Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelin-1 (ET-1) has been implicated in the pathogenesis of pulmonary vascular disease in patients with congenital heart disease. We studied the effect of pulmonary blood flow on plasma ET-1 concentrations. Systemic venous, pulmonary arterial, and pulmonary venous blood samples were obtained from 40 patients with atrial septal defect II (n = 21), ventricular septal defect (n = 10), persistent ductus arteriosus (n = 6), and complete (n = 2) and partial (n = 1) atrioventricular canal at cardiac catheterization and analyzed by radioimmunoassay. Median age (range) was 5.2 years (8 months to 66 years), and the resistance ratio (Rp/Rs) was 0.08 (0.03 to 0.67). Pulmonary vein to pulmonary artery ET-1 ratio in patients with "high flow" (n = 26, Qp/Qs > or = 1.5; ET-1 ratio = 0.8) did not differ from those with "low flow" (n = 14, Qp/Qs < 1.5; ET-1 ratio = 1.0). We conclude that an increase in pulmonary blood flow alone does not result in an increase in plasma ET-1.
 ...
PMID:Plasma endothelin-1 in patients with left-to-right shunt. 896 3

Endothelin-1 (ET), a potent vasoconstrictor peptide, has been found to be elevated in children with pulmonary hypertension associated with congenital heart defects. To evaluate the effect of pulmonary blood flow on ET concentrations, 5 ml blood samples were obtained peripherally at cardiac catheterization from 35 patients, ages 0.13 to 17 years (median 2). Plasma was extracted and ET measured by radioimmunoassay. Patients were classified into 2 groups based on the presence (group A) or absence (group B) of increased pulmonary blood flow defined as a Qp/Qs > or = 1.5. When the 13 patients (37%) in group A were compared with the 22 patients (63%) in group B there were no significant differences in age, cardiac index, or pulmonary and systemic resistances. ET concentrations were significantly higher in group A patients (median 3.25, range 0 to 16.5 vs median 0, range 0 to 6.35 pg/ml; p < or = 0.05). Pulmonary blood flow and pulmonary artery pressure were also higher in group A patients (p < or = 0.01). When patients within group A were subdivided into those with and without pulmonary hypertension, no difference was present in their ET concentrations (mean/SD: 4.4/4.3 vs 4.0/6.4 pg/ml, p = NS). Thus, ET is elevated in patients with congenital heart disease associated with left-to-right shunts and it appears that this increase is related to increased pulmonary blood flow independent of pulmonary artery pressure.
 ...
PMID:Relation of elevated plasma endothelin in congenital heart disease to increased pulmonary blood flow. 848 Jun 47

Endothelin-1 (ET-1) exerts powerful vasoconstrictive and blood pressure elevating properties through endothelial cells. However, no systematic examination of ET-1 in migraine has ever been attempted. The present investigation was focused on evaluating the level of ET-1 in patients with migraine with aura. Studies on ET-1 were made in 17 patients with migraine with aura (age, 23.4 +/- 9.1 years old, mean +/- SD) according to the Classification of Headache of the Ad Hoc Committee. All patients had been free of migraine attacks for at least 7 days prior to the examination. Twenty-eight age-matched healthy volunteers (age, 23.0 +/- 12.3 years old) were similarly used as a control group. None of them revealed evidence of any other disease, such as hypertension, obesity, or heart disease. Informed consent was obtained from each subject. We measured the immunoreactive ET-1 in plasma by radioimmunoassay. The plasma level of ET-1 in migraine was 2.53 +/- 1.06 pg/ml. On the other hand, the level of ET-1 in the controls was 4.24 +/- 0.80 pg/ml. The ET-1 level in migraine was significantly lower than that in the controls (p < 0.002). We also measured the level of ET-1 in the cerebrospinal fluid (CSF). There was no significant difference between migraine (23.2 +/- 3.10 pg/ml) and the control group (20.85 +/- 3.20 pg/ml). In conclusion, the lower plasma level of ET-1 observed in the patients with migraine is consistent with the pathogenesis of migraine, further supporting the hypothesis that a lower ET-1 may be closely related to marked vasodilatation following constriction partly due to a deficiency of ET-1 for maintaining vasoconstriction.
 ...
PMID:[Lower level of endothelin-1 in migraine with aura]. 872 Mar 38

