Abstract 17755: Effects of Multikinase Inhibitors on Right Ventricular Remodeling
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 (PDGFR, VEGFR and KIT tyrosine kinase inhibitor) and sorafenib (raf1/b, VEGFR, PDGFR tyrosine kinase inhibitor) on right ventricular (RV) remodeling in rats.
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 rats were treated with vehicle, sunitinib or sorafenib (10 mg/kg each) for two weeks. PAB rats received daily treatment with vehicle, sunitinib or sorafenib (10mg/kg each), starting 1 week after PAB. RV function and remodeling were studied by serial echocardiographic measurements (VEVO770, Visualsonics). Fulton index was measured. Myocardial fibrosis was determined from picrosirius red stained paraffin-embedded myocardial sections.
Results: Treatment with both sorafenib and sunitinib decreased right ventricular systolic pressure in the MCT model, reversed pulmonary vascular remodeling and reduced RV hypertrophy from 0.58±0.04 to 0.32±0.02 (p<0.05, sorafenib) and 0.38±0.03 (p<0.05, 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 pulmonary banding, both compounds reversed RV chamber and cellular hypertrophy, reduced RV fibrosis, and improved RV function, by normalization of TAPSE to 2.51±0.04 mm (p<0.05, sunitinib) and 2.46±0.04 (p<0.05, sorafenib) as compared to placebo (2.04±0.12).
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.
- © 2010 by American Heart Association, Inc.