Chest
Volume 131, Issue 1, January 2007, Pages 101-108
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Original Research: Pulmonary Hypertension
Endothelin-1/Endothelin-3 Ratio: A Potential Prognostic Factor of Pulmonary Arterial Hypertension

https://doi.org/10.1378/chest.06-0682Get rights and content

Abstract

Background:Pulmonary arterial hypertension (PAH) is a rare condition characterized by elevated pulmonary artery pressure leading to right-heart failure and death. Endothelin (ET)-1 has been shown to play a significant pathogenic role in PAH. ET-3 has not yet been investigated in PAH.

Methods:ET-1 and ET-3 plasma concentrations were measured in 33 PAH patients prior to any specific PAH therapy and in 9 control subjects. In PAH patients, hemodynamic parameters measured by right-heart catheterization, 6-min walk distance (6MWD), New York Heart Association (NYHA) functional class, and time until lung transplantation or death were recorded.

Results:In patients with PAH, levels of ET-1 were increased while those of ET-3 were decreased, as compared to control subjects (p < 0.005 for both comparisons). ET-1/ET-3 ratio varied little in control subjects, while it increased threefold in PAH patients (p < 0.0001). ET-1 correlated positively with right atrial pressure (RAP), indexed total pulmonary resistance, and negatively with cardiac index and venous saturation of oxygen (Svo2). ET-3 correlated positively with 6MWD. ET-1/ET-3 ratio correlated positively with RAP, negatively with Svo2and 6MWD, and was also associated with NYHA functional class. ET-1/ET-3 ratio was associated with prognosis in this sample of PAH patients treated with specific therapies.

Conclusions:PAH is characterized by elevated ET-1 and ET-1/ET-3 ratio and decreased ET-3 plasma concentrations. All of them correlate with hemodynamic and clinical markers of disease severity. ET-1/ET-3 ratio might be a novel prognostic factor in PAH. These preliminary data should be validated in a large prospective multicenter cohort of PAH patients.

Section snippets

Subjects

Thirty-three subjects with PAH were included in this study from three different previous studies15, 16, 17and were enrolled consecutively during three different time periods between February 1994 and April 1998. Institutional Review Board approval was obtained for these studies, and all patients gave informed consent for these studies and for additional biological studies.15, 16, 17PAH was defined by mean pulmonary arterial pressure (mPAP) > 25 mm Hg with normal pulmonary capillary wedge

Characteristics of Subjects

Thirty-three patients with PAH were included in this study, 19 of them with idiopathic PAH, 1 with familial PAH, 6 with appetite suppressant-associated PAH, and 7 with PAH associated with other conditions (portopulmonary hypertension, n = 3; HIV infection-associated PAH, n = 1; systemic sclerosis-associated PAH, n = 2; pulmonary venoocclusive disease, n = 1). At the time of blood sampling for ET plasma concentration measurement, none of these patients had been previously treated with specific

Discussion

In this study, we have demonstrated that PAH is characterized by an imbalance of ET plasma concentrations, with an increase of ET-1 and a decrease of ET-3 plasma concentrations in comparison with control subjects. We have demonstrated that ET-1/ET-3 ratio was well correlated with many clinical and hemodynamic prognostic factors in PAH and that the presence of an increased ET-1/ET-3 ratio was associated with worse prognosis in this sample of PAH patients.

As previously described, we have found

Acknowledgments

We thank Virginie Sippel for expert technical performance in the measurement of ET-1 and ET-3; Olivier Sitbon (Service de Pneumologie et Réanimation respiratoire, Hôpital Antoine-Béclère, Clamart, France) for helpful comments during the preparation of this article; and Frederic Perros for technical support.

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      The underlying mechanisms that are responsible for regulation of vascular tone in the pulmonary circulation are complex, and involve multiple factors such as the dispensability of the pulmonary vasculature, the function of the heart, concentration of oxygen in the blood and the capacity of the endothelium to release vasoactive substances [29]. Studies have found high levels of ET-1 in PH patients [19] and after exposure to cigarette smoke [21], hypoxic-induced PH rats exhibit an elevated ET-1 level in plasma and increased gene expressions for ETA and ETB receptors in lung tissue [30]. The observations that both ET-1 and its receptors are up-regulated in response to hypoxia suggest that ET-1 is a key mediator in the development of hypoxia-induced PH, which are further supported by findings that hypoxic pulmonary vasoconstriction and vascular remodeling can be prevented and reversed by administration of either ETA selective or combined ETA and ETB receptor antagonists [31].

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    An abstract of this work was presented at the 2005 European Respiratory Society Meeting, Copenhagen, Denmark, September 17–21, 2005.

    Support was provided by the European Respiratory Society, Fellowship No. 192.

    The authors have no conflicts of interest to disclose.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestjournal.org/misc/reprints.shtml).

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