The Endothelin Axis is Upregulated in Human and Rat Right Ventricular Hypertrophy
Rationale: Right ventricular (RV) function is the most important determinant of morbidity and mortality in pulmonary arterial hypertension (PAH). Endothelin-1 (ET-1) receptor antagonists (ERAs) are approved therapies for PAH. It is unknown whether ERAs have effects on the RV, in addition to their vasodilating/anti-proliferative effects in pulmonary arteries.
Objective: We hypothesized that the endothelin 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 to 16 non-hypertrophied RV samples; and from rats with normal RV versus RVH due to PAH. Confocal immunohistochemistry showed that RVH myocardial endothelin type A (but not type B) receptor and ET-1 protein levels were increased compared to the non-hypertrophied RVs and positively correlated with the degree of RVH (RV thickness/body surface area) (r2=0.838 and r2=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,-5M) 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 up-regulation of the myocardial endothelin 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 ERA on the RV in patients with RVH and PAH.
- endothelin receptors
- endothelin receptor antagonists
- right ventricle
- pulmonary hypertension
- right ventricular failure
- right ventricular function
- Received November 1, 2012.
- Revision received November 27, 2012.
- Accepted December 4, 2012.
- Copyright © 2012, Circulation Research