Long-Term Effects of Bosentan on Cardiovascular Events in Hispanic Patients with Intermittent Claudication: Four-Year Follow-up of the CLAU Trial

Haro, Joaquín De; Bleda, Silvia; Gonzalez-Hidalgo, Carmen; Michel, Ignacio; Aciń, Francisco

doi:10.1007/s40256-018-0307-y

Cited by 6 publications

(7 citation statements)

References 17 publications

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“…266 Possible long-term coronary benefits are also suggested from the randomized CLAU trial (Clinical and Endothelial Function Assessment on Endothelin Antagonist Therapy in Patients With Intermittent Claudication): in patients with moderate peripheral atherosclerosis, bosentan therapy reduced major cardiovascular adverse events, including myocardial infarction. 267 The prognostic value of circulating ET-1 concentrations patients with acute myocardial infarction has been assessed both on admission and on the first day after PCI. In high-risk STEMI patients, ET-1 levels on admission predict no-flow phenomena after PCI, as well as long-term mortality.…”

Section: Coronary Artery Disease/ischemic Heart Diseasementioning

confidence: 99%

Endothelin: 30 Years From Discovery to Therapy

2019

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Discovered in 1987 as a potent endothelial cell–derived vasoconstrictor peptide, endothelin-1 (ET-1), the predominant member of the endothelin peptide family, is now recognized as a multifunctional peptide with cytokine-like activity contributing to almost all aspects of physiology and cell function. More than 30 000 scientific articles on endothelin were published over the past 3 decades, leading to the development and subsequent regulatory approval of a new class of therapeutics—the endothelin receptor antagonists (ERAs). This article reviews the history of the discovery of endothelin and its role in genetics, physiology, and disease. Here, we summarize the main clinical trials using ERAs and discuss the role of endothelin in cardiovascular diseases such as arterial hypertension, preecclampsia, coronary atherosclerosis, myocardial infarction in the absence of obstructive coronary artery disease (MINOCA) caused by spontaneous coronary artery dissection (SCAD), Takotsubo syndrome, and heart failure. We also discuss how endothelins contributes to diabetic kidney disease and focal segmental glomerulosclerosis, pulmonary arterial hypertension, as well as cancer, immune disorders, and allograft rejection (which all involve ET A autoantibodies), and neurological diseases. The application of ERAs, dual endothelin receptor/angiotensin receptor antagonists (DARAs), selective ET B agonists, novel biologics such as receptor-targeting antibodies, or immunization against ET A receptors holds the potential to slow the progression or even reverse chronic noncommunicable diseases. Future clinical studies will show whether targeting endothelin receptors can prevent or reduce disability from disease and improve clinical outcome, quality of life, and survival in patients.

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Section: Coronary Artery Disease/ischemic Heart Diseasementioning

confidence: 99%

Endothelin: 30 Years From Discovery to Therapy

2019

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“…Patients were randomized to receive bosentan for 12 weeks or placebo, associating the BMT. During the median follow-up of 34 months, five major adverse events (composite of target limb revascularization, amputation, myocardial infarction, allcause death) occurred in the control group; and the ratio of event-free survival for major adverse events was higher in the bosentan group (100% vs. 66%, P ¼ 0.01) [30]. Hence, the use of bosentan in the early stages of PAD may prevent CVE and adverse limb events.…”

Section: Bosentanmentioning

confidence: 94%

“…The Clinical and Endothelial Function Assessment after Endothelin Receptor Antagonist (CLAU) trial [30] was an RCT, assessing the efficacy of bosentan on the endothelial function, inflammatory status and claudication distance among 56 patients with PAD as compared with conventional therapy. Patients were randomized to receive bosentan for 12 weeks or placebo, associating the BMT.…”

Section: Bosentanmentioning

confidence: 99%

“…Bosentan is an endothelin receptor antagonist, and it might be beneficial in patients with low-to-mild stages of PAD, due to its antifibrotic, antihypertrophic, anti-inflammatory properties, and vasodilate function [30]. Hence, bosentan may decrease plasma CRP levels and reverse the pro-inflammatory status by improving endothelial function [30,31].…”

Section: Bosentanmentioning

confidence: 99%

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Review new concepts in pharmacotherapy for peripheral arterial disease

Kotalczyk

Vallabhaneni

Lip

2021

Current Opinion in Cardiology

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Purpose of reviewTo provide an overview of new concepts in the pharmacotherapy of patients with peripheral artery disease (PAD).Recent findingsModern therapeutic strategies for patients with PAD include specific symptom management and multidisciplinary prevention of cardiovascular events. Low-dose rivaroxaban in combination with aspirin improves outcomes compared with aspirin monotherapy among patients with PAD. Other novel concepts include the use of bosentan, vorapaxar or sildenafil among symptomatic patients with PAD. Likewise, lipid-lowering therapy reduces the risk of major cardiovascular and limb events.SummaryPersonalized management, identification of risk factors and shared-decision making are crucial in improving the best medical therapy for patients with PAD. Further studies are needed to assess the long-term safety and efficacy of novel strategies in real-world patients.

