Background/Introduction: Entresto (LCZ696) is a newly approved drug for the treatment of heart failure with reduced ejection fraction (HFrEF). It combines the effects of angiotensin receptor blockade and neprilysin inhibition. In a recent large clinical trial, LCZ969 was shown to yield a major reduction in mortality when compared to current standard therapy for HFrEF. However, it still remains unclear which mechanisms are responsible for the beneficial effects observed. Purpose: To investigate the effects and the mechanisms of actions of LCZ696 on cardiac function and remodeling in a chronic model of increased afterload. Methods: 45 male Sprague Dawley rats were randomly assigned to four different groups: vehicle treated sham operated (Sham, n=5); vehicle treated transverse aortic banding (TAC) (veh, n=12); Valsartan treated TAC (Val, n=15); LCZ696 treated TAC (LCZ, n=13). Oral gavage was performed once daily in all groups for six weeks to deliver vehicle or the active drugs. Echocardiography, pressure readings and MRI were performed at six weeks, organ weights were assessed, and tissues were examined using PCR and HPLC. * indicates p <0.05 for veh vs. LCZ, † indicates p<0.05 for Val vs LZC. Results: MRI demonstrated increased left ventricular mass in TAC animals, with LCZ showing the smallest increase (Sham 197±8,5; LCZ 213±8.46; Val 239±10.6†; veh 248±13.24 mm3*). Pressure readings showed reduced end diastolic left ventricular pressure in LCZ compared to veh (Sham 4±0.71; LCZ 13.3±1.1; Val 15.5±1.9; veh 21.4±2.2 mmHg *). Animals in LCZ had preserved cardiac output, as opposed to Val and veh that had a significant reduction (Sham 31.75±1.68; LCZ 28.7±1.54; Val 27.5±1.14; veh 25.22±1.46 mmHg). MRI showed a trend towards decreased ejection fraction in TAC animals, with LCZ yielding improvement (Sham 71.4±1.64; LCZ 73.8±2.44; Val 71.42±1.5; veh 66.55±2.25%). Conclusion(s): LCZ696 treatment reduces cardiac hypertrophy in this model of sustained pressure overload, and showed improved diastolic function. Our findings support that the beneficial effects observed in recent clinical studies could reflect favorable anti cardiac remodeling properties and that the clinical utility of this novel compound might be extended to patients with diastolic dysfunction secondary to pressure overload.