Prospective Studies; Radioimmunoassay; Severity of Illness Index

We retrospectively analyzed lung biopsy specimens from patients who underwent the Fontan procedure to identify predictive markers of outcome.. We studied the intra-acinar pulmonary arteries present in lung biopsy specimens from 17 patients undergoing the Fontan procedure. We evaluated both their morphology and their expression of endothelial nitric oxide synthase and endothelin 1. We compared these data with those of 6 patients who died of no pulmonary cause (control group).. Eight patients had a good surgical outcome (group 1). Their distal arteries were thin and weakly expressed endothelin 1 and endothelial nitric oxide synthase. The procedure failed in 9 patients (group 2). Their distal arteries displayed muscle extension with an increased wall thickness (P <.01 vs group 1). Their endothelin 1 expression remained low (not significant vs group 1). By contrast, endothelial nitric oxide synthase was markedly overexpressed (P <.001 vs group 1).. Distal pulmonary arteries of patients in whom the Fontan procedure failed exhibited a markedly increased wall thickness and a clear endothelial nitric oxide synthase overexpression. In addition to giving clues to the pathogenesis of the procedure's failure, our study might help to define reliable predictive markers of its outcome.

Topics: Adolescent; Adult; Child; Child, Preschool; Endothelin-1; Female; Fontan Procedure; Heart Defects, Congenital; Humans; Immunohistochemistry; Lung; Male; Nitric Oxide Synthase; Prognosis; Pulmonary Artery; Retrospective Studies

Endothelin-1 (ET-1) has been implicated in the pathophysiology of pulmonary hypertension. In 1-month-old lambs with increased pulmonary blood flow, we have demonstrated early alterations in the ET-1 cascade. The objective of this study was to investigate the role of potential later alterations of the ET cascade in the pathophysiology of pulmonary hypertension secondary to increased pulmonary blood flow.. Eighteen fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt) and were studied 8 weeks after spontaneous delivery. Compared with age-matched control lambs, lung tissue ET-1 levels were increased in shunt lambs (317.2+/-113.8 versus 209.8+/-61.8 pg/g, P<0.05). In shunt lambs (n=9), exogenous ET-1 induced potent pulmonary vasoconstriction, which was blocked by the ETA receptor antagonist PD 156707 (n=3). This pulmonary vasoconstriction was mimicked by exogenous Ala1,3,11,15 ET-1 (4 Ala ET-1), the ETB receptor agonist, and was blocked by the ETB receptor antagonist BQ 788 (n=3). However, in control lambs (n=7), ET-1 and 4 Ala ET-1 did not change pulmonary vascular tone. In contrast to 4-week-old shunt lambs, immunohistochemistry revealed the emergence of ETB receptors on smooth muscle cells in the vasculature of 8-week-old shunt lambs.. Over time, increased pulmonary blood flow and/or pressure results in the emergence of ETB-mediated vasoconstriction, which coincides with the emergence of ETB receptors on smooth muscle cells. These data suggest an important role for ETB receptors in the pathophysiology of pulmonary hypertension in this animal model of increased pulmonary blood flow.

Topics: Animals; Dioxoles; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Heart Defects, Congenital; Hemodynamics; Hypertension, Pulmonary; Lung; Muscle, Smooth, Vascular; Oligopeptides; Piperidines; Pulmonary Circulation; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Sheep; Vasoconstriction

Endothelin-1 concentrations are increased in patients with increased mean pulmonary arterial pressure, pulmonary blood flow, and pulmonary vascular resistance. However, endothelin-1 concentrations have not been well characterized in patients with congenital heart disease and normal pulmonary vascular resistance. In particular, it is unclear whether pressure or flow is the key regulator of endothelin- 1 in this setting. We tested the hypothesis that pulmonary blood pressure and not flow is associated with net endothelin-1 production in patients with congenital heart disease and normal pulmonary vascular resistance.. With a commercially available immunoassay, we measured endothelin-1 concentrations in pulmonary arterial and pulmonary venous plasma of 56 consecutive patients with congenital heart disease and pulmonary vascular resistance less than 2 U. m(2) undergoing cardiac catheterization. We used multiple linear regression to analyze the effect of demographic and hemodynamic variables on pulmonary arterial and venous endothelin-1 concentrations and on the change of endothelin-1 concentration over the pulmonary vascular bed.. Multiple linear regression revealed that of all the hemodynamic variables tested, mean pulmonary arterial pressure had the greatest effect on increasing the change of endothelin-1 concentration over the pulmonary vascular bed (P <.0001). Pulmonary blood flow did not have any effect on endothelin-1 concentrations or on the change of endothelin-1 concentration over the pulmonary vascular bed.. This study shows that pulmonary blood pressure and not flow is associated with net endothelin-1 production in patients with congenital heart disease and normal pulmonary vascular resistance.

