心衰病人心房颤动治疗新策略

1、心衰病人心房颤动治疗新策略心衰病人心房颤动治疗新策略心房选择性抗房颤药物展望心房选择性抗房颤药物展望吡西卡尼西苯唑啉普罗帕酮丙吡胺氟卡尼肺静脉电隔离消融&起搏孤立性 AF阵发性 AF电复律控制心率苄普地尔+/-阿普林定索他洛尔胺碘酮 (口服)首选房颤持续时间短第二 , 第三选择孤立性孤立性AF心律控制策略心律控制策略Circ J. 2008 ; 72 (Suppl.IV) : 15811638持续性AFM2A1Na/KATPase泵CaKI f受体吡西卡尼氟卡尼西苯唑啉普罗帕酮丙吡胺slowmedfastNa通道药物A 作用强度( 低, 中, 高) AAAA 抗心律失常药物作用特征Og

2、awa S: JPN. J. ELECTROCARDIOLOGY 17(2), 191, 1997控制心率阿普林定苄普地尔索他洛尔*胺碘酮 (口服)电复律 肺静脉电隔离消融& 起搏+/-CRT心肌肥厚 心功能不全心肌缺血上游治疗器器质质性心性心脏脏病病AF患者心律控制策略患者心律控制策略Circ J. 2008 ; 72 (Suppl.IV) : 15811638* 除外心功能不全 消融& 起搏= AV 结消融 + 心室起搏延迟外向 K 通道; IK (IKur, IKr, IKs)内向整流 K 通道; IK1瞬时外向 K 通道; ItoATP-敏感性 K 通道; IK.ATP

3、乙酰胆碱-激活 K 通道channel; IK.ACh内 Na-激活 K 通道; IK.Na1 sec.IKr 阻滞阻滞剂剂在在NSR和迷走神和迷走神经诱导经诱导的的AF中中对对心房心房动动作作电电位位时时程的作用程的作用NSR AF+ +2007 AHA Late-Breaking Trial in OrlandoN Engl J Med 2008;358:2667基基线线特征特征% 患者患者心律控制心律控制组组N = 682心率控制心率控制组组N = 694男性78%85%年龄 (岁)66116711NYHA 分级: -32%31%主要的心脏疾病诊断: 冠状动脉疾病 非缺血性心肌病 其它4

4、8%36%16%48%39%13%高血压49%46%糖尿病22%20%左室 EF %, 均数标准差276276AF类型: 阵法性 / 持续性33% / 67%30% / 70%左房直径, mm, 均数标准差497497住院病史: 因为 AF / 因为 CHF51% / 54%55% / 56%药药物治物治疗疗12月后月后% 患者患者心律控制心律控制组组N = 682心率控制心率控制组组N = 694p 值值胺碘酮82%7%0.0001索他洛尔1.8%0.3%多非利特0.4%0.2%阻滞剂80%88%0.0001地高辛51%75%0.0001维拉帕米 或 地尔硫卓1.8%3.3%0.0999AC

5、EI81%82%0.4103ARB16%13%0.0870利尿剂80%82%0.3710螺内酯47%49%0.5071口服抗凝剂88%92%0.0306ASA34%31%0.3066他汀44%46%0.6141N Engl J Med 2008;358:2667心律控制组每次随访中，窦性心律确诊率为 75-80% Vernakalant Hydrochloride 用于房颤快速转复 三期，随机，安慰剂对照试验 AF：336 例 阵发性 220 (3h-7d) 持续性 116 (8d-45d) Circulation 2008; 117:1518-1525转复率：37.6% vs 2.6% (p

6、心室 （ AF时） 电压依赖性阻滞 对去极化细胞敏感 (心房心室)INaItoIKrIKsIKurIK1IKAChICaLNCXDronedaroneCelivaroneATI-2042VernakalantAZD7009TedisamilRanolazineLate INaAVE0118NIP-141/142XEN-D0101AVE1231 NTC-801Arora R et al.: J Am Coll Cardiol 49, 1340-1348 (2007)LAAPLAPVPLALAAP=0.04GIRK4GIRK1PLALAAPVAtrial-Selective K+ Channel

7、BlockerKrapivinsky G et al.: J Biol Chem 270, 28777-28779 (1995)Cha TJ et al. Circulation. 2006;113(14):1730-7.心衰引起心脏交感神经通过gp130介导的细胞因子发生胆碱能分化Hideaki KanazawaDivision of Cardiology, Department of Internal Medicine, Regenerative Medicine and Advanced Cardiac TherapeuticsKeio University School of Medi

8、cine, Tokyo, Japan73rd Annual Scientific Meeting of the Japanese Circulation Society, Young Investigator AwardActininTHWild typeLIF transgenicscale bar 50 mLIF 心心脏脏特异性高表达特异性高表达导导致心致心脏脏交感神交感神经经神神经递质经递质的改的改变变CHTActininWTRelative epicardial nerve area1.00LIF-tg*0.51.5THCHT*LVLVLVLV*：p0.01scale bar 100

9、mChAT+/TH+ ratio 102003040*WTLIF-tg(%)ChAT Toto-3MergedTH Toto-3ChAT Toto-3MergedTH Toto-3*：p0.01LIF 心心脏脏特异性高表达增加星形神特异性高表达增加星形神经节经节的胆碱能特性的胆碱能特性 Stellate gangliaStellate gangliaWild typeLIF transgenicTH : sympatheticChAT : parasympathetic心衰患者心心衰患者心脏脏交感神交感神经经神神经递质经递质的改的改变变THCHTMergedscale bar 50 mLVLV

