Prognostic value of longitudinal strain and ejection fraction in Friedreich's ataxia.

BACKGROUND: Friedreich's ataxia (FA) is a rare autosomal recessive mitochondrial disease most commonly due to a triplet repeat expansion guanine-adenine-adenine (GAA) in the FXN gene. Cardiac disease is the major cause of death, patients with reduced left ventricular ejection fraction (LVEF) having the worse prognosis. Longitudinal strain (LS) appeared to be a better predictor of outcome than LVEF in different diseases. We compared the prognostic value of LS measured from the 4 chambers view to LVEF. METHODS: From 2003 to 2017 consecutive patients with FA were included and LS analysis was retrospectively performed. RESULTS: We studied 140 patients, with a median age of 34 (26-41) years (Q1-Q3) with age at onset of 14 (11-19) years and GAA repeats on the shorter allele of 600 (467-783) pb. Mean LS was 19.9 ± 5.0% and LVEF 64 ± 8%. After a mean follow-up of 7.4 ± 3.9 years, 14 patients died. In univariate Cox analysis, all-cause mortality was associated with: LS (HR 0.83; 95%CI, 0.75-0.91, p = 0.0002), LVEF (HR 0.30; 95%CI, 0.19-0.49, p < 0.0001), GAA repeats on the shorter allele (HR 1.29; 95%CI, 1.10-1.51, p = 0.002), age at onset (HR 0.87; 95%CI, 0.77-0.98, p = 0.018), LVSystolic Diameter (HR 1.17; 95%CI, 1.09-1.26, p < 0.0001), LVMass index (HR 1.02; 95%CI, 1.00-1.04, p = 0.027), and LVDiastolic Diameter (HR1.12; 95%CI, 1.01-1.23, p = 0.028). In multivariate analysis, LVEF was the only independent predictor of mortality (HR 0.41; 95%CI, 0.23-0.74, p = 0.0029). CONCLUSION: In FA, LS was not an independent predictor of mortality, LVEF remained the only independent predictor in the present study.

High efficacy and safety profile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the alfa group.

Pivotal phase II studies in acute myeloblastic leukemia (AML) patients in first relapse have used gemtuzumab ozogamicin (GO) (Mylotarg) at a dose of 9 mg/m(2) on days 1 and 14. These studies showed a 26% response rate (13% complete remission (CR) and 13% CRp (complete remission with incomplete platelet recovery)) but with high degree of hematological and liver toxicities. Based on in vitro studies showing a re-expression of CD33 antigenic sites on the cell surface of blasts cells after exposure to GO, we hypothesized that fractionated doses of GO may be efficient and better tolerated. Fifty-seven patients with AML in first relapse received GO at a dose of 3 mg/m(2) on days 1, 4 and 7 for one course. Fifteen patients (26%) achieved CR and four (7%) CRp. Remission rate correlated strongly with P-glycoprotein and MRP1 activities. The median relapse-free survival was 11 months, similar for CR or CRp patients. Median duration of neutropenia < 500/microl and thrombocytopenia < 50,000/microl were, respectively, 23 and 21 days. No grade 3 or 4 liver toxicity was observed. No veno-occlusive disease occurred after GO or after hematopoietic stem cell transplantation given after GO in seven patients. Mylotarg administered in fractionated doses demonstrated an excellent efficacy/safety profile.

Paraquat poisoning in Western French Guyana: a public health problem persisting ten years after its withdrawal from the French market.

OBJECTIVE: Paraquat poisoning has almost disappeared from metropolitan France following its ban from the European market ten years ago. However, due to neighboring countries still authorizing paraquat use, French Guyana seems in a different situation. Here we aimed to report a series of paraquat-poisoned patients admitted to the emergency department of the Western French Guyana Hospital in Saint-Laurent du Maroni, to raise awareness of national health authorities on this persistent major issue. PATIENTS AND METHODS: We conducted a retrospective observational study describing the clinical features, the prognostic factors and the final outcome of paraquat-poisoned patients admitted to the emergency department between January 2008 and August 2014. RESULTS: Twenty-six paraquat-poisoned patients were included in the study. The median estimated paraquat dose intentionally ingested was 105 mg/kg (interquartile range, IQR: 359). Eighteen patients were treated with the cyclophosphamide/dexamethasone combination and seventeen with N-acetylcysteine in addition to the usual supportive care. Six patients survived and twenty died within a median 36h delay after admission (IQR: 130). Death was associated with cardiovascular (65%) and respiratory (35%) failure. Based on a bivariate analysis, predictive factors of death included (p≤0.05): advanced age, higher ingested paraquat dose, altered renal function, hypokalemia, acidosis, and dark blue dithionite test, observed on hospital admission. CONCLUSIONS: Paraquat poisoning still persists in French Guyana despite its withdrawal from the market. It is possible to determine the probability of death on patient admission based on routine clinical and biological parameters. There is an urgent need to request neighboring countries to ban paraquat with the aim of eradicating this dramatically life-threatening poisoning.