Topics: Blood Pressure; Body Surface Area; Child; Endothelin-1; Female; Heart Defects, Congenital; Humans; Lung; Male; Pulmonary Circulation; Regression Analysis; Vascular Resistance

Postoperative pulmonary hypertension in children after surgical intervention for congenital heart disease has been attributed to failure of the pulmonary endothelium to provide adequate vasodilation. Although we have shown that the impaired vasodilatory component attributable to the l-arginine-nitric oxide pathway is almost completely reversible, a nonrestorable component persists, implying an additional vasoconstrictive mechanism in postoperative pulmonary endothelial dysfunction. In this study of children after surgical intervention for congenital heart disease, we measured endothelin-1 levels and used BQ123, a selective endothelin-A receptor antagonist, together with inhaled nitric oxide to discriminate dysfunctional pulmonary endothelial vasodilation from endothelin-mediated pulmonary vasoconstriction.. All children were examined early after surgical intervention in the intensive care unit. Pulmonary vascular resistance (with respiratory mass spectrometry), as well as arterial and venous endothelin-1 levels (measured by means of a quantitative enzyme-linked immunosorbent assay), were determined in 7 children (age range, 3.3-13.7 months; median age, 6.3 months) with intracardiac shunting defects at baseline and during ventilation with a fraction of inspired oxygen of 0.65, with additional BQ123 (0.1 mg/kg infused over 20 minutes), and with inhaled nitric oxide (20 ppm).. Pulmonary vascular resistance decreased from 7.7 +/- 3.4 at baseline to 6.1 +/- 2.8 Woods units. m(-2) (P =.022) at a fraction of inspired oxygen of 0.65 and to 4.7 +/- 2.7 Woods units. m(-2) (P =.013) during BQ123 infusion. Inhaled nitric oxide had no further effect on pulmonary vascular resistance. Left atrial endothelin-1 levels (1.35-5.12 pg/mL; mean, 2.4 pg/mL) correlated significantly with the decrease in pulmonary vascular resistance in response to BQ123 infusion (r(2) = 0.89, P =.003).. Postoperative elevation of pulmonary vascular resistance in children after surgical intervention for congenital heart disease is responsive to endothelin-A blockade with BQ123. Increased levels of endothelin-1 predict the response to this therapy, which might become an important addition to the clinical armamentarium in postoperative pulmonary hypertensive disease.

Topics: Adolescent; Antihypertensive Agents; Cardiopulmonary Bypass; Child; Child Welfare; Child, Preschool; Endothelin Receptor Antagonists; Endothelin-1; Heart Defects, Congenital; Hemodynamics; Humans; Infant; Infant Welfare; Infusions, Intravenous; London; Lung; Nitric Oxide; Oxygen; Peptides, Cyclic; Predictive Value of Tests; Pulmonary Veins; Pulmonary Wedge Pressure; Receptor, Endothelin A; Receptors, Endothelin; Treatment Outcome; Vascular Resistance; Vasodilation

Genetic disruption of endothelin (ET) 1, endothelin-converting enzyme (ECE) 1, and endothelin receptor A (ET(A)) in "knockout" or mutant mouse models result in defects in branchial arch derived craniofacial tissues and in cardiac outflow and great vessel structures. Interestingly, certain types of human congenital cardiovascular malformations such as Catch 22 syndrome and type B interruption of the aortic arch strongly resemble defects seen in knockout animal models. To better address the exact involvement of the ET system in heart formation we explored the spatiotemporal pattern of expression of the components of the ET system during critical phases of cardiogenesis in the human embryo (3-6 weeks of development; Carnegie stages 10-17) by in situ hybridization. We detected high ET-1 mRNA expression in endocardial cells lining the heart outflow tract in the region where the future aortic valves will form. No hybridization signal corresponding to pre-pro-ET-3 was observed in the heart. At the same location, the underlying myocytes express ET(A) mRNA. Whereas a functional role of ET in the valve formation can be proposed because of the simultaneous presence of all the components of the endothelin system (ET-1/ECE-1/ET(A)), this seems not to be the case for the formation of the ventricular septum where endocardial cells do not express ET-1, and only a weak ET(A) hybridization signal was detected in the surrounding myocardium. An abnormal hemodynamism indirectly due to valve malformation may be the indirect cause of this septal defect. The results of this study suggest an important role for the ET system in the formation of certain anatomical structures of the developing human heart.

