Changing the treatment of heart failure with reduced ejection fraction： clinical use of sacubitril-valsartan combination

Despite significant therapeutic advances, patients with chronic heart failure （HF） remain at high risk of morbidity and mortality. Sacubitill valsartan （previously known as LCZ696） is a new oral agent approved for the treatment of symptomatic chronic heart failure in adults with reduced ejection fraction. It is described as the fast in class angiotensin receptor neprilysin inhibitor （ARNI） since it incorporates the neprilysin inhibitor, sacubitril and the angiotensin Ⅱ receptor antagonist, valsartan. Neprilysin is an endopeptidase that breaks down several vasoactive peptides including natriuretic peptides （NPs）, bradykinin, endothelin and angiotensin II （Ang-II）. Therefore, a natural consequence of its inhibition is an increase of plasmatic levels of both, NPs and Ang-Ⅱ （with opposite biological actions）. So, a combined inhibition of these both systems （Sacubitril / valsartan） may enhance the benefits of NPs effects in HF （natriuresis, diuresis, etc） while Ang-Ⅱ receptor is inhibited （reducing vasoconstriction and aldosterone release）. In a large clinical trial （PARADIGM-HF with 8442 patients）, this new agent was found to significantly reduce cardiovascular and all cause mortality as well as hospitalizations due to HF （compared to enalapril）. This manuscript reviews clinical evidence for sacubitril valsartan, dosing and cautions, future directions and its considered place in the therapy of HF with reduced ejection fraction.

Combination of XianGui capsule and LCZ696 inhibits doxorubicin- induced heart failure in mice

Objective:We used doxorubicin(DOX)-induced heart failure mouse model to investigate the therapeutic effect and involved mechanism of XianGui capsule(XG)combined with Sacubitril Valsartan Sodium tablets(LCZ696)on heart failure.Methods:C57BL/6 mice were divided into control(Ctrl)group,DOX group,XG group,LCZ696 group and combination(XL)group.After the administration,mice heart functions,blood pressure,and serum cardiac injury markers were detected.Heart sections were conducted with HE,Sirius Red and immunohistochemical staining.The heart tissues were collected for the determination of protein or mRNA expression of anti oxidative,fibrosis,inflammation and apoptosis-related genes by Western Blot and qRT-PCR.Results:XG,LCZ696 or XG plus LCZ696 can significantly improve the heart functions of mice,reduce the expression of cardiac injury markers,and inhibit myocardial fibrosis.Mechanically,XG,LCZ696 or their co treatment antagonized myocardial apoptosis,increase forkhead box O3a,superoxide dismutase 2(SOD2)protein,SOD1,catalase mRNA expressions and inhibited the protein and mRNA levels of toll-like 4,nuclear factorkB,and inflammatory cytokines.Conclusion:XG,LCZ696 or XG plus LCZ696 decreases DOX-induced cardiomyocytes apoptosis by reducing inflammatory factors and enhancing expression of antioxidant enzymes,thereby alleviating the development of heart failure.