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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiac preload reduction through venodilatation is beneficial in chronic heart failure. The recent development of endothelin receptor antagonists for possible therapeutic use in heart failure has hastened the need for a clearer understanding of the venoconstrictor actions of endothelin-1 in this disease. Two main subtypes of endothelin receptor, ET(A) and ET(B), exist in human blood vessels. We studied the venoconstrictor effects of endothelin-1 (a non-selective ET(A) and ET(B) agonist) and sarafotoxin S6c (a selective ET(B) agonist) in vivo in patients with chronic heart failure and in age-matched healthy controls. On separate days at least 1 week apart, locally active doses of endothelin-1 or sarafotoxin S6c were infused into a suitable dorsal hand vein for 1 h, and the venous internal diameter was measured using a displacement technique. Venoconstriction in response to endothelin-1 was significantly blunted in heart failure patients compared with controls (26+/-7% and 51+/-6% peak reduction in vein calibre respectively; P=0.013). Venoconstriction to sarafotoxin S6c was similar in heart failure patients and controls (17+/-5% and 17+/-4% peak reduction in vein calibre respectively). Both ET(A) and ET(B) receptors mediate venoconstriction in healthy subjects and in patients with chronic heart failure. Optimal inhibition of the venoconstrictor effects of endothelin-1 in chronic heart failure may therefore require administration of an antagonist with ET(A)- and ET(B)-receptor-blocking properties. Chronic heart failure may be associated with a selective decrease in venous ET(A) receptor sensitivity, but further studies are required to clarify the functional significance of this observation.
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PMID:Venous endothelin receptor function in patients with chronic heart failure. 1060 Jun 60

The term ventricular remodeling has been coined to describe the geometrical changes in size and shape of the left ventricle occurring after large myocardial infarcts. We do not exactly know what initiates this process. Slipping of myofilaments following destruction of connective tissue--probably due to metalloproteinase activation--could be the initial event. As a consequence, wall stress is increased triggering deleterious adaptation processes, such as: - intracardiac angiotensin II generation; - cardiac endothelin formation and release; - pro-apoptotic signals for cardiomyocytes; - hypertrophic signals for fibroblasts and cardiomyocytes. This cascade of events is not only observed in the process of remodeling following myocardial infarction but is also operating during the progression of heart failure. Therapeutic principles therefore are similar in both conditions: - reduction of wall stress (pharmacological or mechanical unloading of the heart); - blockade of angiotensin II generation or of AT1-receptors (ACE-inhibitors or AT1 antagonists); - blockade of endothelin receptors (ET(A)-blockers); - blockade of adrenergic receptors (preferably beta1-adrenergic receptor blockers). Better understanding of the molecular mechanisms of the remodeling process already has fueled the search for new therapeutic interventions (such as endothelin receptor blockers, aldosterone antagonists and growth hormone application). Continuous research in this field may be especially rewarding if we will succeed in identifying the very first step in the cascade.
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PMID:Ventricular remodeling after acute myocardial infarction. 1069 91

