Document Detail

Endothelin axis is upregulated in human and rat right ventricular hypertrophy.
MedLine Citation:
PMID:  23233754     Owner:  NLM     Status:  MEDLINE    
RATIONALE: Right ventricular (RV) function is the most important determinant of morbidity and mortality in pulmonary arterial hypertension (PAH). Endothelin (ET)-1 receptor antagonists (ERAs) are approved therapies for PAH. It is not known whether ERAs have effects on the RV, in addition to their vasodilating/antiproliferative effects in pulmonary arteries.
OBJECTIVE: We hypothesized that the ET axis is upregulated in RV hypertrophy (RVH) and that ERAs have direct effects on the RV myocardium.
METHODS AND RESULTS: RV myocardial samples from 34 patients with RVH were compared with 16 nonhypertrophied RV samples, and from rats with normal RV versus RVH attributable to PAH. Confocal immunohistochemistry showed that RVH myocardial ET type A (but not type B) receptor and ET-1 protein levels were increased compared with the nonhypertrophied RVs and positively correlated with the degree of RVH (RV thickness/body surface area; r(2)=0.838 and r(2)=0.818, respectively; P<0.01). These results were recapitulated in the rat model. In modified Langendorff perfusions, ERAs (BQ-123 and bosentan 10(-7,-6,-5) mol/L) decreased contractility in the hypertrophied, but not normal RV, in a dose-dependent manner (P<0.01).
CONCLUSIONS: Patients and rats with PAH have an upregulation of the myocardial ET axis in RVH. This might be a compensatory mechanism to preserve RV contractility, as the afterload increases. ERAs use might potentially worsen RV function, and this could explain some of the peripheral edema noted clinically with these agents. Further studies are required to evaluate the effects of ERAs on the RV in patients with RVH and PAH.
Jayan Nagendran; Gopinath Sutendra; Ian Paterson; Hunter C Champion; Linda Webster; Brian Chiu; Al Haromy; Ivan M Rebeyka; David B Ross; Evangelos D Michelakis
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-12-10
Journal Detail:
Title:  Circulation research     Volume:  112     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-18     Completed Date:  2013-03-08     Revised Date:  2014-04-23    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  347-54     Citation Subset:  IM    
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MeSH Terms
Child, Preschool
Endothelin-1 / biosynthesis*
Endothelins / biosynthesis*,  physiology
Hypertrophy, Right Ventricular / metabolism*
Middle Aged
Prospective Studies
Receptor, Endothelin A / biosynthesis*,  physiology
Up-Regulation / physiology*
Ventricular Function, Right* / physiology
Young Adult
Grant Support
//Canadian Institutes of Health Research
Reg. No./Substance:
0/Endothelin-1; 0/Endothelins; 0/Receptor, Endothelin A
Comment In:
Circ Res. 2014 Mar 14;114(6):e31   [PMID:  24625731 ]
Circ Res. 2013 Jan 18;112(2):227-9   [PMID:  23329789 ]
Circ Res. 2014 Mar 14;114(6):e30   [PMID:  24625730 ]
Erratum In:
Circ Res. 2014 Mar 14;114(6):e32

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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