Inhibition Of Warburg Effect In Paroxysmal Atrial Fibrillation Canine Model:Its Roles In Energy Metabolism And Fibrosis Remodeling

Experimental background and Objective: Atrial fibrillation is the most common malignant arrhythmia in clinic,and the incidence of atrial fibrillation is increasing year by year.AF can lead to myocardial energy metabolism disorder and myocardial interstitial fiber hyperplasia,which in turn leads to atrial remodeling.Warburg effect is related to myocardial energy metabolism disorder and myocardial remodeling,but its role in atrial fibrillation is unknown.In this experiment,the effects of myocardial Warburg effect on myocardial energy metabolism and myocardial fibrosis in canines with paroxysmal atrial fibrillation were observed.Methods: 12 beagle canines were randomly assigned to one of the following four treatments: Control group,AF group,phenylephrine(PHE)plus AF group and dichloroacetic acid(DCA)plus AF group.In AF group:four beagle canines rapid atrial pacing(RAP)were initiated for six days;In control group: four beagle canines received sham surgery.In PHE plusAF group: four beagle canines were infused with PHE at a dose of 4?g/kg/min for 20 min before RAP,once every 2 days,for a total of 3times.after injection,RAP was given for 24 hours.In DCA plus AF group:four canines were orally DCA(6.25 mg/kg Q12 h,drinking water)for 7days before RAP,and then RAP was given for 24 hours after oral administration.After successful modeling,stopping electrical stimulation,left ventricular blood was collected with 5ml syringe and plasma was collected by centrifugation.Beagle dogs were killed by air embolization,removing heart tissue and part of left atrium was cut off by ophthalmology.The activities of lactate dehydrogenase(LDH),pyruvate dehydrogenase(PDH),pyruvate dehydrogenase kinase-1(pdk-1)and the contents of glycogen,lactic acid,ATP,AMP and phosphocreatine(pCr)in beagle plasma were determined by ELISA.RT-PCR was used to detect PDK-1 and LDH mRNA in left atrial tissue.Western blotting was used to detect PDK-1?LDH?PDH?isocitrate dehydrogenase(IS)?citrate synthase(CS)and matrix metalloprotein-9(MMP-9)in left atrial tissue.PAS staining was used to observe the content of glycogen in the left atrium.The content of collagen fibers in left atrium was detected by Masson staining.Results:1?The results of ELISA showed that compared with the Control group,the plasma PDK-1 activity and lactic acid and AMP levels in the AF group and PHE+AF group were significantly increased(P<0.05),but there was no significant difference in DCA+AF group(P >0.05);Compared with AF group,plasma PDK-1 activity,lactic acid and AMP content in PHE+AF group were significantly increased(P < 0.05),while DCA+AF group was significantly decreased(P < 0.05).There was no significant difference in plasma ATP and pCr levels between the 4groups(P>0.05).2?The results of RT-PCR showed that compared with the Control group,the levels of PDK-1 and LDH mRNA in left atrial tissue of AF group and PHE+AF group were significantly increased(P<0.05),but there was no significant difference in DCA+AF group(P >0.05);Compared with the AF group,the PDK-1 and LDH mRNA levels in the left atrial tissue of the PHE+AF group were significantly increased(P<0.05),while DCA+AF group was significantly decreased(P < 0.05).3?Western blotting results showed that compared with the Control group,the expression levels of PDK-1,LDH and MMP-9 in the left atrial tissue of the AF group and PHE+AF group were significantly increased(P<0.05),and the expression levels of PDH,IS and CS were significantly decreased(P<0.05)?There was no significant difference in the expression of PDK-1,LDH,MMP-9,PDH,IS and CS in left atrium in DCA+AF group(P > 0.05);Compared with AF group,the expression levels of PDK-1,LDH and MMP-9 in left atrium of PHE+AF group were significantly increased(P < 0.05),and the expression levels of),PDH,IS and CS were significantly decreased(P < 0.05).In DCA+AF group,theexpression of PDH,IS and CS in left atrium was significantly increased(P < 0.05),while the expression of PDK-1,LDH and MMP-9 was significantly decreased(P < 0.05).4 ? The results of PAS staining showed that compared with the Control group,the glycogen content of the left atrial tissue of the AF group and PHE+AF group was significantly reduced,but there was no significant difference in glycogen content in DCA+AF group;Compared with AF group,the content of glycogen in left atrium decreased in PHE+AF group and increased significantly in DCA+AF group.5?Masson staining showed that compared with Control group,the deposition of collagen fibers in left atrium of AF group and PHE+AF group was significantly increased,but there was no significant difference in DCA+AF group;Compared with AF group,collagen deposition increased in PHE+AF group and decreased in DCA+AF group.Conclusion: Inhibition of Warburg effect can improve myocardial energy metabolism change and myocardial fibrosis tendency in paroxysmal AF Canine Model.