Clinical Study And Mechanism Of NuoDiKang Capsules Combined With Cardiac Rehabilitation In Improving Cardiopulmonary Exercise Tolerance In Patients With Coronary Heart Disease

Part 1 The effect of NuoDiKang Capsules in coronary heart disease:A systematic review and meta analysisObjectiveTo assess the benefits and security of NuoDiKang Capsules on patients with coronary heart disease.MethodsSearching PUBMED,EMBASE,CBM disc,VIP and CNKI,COJ and some related literatures by hand through electronically by the end of Jul.,2021,with the word"NuoDiKang" or "Rhodiola sacra" and "coronary heart disease" etc.Randomized controlled trials comparing NuoDiKang Capsules with other drugs in the treatment of patients with coronary heart disease were included.The quality of included randomized controlled trials was evaluated by RevMan 5.4 and the clinical data were analysed by State 13.1.Results20 studies with 1945 patients were selected.The meta-analysis showed that compared with other medicines,NuoDiKang Capsules might be more effective in clinical symptom of angina(RR=1.14,95%CI(1.05--1.24)),and the effect was even better(RR=1.28,95%CI(1.17--1.40))combining with conventional treatment.The left ventricular ejection fraction(SMD=1.43,95%CI(0.66-2.20))was increased by NuoDiKang capsules compared with other drugs.However,it did not show a better effect in improving ECG,TCM symptoms,nitrate drug cessation and hemorheology(P<0.05).Compared with other drugs,the mainly adverse reaction of NuoDiKang capsules were mild gastrointestinal reactions,which indicated its safety compared with other drugs(RR=0.80,95%CI(0.22-2.92)).ConclusionNuoDiKang capsules show more effective than other medicines in clinical symptom of angina and improving left ventricular ejection fraction with mild adverse reaction and well security.This conclusion needs to be validated by more high-quality randomized clinical trials due to the influence of low quality of methodology,non-uniform control group,short intervention cycle and other factors in the included studies.Part 2 Clinical study of Nuodikang capsule combined with cardiac rehabilitation to improve cardiopulmonary exercise tolerance in patients with coronary heart diseaseObjectiveTo evaluate the effects of Noudikang capsule combined with cardiac rehabilitation on exercise capacity,anaerobic threshold,TCM syndrome score and quality of life in patients with coronary heart disease.MethodsIn this study,66 patients with CHD were randomly divided into experimental group and control group according to 1:1 by a randomized,double-blind,placebo-controlled method.All patients received cardiac rehabilitation,which consisted of a standardized exercise training program at anaerobic threshold levels,three times a week,for 12 weeks.On this basis,patients in the experimental group were given Noudikang capsules(made by Xizang Kangzhe Pharmaceutical Technology Co.,LTD.),three capsules each time,three times a day;patients in the control group were given placebo capsules(made by Xizang Kangzhe Pharmaceutical Technology Co.,LTD.),three capsules each time,three times a day.The intervention lasted 12 weeks.exercise capacity,anaerobic threshold,TCM syndrome score and SF-36 quality of life score were observed before and after intervention.ResultsThe exercise capacity,anaerobic threshold,TCM syndrome score and quality of life of 2 groups were improved before and after treatment,and the differences were statistically significant(P<0.05).The difference value of A showed that the cardiopulmonary exercise tolerance,anaerobic threshold and TCM syndrome score of experimental group were significantly increased compared with the control group(P<0.05).The improvement of ΔSF-36 score in test group showed an increasing trend,and the difference was not statistically significant(P=0.506).There were no statistically significant differences in heart rate,blood pressure and ventilation function between 2 groups before and after treatment(P>0.05).ConclusionsCompared with placebo,Nuodikang capsule combined with cardiac rehabilitation can improve the exercise capacity,anaerobic threshold and TCM syndrome type score of patients with coronary heart disease cardiac rehabilitation more significantly,and has no significant impact on heart rate,blood pressure and ventilation function,high compliance,and no obvious toxic and side effects and adverse reactions.Part 3 Effects of salidroside on apoptosis of H9c2 cardiomyocytes induced by hypoxia/reoxygenationObjectiveBased on the model of H9c2 cardiomyocyte injury induced by hypoxia/reoxygenation,salidroside,the main component of Nordikang capsule,was tested to investigate the protective effect of salidroside on myocardium from the perspective of cell apoptosis,and to provide theoretical basis for the clinical application of salidroside.MethodsH9c2 cells were cultured in DMEM medium containing 10%(V/V)fetal bovine serum,100U/mL penicillin and 100μg/mL streptomycin.Control H9c2 cells were grown at 37℃,5%CO2 and 95%air.The apoptotic rate was counted under fluorescence microscope and the expression of P-AMPK protein was detected by Western Blot after 24 h culture with different concentrations of salidroside(0μg/mL,10μg/mL,20μg/mL,50μg/mLand 100μg/mL).H9c2 cells in the hypoxic/reoxygenation intervention group were grown in an anoxic incubator containing 94%N2,5%CO2 and 1%O2 for 6 hours and then cultured in an incubator containing 37℃,5%CO2 and 95%air.After 4 hours,the protein levels of Bcl-2,Bax and Cleaved caspase-3 were detected by Western Blot.ResultsH9c2 cells were treated with salidroside at different concentrations(0μg/mL,10μg/mL,20μg/mL,50μg/mL and 100μg/mL),and the relative expression of P-AMPK was analyzed using GAPDH as internal reference.The results showed that:Compared with CTRL group,after salidroside pretreatment,the expression of P-AMPK in 50μg/mL group and 100μg/mL group was significantly increased(P<0.05),and there was no statistical difference between the two groups(P>0.05).The apoptosis rate of H9c2 cells was calculated by fluorescence microscopy.The apoptosis rate of H/R group cells treated with salidroside(concentration 0μg/mL)after hypoxia treatment for 6h and reoxygenation treatment for 4h was significantly increased,and the apoptosis rate of cells pretreated with salidroside was significantly decreased.After hypoxia/reoxygenation-induced injury,GAPDH was used as internal reference to analyze the relative expression of apoptosis-related factors.It was found that compared with CTRL group,hypoxia/reoxygenation-induced injury significantly reduced the expression level of anti-apoptotic protein Bcl-2,and significantly increased the expression levels of pro-apoptotic factors Cleaved-caspase 3 and Bax.ConclusionsHypoxia/reoxygenation injury can significantly induce H9c2 cell apoptosis.Hypoxia/reoxygenation injury can significantly down regulate the expression of anti apoptotic factor Bcl-2 and up regulate the expression of Pro apoptotic factors Bax and cleaved-caspase-3.Salidroside can inhibit the apoptosis of H9c2 cells after hypoxia/reoxygenation injury,up regulate the relative expression of anti apoptotic factor Bcl-2,inhibit the expression of Pro apoptotic factors Bax and cleaved-caspase-3,and promote the activation of AMPK signal pathway.