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.
 ...
PMID:Endothelin-1- and endothelin-receptors in lung biopsies of patients with pulmonary hypertension due to congenital heart disease. 1036 13

Pharyngeal arch artery (PAA) remodeling defects account for several cases of congenital heart disease. Mutations in the Endothelin-1 genetic pathway or Tbx1, a candidate gene for DiGeorge syndrome, cause similar aortic arch defects. Previous research suggests that Tbx1 may trigger diffusible signals from the pharyngeal arches to support the growth of the PAAs that contribute to the mature aortic arch. The demonstration of genetic interaction between Tbx1 and Fgf8 pointed to FGF signaling as a possible candidate. Because Fgf8 interacts with Endothelin-1 signaling and because Endothelin-1 signaling interacts with neural crest-derived cells in the pharyngeal apparatus, we hypothesized that Tbx1 and Endothelin-1 signaling may contribute to the same pathway required for aortic arch morphogenesis. Therefore, we have analyzed mice mutated for the endothelin converting enzyme (Ece1) or Tbx1 genes and compound mutants. Results show that the two genes have different roles in the remodeling of the PAAs and do not interact. We propose that Tbx1 is required for the formation and early growth and remodeling of the PAAs, whereas Ece1 is necessary for regression of the cranial arch arteries and growth of the most caudal arch arteries. The latter function is likely related to the known role of the Endothelin-1 pathway in neural crest function.
 ...
PMID:Ece1 and Tbx1 define distinct pathways to aortic arch morphogenesis. 1295 83

Endothelin-1 (ET-1) is a 21-amino acid polypeptide produced primarily by vascular endothelial cells. First discovered in 1988 as a potent vasoconstrictor, it has subsequently been appreciated to participate in several biologic activities, including vascular smooth muscle proliferation, fibrosis, cardiac and vascular hypertrophy, and inflammation. Increasing data demonstrate alterations in ET-1 signaling in newborns, infants, and children with congenital heart defects that are associated with alterations in pulmonary blood flow. This review outlines the pathophysiologic role of the ET-1 cascade in the development of altered pulmonary vascular tone and reactivity that occurs with congenital heart disease and its repair, following the use of cardiopulmonary bypass. In addition, therapeutic implications for the use of novel ET receptor antagonists will be emphasized.
 ...
PMID:Endothelin-1 in congenital heart disease. 1581 94

The endothelins are peptides with vasoconstricting and growth-promoting properties. Endothelin-1 (ET-1) is known with its direct positive inotropic and chronotropic effects on isolated heart and with growth effects. The aim of this pilot study was to investigate the frequency distribution of the common polymorphism of the ET-1 gene and its possible relation with hemodynamic consequences of malignant ventricular arrhythmias in patients with structural heart disease. We studied 26 consecutive patients with malignant ventricular arrhythmias and implantable cardioverterdefibrillators with a mean age of 62.7 +/- 12.2 years and a mean left ventricular ejection fraction of 0.37 +/- 11.0. Taq polymorphism of ET-1 was detected using our original polymerase chain reaction method. The polymerase chain reaction product with a length of 358 basepairs (bp) (primers 5'-CAA ACC GAT GTC CTC TGT A-3' and 5'-ACC AAA CAC ATT TCC CTA TT-3') in its non-mutated form contains a target sequence for TaqI restrictive enzyme, while a mutated product loses this cleavage site. Of 26 patients, nine (34%) had recurrent palpitations and eight (30.8%) had syncopes during their malignant arrhythmias. Nineteen patients were given amiodarone after implantable cardioverter-defibrillator insertion and seven were not treated with amiodarone. Fifteen patients had (++), 11 (+-) and 0 (- -) ET-1 genotype. The risk for syncopes was associated with the (++) genotype of the ET-1 gene (P = 0.01). Patients receiving amiodarone had significantly higher frequency of the (++) genotype (P = 0.011). All our results indicate that the presence of the ET-1 genotype (++) in patients with structural heart disease, severe left ventricular dysfunction and malignant ventricular arrhythmias increases the risk for these patients of hemodynamic collapse during these arrhythmias.
 ...
PMID:Endothelin-1 gene polymorphism in patients with malignant arrhythmias. 1583 69