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“…In pathologic conditions like chronic heart failure (CHF), ET-1 signaling leads to positive myocardial inotropy, arrhythmogenesis, an acceleration of cardiac hypertrophy and growth of cardiac fibroblasts. − Increased plasma ET-1 levels have been found in animal models of myocardial infarction (MI). − In clinical investigations, elevated levels of ET-1 and related peptides shortly after acute MI positively correlated with infarct size and served as a prognostic factor for survival rates. ,− In mammals, both ET A R and ET B R expression is found throughout the cardiac muscle, including the coronary vasculature. Cardiomyocytes express predominantly ET A R, while both receptors are present on cardiac fibroblasts. ,, In cardiovascular pathologies, ET receptors have been found to be not only up-regulated but also down-regulated, and the largest effects are described for ET A R. − Treatment with ET receptor antagonists in a rat model of myocardial infarction had revealed beneficial effects when these were given delayed after MI but revealed detrimental effects when applied immediately post MI. − A number of endothelin receptor antagonists gave promising results in the treatment of diverse cardiovascular diseases such as pulmonary arterial hypertension (PAH), atherosclerosis, as well as heart and renal failure. − However, results are often contradictory, and elaborated clinical trials with intravenous tezosentan, an unspecific ET A R/ET B R antagonist, ended with disappointing results. , All these findings emphasize the importance of the endothelin axis in the realm of myocardial pathologies. Only a few clinical trials showed benefit when blocking ET action in disease, and the only FDA-approved compounds are the mixed ET A R/ET B R antagonists Macitentan and Bosentan and the ET A R-selective drug Ambrisentan; all of these are approved for the treatment of PAH. ,, In the setting of MI, it seems unclear when and how manipulation of the ET axis improves clinical outcome.…”

Section: Introductionmentioning

confidence: 99%

Targeting Endothelin Receptors in a Murine Model of Myocardial Infarction Using a Small Molecular Fluorescent Probe

et al. 2019

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The endothelin-(ET-)axis plays a pivotal role in cardiovascular diseases.Enhanced levels of circulating ET-1 have been correlated with inferior clinical outcome after myocardial infarction (MI) in humans. Thus, the evaluation of endothelin-A receptor (ETAR) expression over time in the course of myocardial injury and healing may offer valuable information towards the understanding of ET-axis involvement in MI. We developed an approach to track the expression of ETAR with a customized molecular imaging probe in a murine model of MI. The small molecular probe based on the ETAR selective antagonist 3-(1,3-Benzodioxol-5-yl)-5-hydroxy-5-(4-methoxyphenyl)-4-[(3,4,5-tri-methoxyphenyl)methyl]-2(5H)-furanone (PD156707) was labelled with fluorescent dye IRDye800cw. Mice undergoing permanent ligation of the left anterior descending artery (LAD) were investigated at day 1, 7 and 21 post surgery after receiving an i.v. injection of the ETAR probe. Cryosections of explanted hearts were analyzed by cryotome-based CCD and fluorescence reflectance imaging (FRI) and fluorescence signal intensities (SI) were extracted.Fluorescence mediated tomography (FMT) imaging was performed to visualize probe distribution in the target region in vivo. Enhanced fluorescence signal intensity in the infarct area was detected in cryoCCD images as early as day 1 after surgery and intensified up to 21 days post MI. FRI was capable of detecting significantly enhanced SI in infarcted regions of hearts 7 days after surgery. In vivo imaging by FMT localized enhanced SI in the apex region of infarcted mouse hearts. We verified localization of probe and ETAR within the infarct area by immunohistochemistry (IHC). In addition, neovascularized areas were found in the affected myocardium by CD31 staining. Our study demonstrates that the applied fluorescent probe is capable of delineating ETAR expression over time in affected murine myocardium after MI in vivo and ex vivo.

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Long-Term Effects of Bosentan on Cardiovascular Events in Hispanic Patients with Intermittent Claudication: Four-Year Follow-up of the CLAU Trial

Cited by 6 publications

References 17 publications

Endothelin: 30 Years From Discovery to Therapy

Endothelin: 30 Years From Discovery to Therapy

Review new concepts in pharmacotherapy for peripheral arterial disease

Targeting Endothelin Receptors in a Murine Model of Myocardial Infarction Using a Small Molecular Fluorescent Probe

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