| This study consists of three parts:literature review,clinical research,and basic research.1 Literature review This part included the application of meta-analysis to evaluate the efficacy and safety of oral traditional Chinese medicine(TCM)for the treatment of heart failure with preserved ejection fraction(HFpEF),as well as the progress of diagnosis and oral western medicine for the treatment of HFpEF.2 Clinical studies Clinical efficacy of Linggui Qihua formula(LGQHF)in treating Early Stage HFpEF PatientsObjective:To evaluate the clinical efficacy and safety of LGQHF in treating patients of early stage heart failure with preserved ejection fraction(HFpEF).Methods:60 patients of early stage HFpEF admitted to Xiyuan Hospital,China Academy of Chinese Medical Sciences from March 2022 to March 2023.Traditional Chinese medicine syndrome differentiation was characterized by unfavorable qi circulation,with clinical manifestations of fluid retention.60 patients were divided into a control group and an experimental group in a 1:1 ratio based on a random number table.The control group received western medicine treatment according to relevant guidelines.And patients in test group were given with LGQHF on the basis of control group.Both groups were treated for 4 weeks.And statistical analysis was performed between the two groups to compare the changes of each index before and after the treatment.Efficacy measures including the six-minute walk test(6MWT),the Kansas city cardiomyopathy questionnaire(KCCQ-12)score,traditional Chinese medicine(TCM)syndrome score,N-terminal pro-B type natriuretic peptide(NT-proBNP).And left ventricular end diastolic diameter(LVEDD),left atrial internal diameter(LAD),interventricular septal thickness(IVST),left ventricular early diastolic filling peak velocity(E),and atrial systolic left ventricular filling peak velocity(A)were detected by echocardiography during exercise load.And the occurrence of adverse events and reactions were recorded.Result:1.All 60 patients completed the experiment.Compared with before treatment,the 6MWT,KCCQ,TCM syndrome score,as well as E,A under exercise load in the experimental group were significantly improved(P<0.01).The levels of NT-proBNP and LVEDD,LAD,IVST showed a decreasing trend,but the changes were not statistically significant(P>0.05).2.After treatment,compared with the control group,the experimental group showed more significant improvement in TCM syndrome scores and KCCQ(P<0.01),and 6MWT,E and A under exercise load(P<0.05).The NT-proBNP,and LAD,LVEDD,IVST under exercise load of the two groups showed an improvement trend,but the difference between the groups was not statistically significant(P>0.05).3.During the study,neither group of patients experienced any adverse reactions or events.Conclusions:LGQHF can improve the symptoms,cardiac structure and function,especially the improvement of exercise tolerance of patients on early HFpEF stage who have unfavorable qi circulation,with clinical manifestations of fluid retention.This indicates that LGQHF can improve the heart diastolic function,inhibit heart remodeling,and delay the development process of HFpEF.3 Basic research Mechanism of Linggui Qihua formula in treating HFpEFObjective:To observe the effects of LGQHF on cardiac structure and function,serum and myocardial tissue in HFpEF rats,and to investigate the possible mechanisms of the intervention of LGQHF on HFpEF.Methods:SPF grade,50 4-week-old spontaneously hypertensive rats(SHR)and 10 WKY rats were adaptively fed for 4 weeks,of which 10 SHR and WKY rats were belong to control group and were fed with normal chow,and the remaining 40 SHR were fed with high-salt,high-fat,and high-glucose chow for 16 weeks,after which they received intraperitoneal streptozotocin solution(STZ)and continued high-salt,high-fat.and high-glucose chow for 8 weeks to induce the establishment of a compound model of hypertension,hyperlipidemia,and diabetes.The success of the modeling was verified by cardiac ultrasound detection.The modeled rats were randomly divided into four groups:HFpEF model group(HFpEF group),LGQHF low-dose group,given LGQHF raw drug 3.87 g/(kg·d).LGQHF high-dose group,given LGQHF raw drug 7.74 g/(kg·d).Sacubitril valsartan sodium group(Entresto group),and given Entresto 18 mg/(kg·d).10 rats in each group.Equal doses of saline were given to the control and HFpEF groups.After 6 consecutive weeks,structural and functional related indexes of the rats heart,including the left ventricular anterior wall thickness(LVAWD),left ventricular posterior wall thickness(LVPWD),LVEDD,and the left and right diameters and anterior and posterior diameters of the LAD and right atrial internal diameter(RAD),E,A,early diastolic lateral mitral annulus velocity(E’),E/A,E/E’,isovolumetric relaxation time(IVRT),were detected by ultrasound.And blood samples were taken from the abdominal aorta to detect atrial natriuretic peptide(ANP)and B-type natriuretic peptide(BNP).The cardiac tissue of rats were removed for HE and Masson staining.Atria and ventricles were isolated.And the expression of PI3K/AKT/GSK3β signaling pathway related proteins was detected by western blot.Result:1.Cardiac structure measured by ultrasound:Compared with the WKY group,the HFpEF group rats had significantly increased values of LVEDD,LVAWD,LVPWD,LAD,and RAD(P<0.01).Compared with the HFpEF group,the LVEDD,LVAWD,LVPWD,as well as LAD and RAD in all directions of Entresto group,LGQHF low-dose group and LGQHF high-dose group were significantly improved(P<0.01).2.Cardiac function measured by ultrasound:Compared with the WKY group,the HFpEF group had significantly different values for all indexes,with lower values for A and E’(P<0.01)and higher values for E/A,E/E’ and IVRT(P<0.01).E’,E/A,E/E’,and IVRT were significantly improved(P<0.01)in all treat groups when compared with the HFpEF group.with a high value of A in rats of Entresto group and LGQHF low-dose group(P<0.05),and a higher value in rats of the LGQHF high-dose group(P<0.01).LVEF and E were not significantly different between the groups(P>0.05).3.Blood examination:Compared with the WKY group,the HFpEF group had higher levels of BNP and ANP(P<0.01).Compared with the HFpEF group.BNP and ANP levels were lower in all treat groups(P<0.01).4.Levels of signaling pathway related proteins:Compared with the WKY group,the expression levels of PI3K,p-AKT,p-GSK3β in HFpEF group were up-regulated,and the expression levels of AKT,GSK3β were down-regulated.Compared with the HFpEF group,the expression levels of PI3K,p-GSK3β in Entresto group,LGQHF low-dose group and LGQHF high-dose group were down-regulated,and the expression levels of p-AKT,GSK3β were up-regulated.Conclusion:HFpEF rats with the treatment of LGQHF can inhibited cardiac remodeling,improved cardiac diastolic function,and reduced serum BNP and ANP,thus achieving the therapeutic goal of HFpEF,which may be mediated through PI3K/AKT/GSK3β signaling pathway. |
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