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      ET-1 Lys198Asn and ET A Receptor H323H Polymorphisms in Heart Failure

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          Background: The endothelin (ET) system plays a central role in the control of myocardial function and its pathophysiology. The aim of the present study was to explore whether genetic variations of ET-1 (G/T substitution that predicts an Lys/Asn change at codon 198) and its receptor ET<sub>A</sub> (T/C in exon 6, H323H) could predispose carriers to heart failure (HF). Methods: Genotyping at these two loci was done in 122 patients with HF [echocardiographic left ventricular ejection fraction (LVEF) ≤40%] and 216 age-matched subjects without HF. Causes of HF included ischemic (n = 96) and idiopathic cardiomyopathies (n = 26). Results: The ET-1 Lys198Asn was significantly associated with the occurrence of HF (p = 0.005). The risk of HF was independently increased among Asn/Asn in comparison to Lys carriers (OR = 3.2, p = 0.03). Moreover, homozygous carriers of both ET-1 and ET<sub>A</sub> variants showed a marked increase in the risk of HF (adjusted OR = 8.6, p = 0.005), displayed significantly lower LVEF (p = 0.002) and higher left ventricular end-diastolic (p = 0.03) and end-systolic diameters (p = 0.04; for Asn/Asn and TT vs. Lys and C carriers of the ET-1 and ET<sub>A </sub>polymorphisms, respectively). Furthermore, the extent of coronary artery disease (r = –0.62, p < 0.0001) and the Asn/Asn and TT double genotype (r = –0.30, p = 0.0001) were the only significant and independent predictors of LVEF by multivariate analysis. Conclusions: The ET-1 Lys198Asn and ET<sub>A</sub> receptor H323H polymorphisms seem to act synergistically to increase the risk of HF.

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          Most cited references 22

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          Guidelines for the diagnosis and treatment of chronic heart failure.

           ,  Espen Remme,  K Swedberg (2001)
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            Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the EndothelinA Receptor Antagonist Trial in Heart Failure (EARTH): randomised, double-blind, placebo-controlled trial.

            Endothelin-receptor blockade provides haemodynamic benefit in experimental and clinical heart failure. We aimed to measure the effects of long-term endothelin-blockade on left-ventricular (LV) remodelling and clinical outcomes in patients with chronic heart failure. 642 patients with chronic heart failure were assigned the oral endothelin(A)-antagonist darusentan at 10, 25, 50, 100, or 300 mg daily or placebo for 24 weeks in addition to standard therapy in a randomised, double-blind, placebo-controlled trial. In the 50-300 mg groups, darusentan was uptitrated over 6 weeks. Primary endpoint was change in LV end-systolic volume (LVESV) at 24 weeks from baseline, measured by MRI. All patients for whom assessable MRI scans were available at baseline and follow-up were included in the analysis. Darusentan was well tolerated. LVESV could be assessed in 485 (76%) patients with paired MRI data at baseline and 6 months. The change in LVESV was not significantly different from that with placebo at any dose (mean difference from placebo 1.27 mL [95% CI -9.9 to 12.4] with 10 mg dose, -1.84 mL [-13.0 to 9.3] with 25 mg, -5.68 mL [-16.9 to 5.6] with 50 mg, -4.05 mL [-15.5 to 7.4] with 100 mg, and -4.34 mL [-15.7 to 7.0] with 300 mg). Heart failure worsened in 71 (11.1%) patients, and 30 (4.7%) died during the study with no difference between groups. Endothelin(A) blockade with darusentan did not improve cardiac remodelling or clinical symptoms or outcomes in patients with chronic heart failure receiving an angiotensin-converting-enzyme inhibitor, beta blocker, or aldosterone antagonist. Thus, endothelin(A) blockade is unlikely to be useful as an add-on treatment in such patients.
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              Inhibition of myocardial endothelin pathway improves long-term survival in heart failure.

              Occlusion of the diseased coronary artery in humans causes acute myocardial infarction, survivors of which have a high risk for the development of chronic heart failure. Cardiac myocytes and vascular endothelial cells produce endothelin-1 (refs 2-4), which increases the contractility of cardiac muscle and of vascular smooth muscle cells. Endothelin-1 also exerts long-term effects such as myocardial hypertrophy, and causes cellular injury in cardiac myocytes. Production of endothelin-1 is markedly increased in the myocardium of rats with heart failure, and acute application of an endothelin-receptor antagonist decreases myocardial contractility in such rats, indicating that myocardial endothelin-1 may help to support contractility of the failing heart. But we report here that the upregulated myocardial endothelin system may contribute to the progression of chronic heart failure, because long-term treatment with an endothelin-receptor antagonist greatly improved the survival of rats with chronic heart failure. This beneficial effect was accompanied by significant amelioration of left ventricular dysfunction and prevention of ventricular remodelling, in which there is usually an increase in the ventricular mass and cavity enlargement of the ventricle.

                Author and article information

                S. Karger AG
                May 2006
                11 May 2006
                : 105
                : 4
                : 246-252
                aCNR Institute of Clinical Physiology, Massa, and bS. Anna School of University Studies and Doctoral Research, University of Pisa, Pisa, Italy
                92374 Cardiology 2006;105:246–252
                © 2006 S. Karger AG, Basel

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                Figures: 1, Tables: 4, References: 31, Pages: 7
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