oa Reversal of Right Ventricular Hypertrophy and Dysfunction by Treprostinil in a Rat Model of Severe Angioproliferative Pulmonary Arterial Hypertension

Purpose

Pulmonary arterial hypertension (PAH) is a devastating cardiovascular disease of the pulmonary vasculature that remains poorly understood. Despite a number of available FDA approved drugs, survival remains low, reaching an estimated 5-year survival as low as 27%. This severe disease is characterized by dysfunction and eventual failure of the right ventricle (RV) of the heart. The main focus of therapeutic strategies thus far has been to target the pathways of pulmonary vascular remodeling that lead to the hypertensive phenotype. It is not known however, if there is an added therapeutic benefit in targeting the RV directly. Prostacyclin analogues are among the most widely used therapies for PAH. However, it is unknown whether they confer protection exclusively via attenuating pulmonary vascular remodeling and constriction or if RV myocardio-specific mechanisms are also involved. Moreover, their use in severe models of PAH has not been adequately tested. Insight into these two major unknowns could not only blaze the trail of new effective therapies for PAH to improve survival, but would also open new avenues for targeting other major forms of heart failure. To address gaps in knowledge of the underlying responses to prostacyclin, the analogue treprostinil was used in a pre-clinical rat Sugen-hypoxia (SuHx) model of angioproliferative severe PAH that closely resembles the human disease.

Methods

Male Sprague-Dawley rats (300g) were implanted with ALZET osmotic pumps containing vehicle or treprostinil (900 ng/kg/min), injected concurrently with a bolus of Sugen (SU5416; 20 mg/Kg) and exposed to 3 wk hypoxia (10% O2) followed by 3 wk normoxia (21% O2). RV function was assessed using pressure-volume loops measured using an admittance catheter and hypertrophy assessed by Fulton Index (FI; RV/LV+Septum wet weight).

Results

Treprostinil significantly reduced SuHx-associated RV hypertrophy and rise in systolic pressure (FI: 0.26 ± 0.02, 0.58 ± 0.04 & 0.37 ± 0.05, P