Pneumologie 2011; 65 - P327
DOI: 10.1055/s-0031-1272117

Effects of multi-kinase inhibitors on pulmonary vascular and right ventricular remodelling

B Kojonazarov 1, A Sydykov 1, H Luitel 1, D Kosanovic 1, S Pullamsetti 1, X Tian 1, S Evans 2, P Phillips 2, N Davie 2, N Weissmann 1, F Grimminger 1, W Seeger 1, HA Ghofrani 1, RT Schermuly 1
  • 1University of Gießen Lung Center, Excellence Cluster Cardiopulmonary System
  • 2Pfizer Global Research and Development, Sandwich

Background: Inhibition of receptor tyrosine kinases has been shown to improve experimental pulmonary hypertension (PH) and PAH in patients. However, little is known about the effects of current PAH therapies including receptor tyrosine kinase inhibitors on heart remodeling.

Aim of this study was to investigate the effects of the multikinase inhibitors sunitinib and sorafenib on right ventricular (RV) remodeling.

Methods: We compared the effects of two multi-kinase inhibitors on RV remodeling in rats subjected either to monocrotaline (MCT)-induced PH or pulmonary artery banding (PAB). MCT and PAB rats were treated with vehicle, sunitinib or sorafenib (10mg/kg each) for two weeks. RV function and remodeling were studied by serial echocardiographic measurements (VEVO770, Visualsonics). Fulton index was measured to quantify RV hypertrophy. Myocardial fibrosis was determined.

Results: Treatment with both sorafenib and sunitinib decreased RV systolic pressure in the MCT model, reversed pulmonary vascular remodeling and reduced RV hypertrophy from 0.58±0.04 to 0.32±0.01 (p<0.001, sorafenib) and 0.38±0.03 (p<0.01, sunitinib). In addition, treatment with both compounds was associated with an improvement of RV function, reversal of RV fibrosis and maladaptive RV remodeling. Importantly, after PAB (where RV afterload is constant), both compounds reversed RV chamber and cellular hypertrophy, reduced RV fibrosis, and improved RV function, by normalization of TAPSE to 2.35±0.07mm (p<0.05, sunitinib) and 2,25±0.03 (p<0.05, sorafenib) as compared to placebo (2.06±0.08).

Conclusion: We demonstrated for the first time that sunitinib and sorafenib effectively suppress RV remodeling and significantly improves RV function, measured via a range of invasive and non-invasive cardiopulmonary endpoints in two experimental models of RV hypertrophy. These compounds exert their effects not only through an indirect action via RV unloading but also through direct actions on RV myocardial remodeling.