Heart Versus Lungs in Hypertension Tug-of-War

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Science Translational Medicine  13 Mar 2013:
Vol. 5, Issue 176, pp. 176ec45
DOI: 10.1126/scitranslmed.3006079

Pulmonary arterial hypertension (PAH) is a progressive and devastating condition characterized by narrowing of the vessels in the pulmonary circulation, eventually leading to heart failure. Most investigators agree that endothelin-1 constricts vessels and is a major contributor to PAH. But most research to date has focused on the pulmonary circulation and not on heart function. In response, Nagendran and colleagues investigated the effect of endothelin-1 and endothelin receptor antagonists (ERAs) in the right ventricle (RV) myocardium of both rats and humans.

Nagendran et al. showed that endothelin-1 is directly associated with the degree of RV hypertrophy in humans, as demonstrated by higher levels of endothelin-1 and endothelin type A receptor in hypertrophied RV myocardium. Notably, these findings were recapitulated in rats, which allowed the authors to use this animal model to study RV contractility while maintaining a constant pulmonary vascular resistance. In the rat model, they found an increase in RV contractility in hearts treated with endothelin-1 and a dose-dependent decrease in RV systolic function when ERAs were administered. Therefore, the beneficial effect that ERAs have on the lungs in PAH may be reduced by a negative effect on RV contractility.

This study by Nagendran et al. explains why ERAs have failed to improve RV systolic function in clinical studies despite a decrease in pulmonary arterial pressure. Results of this reverse-translation study could help uncover the molecular basis of RV function and reveal new therapeutic targets for improving RV contractility in patients with PAH.

J. Nagendran et al., Endothelin axis is upregulated in human and rat right ventricular hypertrophy. Circ. Res. 112, 347–354 (2013). [Abstract]

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