Population pharmacokinetic-pharmacodynamic analysis of fluindione in patients.

OBJECTIVE: Fluindione is a vitamin K antagonist with a long half-life. This study was designed to investigate the pharmacokinetics and pharmacodynamics of multiple doses of fluindione in patients. METHODS: In a learning group of 49 patients who began fluindione treatment, blood samples were taken 12, 18, or 24 hours after one, three, and five doses. Concentration of fluindione, activity of clotting factors II, VII, IX and X, prothrombin complex activity (PCA), and international normalized ratio (INR) were measured. An indirect-response pharmacodynamic model was used for each effect. A comprehensive analysis was performed with a nonparametric population approach. The model was evaluated in 24 other patients: blood samples were taken 24 hours after two, three, four, and six doses; and PCA and INR were observed. RESULTS: Analysis of concentrations and clotting factor activities showed notably that (1) fluindione has a long half-life (median, 69 hours), and (2) concentration that inhibits the synthesis of the clotting factors by 50% varied for each factor, with a median ranging from 0.25 to 2.05 mg.L-1 for factors VII and II, respectively. The results obtained for INR and PCA were validated in the 24 subsequent patients. CONCLUSION: The population approach allowed the comparison of several pharmacodynamic submodels. This first application of the indirect-response model to multiple oral anticoagulant doses in patients confirmed that both the pharmacokinetics and the pharmacodynamics of fluindione show substantial interindividual variability.

Characterization of interleukin-1 receptor antagonist isoform expression in the brain of lipopolysaccharide-treated rats.

The endogenous interleukin-1 receptor antagonist is the natural inhibitor of the biological effects of interleukin-1 during inflammation. Interleukin-1 receptor antagonist refers to three isoforms: one secreted and two intracellular forms (types I and II). The objective of the present study was to investigate the expression of interleukin-1 receptor antagonist isoforms in the rat brain in vivo in response to an i.p. injection of lipopolysaccharide. The interleukin-1 receptor antagonist was studied at the messenger and protein levels by reverse transcription-polymerase chain reaction and western blot analysis, respectively. Interleukin-1 receptor antagonist messenger RNA was constitutively expressed in the brain and its expression increased in response to lipopolysaccharide. The three interleukin-1 receptor antagonist protein isoforms were up-regulated after lipopolysaccharide treatment in a time-dependent manner. Their relative expression differed according to the isoform and brain region studied. Double immunofluorescence staining revealed interleukin-1 receptor antagonist positive neurons and microglia in hippocampus 24h after lipopolysaccharide stimulation. These results demonstrate for the first time that brain cells are able to produce interleukin-1 receptor antagonist isoforms in response to a peripheral immune challenge with a predominance of the secreted over intracellular forms.

Effects of bisoprolol on heart rate variability in heart failure.

Analysis of heart rate variability (HRV) provides a non-invasive index of autonomic nervous system activity. HRV has been shown to be reduced in heart failure. Preliminary data indicate that beta blockers improve clinical status in patients with heart failure, but HRV improvement remains to be demonstrated. Fifty-four patients from the randomized double-blind, placebo-controlled Cardiac Insufficiency Bisoprolol Study were included in the HRV study. The bisoprolol daily dose was 5 mg once daily. We assessed HRV during 24-hour Holter recordings before randomization and after 2 months of treatment. HRV as measured in the time domain by root-mean-square successive differences (rMSSD), the percentage of adjacent RR differences >50 ms (pNN50), and the SD of RR intervals (SDNN), and in the frequency domain by high-frequency (0.16 to 0.40 Hz) and low-frequency (0.04 to 0.15 Hz) power. Most patients were in New York Heart Association functional class III. The mean left ventricular ejection fraction was 27 +/- 7%, and heart failure was idiopathic or ischemic. After 2 months, the patients receiving bisoprolol had a reduced mean heart rate compared with that in placebo patients (p=0.0004). Bisoprolol increased 24-hour rMSSD (p=0.04) and 24-hour pNN50 (p=0.04), daytime SDNN (p=0.05), and daytime high-frequency power (p=0.03) power. Bisoprolol induced a significant increase in HRV parameters related to parasympathetic activity in heart failure. Increased vagal tone may contribute to the protective effect of beta blockers and may have prognostic implications.

