心房颤动从阵发到持续的进展过程及其机制

1心房颤动：从阵发到持续的进展过程及其机制吴林北京大学第一医院心内科2Overview心房颤动：我们面对的现状与挑战心房颤动的进展过程及电、分子、组织和解剖学异常心房纤维化在房颤进展过程中的作用新的治疗靶点及展望3PrevalenceofAtrialFibrillationGoetal.JAMA2001285:2370-2375↑Stroke（4-6x)，↓Cardiacfunction(CO15-30%)，↑Morbidityandmortality（2x）AdultsWithAF(millions)7.02.085.615.425.164.784.343.803.332.942.662.442.266.05.04.03.04.02.01.001990199520002005201020152020202520302035204020452050YearA.AgeB.YearVolume29，Number1，2013JalifeJ：心房颤动的药物治疗：复发率和总死亡率A.AAD治疗N.Freemantle,S.Mitchell,M.Orme,L.Eckert,M.ReynoldsACC20100.10.20.50.10.20.50.10.20.512510100DronedaroneN=33780.165AmiodaroneN=6530.049SotalolN=8730.013DronedaroneN=11310.0002PropafenoneN=1228AmiodaroneN=978SotalolN=1404FlecainideN=305房颤复发率总死亡率P值0.00010.00010.00010.0001药物毒副作用B.上游治疗ACEIs/ARBs他汀类s激素类体力锻炼Omega-3脂肪酸炎症氧化应激RAAS活性内皮功能自主神经系统活动稳定斑块心房重塑稳定左房心内膜房颤发生率房颤上游治疗的疗效不理想AnalysisbasedonCoxmodel:log(HR)=treatment+region+ACE/ARB+Statin+StrataHR:1.22CI:(0.98,1.52)Pvalue:0.081PLA:147/323(46%)P-OM3:167/322(52%)安慰剂Omega-3脂肪酸A.RAAS阻断剂B.Omega-3脂肪酸房颤的类型与进展过程1.阵发性（Paroxysmal，PAF)：反复发作，7天内自行终止2.持续性（Persistent）：连续房颤超过7天，或不足7天复律者3.长时间持续（Longstanding):联续房颤超过一年4.慢性房颤或永久房颤（ChronicorPermanent)进展过程7房颤发展过程中的病理生理学变化基因学年老器质性心脏病(e.g.,HF、LVH)↑心房内压新房扩张Atrialfibrosis↓conduction,↓ERP↑reentry离子通道及电重塑↑,TGF-β,galectin，ANP,BNPPermanentAtrialremodelingandcellapoptosisPersistent结构重塑AFParoxysmalAFbegetsAF房颤发展过程中的电重塑8Ito1IKurIKrINaICaIKsIK-ACh,IK-ATPIK1Ito1IKurIKrINaICaIKsIK-ACh,IK1(CA)NormalatriaRemodeledatriaA.细胞膜电流B.电生理指标心房颤动的发生与进展机制9房颤患者及动物的肺静脉结构重塑10A.人肺静脉标本B.狗心房肌及心室肌标本肺静脉扩张及心房肌纤维化房颤发生时间延长增加心房纤维化程度11A.不连续反复心房快速起搏导致房颤持续时间延长B.持续性房颤动物（羊）的心房纤维化程度增加心房纤维化在房颤进展中的作用12Volume29，Number1，2013JalifeJ：(半乳糖凝集素）的作用北京大学-密西根联合研究所A.TGF-β1水平13晚钠电流增大引起急性AFTriggeredSubstratesforIntra-atrialreentryAtrialFibrillation↑APD,↑ERP↑Inhomogeneousrepolarization↑CaMK-IISpontaneousTriggeredactivity↑[Ca2+]ICa2+overloadNCX↑[Na]iPhysiological(endogenous)PathologicalLQT3MyocardialI/RHFHypertrophy↑ROS↑CO2levelsPharmacologicalDrugs(digitalis)Toxins:ATX-II↑lateINaCircResWuL，etal:AHA201114药物诱发急性房颤的发生机制ModelsofAFTargetHRAPDERPDroneRan↓LateINa↓CaMK-II↓IKur↓IKAchAch↑M1↑IKAch↓↓↓+++?(+)?(+)??ISO↑β1↑-↓?(+)+++++++??↑INa↑LateINa-↑↑?(+)+++++?(+)??Reentry:fibroblastandmyofibroblast15168.16147169.66147171.16147172.66147seconds-0.736410-0.618205-0.500000-0.381795VoltsA-MAPA.ControlInducibilityofAFinthewholeheartAR167bpmLeftatrialMAPS1S1S1S21255.661471257.161471258.661471260.16147seconds-0.736410-0.618205-0.500000-0.381795VoltsA-MAPB.Ach0.6µMAR958bpmDurationofAF:318sS1S1S1S24824.161474825.661474827.16147seconds-0.736410-0.618205-0.500000-0.381795VoltsA-MAPD.Ach(0.6µM)+联合使用低剂量抗心律失常药AR817bpmDurationofAF:2sS1S1S1S25521.661475523.161475524.661475526.16147seconds-0.736410-0.618205-0.500000-0.381795VoltsA-MAPE.Ach(0.6µM)+联合使用治疗剂量抗心律失常药S1S1S1S2S1S23618.161473619.661473621.161473622.66147seconds-0.736410-0.618205-0.500000-0.381795VoltsA-MAPC.Ach(0.6µM)+新型抗心律失常药AR895bpmDurationofAF:4sS1S1S1S21600.10.3130204060ATX-II(nM)**n=6AFwindow(ms)00.10.3130204060ATX-II(nM)Ctrl**AFBurden(ms)n=60.0.10.31368-10020406080100ATX-II(nM)SpontaneousAFInducibelAFIncidenceofinducible/spontaneousAF(%)A.诱发性和自发性AF的发生率B.AFWindowC.AFBurden房颤的发生率、房颤诱发窗口及房颤负荷17急慢性房颤从阵发到持续进展过程的研究+AcuteAFChronicAFCardiacfibrosisScartissueHypertrophyIschemia/infarctionDHFDM↑Ach↑β1activity↑LateINa↑CaMK-II↑AT-II,U-II↑InflammationH2O2,ILTriggersSubstratesAF:fromparoxysmaltopersistent总结心房颤动从阵发到持续及慢性房颤中房颤的促房颤过程有电学、心肌组织学及心脏结构的重塑过程心肌纤维化及促心肌纤维化过程在房颤进展过程中起重要作用对急慢性房颤进展机制的研究可以帮助我们寻找新的治疗靶点及更有效及安全的治疗方法1819致谢