Abstract 15583: GS-458967, A Selective Late Na Current Inhibitor, Effectively Improves Diastolic Function in Dahl Salt-Sensitive Rats
Heart failure with preserved systolic function (HFpEF) is a clinical condition for which no specific treatment is currently available. Ranolazine, a late sodium current (INa) inhibitor, has been shown to improve diastolic function in both pre-clinical and clinical studies. However, other known actions of ranolazine (e.g. β-AR blockade) may contribute to this effect. Therefore, in current study, we tested the effects of GS-458967 (GS-967), a selective and potent late INa inhibitor (IC50 0.13 μM), in an animal model of HFpEF. Dahl salt-sensitive (DSS) rats were fed high salt diet (8.0% NaCl, HS) for 8 weeks to develop hypertension and subsequent diastolic heart failure. After 3 weeks of HS diet feeding (hypertension established), rats were treated with GS-967 at 0.5 and 1.0 mg/kg/day (in diet) or vehicle (Veh) for 5 weeks. Two additional groups of rats were fed normal salt diet (0.3% NaCl, NS) and treated with either Veh or GS-967 (1.0 mg/kg/day) as controls. LV function was assessed using serial echocardiography and ECG throughout the study. Rats fed HS diet developed LV hypertrophy and diastolic dysfunction as evidenced by increased isovolumic relaxation time (IVRT) and mitral valve (MV) E/E’ ratio, whereas rats fed NS diet did not. However, ejection fraction (EF), fraction shortening (FS) and isovolumic contraction time (IVCT), indices of systolic function, were same in HS- and NS-fed rats. GS-967 dose-dependently reduced LV mass and improved diastolic function in HS rats, but did not affect LV systolic function. GS-967 also had no effect on either diastolic or systolic function in normal rats. QTc interval was prolonged in HS rats, indicating an electrical remodeling, and GS-967 dose-dependently shortened the prolonged QTc. These results indicate that late INa plays an important role in the pathogenesis of HFpEF. In addition, QTc can be used as a marker for the mechanism of action for late INa inhibitors.
- © 2013 by American Heart Association, Inc.