Parasympathetic activity in Friedrich's ataxia.

We compared 19 patients with Friedreich's ataxia, a progressive hereditary neuromuscular disorder, with 19 healthy age-matched subjects. During nighttime, patients had shorter mean RR and decreased heart rate variability parameters related to parasympathetic activity than healthy subjects, whereas no difference occurred during daytime.

Prognostic value of neurohormonal activation and cardiopulmonary exercise testing in patients with chronic heart failure.

We compared the value of plasma neurohormones and cardiopulmonary exercise testing for predicting long-term prognosis in patients with moderate congestive heart failure (CHF). We studied 264 consecutive patients with CHF due to left ventricular systolic dysfunction. Plasma atrial natriuretic peptide (ANP), norepinephrine, and endothelin-1 were measured at rest in all patients, who also underwent a symptom-limited maximal exercise with oxygen consumption (VO(2)) determination. After a median follow-up of 789 days, 52 deaths and 31 heart transplantations occurred, of which 4 were urgent. In an univariate analysis, New York Heart Association functional class, systolic blood pressure at rest, left ventricular end-diastolic diameter, left ventricular ejection fraction, peak VO(2), percent of predicted peak VO(2), plasma ANP, plasma norepinephrine, and plasma endothelin-1 were associated with survival without urgent heart transplantation. In a multivariate stepwise regression analysis, only plasma ANP (p = 0.0001), left ventricular ejection fraction (p = 0.007), and plasma norepinephrine (p = 0.035), but neither peak VO(2) nor percentage of predicted peak VO(2), were independent predictors of death or urgent heart transplantation. Determination of plasma ANP and norepinephrine provides additional independent information for long-term prognostic determination compared with exercise testing alone. Measurement of plasma neurohormones should therefore be considered routinely as a complementary or alternative tool for identifying high-risk patients with moderate CHF.

Plasma levels and molecular forms of proatrial natriuretic peptides in healthy subjects and in patients with congestive heart failure.

A specific and sensitive radioimmunoassay (RIA) for the N-terminal fragment of proatrial natriuretic peptide (NproANP) was developed. Antiserum raised in rabbits against a mixture enriched with prohormone was 100% cross-reactive with human proANP(1-30). Plasma concentrations of proANP(1-30) and ANP immunoreactivities (ir-) were simultaneously measured in healthy subjects and patients with congestive heart failure (CHF; 26 dilated cardiomyopathy and 5 ischemic heart disease). High plasma levels of both ir-proANP(1-30) and ir-ANP were detected in CHF patients. Circulating ir-ANP levels were elevated in New York Heart Association functional Classes II and III patients but not in Class I patients. However, plasma levels of ir-proANP(1-30) were higher in asymptomatic patients than in healthy subjects, and markedly increased in patients of Classes II and III. Analysis of ir-proANP(1-30) by gel filtration chromatography or reverse-phase high pressure liquid chromatography revealed a 10 kDa peptide circulating as a distinct entity. These findings indicate that: (i) the most probable form of NproANP in human plasma is a 10 kDa peptide and (ii) in CHF patients the rise in plasma ir-proANP(1-30) levels is more pronounced than the variation in plasma ir-ANP. Thus, NproANP plasma levels may prove to be a more sensitive marker of left ventricular dysfunction than ANP.

Central injection of IL-10 antagonizes the behavioural effects of lipopolysaccharide in rats.

