| Background:Atrial fibrillation (AF) is the most severe disorder of atrial electricalactivity, and the most common arrhythmia in clinical practice. AF ischaracterizing with high prevalence, high risk of disability rate, substantiallyaffecting patients life quality. Rate control, rhythm control andantithrombotic therapy are the fundamental treatment strategies for AF。Although clinical trials showed conflicting results, rhythm control strategystill has its theoretical and practical advantages. Despite the remarkabledevelopment in the methods for rhythm control in recent years, long termoutcome of AF patients remains unsatisfied. A safe and effective rhythmcontrol method is urgently needed, and exploration of new treatmentstrategy for AF has clinical significance. Over-activity of renin angiotensinsystem (RAS) plays an important role in the pathogenesis of AF. However,whether inhibiting RAS activity can substantially decrease the risk of AF development remains to be investigated, and the specific molecularmechanism between RAS blockade and atrial fibrillation remains elusive.Purpose:The aim of present study is two-fold; firstly, to discuss whether clinicaluse of RAS inhibitors (RASI) has a significant effect on decreasing the riskof AF by conducting a systematic review and meta-analysis. Secondary, weaim to investigate the potential molecular mechanisms underlying RASinhibiting (through target gene transfer) and atrial extracellular matrixremodeling by conducting an experimental study.Methods:For the meta-analysis at clinical study level, medical databases weresearched by using predefined searching strategy. We identified studies thatcompared RAS inhibitors with no RAS inhibitors in AF population, onlyrandomized controlled trials were included. The primary outcome wasincidence of AF. Meta-analysis was performed accordance with theguideline of Cochrane Handbook. Random-effect model was used for effectestimation.For the experimental study, according to a predefined inclusion criteria,32healthy Mongrel dogs were randomized into sham control group (onlyreceived open heart operation), right atrial rapid pacing group (pacingcontrol group), EGFP (enhanced green fluorescent protein) group (rightatrial rapid pacing and EGFP gene painting transfection), ACE2(angiotensin converting enzyme2) group (right atrial rapid pacing and ACE2genepainting transfection). After two weeks of inclusion, all groups underwentbaseline atrial electrophysiological measurement, and pacing control group,EGFP group and ACE2group underwent gene painting epicardially in openheart surgery; thereafter at three weeks, follow-up atrial electrophysiologicalmeasurements were performed in all groups, after which experimentalanimals were euthanized. The atrial samples were harvested for histological,special stain techniques, immunohistochemical, and protein-molecular exam.The outcome parameters included incidence of induced AF, HemateinEosin(HE stain), Masson stain, sirius stain, atrial expression level of ACE2,angiotensin II, angiotnsin (1-7), transforming growth factorβ (TGFβ),connective tissue growth factor (CTGF), collagen I, collagen III, metalmatrix proteinase2(MMP2), MMP9, tissue inhibitor of metalloproteinase1(TIMP1), and TIMP2.Results:By searching PubMed, Cochrane Library, and clinicaltrial.gov database,thirty two relevant studies were identified, of which26randomized trialscharacterizing95623patients were finally enrolled, methodologicalassessment showed high quality of included studies. Meta-analysisdemonstrated RAS inhibitor was associated with a significantly decreasedoverall risk of AF (odds ratio[OR]=0.68，95%confidence interval[CI]：0.60-0.79，p＜0.0001，Z=5.41), and new-onset AF (OR=0.75，95%CI： 0.65-0.87， p=0.0001， Z=3.86). Both angiotensin converting enzeyminhibitor (ACEI) and angiotensin receptor blocker (ARB) had significanteffect to decrease the risk of AF (ACEI: OR=0.68，95%CI：0.53-0.88，p=0.003，Z=2.93； ARB：OR=0.72，95%CI：0.61-0.86，p=0.0004，Z=3.57).The result of experimental study showed that atrial rapid pacing iseffective to establish atrial fibrillation model; the method of epicardiallyatrial gene painting transfection in open-heart surgery is feasible andeffective. As compared with baseline AF inducement, the rate of induced AFin sham control group and ACE2group at secondary electrophysiologicaltest seemed to have insignificantly changes, however, the pacing controlgroup and EGFP group showed a trend towards an increased risk of inducedAF at the secondary electrophysiological test. After three weeks of genepainting transfection, ACE2group showed a significantly increasedexpression of ACE2in the atria tissue as compared with sham control group(P＜0.05), on contrary, pacing control group and EGFP group showed atrend towards decreased expression of ACE2. After three weeks of genetransfection, ACE2group did not showed a significant change of expressionof angiotensin II in the atria tissue as compared with sham control group(P＞0.05), however, pacing control group and EGFP group showedsignificantly increased expression of angiotensin II (P＜0.05, P＜0.05,respectively). After three weeks of gene transfection, ACE2group did not showed a significant change of expression of angiotensin (1-7) in the atriatisssue as compared with sham group (P＞0.05), however, pacing controlgroup and EGFP group showed significantly decreased expression ofangiotensin (1-7)(P＜0.05, P＜0.05, respectively). After three weeks ofgene transfection, the atrial TGFβ expression level in pacing control group,EGFP group and ACE2group were increased as compared with shamcontrol group, but the increasement was more pronounced in pacing controlgroup and EGFP group (P＜0.05). After three weeks of gene transfection,the atrial CTGF expression level in pacing control group, EGFP group andACE2group were increased as compared with sham control group, but theincreasement was more pronounced in pacing control group and EGFPgroup (P＜0.05). The semi-quantitative results of atrial Masson stain, siriusstain, and immunohistochemical results of atrial collagen I and collagen IIIshowed that after three weeks of gene transfection, the atrial interstitial fiberexpression level in pacing control group, EGFP group and ACE2group wereincreased as compared with sham control group, but the increase is morepronounced in pacing control group and EGFP group (P＜0.05). Furtherinvestigation for MMPs and TIMPs showed after three weeks of genetransfection the atrial MMP2, MMP9, TIMP1and TIMP2expression levelwere increased in pacing control group, EGFP group and ACE2group, butthe increase was more significant in pacing control group and EGFP group(P＜0.05). Conclusions:The results of meta-analysis of clicnial studies demonstrated that RASinhibitor has the potential to decrease the overall risk of AF and new-onsetAF. ACEI and ARB seems to have equivalent effect in AF prevention. RASinhibitor has protective effect in AF prevention. The results of experimentalstudy demonstrated the feasibility and efficacy of atrial rapid pacing AFmodel and the gene painting trasfection method. In the atrial rapid pacing AFmodel, atrial ACE2gene trasfection is associated with significantlyincreased expression of atrial ACE2, exerting an antagonistic effect on RASover activity in atrial tissue. Atrial ACE2gene transfection can decrease therisk of AF inducement. Atrial ACE2gene transfection can down-regulatethe expression of atrial TGFβand CTGF level. Atrial ACE2genetransfection can decrease the severity of atrial interstitial fibrosis. AtrialACE2gene transfection can down-regulate the expression of atrial MMP2,MMP9, TIMP1and TIMP2. |
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