心衰病人心房颤动治疗新策略课件

P1 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 Satoshi Ogawa, M.D. Satoshi Ogawa, M.D. Director, Mita Hospital (Tokyo)Director, Mita Hospital (Tokyo) International University of Health 65(Suppl): 931-978Japanese Circulation J 2001; 65(Suppl): 931-978 Circulation J 2008;72 (Supple IV): S1581-1658 Circulation J 2008;72 (Supple IV): S1581-1658 P5 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 72 (Suppl.IV) : 15811638 持续性AF M2A1 Na/K ATPase 泵泵 CaKI f 受体 吡西卡尼 氟卡尼 西苯唑唑啉 普罗罗帕酮酮 丙吡胺 slowmedfast Na 通道 药药物 A 作用强度( 低, 中, 高) A A A A 抗心律失常药物作用特征 Ogawa S: JPN. J. ELECTROCARDIOLOGY 17(2), 191, 1997 P6 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 72 (Suppl.IV) : 15811638 * 除外心功能不全 消融 IK (IKur, IKr, IKs) 内向整流 K 通道; IK1 瞬时时外向 K 通道; Ito ATP-敏感性 K 通道; IK.ATP 乙酰酰胆碱-激活 K 通道channel; IK.ACh 内 Na-激活 K 通道; IK.Na K K 离子通道离子通道亚亚亚亚型型 P9 IKr IKr 特异性阻滞特异性阻滞剂剂剂剂, MS551, MS551, 在急性缺血中在急性缺血中 对动对动对动对动作作电电电电位的位的调调调调控作用控作用 P10 1 sec. IKr 阻滞剂剂在NSR和迷走神经诱导经诱导的AF中 对对心房动动作电电位时时程的作用 对对对对照照组组组组 MS-551MS-551组组组组 NSR AF P11 阻断阻断强强度度: : 低低 中中 高高 奎尼丁奎尼丁 丙吡胺丙吡胺 西苯西苯唑唑唑唑啉啉 吡美吡美诺诺诺诺 K K 通道通道选择选择选择选择 性性 I I K K I I K1K1 I I toto 胺碘胺碘酮酮酮酮 I I KurKur I I KrKr I I KsKs I I K.ATPK.ATP I I K.AChK.ACh directdirect M2M2 K K + + + + + + + + + + + + + + + + + + + + + P12 2007 AHA Late-Breaking Trial in Orlando 心房心房颤动颤动颤动颤动和充血性心力衰竭和充血性心力衰竭 (AF-CHF)(AF-CHF) P13 N Engl J Med 2008;358:2667 P14 基线线特征 % 患者 心律控制组组 N = 682 心率控制组组 N = 694 男性78%85% 年龄 (岁)66116711 NYHA 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 48% 36% 16% 48% 39% 13% 高血压49%46% 糖尿病22%20% 左室 EF %, 均数标准差276276 AF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% P15 药药物治疗疗12月后 % 患者 心律控制组组 N = 682 心率控制组组 N = 694 p 值值 胺碘酮82%7%心室 （ AF时时） 电压电压依赖赖性阻滞 对对去极化细细胞敏感 (心房心室) P20 新型抗心律失常新型抗心律失常药药药药物离子通道作用特征物离子通道作用特征 INaItoIKrIKsIKurIK1IKAChICaLNCX Dronedarone Celivarone ATI-2042 Vernakalant AZD7009 Tedisamil Ranolazine Late INa AVE0118 NIP-141/142 XEN-D0101 AVE1231 NTC-801 P21 心房特异性心房特异性 I I K.AChK.ACh 阻滞阻滞剂剂剂剂, , NTC-801NTC-801 ， ， 正在日本作正在日本作临临临临床研究，有望成床研究，有望成为为为为抗抗-AF-AF药药药药物物 P22 K.ACh K.ACh 通道在心通道在心脏脏脏脏中的分布中的分布 靶向靶向 I I K.AChK.ACh药药药药物治物治疗疗疗疗的可行性的可行性 P23 靶向靶向 IK.AChIK.ACh药物治疗的可行性药物治疗的可行性 Acetylcholine (ACh)Acetylcholine (ACh) G-proteinG-protein Vagal nerve (Parasympathetic nerveVagal nerve (Parasympathetic nerve) ) GIRK1GIRK1 GIRK4GIRK4 a a bgbg K K AChACh channel channelMM 2 2 receptor receptor CloseClose ExtracellularExtracellular IntracellularIntracellular K K+ + I I K.K.AChACh a a bgbg ActiveActive OpenOpen ExtracellularExtracellular IntracellularIntracellular ActiveActive InactiveInactiveInactiveInactive P24 Arora R et al.: J Am Coll Cardiol 49, 1340-1348 (2007) IK.ACh IK.ACh 在在PV, PLA PV, PLA 和和 LAA LAA 组织组织组织组织分布的异分布的异质质质质性及其引起的迷走神性及其引起的迷走神经经经经 