Peripheral (i.p.) and central (i.c.v.) injections of lipopolysaccharide (LPS) have been shown to induce brain expression of proinflammatory cytokines and to depress social behaviour in rats, increase duration of immobility and induce body weight loss. To determine if the anti-inflammatory cytokine, interleukin-10 (IL-10) is able to modulate these effects, recombinant rat IL-10 was injected in the lateral ventricle of the brain (30, 100, 300 ng/rat) prior to i.p. or i.c.v. injection of LPS (250 micrograms/kg or 60 ng/rat, respectively). Social exploration was depressed for 6 h after i.p. LPS injection. This effect was attenuated by IL-10 (30 and 100 ng) 2 h after injection, whereas the highest dose of IL-10 blocked the depression of social interaction for 6 h after LPS injection. IL-10 produced the same effects on the increase of immobility although the results did not reach significance. Social exploration was depressed 3 h after i.c.v. LPS injection, and this was accompanied by increased immobility. These effects were totally blocked by i.c.v. IL-10 (300 ng/rat). Rats lost body weight after i.c.v. LPS, and this effect was attenuated by i.c.v. IL-10. These results indicate that IL-10 is able to modulate the production and/or action of central proinflammatory cytokines.

Effect of serotonin on cytokine mRNA expression in rat hippocampal astrocytes.

Serotonin is a widely distributed neurotransmitter which elicits a range of central activities. We examined the effect of serotonin on cytokine mRNA expression by rat hippocampal astrocytes in primary cultures. Semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis shows that interleukin-6 (IL6) mRNA is expressed after 10(-12) M serotonin stimulation whereas transforming growth factor-beta (TGF beta) and tumor necrosis factor (TNF alpha) are induced by 10(-10) M serotonin. These inductions appeared after 1 h stimulation for IL6 and TNF alpha, whereas that of TGF beta appeared after 4 h. The present results provide the first evidence that serotonin can influence astrocyte cytokine production, and thus this neurotransmitter may be considered a potential neuroimmunomodulator.

NF kappa B activation in mouse pituitary: comparison of response to interleukin-1 beta and lipopolysaccharide.

The mouse anterior pituitary contains both types of interleukin (IL)-1 receptors, IL-1 receptor type I (IL-1RI) and IL-1 receptor type II (IL-1RII). These receptors are expressed mainly on somatotroph cells. In the present study, the ability of the mouse pituitary to respond in vivo to IL-1 or to lipopolysaccharide (LPS) was demonstrated by measuring, with an electrophoretic mobility shift assay, the presence of an active NF kappa B complex in cell nuclei from pituitaries of mice injected intraperitoneally with recombinant rat-IL-1 beta or LPS. Using immunohistochemistry with an antibody directed against the p65 NF kappa B subunit, a rapid and transient NF kappa B response to LPS was observed. This response was present predominantly in the nuclei of glial fibrillary acidic protein (GFAP)-positive cells and F4/80-labelled cells of the posterior and the anterior pituitary 15 min after stimulation and became faint after 2 h. In comparison, the early and strong NF kappa B response to IL-1 beta treatment was localized into somatotroph cells, GFAP positive cells and F4/80-labelled cells of the posterior and anterior pituitary. Activation of NF kappa B in response to IL-1 beta was no longer apparent in IL-1RI knockout mice, confirming that this receptor is essential for the transduction of IL-1 signal in the pituitary, but remained after LPS treatment. In addition, we investigated the effect of IL-1 on target genes by measuring the mRNA and proteins synthesis of growth hormone (GH), IL-6 and IL-1ra in the pituitary and the plasma. IL-1 beta was shown to induce a rapid and strong synthesis of IL-6 and IL-1ra in the pituitary but failed to regulate GH contents or release. These data suggest that the pituitary is able to respond to a systemic infection via cytokine-mediated responses transduced by IL-1.

Developmental expression of cytokine genes in the cortex and hippocampus of the rat central nervous system.

Cytokines are now considered as constitutive factors of the brain. Some of them are involved in the mechanism regulating lineage commitment and cellular differentiation of the central nervous system (CNS). We describe here the analysis of gene expression in cortex and hippocampus, of interleukin-1 alpha (IL1), interleukin-2 (IL2), interleukin-6 (IL6), macrophage-colony stimulating factor-1 (MCSF) and monocyte chemoattractant protein-1 (MCP1) in fetal (day 18 of gestation; G18), newborn (postnatal day 2; P2), young (postnatal day 21; P21) and adult rat using the reverse transcriptase-polymerase chain reaction (RT-PCR). IL6 and MCP1 mRNA presented distinct patterns of expression levels: IL6 mRNA level is most highly expressed in the embryonic cortex, whereas MCP1 is expressed at a maximal level in the postnatal day 2 cortical area. In the hippocampus, IL6 is most expressed at the adult stage and MCP1 exhibits an equal level of expression from day two to the adult stage. However, under our experimental conditions, IL1 alpha, IL2 and MCSF mRNA were not observed. Thus, certain cytokine genes, each with a specific pattern, are expressed in the rat CNS in adult and during ontogenesis. These observations suggest that cytokines might be involved as regulating factors promoting CNS development.