Topics: Aorta, Thoracic; Aspartic Acid Endopeptidases; Endothelin-1; Endothelin-2; Endothelin-Converting Enzymes; Female; Fetal Heart; Gene Expression Regulation, Developmental; Gene Expression Regulation, Enzymologic; Heart Defects, Congenital; Heart Septal Defects, Ventricular; Humans; In Situ Hybridization; In Vitro Techniques; Metalloendopeptidases; RNA, Messenger

Various vasoactive substances are released during cardiopulmonary bypass. They may deteriorate pulmonary circulation after the Fontan operation. Effects of plasma endothelin-1 (ET-1), a vasoconstricting peptide, on the Fontan circulation have not been investigated.. Eleven patients (aged 11.1+/-7.5 years) who underwent the modified Fontan operation (group F) and seven patients (aged 9.9+/-6.0 years) who underwent the biventricular repair (group C) were studied. Plasma samples were obtained for measuring ET-1 on the first postoperative day (Early I), on returning to floor care from the intensive care unit (Early II), and during postoperative cardiac catheterization (Late).. Plasma concentrations of ET-1 increased in group F (Early I, 4.37+/-1.78 pg/ml; Early II, 4.07+/-1.90 pg/ml) as compared with the basal value of 1.0+/-0.5 pg/ml. The central venous pressure, which reflects the pulmonary circulatory state, soon after the Fontan operation correlated significantly with the increased ET-1 concentration (y=1.809 x+6.484; r=0.809; p=0.0026). Although the Late ET-1 concentrations in group F were significantly decreased, the central venous pressure and the ET-1 concentrations demonstrated a significant correlation (y=3.074 x +5.427; r=0.740; p=0.0227).. The increased humoral vasoactive substances such as ET-1, which induces pulmonary vasoconstriction following the Fontan operation, may have important implications for the Fontan circulation.

Topics: Adolescent; Biomarkers; Cardiopulmonary Bypass; Case-Control Studies; Central Venous Pressure; Child; Child, Preschool; Endothelin-1; Female; Follow-Up Studies; Fontan Procedure; Heart Defects, Congenital; Hemodynamics; Humans; Male; Postoperative Period; Prognosis; Pulmonary Circulation; Sampling Studies; Sensitivity and Specificity; Severity of Illness Index; Treatment Outcome

This study was performed to evaluate the role of endogenous endothelin-1 (ET-1), atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP) in patients with left-to-right shunt and pulmonary hypertension. Further objectives were to study a possible feedback mechanism between ANP and ET-1 and to examine the influence of ANP on cGMP plasma levels. Finally, the role of these hormones in oxygen-mediated pulmonary vasodilation was examined. Plasma concentrations of ET-1, ANP and cGMP were studied in 39 patients with congenital heart disease and left-to-right shunt. Blood samples were taken from the pulmonary artery and pulmonary vein at cardiac catheterization at baseline and after breathing oxygen for 20 min. Patients were grouped according to the presence or absence of pulmonary hypertension (defined as mean Pp/Ps > or = 0.5). Patients with pulmonary hypertension (n = 18) were found to have significantly higher plasma ANP (665 [59-1358] versus 267 [47-832] pg/ml) and cGMP (21.5 [3.6-82.2] versus 7.8 [0-14.6] nM/L) levels than patients without pulmonary hypertension (n = 21). Pulmonary venous ET-1 plasma concentrations were above normal limits in one patient only. ANP plasma levels were not related to ET-1 and cGMP concentrations. There was no transpulmonary gradient for any of the factors. Pulmonary vasodilation in response to oxygen was found in 7 of 18 patients with PH, but was not associated with significant changes in ET-1, ANP or cGMP plasma concentrations. Patients with congenital heart disease and PH show an increase both in vasoconstrictive and vasodilating factors. The mechanism of oxygen-mediated vasodilation in these patients remains to be elucidated.

Topics: Adolescent; Atrial Natriuretic Factor; Child; Child, Preschool; Cyclic GMP; Endothelin-1; Feedback; Female; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Infant; Lung; Male; Oxygen Inhalation Therapy; Reference Values; Vasodilation

