| Atrial fibrillation (AF) is the most common arrhythmia in clinical practice, present in2%of the general population. The prevalence of AF increases markedly with age,affecting as many as9%of individuals80years or older. AF has several complicationssuch as thromboembolism and heart failure and is regarded as an independent risk factorfor cardiovascular mortality.Numerous studies have focused on the pathogenesis of AF. It is generally accepted thatAF may be multifactorial and has been linked to, among others, ectopy from thepulmonary veins, catecholamine release and large atrial size. However, the fundamentalarrhythmia mechanisms of AF are rapid ectopic firing and reentrant activity. Atrialremodeling may increase the risk of ectopic or reentrant activity through a multitude ofpotential mechanisms and is considered to be the new pathophysiological mechanism of AF. In the past few years the relationship between inflammation and AF has drawnsignificant attention. Inflammation may be a cause of AF and this is supported by the highincidence of AF in post-operative cardiac surgery, a state of severe inflammatory process.However, evidence suggests that inflammation may also play a prominent role innonoperative onset of AF.Programmed cell death-1(PD-1, Pdcd-1) is a negative immunoreceptor belonging to theCD28/CTLA-4family. It can be inducibly expressed on CD8and CD4T cells, naturalkiller T cells, B cells and activated monocytes. The ligands for PD-1(PD-Ls) are PD-L1and PD-L2; PD-1–PD-Ls pathways control the induction and maintenance of peripheral Tcell tolerance and PD-1deficiency enhances T-cell activation and increases theinflammation level.Then whether the high inflammation level in the PD-1deficiency mice will participatein the pathogenesis of AF? In this study, we compared the expression of inflammatorycytokines, the level of atrial myocyte oxidative stress, the atrial effective refractory period(AERP), the dispersion of AERP(dAERP) and the atrial myocardial fibrosis level of theC57BL/6PD-1-/-in the C57BL/6mice.Study have shown that dietary intervention with n-3PUFAs could reduce systemicinflammation and proinflammatory cytokines, So aim to futher confirm the relationshipbetween the inflammation in the C57BL/6PD-1-/-mice and the pathogenesis of AF. Oraladministration of eicosapentaenoic+docosahexaenoic acid (EPA+DHA),5mg/day wasstarted4weeks before the study in C57BL/6PD-1-/-mice. We observed the change ofinflammatory cytokines, the atrial effective refractory period (AERP), the dispersion ofAERP(dAERP) and the atrial myocardial fibrosis level in the PUFAs-C57BL/6PD-1-/-mice after oral administration of PUFAs.There are two parts in this study.PART ONEStudy of inflammatory cytokines，atrial myocyte oxidative stress and the atrialremodeling in the C57BL/6PD-1-/-mice Aim: the deficiency of programmed cell death1(PD-1) can enhance T-cell activation andimprove the inflammation level, meanwhile it has been reported that atrial fibrillation (AF)has a close relationship with inflammation and inflammatory cytokines, this study wasdesigned to investigate the roles of PD-1deficiency in the pathogenesis of atrialfibrillation.Methods: two groups of mice were used to carry out our experiment: C57BL/6group (15mice, male) and C57BL/6-PD-1-/-group (15mice, male), the expression of inflammatorycytokines: interleukin (IL)-2,(IL)-4,(IL)-6,(IL)-10,(IL)-17,interferon (IFN)-γ and tumornecrosis factor(TNF), the myocardial fibrosis level, the atrial effective refractory period(AERPs)and the level of Cardiac Atrium Myocytes Oxidative Stress were determined.Results: inflammatory cytokines were significant increase in the PD-1-/-groupcompare to the C57BL/6group:(IL-10,1212.35±300.42vs208.8±57.25pg/ml, p<0.001;IL-6,165.21±42.49vs35.47±6.04pg/ml, p<0.001; IL-2,3.95±1.06vs2.8±0.63pg/ml,p<0.01,IL-4,7.19±1.07vs3.11±0.35pg/ml, p<0.001, IFN-γ,22.1±4.72vs5.17±1.27pg/ml,p<0.001, TNF,36.49±8.21vs24.55±4.29pg/ml, p<0.001,IL-17A,42.03±8.53vs8.05±1.76pg/ml, p<0.001); The level of PD-1-/-group Cardiac Atrium Myocytes Oxidative Stresswas higher also(the mean DCF fluorescence intensity:30.21±1.66vs24.35±1.82,p<0.001).They have a shorter atrial effective refractory period compare to the C57BL/6group(45.40±2.16vs43.93±1.10,P<0.05). Meanwhile the PD-1-/-group presentedmyocardial fibrosis but the C57BL/6group did not.Conclusion: Our findings strongly suggest that the higher level of inflammatory cytokinesand Atrium Myocytes Oxidative Stress accompanying with the PD-1-/-mice results inAtrial electricity and structural remodeling in C57BL/6mice. Because of the Atrialremodeling the PD-1-/-mice may more easily develop Atrial fibrillationPART TWON-3polyunsaturated fatty acids prevents atrial remodeling by inhibitinginflammation in C57BL/6-PD-1-/-miceBackground: it has been reported that atrial fibrillation (AF) has a close relationship with inflammation and n-3polyunsaturated fatty acids can play an anti-inflammatory effects.Meanwhile the deficiency of programmed cell death1(PD-1) will result in T-cellactivation and improve the inflammation level; this study was designed to investigate theeffect of dietary polyunsaturated fatty acids on the vulnerability to atrial fibrillation inPD-1deficiency mice.Methods: three groups of mice were used to carry out our experiment: C57BL/6group,C57BL/6-PD-1-/-group and PUFA group, the expression of inflammatory cytokines:interleukin (IL)-2,(IL)-4,(IL)-6,(IL)-10,(IL)-17,interferon (IFN)-γ and tumor necrosisfactor(TNF), the atrial effective refractory period (AERPs), the atrial myocardial fibrosislevel were examined.Results: inflammatory cytokines were significant increase in the PD-1-/-group compareswith the C57BL/6group; meanwhile the PD-1-/-mice group have a shorter atrial effectiverefractory period compares with the C57BL/6group, moreover they presented atrialmyocardial fibrosis but the C57BL/6group did not. However after dietary n-3PUFAsupplementation the inflammatory cytokines obviously decreased and the PUFA groupappeared longer atrial effective refractory period and lower atrial myocardial fibrosis levelcompare with the C57BL/6PD-1-/-groupConclusion: Our findings strongly suggest that dietary n-3PUFA supplementation canattenuate the atrial remodeling result from the higher level of inflammatory cytokines inthe C57BL/6PD-1-/-mice, so as to reduce the vulnerability of atrial fibrillation. |
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