Endothelin-1 is a potent vasoconstrictor and mitogen that is primarily synthesized and released from vascular endothelial cells. Bosentan is a dual endothelin-receptor antagonist that initially received approval for treatment of WHO group I pulmonary arterial hypertension (PAH) for patients in functional classes III and IV. Analysis of a study conducted in functional class II patients (Endothelin Antagonist Trial in Mildly Symptomatic PAH Patients [EARLY] trial) suggest its efficacy for these less symptomatic patients. In addition, bosentan has demonstrated efficacy in patients with congenital heart disease and Eisenmengers syndrome with right to left shunting and in HIV-related PAH. Studies of bosentan in inoperable or residual chronic thromboembolic pulmonary hypertension suggest possible efficacy. Bosentan appears promising in patients with idiopathic pulmonary fibrosis who do not have pulmonary hypertension. Combinations of bosentan with other PAH therapies such as iloprost and sildenafil may have incremental benefit over monotherapy.
 ...
PMID:Bosentan for pulmonary hypertension and other pulmonary diseases: emerging evidence. 1980 40

The risk and progression of pulmonary vascular disease in patients with congenital heart disease is dependent on the hemodynamics associated with different lesions. However, the underlying mechanisms are not understood. Endothelin-1 is a potent vasoconstrictor that plays a key role in the pathology of pulmonary vascular disease. We utilized two ovine models of congenital heart disease: (1) fetal aortopulmonary graft placement (shunt), resulting in increased flow and pressure; and (2) fetal ligation of the left pulmonary artery resulting in increased flow and normal pressure to the right lung, to investigate the hypothesis that high pressure and flow, but not flow alone, upregulates endothelin-1 signaling. Lung tissue and pulmonary arterial endothelial cells were harvested from control, shunt, and the right lung of left pulmonary artery lambs at 3-7 weeks of age. We found that lung preproendothelin-1 mRNA and protein expression were increased in shunt lambs compared to controls. Preproendothelin-1 mRNA expression was modestly increased, and protein was unchanged in left pulmonary artery lambs. These changes resulted in increased lung endothelin-1 levels in shunt lambs, while left pulmonary artery levels were similar to controls. Pulmonary arterial endothelial cells exposed to increased shear stress decreased endothelin-1 levels by five-fold, while cyclic stretch increased levels by 1.5-fold. These data suggest that pressure or an additive effect of pressure and flow, rather than increased flow alone, is the principal driver of increased endothelin signaling in congenital heart disease. Defining the molecular drivers of the pathobiology of pulmonary vascular disease due to differing mechanical forces will allow for a more targeted therapeutic approach.
 ...
PMID:Mechanical forces alter endothelin-1 signaling: comparative ovine models of congenital heart disease. 3248 41

Pulmonary hypertension due to left heart disease (PH-LHD; Group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most frequent cause of PH. Despite its prevalence, no effective therapies for PH-LHD are available at present. This is largely due to the lack of a concise definition for hemodynamic phenotyping, existence of significant gaps in the understanding of the underlying pathology and the impact of associated comorbidities, as well as the absence of specific biomarkers that can aid in the early diagnosis and management of this challenging syndrome. Currently, B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are guideline-recommended biomarkers for the diagnosis and prognosis of heart failure (HF) and PH. Endothelin-1 (ET-1), vascular endothelial growth factor-D (VEGF-D), and microRNA-206 have also been recently identified as new potential circulating biomarkers for patients with PH-LHD. In this review, we aim to present the current state of knowledge of circulating biomarkers that can be used to guide future research toward diagnosis, refine specific patient phenotype, and develop therapeutic approaches for PH-LHD, with a particular focus on PH-HFpEF. Potential circulating biomarkers identified in pre-clinical models of PH-LHD are also summarized here.
 ...
PMID:Current Understanding of Circulating Biomarkers in Pulmonary Hypertension Due to Left Heart Disease. 3311 32


1