Endothelin-converting enzyme-1 and -2 (ECE-1 and -2) are membrane-bound metalloproteases that can cleave biologically the inactive endothelin-1 (ET-1) precursor to form active ET-1 in vitro. We previously reported developmental defects in specific subsets of neural crest-derived tissues, including branchial arch-derived craniofacial structures, aortic arch arteries, and the cardiac outflow tract in ECE-1 knockout mice. To examine the role of ECE-2 in cardiovascular development, we have now generated a null mutation in ECE-2 by homologous recombination. ECE-2 null mice develop normally, are healthy into adulthood, are fertile in both sexes, and live a normal life span. However, when they are bred into an ECE-1-null background, defects in cardiac outflow structures become more severe than those in ECE-1 single knockout embryos. In addition, ECE-1(-/-); ECE-2(-/-) double null embryos exhibited abnormal atrioventricular valve formation, a phenotype never seen in ECE-1 single knockout embryos. In the developing mouse heart, ECE-2 mRNA is expressed in the endocardial cushion mesenchyme from embyronic day (E) 12.5, in contrast to the endocardial expression of ECE-1. Levels of mature ET-1 and ET-2 in whole ECE-1(-/-); ECE-2(-/-) embryos at E12.5 do not differ appreciably from those of ECE-1(-/-) embryos. The significant residual ET-1/ET-2 in the ECE-1(-/-); ECE-2(-/-) embryos indicates that proteases distinct from ECE-1 and ECE-2 can carry out ET-1 activation in vivo.

Topics: Animals; Aspartic Acid Endopeptidases; Base Sequence; DNA Primers; Endothelin-1; Endothelin-2; Endothelin-Converting Enzymes; Female; Fetal Heart; Gene Expression Regulation, Developmental; Gene Expression Regulation, Enzymologic; Heart Defects, Congenital; In Situ Hybridization; In Vitro Techniques; Male; Metalloendopeptidases; Mice; Mice, Inbred C57BL; Mice, Knockout; Pregnancy; RNA, Messenger; Tissue Distribution

Topics: Animals; Aspartic Acid Endopeptidases; Autonomic Nervous System Diseases; Blotting, Western; CHO Cells; Cricetinae; Endothelin-1; Endothelin-3; Endothelin-Converting Enzymes; Endothelins; Exons; Heart Defects, Congenital; Hirschsprung Disease; Humans; Incidence; Infant, Newborn; Metalloendopeptidases; Molecular Sequence Data; Mutation; Protein Precursors

Endothelin-1 (ET-1), with its vasoconstrictive and proliferation-stimulating effects, could play a role in the pathogenesis of primary pulmonary hypertension. We investigated the relationship between the ET-1 like immunoreactivity and the ET-receptor density, the grade of the pulmonary vasculopathy, and properties of the pulmonary circulation in patients with pulmonary hypertension due to congenital heart disease. Twenty-six patients with a median age of 1 year and 1 month (6 weeks - 17 years - 9 months) were assigned to group I (n = 15) with a pulmonary to systemic flow ratio (Qp/Qs) > or = 1.5 and a pulmonary to systemic resistance ratio (Rp/Rs) < or = 0.3 ("high flow - low resistance group") and to group II (n = 11) with a Qp/Qs < 1.5 and an Rp/Rs > 0.3 ("low flow - high resistance group"). Patients belonging to group II showed a higher ET(A)-receptor density in lung arteries (p < 0.05) and parenchyma (p < 0.01) than patients in group I. Patients with the highest ET-1 like immunoreactivity in lung artery walls also showed a trend towards a higher ET(A)-receptor density. The ET(B)-receptor expression was low and not related to any of the above factors. Our results suggest that the paracrine lung ET-1 system is up-regulated in pediatric patients with secondary pulmonary hypertension associated with congenital heart disease.

Topics: Adolescent; Child; Child, Preschool; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Immunohistochemistry; Infant; Lung; Male; Receptors, Endothelin

The aim of this study was to evaluate the role of endothelin-1 (ET-1) in pathophysiology of pulmonary hypertension (PH) secondary to congenital heart disease with left-to-right shunt. Twenty-three children (12 male, 11 female) aged 0.58-13 years were enrolled the study. Blood samples were drawn from superior vena cava, right atrium, right ventricle, pulmonary artery and pulmonary wedge or pulmonary vein during cardiac catheterization. Plasma ET-1 levels were assayed by ELISA. Patients were divided into two groups according to the presence or absence of PH. Plasma ET-1 levels of the study group were compared to the peripheral venous and arterial ET-1 levels of 11 healthy infants and children (aged 0.75-13 years). Plasma ET-1 levels in patients with left-to-right shunt were found significantly higher than those of controls. However, plasma ET-1 levels were similar between the two groups of the patients. Pulmonary venous ET-1 levels were higher than the levels of superior vena cava, this suggested an increased production of ET-1 in pulmonary vascular bed in patients with PH. No correlations were found between plasma ET-1 levels and pulmonary arterial pressure, pulmonary vascular resistance and pulmonary blood flow in the patients. Plasma ET-1 levels of the patients with left-to-right shunt were increased independently from pulmonary arterial pressure and pulmonary vascular resistance. This increase was related to the production of ET-1 in pulmonary vascular bed in patients with PH. ET-1 could not be found to be directly related to the development of PH in the patients with left-to-right shunt.

