The Preventive Effect And Mechanism Of Early Passive Leg Movement On Cardiac Function In A Rat Model Of Heart Failure With Preserved Ejection Fraction

Background: The patients of Heart Failure With Preserved Ejection Fraction(HFpEF)has high morbidity and mortality in clinical heart failure,but their survival rate has not significantly improved,which brings significant economic and national burden to the country.Based on evidence-based medical events,currently there are few drugs that clearly improve the clinical outcome of HFpEF.Therefore,it is extremely urgent to investigate its pathophysiological mechanism and look for effective treatments.In previous studies,device-assisted passive exercise was an effective way of exercise and also showed good tolerance and safety.According to the American College of Cardiology about the Stage of Heart Failure,Pre-clinical diastolic dysfunction(PDD)belongs to stage B.PDD has a high clinical incidence,especially in elderly patients,which is closely related to decreased quality of life and abnormal cardiac structure.PDD can progress to HFpEF.When salt-sensitive rats developped into PDD,they were exercised by passive leg exercise(ie,early intervention was carried out from PDD to HFpEF)to explore the effect and mechanism of early Passive Leg Movement(ePLM)in a rat model of HFpEF rats,which can provide a new targeted treatment for heart failure with ejection fraction.Objective: Salt-sensitive Dahl rats were fed a high-salt diet to establish a model of preclinical diastolic dysfunction,and then with Passive Leg Movement(PLM)intervention,which was used to explore the effect and the possible mechanism of ePLM on heart function in rats.Methods: 7-week-old salt-sensitive Dahl rats induced hypertension through a high-salt diet for 5 weeks,and assessed cardiac function by echocardiography to establish a model of preclinical diastolic dysfunction.Afterwards,rats continued with a high salt diet and and randomly divided into groups as follows: high-salt group(HS,n=12),High Salt+Passive Leg Movement group(HS+PLM,n=12)and the Anesthetic group(High Salt+Isoflurane,n=12)for the following 8 weeks.The normal group(Normal salt,n=12)was given a normal low-salt diet for 13 weeks.The bloodpressure,heart rate,and body weight were measured in the surviving salt-sensitive Dahl rats at 20 weeks.Cardiac ultrasound and hemodynamics were used to assess diastolic and systolic function.After the rats were euthanized,heart and lung were weighed.Then,take the same part of the heart tissue as paraffin embedding for hematoxylin-eosin(HE)staining,Masson staining to assess cardiac pathological changes and fibrosis;as Weston blotting to detect the expression of collagenI,TGF?1,p-smad3/smad3,MMP2,MMP9,p-Akt/Akt,p-eNOS/eNOS in rat heart tissue.Results:(1)Salt-sensitive Dahl rats developed hypertension and with preclinical diastolic dysfunction through a 5-week high-salt diet.(2)Compared with the normal group,the heart rate of the rats in the high-salt group and the anesthetic group did not change significantly,but the blood pressure increased significantly and the body weight decreased significantly.However,after PLM treatment,there was no difference in blood pressure and heart rate in the passive exercise group,but the weight loss was significantly reversed.(3)Compared with the normal group,the level of plasma BNP,the heart weight,heart weight/body weight,the lung weight/body weight of the rats in the high-salt group and the anesthetic group increased significantly;but after PLM treatment,compared with the high-salt group and the anesthetic group,there was no difference in heart weight and heart weight/weight,but the level of plasma BNP and lung weight/body weight decreased significantly in the passive exercise group.(4)Compared with the normal group,there was no significant difference in EF,FS,dP/dt max,the systolic function of the rats in the high-salt group and the anesthetic group remained,but the diastolic function was impaired,showing as an increased E/A,decreased dP/dt min,increased LVEDP;but after PLM treatment,there was no difference in cardiac systolic function in the passive exercise group,but the diastolic function was significantly improved.(5)Compared with the normal group,the high-salt group and the anesthetic group showed cardiac structural disorder and obvious inflammatory cell infiltration by HE staining,and the obvious fibrosis of the heart by Masson staining.However,after PLM treatment,the above pathological phenomenonthe was significantly reversed in the passive exercise group.(6)Compared with the normal group,the expression of collagenI,TGF?1,p-Smad3/Smad3,MMP2 and MMP9 proteins in the heart tissue of the high-salt groupand the anesthetic group were significantly increased,but after the PLM treatment,these proteins were significantly reversed its rising level in the passive exercise group.(7)Compared with the normal group,the p-Akt/Akt and p-eNOS/eNOS proteins in the heart tissue of the high-salt group and the anesthetic group were significantly reduced,but after the PLM treatment,these proteins were significantly reversed its decreasing level in the passive exercise group.Conclusions: Early passive leg movement intervention improved diastolic function in a rat model of heart failure with preserved ejection fraction by improving cardiac structural disturbances,reducing myocardial interstitial fibrosis,and partially relying on AKT/eNOS signaling pathways.