| Background: The patients of Heart failure with preserved ejection fraction(HFpEF),has a high morbidity,rehospitalization rate and mortality,and it increases year by year,bringing a heavy economic burden to society and citizens.However,there is still no definite therapeutic drug to improve the prognosis of HFpEF,and the pathophysiological mechanism of HFpEF is still unclear.Therefore,deep exploration of its pathophysiological mechanism,and looking for effective therapeutic drugs which improve prognosis in order to achieve the optimal curative effect have become a hot spot in cardiovascular research nowadays.In previous clinical trials,Sacubitril Valsartan(Sac / Val)can significantly reduce NT-proBNP and reduce the volume of the left atrium in patients with HFpEF.Compared with valsartan,Sac / Val has a tendency to further reduce the mortality of HFpEF patients and the rate of rehospitalization of heart failure,and can significantly reduce mortality and heart failure rehospitalization rates in female patients and in heart failure patients with ejection fractions between 45-57%.In order to explore the potential mechanism of Sac / Val's effect on HFpEF,we use HFpEF model rats to study its therapeutic effects on the heart and blood vessels and its molecular mechanism.Objective: To evaluate the effect of Sac / Val on the function of heart and vascular endothelium in HFpEF rats(Dahl / SS)model induced by high-salt diet,and to explore its possible mechanism.Methods: 36 Dahl / SS male rats of 7 weeks old were selected to induce hypertension through a high-salt diet for 12 weeks,and the diastolic function of the heart was evaluated by echocardiography to make sure the HFpEF model has established.Then the rats were randomly divided into groups: the high-salt group(Saline,n = 12),Sacubitril Valsartan group(Sac/Val,n = 12),and Valsartan group(Val,n = 12).The normal control group(Con,n=8)selected SS-Chr 13 BN rats given 0.3% sodium diet.The rats were observed for four weeks.At 23 weeks of age,blood pressure,heart rate,body weight,echocardiography and invasive hemodynamics were measured to assess cardiac diastolic function;after the rats were sacrificed,the heart,lung and other tissues were extracted and weighed;and carotid artery vasodilator function experiments were carried out to evaluate the endothelial diastolic function.ELISA method was used to detect the level of serum NT-proBNP.HE staining and Masson staining were respectively used to evaluate the pathological changes and fibrosis of heart and vessels;immunohistochemistry was used to evaluate Col1a1 and Col3a1 protein expression in semi-quantitative way.Western blotting was used to detect the protein expression levels of Col1a1,Col3a1,TGF?1 / smad pathway,matrix metalloproteinase and their inhibitors in rat heart tissue.RT-PCR was used to detect mRNA levels of Col1a1,Col3a1,TGF?1 / smad pathway expression.Results:(1)During the 12-week high-salt diet,24 rats were dead or the model was not established,and 36 models were successfully confirmed by Echocardiography.36 rats were randomly divided into the high-salt group,the sacubatril-valsartan treatment group,and 12 in valsartan group.After 4 weeks of drug intervention,6 in the high-salt group died,2 in the sacubatril valsartan treatment group,3 in the valsartan group,and none in the control group.There were 25 rats in the final analysis,including: 10 in Sac/Val group,9 in Val group,6 in Saline group and 8 in Con group..(2)There was no significant difference in body weight between the Sac / Val group,Val group,and Saline group,and they were all lower than those in Con group;there was no significant difference in heart rate in among;the blood pressure drop in Sac / Val group was more obvious than that in Val group.(3)Compared with Con group,left ventricle weight / body weight ratio,left atrium weight/ body weight ratio,and(wet lung-dry lung)weight / body weight ratio increased in Sac/Val group,Val group and Saline group;left ventricle weight / body weight,left atrium weight / body weight,(wet lung-dry lung)weight / body weight in Sac / Val were lower than those in Val group and Saline group.(4)The expression level of serum NT-ProBNP in Sac / Val group was lower than that in Val group and Saline group.(5)At 23 weeks of age,compared with Saline group,the Sac / Val group diastolic function showed by diastolic function-related parameters of echocardiography and hemodynamics such as LVPWD-D,IVS-D,LVmass,E / A,E / E ',LA,LVEDP and Tau etc,and better than the Val group.There were no statistically significant differences between the 4 groups in EF,FS,+dP/dt min and other parameters related to contractile function.(6)HE staining and Masson staining showed that the degree of structural disorder,fibrosis,myocardial hypertrophy and blood vessel thickness in Sac / Val group were slighter than those in Val group and Saline group.(7)Compared with Con group,the expression of Col1a1 and Col3a1 in the heart and blood vessels of Sac / Val group,Val group and Saline group were higher in immunohistochemistry;the expression of Sac / Val group was lower than that of Val group and Saline group.(8)Compared with Con group,through Western Blot,the expression of Col1a1,Col3a1,TGF?1,Smad3 protein and MMP2 / TIMP2 ratio in heart tissues of Sac / Val group,Val group and Saline group were significantly higher,and smad7 expression was lower.The Sac / Val group significantly reversed the expression of these proteins.Conclusions: Sac/Val improves the cardiac diastolic function and vascular endothelial function in heart failure rats with preserved ejection fraction.This effect is related to the improvement of myocardial and vascular fibrosis and inhibition of TGF?1 / smad signal pathway by Sac/Val. |
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