Topics: Adolescent; Blood Pressure; Child; Child, Preschool; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Male; Pulmonary Artery; Vascular Resistance

Plasma thromboxane B2 (TXB2), leukotriene B4 (LTB4), and endothelin-1 (ET-1) levels increase on cardiopulmonary bypass (CPB). Elevated levels of TXB2 and ET-1 have been correlated with postoperative pulmonary hypertension in infants undergoing repair of congenital heart defects. LTB4 is a potent chemotactic cytokine whose levels correlate with leukocyte-mediated injury. Modified ultrafiltration (MUF) has been associated with improved hemodynamics and pulmonary function, in addition to its beneficial effects on fluid balance and blood conservation. Recent investigations have suggested that removal of cytokines may be the cause of the improved cardiopulmonary function seen with MUF.. Plasma TXB2, ET-1, and LTB4 levels were measured in 34 infants undergoing CPB: 22 underwent MUF (group 1), and 12 did not (group 2). Samples were obtained at various time points. All patients underwent conventional ultrafiltration during the rewarming phase of cardiopulmonary bypass.. In group 1, mean end-CPB TXB2 level was 101.2 pg/mL versus 46.9 pg/mL post-MUF (p < 0.05). The mean TXB2 level 1 hour post-CPB (54.1 pg/mL) was not significantly different from the post-MUF level. In group 2, the mean end-CPB TXB2 level was 123.6 pg/mL versus 53.2 pg/mL 1 hour post-CPB. Hence, TXB2 levels decreased by similar amounts and to similar levels by 1 hour post-CPB in both groups. ET-1 levels increased after CPB and were unaffected by MUF: 1.45, 1.80, 2.55 pg/mL at end-CPB, post-MUF, and 1 hour post-CPB, respectively, in group 1; and 1.51, and 2.73 pg/mL at end-CPB and 1 hour post-CPB in group 2. LTB4 levels post-MUF were 119% of pre-MUF values, and were similar at 1 hour post-CPB in both groups.. Despite reduction in TXB2 by MUF, values were similar and approached baseline 1 hour post-CPB in both groups. LTB4 levels increased slightly with MUF. ET-1 levels increased during and post-CPB and were unaffected by MUF. MUF does not appear to have a significant effect on post-CPB levels of TXB2, ET-1, and LTB4. Therefore, the improved hemodynamics observed with MUF do not appear to be related to removal of these cytokines.

Topics: Cardiopulmonary Bypass; Endothelin-1; Female; Heart Defects, Congenital; Hemofiltration; Humans; Hypertension, Pulmonary; Infant; Leukotriene B4; Male; Postoperative Complications; Risk Factors; Thromboxane B2; Treatment Outcome

Congenital heart disease with increased pulmonary blood flow commonly leads to the development of pulmonary hypertension and increased vascular reactivity. These serious sequelae are associated with the following two major categories of congenital heart defects: those resulting in increased pulmonary blood flow and increased pulmonary arterial pressure and those resulting in increased pulmonary venous pressure. Recent evidence that the pulmonary vascular endothelium is an important determinant of vascular tone has led to the hypothesis that endothelial injury, secondary to congenital heart disease with increased pulmonary blood flow, disrupts these regulatory mechanisms and thereby plays a role in the development of pulmonary hypertension and its associated increased vascular reactivity. In many animal models, endothelial dysfunction is a precursor for smooth muscle dysfunction, and there is an apparent progression from endothelial dysfunction to smooth muscle dysfunction as vascular changes progress. We established a chronic model of pulmonary hypertension with increased pulmonary blood flow in young lambs by placing a systemic-to-pulmonary shunt in utero. In this model, we found significant physiologic and molecular alternations of both the nitric oxide (NO) and endothelin signaling pathways, two important mechanisms by which the endothelium regulates pulmonary vascular tone. These alterations occur extremely early and precede severe anatomic changes. Early endothelial damage may contribute to the development of pulmonary hypertension and its associated enhanced pulmonary vascular reactivity.

