Elucidating the Mechanisms By Which an Endothelin-1 Antagonist Can Reverse Right Ventricular Dysfunction in Pulmonary by Hypertension Models: In Vitro and in Vivo Studies

Utilising heart and lung tissue harvested from all arms of the SuHx animal study we will elucidate possible pathways in both of these organs which undergo changes to treatment. These will include metabolic pathways, endothelial improvements, canonical BMPRII signalling, pro-fibrotic markers and apoptosis markers.

A reversal strategy of right heart dysfunction and pressure overload by Macitentan treatment would be utilised using the pulmonary artery banding model. This study will allow us to determine if Macitentan can have a DIRECT treatment effect on the heart. We will utilise serial MRI to obtain the best possible data on these animals whilst using conventional right heart catheterisation on a small group to determine pulmonary artery pressures.

This would be the first study to fully elucidate whether the changes we see in animal and human models using Macitentan have a direct effect on the heart rather than a consequence of improvements to the lung circulation.