Hirschsprung's disease occurs rarely and sporadically in adult, involving males. In cases, which are manifested perinatally, the so called Hirschsprung-associated congenital anomalies (mainly central nervous system, urogenital and cardiovascular) may present (2-21%), which have not observed in adult. Mental retardation and Hirschsprung's disease more frequently are associated with Down syndrome (5-10%). The discoveries of molecular genetics in the last 4-5-years through the examination of transgenic ("knockout") mice, proved the basic role the mutation of 4 genes: the RET (receptor tyrosin kinase), a proto-oncogene, coding its ligand, the glial cell-line derived neutrophic factor (GDNF), the gene of the endothelin-B receptor (ENDRB) and the gene one of its ligand, the endothelin-3 (EDN3), in the pathogenesis of Hirschsprung's disease. In our case, the short segment Hirschsprung's disease caused respiratory and cardiac failure, which was recognized by autopsy. Besides, the severe mental retardation, the role of the long term use of antipsychotic medicines comes up in the prolongation and masking of the symptoms. The accompanied mental retardation and microcephalia in early childhood are known, which are associated anomalies with Hirschsprung's disease. In cases of Hirschsprung diseases at adults, no other associated congenital anomalies has been published. The mental retardation in Down-syndrome, in association with Hirschsprung's disease (and presumable in our case, too) is supposed to be the consequence of the mutation in the gene of GDNF. In this case, we observed, that the so called short segment H-d was accompanied at a 33 years old men patient with mental retardation (who was originated from a gypsy ethnic minority), because of it the connection of the nurses and the patient was disturbed and the main symptom of the H-d (chronic obstipation) remained hidden. The mechanic ileus was going on behind the scenes, and in addition to the cardiac failure caused the death of the patient. Practical conclusion of the case is that, Hirschsprung's disease should be suspected in all adult patients, who had severe obstipation persisting since childhood, especially in males.
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PMID:[Adult Hirschsprung's disease with mental retardation and microcephaly]. 1096 5

Atherosclerosis, a chronic systemic disease of the vasculature with an inflammatory component, is the primary cause of cardiovascular morbidity and mortality in industrialized countries. It is associated with the impairment of endothelium-dependent relaxation in the coronary, systemic circulation due to decreased bioavailability of nitric oxide, and increased release oxygen-derived free radicals, thus promoting vasoconstriction, leukocyte adhesion, thrombosis, inflammation, and cell proliferation. Expression of endothelin (ET)-1, a 21-amino acid peptide and major isoform of the endothelin peptide family, is produced by endothelial, vascular smooth muscle cells, and macrophages and acts through Gi-protein-coupled ET(A) and ET(B) receptors. Endothelin-1 increases in hypercholesterolemia and atherosclerosis in humans and experimental animals. This paper reviews current experimental and clinical evidence for the involvement of ET-1 in atherogenesis. Furthermore, the effects of ET receptor blockade on experimental hypercholesterolemia and atherosclerosis will be discussed. As chronic endothelin blockade inhibits fatty streak formation and improves vascular function in experimental hypercholesterolemia, hypertension, and heart failure, and as it restores nitric oxide (NO)-mediated endothelial function and reduces atheroma formation in animals with atherosclerosis, endothelin receptor blockade may therefore offer a novel approach for the treatment of atherosclerosis and its vascular complications.
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PMID:Endothelial dysfunction and atherosclerosis: endothelin receptor antagonists as novel therapeutics. 1098 Nov 33

Despite conventional therapy, there is still much room for improvement in the prognosis of patients with chronic systolic heart failure. Evidence supports a role for endothelin-1 (ET-1), a potent vasoconstrictor, in the pathophysiology of heart failure. Given its potentially deleterious effects, the optimal treatment of heart failure may need to include efforts directed toward antagonizing this hormone. In support of this notion, the use of ET receptor antagonists produces a number of beneficial effects in heart failure, including both improvements in hemodynamics and reductions in the levels of other vasoconstricting neurohormones. There are at least 2 receptors for ET-1 (the ET-A and ET-B receptor), and the effects of ET-1 binding differ depending on the receptor involved. It is still unclear whether blockade of the ET-A receptor alone or the combined blockade of both the ET-A and ET-B receptors will be most efficacious as a therapeutic strategy. Long-term benefits have been achieved with the use of a mixed ET-A/B receptor antagonist, when added to standard triple-drug therapy, in patients with severe heart failure. We await the results of ongoing trials to determine if these agents will fulfill the promise of adding substantial incremental benefit to the treatment of the disease.
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PMID:New developments in heart failure: role of endothelin and the use of endothelin receptor antagonists. 1114 61