Topics: Animals; Blood Pressure; Cyclic GMP; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Heart Defects, Congenital; Hypertension, Pulmonary; Muscle, Smooth, Vascular; Nitric Oxide; Pulmonary Circulation; Sheep; Signal Transduction; Vasodilator Agents; Vasomotor System; Venous Pressure

Neural crest cells arise in the dorsal aspect of the neural tube and migrate extensively to differentiate into a variety of neural and non-neural tissues. While interactions between neural crest cells and their local environments are required for the proper development of these tissues, little information is available about the molecular nature of the cell-cell interactions in cephalic neural crest development. Here we demonstrate that mice deficient for one type of endothelin receptor, ETA, mimic the human conditions collectively termed CATCH 22 or velocardiofacial syndrome, which include severe craniofacial deformities and defects in the cardiovascular outflow tract. We show that ETA receptor mRNA is expressed by the neural crest-derived ectomesenchymal cells of pharyngeal arches and cardiac outflow tissues, whereas ET-1 ligand mRNA is expressed by arch epithelium, paraxial mesoderm-derived arch core and the arch vessel endothelium. This suggests that paracrine interaction between neural crest-derived cells and both ectoderm and mesoderm is essential in forming the skeleton and connective tissue of the head. Further, we find that pharyngeal arch expression of goosecoid is absent in ETA receptor-deficient mice, placing the transcription factor as one of the possible downstream signals triggered by activation of the ETA receptor. These observations define a novel genetic pathway for inductive communication between cephalic neural crest cells and their environmental counterparts.

Topics: Animals; Animals, Newborn; Base Sequence; Brain; Branchial Region; Craniofacial Abnormalities; DNA Primers; DNA-Binding Proteins; Endothelin-1; Female; Gene Expression Regulation, Developmental; Goosecoid Protein; Heart Defects, Congenital; Homeodomain Proteins; Humans; In Situ Hybridization; Mice; Mice, Knockout; Neural Crest; Polymerase Chain Reaction; Pregnancy; Receptor, Endothelin A; Receptors, Endothelin; Repressor Proteins; RNA, Messenger; Signal Transduction; Transcription Factors

Adrenomedullin is a newly identified peptide with profound hypotensive effects. We investigated perioperative adrenomedullin levels among patients with congenital heart disease with and without pulmonary hypertension.. Levels of plasma adrenomedullin, endothelin-1, and nitric oxide metabolites were measured in three groups: (1) low pulmonary flow (n=11); (2) high flow/low pulmonary arterial pressure (less than 60% systemic pressure) (n=9); and (3) high flow/high pressure (n=10). Samples were obtained preoperatively, on and off pump, and 3, 6, and 12 hours after bypass.. Adrenomedullin levels were highest in the low pulmonary flow group (189.7+/-15 pg/mL low flow versus 103.1+/-9.5 pg/mL high flow/low pulmonary and 139+/-17.5 pg/mL high flow/high pressure at 12 hours; p < or = 0.05). The arterial pressure/systemic pressure remained significantly lower in the high flow/low pulmonary pressure compared with the high flow/high pressure group (0.37+/-0.08 versus 0.62+/-0.11; p < 0.005). Perioperative endothelin-1 and nitric oxide levels remained low in the low pulmonary flow group but increased progressively in both high flow groups.. Circulating plasma adrenomedullin appears to affect baseline vascular tone in patients with intact endothelial function. It may interact with nitric oxide and endothelin-1 to help regulate blood pressure perioperatively in patients with congenital heart disease.

Topics: Adrenomedullin; Blood Pressure; Child, Preschool; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; Nitric Oxide; Peptides; Pulmonary Circulation; Risk Factors

To investigate the changes in plasma endothelin-1 (ET-1) concentrations in patients with congenital heart defects.. Plasma ET-1 concentrations were measured by using radio-immunoassay in 50 patients in a prospective study. In 35 patients with ventricular septal defect, 20 cases had pulmonary hypertension (group 1) and 15 cases had normal pulmonary artery pressure (group 2). The other 15 patients with atrial septal defect had normal pulmonary artery pressure (group 3). Blood samples were obtained from pulmonary artery, aorta and radial artery.. Plasma ET-1 concentration in group 1 was significantly higher than those in group 2 and group 3 at all sampling sites and all different times (p < 0.01), and plasma ET-1 concentration was slightly higher in group 3 than in group 2 (p > 0.05). Plasma ET-1 concentration at aorta were also significantly higher than that at pulmonary artery in group 1 (p < 0.01). In patients with ventricular septal detect, pulmonary blood flow had a linear positive correlation with plasma ET-1 concentration (r = 0.75, p < 0.01) and there was also a significant positive correlation between plasma ET-1 concentration and pulmonary artery pressure (r = 0.68, p < 0.05). After surgical repair of the defects, plasma ET-1 concentration decreased except for 6 cases with the pulmonary resistance more than 800 dyne.sec.cm-5.. Plasma ET-1 concentrations are elevated in patients with congenital heart defect associated with left-to-right shunt and may have an important role in the pathogenesis of pulmonary hypertension.

