Enhanced β1 Adrenergic Receptor Antibodies Levels Are Associated With Atrial Fibrillation And Atrial Remodeling

Objective To investigate the electrophysiological effects of enhancedβ1 adrenergic receptor antibodies（β1AAR）levels on atrial fibrillation（AF）and atrial remodeling.Methods 24 New Zealand white rabbits were divided into control group andβ1AAR group randomly,all the rabbits immunized with peptide developed anti-peptide antibodies.Autoantibodies against the second extracellular loop ofβ1AAR were persistently detected by enzyme-linked immunosorbent assay（ELISA）,as early as 2week,4week,6week after starting immunization,inβ1AAR groups,but not in the control group.Antibody titers in serum to verify the success of the model.A catheter-based electrophysiologic study was performed on anesthetized rabbits before and after immunization,the atrial effective refractory period（AERP）was measured by S₁S₂ decreasing stimulation,and the induction rate and duration of atrial fibrillation were determined in response to burst pacing.Atrial muscle tissue was taken after immunization,western blots and reverse transcription Polymerase Chain Reaction（RT-PCR）were also performed to determine L-type calcium channel,acetylcholine activated potassium channel,Transforming growth factorβ1（TGFβ1）,Samd,samd3,samd7,Collagen I,Collagen III,and communication junction connexin expression.Results（1）Compared with before immunization,theβ1AAR group rabbits in 2week,4week,6week after starting immunization,the serum level ofβ1AAR increased significantly at different time points（P<0.05）.In control rabbits,the serum level ofβ1AAR no significantly at different time points（P>0.05）.Compared with control rabbits,except that there was no significantly between the two groups at 0 week,the serum level ofβ1AAR in the otherβ1AAR groups increased significantly（P<0.05）.The camp trend was the same as the serum level ofβ1AAR.The above indicated that the model has been successfully established.（2）HRV at each time point:Compared with baseline,low-frequency（LF）,high-frequency（HF）,and LF/HF increased at 2,4,and 6weeks in theβ1AAR group at each time point（P<0.05）,while there was no difference at each time point in the Control group（P>0.05）.Compared with Control group,all theβ1AAR groups were significantly increased except that there was no difference between the two groups at 0 weeks（P<0.05）.Compared with the baseline,SDNN decreased at 2,4,and 6 weeks in theβ1AAR group at all time points（P<0.05）,while there was no difference at all time points in the Control group（P>0.05）.Compared with Control group,all theβ1AAR groups were significantly reduced except that there was no difference between the two groups at 0 weeks（P<0.05）.（3）Compared with before immunization,theβ1AAR group rabbits after immunization showed heart rates increased significantly（P<0.05）,AERP was significantly shorter（P<0.05）.Compared with control rabbits,theβ1AAR group rabbits showed heart rates increased significantly（P<0.05）,AERP was significantly shorter（P<0.05）.Compared with before immunization,the episodes of atrial fibrillation induced by Burst pacing is higher inβ1AR group（P<0.05）and the duration of atrial fibrillation have increased（P<0.05）;Compared with control group,the episodes of atrial fibrillation induced by Burst pacing is higher inβ1AAR group（P<0.05）and the duration of atrial fibrillation have increased（P<0.05）.（4）The mRNA level and protein levels of Kir3.1 and Kir3.4 genes,which composed with muscainic-activated K channels（KAch）,in left atrium are up-regulated inβ1AAR group compared with control rabbits（P<0.05）.The mRNA level and protein levels of Kir4.3 genes,which composed with Transient outward K+current（Ito）,in left atrium are reduced inβ1AAR group compared with control rabbits（P<0.05）.The mRNA and protein level of Cav1.2 of L-type calcium channel are reduced inβ1AAR group compared with control rabbits（P<0.05）.The mRNA level and protein levels of Cx43 are reduced inβ1AAR group compared with control rabbits（P<0.05）.The mRNA level and protein levels of Cx40 are up-regulated inβ1AAR group compared with control rabbits（P<0.05）.The mRNA level and protein levels of TGFβ1,Samd,Samd3,Collagen I and Collagen III are up-regulated inβ1AAR group compared with control rabbits（P<0.05）.The mRNA level and protein levels of Samd7 are up-regulated inβ1AAR group compared with control rabbits（P<0.05）.Conclusion In this model,β1AR-activating autoantibodies by changing the cardiac ion channel make reduce atrial effective refractory period and facilitate atrial fibrillation induction.