Endothelin (ET) is a peptide composed of 21 amino acids, derived from a larger precursor, the big-endothelin, by action of the endothelin-converting enzyme (ECE) family; three isoforms of endothelin, named ET-1, ET-2 and ET-3, have been identified. Endothelin-1 is generated mainly by vascular endothelial cells and exerts various important biological actions, mediated by two receptor subtypes, ET-A and ET-B, belonging to the G protein-coupled family that have been identified in various human tissues such as the cardiac tissue. Endothelin-1 is a potent vasoconstrictive agent, has inotropic and mitogenic actions, modulates salt and water homeostasis and plays an important role in the maintenance of vascular tone and blood pressure in healthy subjects. Endothelin-1, as well as ET-A and ECE-1, also has an important role in cardiovascular development, as observed by the variety of abnormalities related to neural crest-derived tissues in mouse embryos deficient of a member of the ET-1/ECE-1/ET-A pathway. Various evidence indicates that endogenous endothelin-1 may contribute to the pathophysiology of conditions associated with sustained vasoconstriction, such as heart failure. In heart failure, elevated circulating levels of both endothelin-1 and big-endothelin-1 are observed; in failing hearts an activation of the endothelin system is found: tissue level of ET-1 is increased with respect to non-failing hearts as well as receptor density, due mainly to an upregulation of the ET-A subtype, the prevalent receptor subclass in cardiac tissue. Finally, studies in both humans and animal models of cardiovascular disease show that inhibition of the endothelin function (anti-endothelin strategy) is associated with an improvement of haemodynamic conditions; these observations indicate that endothelin receptor antagonists or endothelin-converting enzyme inhibitors may constitute a novel and potentially important class of agents for the treatment of this disease.
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PMID:The role of endothelins and their receptors in heart failure. 1124 12

Heart failure is a major health problem and is associated with a high mortality and morbidity. Recently, the role of the genetic background in the onset and development of the disease has been evidenced in both heart failure with and without systolic dysfunction, and in familial and non-familial forms of this condition. Familial forms of dilated cardiomyopathy are more frequent than previously thought. Various modes of inheritance and phenotypes have been reported and this condition appears genetically highly heterogenous. Five genes (dystrophin, cardiac actin, desmin, lamin A/C and delta-sarcoglycan), and additional loci, have been identified in families in which dilated cardiomyopathy is isolated or associated with other cardiac or non-cardiac symptoms. It has been postulated that the molecular defect involved could lead to abnormal interactions between cytoskeletal proteins, responsible either for defect in force transmission or for membrane disruption. More recently, the identification of mutations in genes encoding sarcomeric proteins has led to a second hypothesis in which the disease might also result from a force generation defect. In non-monogenic dilated cardiomyopathy, susceptibility genes (role in the development of the disease) and modifier genes (role in the evolution/prognosis of the disease) have so far been identified. Some data suggest that the efficacy of angiotensin converting enzyme inhibitors, and side-effects, might be related to some genetic polymorphisms, such as the I/D polymorphism of the angiotensin converting enzyme gene. Although preliminary, these data are promising and might be the first step towards application of phamacogenetics in heart failure. This is of paramount importance as the medical treatment of heart failure is characterized by the need for polypharmacy. One of the major challenges of the next millenium, therefore, will be to identify genetic factors which might help define responders to major treatment classes, including angiotensin converting enzyme inhibitors, beta-adrenoreceptor antagonists, angiotensin AT1 receptor antagonists, spironolactone, vasopeptidase inhibitors and endothelin receptor antagonists.
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PMID:Are we ready for pharmacogenomics in heart failure? 1130 Oct 53