Cytokines and the brain. Bischenberg, October 11-15 1992.

The congress on cytokines, held in Bischenberg (October 11-15, 1992), was marked by the quality of the presentations and a limited number of participants which helped to foster communication. Recent data on biological activities of cytokine and cytokine receptor interactions of the oldest members of this family were reported as well as the mechanisms of inhibition of their activities. Other reports highlighted the growing number of cytokines identified in the brain, their central distribution, and the relationship between peripheral and central compartments of cytokines. But this meeting was also marked by a number of reports, based on different experimental models, that the biological activities of cytokines were of physiological relevance in fever, neuropathologies and behaviour. Interesting discussions raised fundamental questions about whether cytokines could be considered as neurotrophic factors, the role of the blood brain barrier and the signals regulating transmission between the immune and nervous systems. The implication of cytokines in central functions reinforces the concept of a central immune response encompassing soluble and cellular interactions between cerebral cells themselves and between cerebral and immune cells.

Interleukin-1 signaling in mouse astrocytes involves Akt: a study with interleukin-4 and IL-10.

Although astrocytes are well known to respond to the pro-inflammatory cytokine, interleukin-1 (IL-1), the receptor and post-receptor mechanisms that mediate IL-1 effects in this cell type are complex and need further investigation. Using electrophoretic mobility shift assay (EMSA), we show that IL-1beta-induced NFkappaB activation in primary culture of mouse astrocytes is mediated by the interaction of this cytokine with the IL-1 type I receptor/IL-1 receptor accessory protein complex, as demonstrated by the ability of blocking monoclonal antibodies against these receptors to attenuate NFkappaB activation. In addition to NFkappaB activation, IL-1beta is also able to phosphorylate Akt, as demonstrated by Western blot. The observation that addition of wortmanin, that specifically blocks Akt phosphorylation, also attenuates NFkappaB activation can be interpreted that Akt phosphorylation interacts with IL-1 signaling pathways. Furthermore, anti-inflammatory cytokines such as IL-4 and IL-10 that block IL-1b-induced NFkappaB activation also attenuate IL-1beta-induced Akt phosphorylation, despite the fact that IL-4 and IL-10 in isolation induced Akt phosphorylation. All these findings point to an interaction between Akt and NFkappaB-dependent IL-1 signaling in the primary culture of astrocytes.

Production of interleukin-1 receptor antagonist isoforms by microglia in mixed rat glial cells stimulated by lipopolysaccharide.

Although the natural interleukin-1 receptor antagonist (IL-1Ra) has been shown to be produced by microglial cells in response to immune stimuli, nothing was known about the ability of these cells in primary culture to produce the different isoforms of IL-1Ra. Using RT-PCR, we first confirmed that mixed glial cell cultures from newborn rats respond to the cytokine inducer, lipopolysaccharide, by synthesizing IL-1Ra mRNA. Using double immunostaining, we showed that IL-1Ra was detected in microglia but not in astrocytes. Using Western blotting, we finally demonstrated that the IL-1Ra1 isoform was secreted in the supernatant of mixed glial cell cultures, and its production increased in response to lipopolysaccharide. The three different IL-1Ra isoforms were constitutively expressed in cell lysates and their levels increased after lipopolysaccharide treatment, except for IL-1Ra3. These results point to the ability of microglial cells in primary culture to produce the different isoforms of IL-1Ra.

Hemodynamic and neurohormonal effects of flosequinan in patients with heart failure.

