Molecular Mechanisms Of Atrial Fibrosis In Patients With Atrial Fibrillation During Rheumatic Heart Disease

Objective To determine the molecular mechanisms involved in atrial fibrosis whichoccurs in patients with atrial fibrillation (AF) and to investigate their effects on theinitiation and maintenance of AF.Methods The right atrial tissue samples were taken from 75 patients with rheumaticheart disease who underwent heart valve replacement surgery. 34 patients were insinus rhythm, 11 patients had paroxysmal AF and 30 patients had persistent AF.Picrosirius red staining were used for quantitative analysis of collagen accumulation.The mRNA and protein level of collagen type I and type III, MMP-2, MMP-9,TIMP-1, TIMP-2 were measured by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western-blot analysis respectively. Theactivity of MMP-2 and MMP-9 was measured by zymographic analysis.Results (1)Atrial fibrosis tissue content significantly increased in both theparoxysmal AF and persistent AF groups than that in the sinus rhythm group. ThemRNA of collagen type I increased significantly in the persistent AF group followedby the paroxysmal AF group compared with the sinus rhythm group. The mRNA ofcollagen type III was slightly higher in both AF groups than that in the sinus rhythmgroup , but the differences were not statistically significant. Collagen volumefraction(CVF) and the mRNA of collagen type I significantly correlated with leftatria(LA) dimension and AF duration.(2)The mRNA level of MMP-2 increasedsignificantly in the persistent AF group followed by the paroxysmal AF groupcompared with the sinus rhythm group. MMP-9 mRNA expression remainedcompatible within groups. MMP-2 and MMP-9 protein expression was prominent inthe persistent AF group compared with the sinus rhythm and paroxysmal AF groups.TIMP-1 and TIMP-2 expression at mRNA and protein level were all down-regulatedin the persistent AF group, however, the trends of reduce did not reach statisticalsignificance in the paroxysmal AF group. The activity of MMP-2 and MMP-9significantly increased in both paroxysmal AF and persistent AF groups comparedwith the sinus rhythm group. The significant difference in MMP-9 was also observedbetween the paroxysmal AF and persistent AF groups. MMP-2 and MMP-9expression at mRNA and protein level were positively correlated with LA dimensionand AF duration and were negatively correlated with the mRNA and protein level ofTIMP-2 and TIMP-1 respectively . The mRNA level of MMP-2 was closelycorrelated with the mRNA of collagen type I .MMP-2 and MMP-9 expression atprotein level were positively correlated with CVF.Conclutions The upregulation of MMP-2,9 gene expression and activity , alongwith the selective downregulation of TIMP-1,2 ,may have contributed to the atrialstructural remodeling during AF through influencing collagen metabolism.