Endothelin (ET)-1 is a potent vasoconstrictor peptide produced in the myocardium that can exert important effects on cardiac myocyte growth and phenotype; cardiac natriuretic peptides (ANP and BNP) are known to act as physiological antagonists of ET-1. In this study a comparative determination of ET-1 receptors and of the local productions of ET-1 and of ANP and BNP was made in different sites of failing and nonfailing hearts. Tissue from right and left atrium, right and left ventricle and interventricular septum from seven adult heart transplant recipients with end-stage idiopathic dilated cardiomyopathy (functional class III and IV, with ejection fraction < 35%) and from four postmortem subjects without cardiac complications was analyzed. In failing hearts we observed a tendency to increase of density of binding sites, most evident in left ventricle (62.6+/-22.6 fmol/mg protein vs. 29.0+/-3.3, mean +/- SEM, p = ns). A prevalence of ET-A subclass, observed in all samples, resulted more pronounced in failing hearts where this increase, found in all the cardiac regions, was more evident in left ventricle (p = 0.0007 vs nonfailing hearts). The local concentrations of ET-1, ANP and BNP resulted significantly increased in failing hearts with respect to controls in all sides of the heart. In failing hearts we have observed a tendency to increase in endothelin receptor density mainly due to a significant upregulation of ET-A subtype and a parallel increase of the tissue levels of ANP, BNP and ET-1 indicating an activation of these systems in heart failure.
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PMID:Endothelin-1, endothelin-1 receptors and cardiac natriuretic peptides in failing human heart. 1140 Sep 14

Our understanding of the role of the endothelin system in human cardiovascular physiology and pathophysiology has evolved very rapidly since the initial description of its constituent parts in 1988. Endothelin-1 (ET-1) is the predominant endothelin isoform in the human cardiovascular system and has potent vasoconstrictor, mitogenic and antinatriuretic properties which have implicated it in the pathophysiology of a number of cardiovascular diseases. The effects of ET-1 have been shown to be mediated by 2 principal endothelin receptor subtypes: ET(A) and ET(B). The development of a range of peptidic and nonpeptidic endothelin receptor antagonists represents an exciting breakthrough in human cardiovascular therapeutics. Two main classes of endothelin receptor antagonist have been developed for possible human therapeutic use: ET(A)-selective and nonselective antagonists. Extensive laboratory and clinical research with these agents has highlighted their promise in various cardiovascular diseases. Randomised, placebo-controlled clinical trials have yielded very encouraging results in patients with hypertension and chronic heart failure with more preliminary data suggesting a possible role in the treatment and prevention of atherosclerosis and stroke. Much more research is needed, however, before endothelin receptor antagonists can be considered for clinical use.
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PMID:Endothelin receptor antagonists and cardiovascular diseases of aging. 1141 17

Evidence suggests that endothelin receptor antagonists may have therapeutic potential for the chronic treatment of heart failure. In the current study, the effects of an orally active mixed endothelin-A/endothelin-B (ETA /ETB ) receptor antagonist (enrasentan) were assessed in a model of cardiac hypertrophy and dysfunction (spontaneously hypertensive stroke prone rats) maintained on a high-salt/high-fat diet. Echocardiography was used to quantify cardiac performance and left ventricular dimensions. Enrasentan (1,200 and 2,400 parts per million in the high-salt/high-fat diet) had no significant effects on body weight and systolic blood pressure. However, increases in heart rate were not observed in the enrasentan-treated groups at 12 weeks (p < 0.05). Enrasentan-treated groups exhibited significantly improved survival (90-95% vs. 30% [control rats] at 18 weeks; p < 0.001). Enrasentan treatments also increased stroke volume (at 8, 12, and 16 weeks) and cardiac index (at 8 and 16 weeks) 33-50% and 45-63%, respectively. Enrasentan treatments reduced the relative wall thickness (14-27% at 8 and 12 weeks), ratio of left ventricular mass to body weight (20% at 12 weeks), and ratio of terminal heart weight to body weight (16-23%, p < 0.05). Finally, circulating aldosterone concentration (54-57%) and proANF fragment (33%) were reduced in enrasentan-treated groups (54-57% and 33%, respectively). Mixed ETA /ETB receptor antagonism improves cardiac performance and attenuates ventricular remodeling and premature mortality in an aggressive hypertension model.
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PMID:Enrasentan improves survival, limits left ventricular remodeling, and preserves myocardial performance in hypertensive cardiac hypertrophy and dysfunction. 1158 31


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