诱导诱导诱导诱导的的ERPERP减少在各减少在各组织组织组织组织中的异中的异质质质质性性 LAAPLA PVPLALAA P=0.04 GIRK4 GIRK1 PLALAAPV P25 Atrial-Selective K+ Channel Blocker I I K.AChK.ACh 在慢性在慢性 AF AF 中的作用中的作用 Krapivinsky G et al.: J Biol Chem 270, 28777-28779 (1995) Dobrev D et al.: Dobrev D et al.: Circulation Circulation 112112, , 3697-3706 (2005)3697-3706 (2005) SR: Normal sinus rhythmSR: Normal sinus rhythm cAF: Chronic AFcAF: Chronic AF Tertiapin: Selective IKTertiapin: Selective IKAChACh blocker blocker (Peptide) (Peptide) P26 Cha TJ et al. Circulation. 2006;113(14):1730-7. I I K.AChK.ACh 在心房快速起搏在心房快速起搏 诱导诱导诱导诱导房房颤颤颤颤模型中的作用模型中的作用 P27 Acetylcholine (ACh)Acetylcholine (ACh) G-proteinG-protein Vagal nerve (Parasympathetic nerveVagal nerve (Parasympathetic nerve) ) GIRK1GIRK1 GIRK4GIRK4 a a bgbg MM 2 2 receptor receptor ExtracellularExtracellular IntracellularIntracellular K K+ + I I K.K.AChACh OpenOpen ActiveActiveInactiveInactive Constitutively activeConstitutively active K K AChACh channel channel 持持续续续续激活的激活的 I I K.AChK.ACh P28 心衰患者中，心衰患者中， I I K K . . AChACh 在在AFAF发发生的作用生的作用 有充分的有充分的证证证证据表明心衰后心肌分泌的据表明心衰后心肌分泌的细细细细胞因子胞因子 可介可介导导导导心心脏脏脏脏交感神交感神经经经经胆碱能分化胆碱能分化。 。 因此，没有理由不因此，没有理由不认为认为认为认为 I IK.AChK.ACh 在心衰患者在心衰患者 AFAF发发发发生中起了关生中起了关键键键键作用。作用。 P29 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 Kanazawa Division of Cardiology, Department of Internal Medicine, Regenerative Medicine and Advanced Cardiac Therapeutics Keio University School of Medicine, Tokyo, Japan 73rd Annual Scientific Meeting of the Japanese Circulation Society, Young Investigator Award P30 什么是胆碱能分化什么是胆碱能分化 ? ? 衰竭心衰竭心脏脏脏脏的去甲的去甲肾肾肾肾上腺素（上腺素（NENE）含量）含量显显显显著降低。著降低。 其原因包括其原因包括NENE的的过过过过度分泌，度分泌， 神神经经经经末梢再末梢再摄摄摄摄取降低和交感神取降低和交感神经经经经末梢的末梢的丢丢丢丢失。失。 Dr. Kanazawa Dr. Kanazawa 阐阐阐阐明了一个新明了一个新观观观观点：点： 心衰后增高的心衰后增高的细细细细胞因子，如胞因子，如 IF IF 和和 CT-1, CT-1, 使交感神使交感神经递质经递质经递质经递质从从 NE NE 变变变变成成 Ach, Ach, 这这这这也也导导导导致了衰竭的心肌致了衰竭的心肌 NE NE 含量降低含量降低 P31 ActininTH Wild typeLIF transgenic scale bar 50 m LIF 心脏脏特异性高表达导导致心脏脏交感神经经神经递质经递质的改变变 CHTActinin WT Relative epicardial nerve area 1.0 0 LIF-tg * 0.5 1.5 TH CHT * LVLV LVLV * ：pventricle during AF Voltage-dependent block Sensitive to depolarized cells (atriumventricle) P55 Ion channel profiles of novel Ion channel profiles of novel antiarrhythmicantiarrhythmic agents agents INaItoIKrIKsIKurIK1 IKACh ICaL NCX Dronedarone Celivarone ATI-2042 Vernakalant AZD7009 Tedisamil Ranolazine Late INa AVE0118 NIP-141/142 XEN-D0101 AVE1231 NTC-801 P56 AtrialAtrial-specific -specific I I K.AChK.ACh blocker, blocker, NTC-801 being under clinical investigation NTC-801 being under clinical investigation in Japan can be a potential anti-AF agent.in Japan can be a potential anti-AF agent. P57 Distribution of K.ACh channels in the heartDistribution of K.ACh channels in the