Effect And Mechanism Of Sacubitril/Valsartan On Atrial Remodeling Induced By Hypertension

Atrial fibrillation（AF）is one of the most common persistent arrhythmias in clinical practice,and its complications can lead to disability or even death of patients,posing a great burden on social and public health.Hypertension is an important independent risk factor of AF.The activation of renin-angiotensin system（RAS）in hypertension promotes atrial structural and electrophysiological remodeling,and ultimately leads to the occurrence and maintenance of AF.Existing antiarrhythmic drugs have limited efficacy and many side effects.The beneficial effect of inhibiting RAS as the upstream treatment of AF in reversing atrial remodeling has been recognized,but the exact efficacy of inhibiting RAS in the prevention and treatment of AF is still uncertain,and the reported results are contradictory.In recent years,several studies have confirmed that angiotensin receptor-neprisy inhibitor sacubitril/valsartan（ARNI/Sac/Val）effect in the treatment of heart failure and is widely recommended in clinical application,also found that it can obviously improve cardiac fibrosis reduced and the incidence of arrhythmia in heart failure.However,the studies on the prevention and control of AF induced by hypertension has not yet been reported,which worths further study.Objective:To investigate the effect of shakubactrovalsartan on atrial remodeling induced by hypertension and its mechanism.Methods:The effects of Sac/Val on atrial structural remodeling and electrical remodeling induced by hypertension in rats and high hydrostatic pressure in vitro were observed by ultrasound,Western blot and whole-cell patch-clamp.Results:（1）Both Sac/Val and valsartan could reduce blood pressure in spontaneously hypertensive rats（SHR）,and the effect of Sac/Val was better than that of valsartan.（2）Both Sac/Val and valsartan can significantly improve cardiac hypertrophy in SHR,which is shown as cardio-tibium ratio,LVAWS/LVAWD index and LVPWS/LVPWD index,and can also reduce the left atrial size index in SHR.The above effect Sac/Val is superior to valsartan.（3）Sac/Val can reduce the susceptibility and duration of AF in SHR,and the effect is better than that of valsartan.（4）Both Sac/Val and valsartan can inhibit the expression of fibrosis related proteins Col1A1,Col3A1,TGF-β1 and MMP9 in atrial tissues of SHR,and improve atrial structural remodeling.Sac/Val and valsartan can inhibit APD shorting and ion channel changes in SHR atrial myocytes,including the down-regulation of I_Ca,L and the up-regulation I_Kurpeak current density.At the same time,Sac/Val and valsardan can also inhibit the changes of the corresponding ion channel proteins Cav1.2 and Kv1.5 to improve atrial electrical removals.Sac/Val was better than valsartan in improving atrial structural remodeling and electrical remodeling in SHR.（5）Sac/Val can inhibit the protein expression of ACE-1 and angiotensin in the atrium of SHR,and enhance the natriuretic peptide system（NPs）in the atrium of SHR,which can inhibit RAS more strongly than valsartan.（6）Atrial myocyte lines（HL-1 cells）were interfered in vitro with different hydrostatic pressure（0 and 40mm Hg）to simulate normal and high hydrostatic pressure,and Val and Val+LBQ657（active drug of xacubactrel）were given simultaneously.It was found that Val+LBQ657 could better reduce the expression of fibrosis related proteins in HL-1 cells induced by high hydrostatic pressure than Val,as well as inhibit the down-regulation of I_Ca,L,up-regulation of I_Kurand shortener of APD induced by high hydrostatic pressure.Conclusion:Sac/Val can improve atrial structural remodeling and electrical remodeling induced by high pressure,and reduce the occurrence of AF by inhibiting RAS and enhancing the level of peptide related to natriuretic peptide system,and the above effects are better than those of valsartan.