Topics: Child; Child, Preschool; Data Interpretation, Statistical; Endothelin-1; Female; Heart Defects, Congenital; Heart Septal Defects, Atrial; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Infant; Male; Prospective Studies; Radioimmunoassay

The endothelium-derived vasoconstrictor endothelin-1 (ET-1) may be involved in pulmonary hypertension (PH), but production of the endothelium-derived vasodilator nitric oxide (NO) after cardiopulmonary bypass (CPB) in congenital heart disease is unclear.. Twenty patients (age, 4 months to 12 years) were divided into three groups: severe PH (mean pulmonary-to-systemic arterial pressure ratio > 0.5) and high pulmonary flow (n = 8), mild PH (mean pulmonary-to-systemic arterial pressure ratio < 0.35) and high pulmonary flow (n = 6), and no PH and low pulmonary flow (n = 6). The mean pulmonary-to-systemic arterial pressure ratio was calculated and blood samples were taken, and NO3-, an NO metabolite, was measured.. Levels of ET-1 in the group with severe PH and high pulmonary flow were higher than in the other groups until 6 hours after CPB, and NO3- was not changed significantly in the group with severe PH and high pulmonary flow and or the group with mild PH and high pulmonary flow during CPB. Endothelin-1 in the group with no PH and low pulmonary flow was higher than in the group with mild PH and high pulmonary flow after CPB, and NO3- in the group with no PH and low pulmonary flow significantly decreased after CPB. A positive correlation was obtained between mean pulmonary-to-systemic arterial pressure ratio and ET-1 (r = 0.742 before CPB; r = 0.689 after CPB).. Imbalance between increased ET-1 and constant NO after CPB in the group with severe PH and high pulmonary flow could contribute to dominant effects of ET-1, which may injure the lung. The increased ET-1 and the decreased NO after CPB in the group with no PH and low pulmonary flow may induce a mechanism of protective vasoconstriction against an acute increase in pulmonary flow.

Topics: Cardiopulmonary Bypass; Case-Control Studies; Child; Child, Preschool; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Male; Nitrates; Nitric Oxide; Pulmonary Circulation; Time Factors

Pulmonary hypertension causes major morbidity and mortality after congenital heart surgery, but its mechanism remains unclear.. Plasma endothelin-1 (ET-1), nitric oxide (NO), and cyclic GMP (cGMP) were assayed at 6 intervals in 50 children undergoing cardiopulmonary bypass (CPB): before CPB, 10 minutes into CPB, and 0, 3, 6, and 12 hours after CPB. Three groups based on pulmonary flow and pressure were analyzed: low flow (LF, n=21), high flow/low pressure (systolic pulmonary pressure/systemic pressure ratio, Pp/Ps<50%, HF-LP, n=11), and high flow/high pressure (Pp/Ps> or =50%, HF-HP, n=19). HF-HP and HF-LP received alpha-blockers (chlorpromazine and/or prazosin). HF-HP patients received nitric oxide donors (nitroglycerin/sodium nitroprusside). ET-1 peaked at 6 hours, with its highest level in the HF-HP group (P<.01, by ANOVA). ET-1 correlated significantly with Pp/Ps at 6 hours (r2=.43, P<.005). In the HF-HP group, ET-1 remained above the other groups at 12 hours (12.7+/-2.5 pg/mL versus 6.4+/-1.1 pg/mL versus 6.5+/-3.8 pg/mL P<.05 by ANOVA). NO metabolites were elevated equivalently for the HF-HP and HF-LP groups (5.7+/-2.6 micromol/L versus 0.3.5+/-2.5 micromol/L at 12 hours, P=NS) despite nitric oxide donors and the excess ET-1 in HF-HP patients. Levels of cGMP were similarly elevated in HF-HP and HF-LP patients during this study.. Endogenous NO may decrease vascular tone and maintain low pulmonary pressure in HF-LP patients. High levels of ET-1, inadequate NO production, and/or impaired responses to NO may increase pulmonary pressure in HF-HP patients.

Topics: Blood Pressure; Cardiopulmonary Bypass; Child, Preschool; Cyclic GMP; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Male; Nitric Oxide; Postoperative Complications

Plasma endothelin (ET) concentration was measured by means of radioimmunoassay in 38 patients with congeital heart defects among whom 15 patients with pulmonary hypertension (PH) and 23 patients without pulmonary hypertension (non-PH). Blood samples were obtained separately from the femoral vein, right atrium, right ventricle, main pulmonary artery and the femoral artery during catherization. Plasma ET concentration in the PH group was significantly higher than that in the non-PH group at all four sampling sites. In the PH group plasma ET concentration in the pulmonary artery showed higher than that of the right ventricle and the femoral artery, which was significantly in positive correlation with pulmonary artery pressure. It is considered that the elevation of ET plays an important physiological role in the formation of pulmonary hypertension.