10、THCHTMergedNormalHeart failureRelative TH+ nerve area0.20.40.80Relative CHT+ nerve area20 5101500.625*1.01.2NormalHeart failureNormalHeart failure*：p0.01TH : sympathetic markerCHT : parasympathetic marker慢性 AF 患者中，独立于激动剂的，心房-IK.ACh活性增高。 持续激活的 IK.ACh 增加心房发生心动过速的易感性，并维持 AF。心脏交感神经胆碱能分化可能是 AF 的基质Pilsica

11、inideCibenzolinePropafenoneDisopyramideFlecainidePVIsolationAblate&PaceLone AFParoxysmal AFElectrical ConversionRate controlBepridil+/-AprindineSotalolAmiodarone (po)First choiceIn case of short AF durationSecond , third choiceRhythm Management Strategy for Patients With Lone AFCirc J. 2008 ; 72

12、 (Suppl.IV) : 15811638Persistent AFM2A1Na/KATPasePumpsCaKI fReceptorsPilsicainideFlecainideCibenzolinePropafenoneDisopyramideslowmedfastNaChannelsDrugAThe intensity of the action is indicated ( low, moderate, high ) AAAAProfiles of Antiarrhythmic Agentsin the Framework of the Sicilian GambitOgawa S:

13、 JPN. J. ELECTROCARDIOLOGY 17(2), 191, 1997Rate controlAprindineBepridilSotalol*Amiodarone (po)Electrical ConversionPVIsolationAblate& Pace+/-CRTHypertrophic heart Failed heartIschemic heartUpstream therapyRhythm Management Strategy for AF Patients With Organic Heart DiseaseCirc J. 2008 ; 72 (Su

14、ppl.IV) : 15811638* Excluding failed heart Ablate& Pace= AV nodal ablation + ventricular pacingdelayed outward K channel; IK (IKur, IKr, IKs)inward rectifier K channel; IK1transient outward K channel; ItoATP-sensitive K channel; IK.ATPacetylcholine-activated K channel; IK.AChinternal Na-activate

15、d Kchannel; IK.Na1 sec.Effect of IKr blocker on atrial action potential duration during NSR and vagally-inducedAFNSR AF+ +2007 AHA Late-Breaking Trial in OrlandoN Engl J Med 2008;358:2667Baseline Characteristics% of ptsRhythm Control GroupN = 682Rate Control GroupN = 694Male Sex78%85%Age (yrs)661167

16、11NYHA class: -32%31%Predominant cardiac diagnosis: Coronary artery disease Non-ischemic cardiomyopathy Other48%36%16%48%39%13%Hypertension49%46%Diabetes22%20%Left ventricular EF %, meanSD276276Type of AF: proxysmal / persistent33% / 67%30% / 70%Left atrial dimension, mm, meanSD497497Prior hospitali

17、zation: for AF / for CHF51% / 54%55% / 56%Medical Therapy at 12 months% of ptsRhythm Control GroupN = 682Rate Control GroupN = 694p ValueAmiodarone82%7%0.0001Sotalol1.8%0.3%Dofetilide0.4%0.2%Beta-blocker80%88%0.0001Digoxin51%75%0.0001Verapamil or diltiazem1.8%3.3%0.0999ACE inhibitor81%82%0.4103ARB16

18、%13%0.0870Diuretic80%82%0.3710Spironolactone47%49%0.5071Oral anticoagulant88%92%0.0306ASA34%31%0.3066Statins44%46%0.6141N Engl J Med 2008;358:2667Sinus rhythm was documented in 75-80% of patients in the rhythm control group at each visitVernakalant Hydrochloride for Rapid Conversion of Atrial Fibril

19、lation A Phase 3, Randomized, Placebo-Controlled Trial AF：336 cases paroxysmal 220 (3h-7d) persistent 116 (8d-45d) Circulation 2008; 117:1518-1525Conversion rate：37.6% vs 2.6% (pventricle during AF Voltage-dependent block Sensitive to depolarized cells (atriumventricle)INaItoIKrIKsIKurIK1 IKACh ICaL

20、 NCXDronedaroneCelivaroneATI-2042VernakalantAZD7009TedisamilRanolazineLate INaAVE0118NIP-141/142XEN-D0101AVE1231 NTC-801Arora R et al.: J Am Coll Cardiol 49, 1340-1348 (2007)LAAPLAPVPLALAAP=0.04GIRK4GIRK1PLALAAPVAtrial-Selective K+ Channel BlockerKrapivinsky G et al.: J Biol Chem 270, 28777-28779 (1

21、995)Cha TJ et al. Circulation. 2006;113(14):1730-7.Heart failure causes cholinergic transdifferentiation of cardiac sympathetic nerves via gp130-mediated cytokines Hideaki KanazawaDivision of Cardiology, Department of Internal Medicine, Regenerative Medicine and Advanced Cardiac TherapeuticsKeio Uni

22、versity School of Medicine, Tokyo, Japan73rd Annual Scientific Meeting of the Japanese Circulation Society, Young Investigator AwardActininTHWild typeLIF transgenicscale bar 50 mCardiac-specific overexpression of LIF induced neurotransmitter switching in the cardiac sympathetic nerve CHTActininWTRelative epicardial nerve area1.00LIF-tg*0.51.5THCHT*LVLVLVLV*：p0.01scale bar 100 mChAT+/TH+ ratio 102003040*WTLIF-tg(%)ChAT Toto-3MergedTH Toto-3ChAT Toto-3MergedTH Toto-3*：p0.01Cardiac-specific overexpression