In a double-blind, placebo-controlled study, the central and peripheral hemodynamic effects of 100 mg oral flosequinan and the impact of this drug on neurohormonal activation were noninvasively evaluated in 18 patients with congestive heart failure, after the first administration and after 10 days of treatment. No significant hemodynamic and neurohormonal changes were observed after acute administration. After 10 days, flosequinan produced central and peripheral hemodynamic improvement characterized by an increase in left ventricular circumferential fiber shortening velocity (+12%), a decrease in total systemic resistance (-36%), and an increase in leg blood flow (+37%). No significant changes were observed in heart rate and arterial pressure in patients receiving flosequinan, though a slight increase in heart rate (+17%) was recorded. Despite these favorable hemodynamic effects, flosequinan significantly increased plasma norepinephrine (+38%) and plasma renin activity (+13%) after 10 days of treatment. Thus, the beneficial central and peripheral hemodynamic effects of flosequinan are accompanied by activation of the sympathetic and reninangiotensin systems. This might be related to the unfavorable effects of the drug on survival in patients with heart failure.

Cytokines as mediators in the central nervous system.

Cytokines are soluble mediators involved in cell-cell regulations in the immunological and the hematopoietic system. We review various cytokine effects on the central nervous system, including growth-promoting activity, neuro-modulatory action, fever induction, sleep and decreased food intake. In addition, cytokines, neuropeptides, neurotransmitters and hormones all participate in an intricate inter-relationship to contribute to the development and maintenance of brain homeostasis. Cytokines are also involved in the wounding responses of injured brain after trauma, infection or neuro-degenerative processes. Pharmacological modulation of the expression and/or actions of cytokines in the brain may represent a new field of research of therapeutic benefit in the treatment of central disorders.

[Role of intravascular brachytherapy in the prevention of vascular restenosis after angioplasty]. / Rôle de la curiethérapie endovasculaire dans la prévention de la resténose vasculaire après angioplastie.

About 30% of patients who underwent percutaneous transluminal coronary angioplasty show evidence of restenosis, which appears to be independent of the angioplasty method used. The restenosis is due of two factors, firstly migration of smooth vascular muscle cells of the vascular media to the intima and multiplication which lead to the formation of a neo-intima. Irradiation limits the proliferation by acting of the cells in the mitotic stage. The vascular target volume is not very thick and is difficult to define it, that why brachytherapy seems to be the best procedure to prevent restenosis. However, the development of this treatment present many difficulties. Different irradiation techniques have been studied. Such techniques include catheter containing radioactive sealed source, radioactive stent, or balloon containing radioactive liquid inside. Each of these methods have their own advantages, inconveniences, problems and risks. Radioisotope may be either beta or gamma emitters. Gamma emitter presents problems for radioprotection but the satisfactory dose distribution may be difficult to obtain using beta emitter. Choice of dose, dose rate and delay between the end of angioplasty and the beginning of brachytherapy is subject to some discuss. Animal experiments using radioisotope have shown reduction in cell proliferation. Human trials showed feasibility, safety of the method and real impact on restenosis prevention. However, long-term efficacy has not been proved because the follow-up of the patients is too short. A randomized trial of 192Ir brachytherapy for prevention of restenosis has recently shown the efficacy in short and median term. However, long term efficiency and secondary effects have not yet been established as the follow up time of this study is still too short. That is why, collaboration between cardiologists and radiotherapists and physicists is indispensable to enable the development of an optimal technique.

[Endothelins in chronic cardiac insufficiency]. / Les endothélines dans l'insuffisance cardiaque chronique.

The endothelins are a family of three structurally related peptides. Endothelin-1 (ET-1) is formed from the big endothelin by the action of the endothelin converting enzyme. It acts on two types of receptor, ETA and ETB. ET-1 is a powerful vasoconstrictor but also has a number of other effects: positive inotropism and stimulation of cell growth, for example. Endothelin is found in the general circulation but its role is mainly local in maintaining vascular tone. The endothelin system is activated in cardiac failure and increased concentrations of plasma endothelin increased, ET-1 converting enzyme and increased density of endothelin receptors are observed. The action of the endothelin system and its relationships with other neuro-hormonal systems activated in cardiac failure are not fully understood but research is under way which should clarify these mechanisms in the next few years. In view of the properties of endothelin, inhibition of its action might be particularly useful in patients with cardiac failure. Its action can be blocked either by preventing its synthesis by inhibiting the endothelin converting enzyme or by blocking the endothelin receptor. Endothelin receptor blockade is associated with beneficial haemodynamic changes, an action on ventricular remodelling and possibly an improved prognosis. Many substances, either selective for ETA receptors or mixed ETA and ETB receptor blockers, are under development. The benefits of these products will require confirmation by large scale clinical trials.