Abstract 3572: Endothelin Receptor Inhibitors Decrease Contractility in the Hypertrophied Right Ventricle: Direct Clinical Implications for Patients with Pulmonary Arterial Hypertension
Patients with pulmonary arterial hypertension (PAH) often have significant right ventricular hypertrophy (RVH). Approved 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 its critical role in PAH and the fact that ETRIs were associated with increased mortality in early left ventricular failure trials. We hypothesized that the modest effects of ETRIs in PAH might be in part due to a negative inotropic effect in the RV, which might antagonize their beneficial vasodilating and anti-proliferative effects in pulmonary vessels. We examined 28 surgical biopsies of patients with RVH (confirmed macroscopically at surgery and by pre-op ECHO) compared to 3 normal RV samples; and 24 rats with PAH (monocrotaline) and RVH (RV/LV+septum increase by 56.2±7.4%) versus 32 normal controls. Confocal immunohistochemistry showed that in RVH, ET Receptor-A (ETR-A) expression increased by 105% in humans and 94% in rats over normal myocardium (p<0.01), while ET Receptor-B and ET-1 levels were not different. This was confirmed with immunoblots. qRT-PCR in laser-capture microdissected RV myocardium showed increased ETR-A mRNA in RVH versus normal RVs in patients (164.1±23.6%) and rats (202.4±16.5%), p<0.01 for both. In modified Langendorff perfusions ETRIs (BQ-123 and Bosentan 10 –7–10 –5M) decreased contractility (developed pressure) in RVH (but not normal RV) by 32.2±8.3% over vehicle in a dose-dependent manner (p<0.01). Isoproterenol caused an increase of ET-1 levels in coronary effluent (23.5±4.2% in normal and 40.1±6.3% in RVH hearts), suggesting that myocardial ET-1 might have important and unrecognized paracrine effects on the RV. Patients and rats with RVH have an increase in ET Receptor-A expression in their myocardium. This might be a compensatory mechanism to preserve RV contractility when the afterload increases in PAH. ETRIs might be inhibiting RV contractility and limiting their efficacy. Further studies are needed particularly in patients with RVH (i.e. in congenital heart disease) and caution is needed interpreting data from clinical trials using ETRIs. Our results might not be applicable to patients with non-hypertrophied, dilated RVs.