Abstract 3467: The Endothelin Axis is Upregulated in Human and Rat Right Ventricular (RV) Hypertrophy and Its Inhibition Decreases RV Contractility
In pulmonary arterial hypertension (PAH) right ventricular (RV) function determines morbidity and mortality. PAH therapies include Endothelin-1 (ET-1) receptor inhibitors (ETRIs), which modestly improve functional capacity. The effects of ETRIs on the RV are unknown, despite the increased mortality in early left ventricular failure trials with ETRIs. We hypothesized that the modest effects of ETRIs in PAH might be in part due to a negative inotropic effect in the RV, antagonizing their beneficial vasodilating and anti-proliferative effects in pulmonary vessels. We examined 42 human RVs (13 non-hypertrophied and 29 hypertrophied) obtained at the time of surgery/transplantation, for which hypertrophy (RVH) was proven by both macroscopic criteria at the time of surgery and by measurement of the RV free wall thickness by echocardiography preoperatively. qRT-PCR in laser-capture microdissected (LCM) myocardium showed increased ET-Receptor A (ETRA) mRNA in hypertrophied versus non-hypertrophied RVs (+164.1±23.6%). By both qRT-PCR and immunohistochemistry (co-localization with myosin heavy chain vs smooth muscle actin), ETR-B was only expressed in the vasculature, whereas both ETR-A and ET-1 were increased in the myocardium. There was a very strong positive correlation between the degree of RVH and the expression of ETR-A and ET-1 in human hearts (R2=0.94 and 0.90 respectively). Very similar results (LCM-qRT-PCR, immunoblots and immunohistochemistry) were obtained in rat RVH in the monocrotaline-induced PAH model. In modified Langendorff rat heart perfusions, ETRIs (BQ-123 and Bosentan 10 –7–10 –5M) decreased contractility in RVH (but not normal RV) by 32.2±8.3% (p<0.01) in a dose-dependent manner (p<0.01). The increase in ET-1 and ETRA in RVH myocardium is likely a compensatory mechanism to preserve RV contractility when the afterload increases in PAH. ETRIs might be inhibiting this potentially beneficial ET axis up-regulation, limiting their overall efficacy. Our work might explain the recently well-described increased incidence of RV failure and lower extremity edema in a significant population of PAH patients, soon after the onset of ETRI therapy. Our results might not be applicable to patients with non-hypertrophied, dilated RVs.