Topics: Adolescent; Adult; Child; Child, Preschool; Double Outlet Right Ventricle; Endothelin-1; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male

This study applied bronchoalveolar lavage (BAL) to children with congenital heart disease (CHD) prior to elective cardiac catheterization (n = 48), to determine the influence of pulmonary blood flow and viral infection on the alveolar epithelial lining fluid (ELF) concentration of leucocytes, protein and endothelin-1 (ET-1). Lower respiratory tract (LRT) viral infection was defined as either a positive immunofluorescence for virus, or a virus cultured from the bronchoalveolar lavage fluid (BALF). Haemodynamic status was determined at cardiac catheterization. Normative data for BALF, but not ELF parameters, were obtained from 26 asymptomatic, noninfected normal children undergoing elective surgery. In the absence of LRT infection, the BALF macrophage, lymphocyte and neutrophil differential in CHD was not significantly different from the normal controls. In CHD, both increased pulmonary-to-systemic flow ratio (Q'p/Q's) and increased pulmonary artery-to-left ventricular pressure ratio PAP/LVP were associated with a decrease in ELF protein (rs = -0.59; p < 0.0001; and rs = -0.50; p < 0.0001 respectively). A respiratory virus was isolated from the BALF in 8 (17%) of CHD children. Virus isolation was associated with an increased ELF total protein (p < 0.05 vs no infection), a decreased alveolar macrophage differential count (p < 0.01), and an increased neutrophil differential count (p < 0.05). ET-1 was detected in the BALF of 83% of the noninfected CHD children compared to only 23% of the controls (p < 0.001). ELF ET-1 concentrations did not correlate with haemodynamic status in CHD, but were up to 100 times higher than paired plasma levels. We conclude that, in congenital heart disease, both lower respiratory tract viral infection and increased pulmonary blood flow and/or pulmonary vascular pressure influence the alveolar milieu. High alveolar epithelial lining fluid concentrations of endothelin-1 occur in congenital heart disease, but the stimulus for pulmonary endothelin-1 production is unclear.

Topics: Bronchoalveolar Lavage Fluid; Cardiac Catheterization; Case-Control Studies; Cell Count; Endothelin-1; Heart Defects, Congenital; Humans; Infant; Leukocytes; Pulmonary Alveoli; Pulmonary Circulation; Respiratory Tract Infections; Virus Diseases

To evaluate whether circulating endothelin, a peptide that is thought to play a part in mediating vascular tone, might be high in pulmonary hypertensive congenital heart disease.. A prospective study with a radioimmunoassay technique to estimate urinary and plasma endothelin concentrations.. A supraregional referral centre for patients with congenital heart disease.. The 12 hour urinary endothelin concentration in young children with an increased pulmonary blood flow (n = 24, median age eight months) were compared with those in children with right ventricular outflow tract obstruction (n = 14, median age 1.5 years) and with those in healthy controls (n = 16, median age 1.8 years). The concentrations were also measured in adolescents with irreversible pulmonary vascular disease (n = 17, median age 18 years) and compared with those in controls of similar age (n = 19, median age 18.5 years). Also the plasma concentrations in the left atrium and pulmonary artery were measured in young children with either high (n = 11, median age 10.8 months) or low (n = 5, median age 1.0 year) pulmonary blood flow, in the peripheral arterial and venous blood of young children with either high (n = 13, median age 10.8 months) or low (n = 6 median age 1.9 years) pulmonary blood flow, and in the peripheral venous blood of seven healthy young children (median age 1.7 years).. The urinary excretion of endothelin was similar in young children of a similar age, whether they had high, low, or normal pulmonary blood flow. Also, urinary endothelin excretion in older patients with irreversible pulmonary vascular disease was similar to that in normal subjects of similar age. Urinary endothelin excretion in normal young children, however, was significantly greater than that in normal older subjects (p = 0.0001). There was no transpulmonary or arteriovenous difference detected in either children with high or low pulmonary blood flow, and plasma concentrations sampled from the left atrium, pulmonary artery, and systemic artery and vein were similar in both groups.. There was no evidence to implicate circulating endothelin in the pathogenesis of pulmonary vascular disease.

Topics: Adolescent; Endothelin-1; Endothelins; Female; Heart Defects, Congenital; Humans; Infant; Male; Prospective Studies; Protein Precursors; Pulmonary Heart Disease; Radioimmunoassay