heart More PertinentMore Pertinent Pharmacological Target Pharmacological Target I IK.AChK.ACh P58 More PertinentMore Pertinent Pharmacological Target Pharmacological Target I IK.AChK.ACh Acetylcholine (Acetylcholine (AChACh) ) G-proteinG-protein Vagal nerve (Parasympathetic nerveVagal nerve (Parasympathetic nerve) ) GIRK1GIRK1 GIRK4GIRK4 a a bgbg K K AChACh channel channelMM 2 2 receptor receptor CloseClose ExtracellularExtracellular IntracellularIntracellular K K+ + I I K.K.AChACh a a bgbg ActiveActive OpenOpen ExtracellularExtracellular IntracellularIntracellular ActiveActive InactiveInactiveInactiveInactive P59 Arora R et al.: J Am Coll Cardiol 49, 1340-1348 (2007) Heterogeneity of Heterogeneity of vagallyvagally-induced ERP shortening within the PV, PLA and LAA -induced ERP shortening within the PV, PLA and LAA corresponds with heterogeneity of corresponds with heterogeneity of IK.AChIK.ACh distribution distribution within each regionwithin each region LAAPLA PVPLALAA P=0.04 GIRK4 GIRK1 PLALAAPV P60 Atrial-Selective K+ Channel Blocker Role of Role of I IK.AChK.ACh in Chronic AF in Chronic AF Krapivinsky G et al.: J Biol Chem 270, 28777-28779 (1995) Dobrev D et al.: Dobrev D et al.: Circulation Circulation 112112, , 3697-3706 (2005)3697-3706 (2005) SR: Normal sinus rhythmSR: Normal sinus rhythm cAFcAF: Chronic AF: Chronic AF Tertiapin: Selective IKTertiapin: Selective IKAChACh blocker blocker (Peptide) (Peptide) P61 Cha TJ et al. Circulation. 2006;113(14):1730-7. Role of IRole of IK.AChK.ACh in in rapid rapid atrialatrial pacing model pacing model P62 Acetylcholine (Acetylcholine (AChACh) ) G-proteinG-protein Vagal nerve (Parasympathetic nerveVagal nerve (Parasympathetic nerve) ) GIRK1GIRK1 GIRK4GIRK4 a a bgbg MM 2 2 receptor receptor ExtracellularExtracellular IntracellularIntracellular K K+ + I I K.K.AChACh OpenOpen ActiveActiveInactiveInactive Constitutively activeConstitutively active K K AChACh channel channel Constitutively Active Constitutively Active I IK.AChK.ACh P63 Role of Role of I I K K . . AChACh in the Development in the Development of AF in Heart Failure Patientsof AF in Heart Failure Patients There is strong evidence that heart There is strong evidence that heart failure causes failure causes cholinergic cholinergic transdifferentiationtransdifferentiation of cardiac sympathetic nervous systemof cardiac sympathetic nervous system mediated by cytokines secreted by mediated by cytokines secreted by the failing myocardium. the failing myocardium. Thus, there seems to be no reason not to Thus, there seems to be no reason not to think that think that I IK.AChK.ACh plays a pivotal role in plays a pivotal role in the pathogenesis of AF in heart failure patients.the pathogenesis of AF in heart failure patients. P64 Heart failure causes cholinergic transdifferentiation of cardiac sympathetic nerves via gp130-mediated cytokines Hideaki Kanazawa Division of Cardiology, Department of Internal Medicine, Regenerative Medicine and Advanced Cardiac Therapeutics Keio University School of Medicine, Tokyo, Japan 73rd Annual Scientific Meeting of the Japanese Circulation Society, Young Investigator Award P65 What is cholinergic What is cholinergic transdifferentiationtransdifferentiation? ? It is well known that NE content of theIt is well known that NE content of the myocardium is markedly reduced in heart failure. myocardium is markedly reduced in heart failure. Excessive NE secretion, decreased re-uptake by Excessive NE secretion, decreased re-uptake by nerve endings, and loss of sympathetic nerve nerve endings, and loss of sympathetic nerve endings have been cited as reasons for this.endings have been cited as reasons for this. Dr. Kanazawa elucidated a new concept, that Dr. Kanazawa elucidated a new concept, that cytokines that increase in heart failure, such as cytokines that increase in heart failure, such as LIF and CT-1, change the neurotransmitter in LIF and CT-1, change the neurotransmitter in sympathetic neurons from NE to Ach, sympathetic neurons from NE to Ach, and are involved in the decrease in NE content and are involved in the decrease in NE content in the failing myocardium.in the failing myocardium. P66 ActininTH Wild typeLIF transgenic scale bar 50 m Cardiac-specific overexpression of LIF induced neurotransmitter switching in the cardiac sympathetic nerve CHTActinin WT Relative epicardial nerve area 1.0 0 LIF-tg * 0.5 1.5 TH CHT * LVLV LVLV * ：p0.01 P67 scale bar 100 m ChAT+/TH+ ratio 10 20 0 30 40* WTLIF-tg (%) ChAT Toto-3MergedTH Toto-3 ChAT Toto-3MergedTH Toto-3 * ：p0.01 Cardiac-specific overexpression of LIF increased cholinergic properties in the stellate ganglia Stellate ganglia Stellate ganglia Wild typeLIF transgenic TH : sympathetic ChAT : parasympathetic P68 Neurotransmitter switching in cardiac sympathetic nerves in patients with heart failure THCHTMerged scale bar 50 m LV LV THCHTMerged NormalHeart failure Relative TH+ nerve area 0.2 0.4 0.8 0 Relative CHT+ nerve area 20 5 10 15 0 0.6 25 * 1.0 1.2 Normal Heart failure Normal Heart failure * * ：p0.01 TH : sympathetic marker CHT : parasympathetic marker P69 Because the postganglionic fibers that exit Because the postganglionic fibers that exit stellatestellate ganglion supply ganglion supply atrialatrial myocardium as myocardium as well as ventricular myocardium,well as ventricular myocardium, even greater involvement of even greater involvement of IK.AChIK.ACh is inferred is inferred to be a factor in t