心力衰竭与心室重构

芪苈强心抑制心室重构抗心力衰竭芪苈强心抑制心室重构抗心力衰竭基础与临床研究证据基础与临床研究证据CADHypCMValvLVDRemodelingLow EFArrhythmiasDeathPump FailureCHFSymptomsNon CardiacFactorsVentricular Remodeling after Infarction and in Diastolic and Systolic Heart FailureJessup et al. N Engl J Med 2003;348:2007-2018Neurohormonal model of HFMcMurray J, Pfeffer MA.Circulation. 2002;105:2099-106.Primary targets of treatment in HFJessup M, Brozena S. N Engl J Med. 2003;348:2007-18.气阳虚乏气阳虚乏脉络瘀阻脉络瘀阻 尿少水肿尿少水肿络息成积络息成积心室重构、心脏扩大心室重构、心脏扩大 “气分气分”（神经体液调节异常）（神经体液调节异常） “水分水分”（钠水滁留）（钠水滁留） “血分血分”（血流动力学异常）（血流动力学异常） 益气温阳益气温阳黄芪、附子、人参、桂枝黄芪、附子、人参、桂枝活血通络活血通络丹参、红花丹参、红花利水消肿利水消肿 葶苈子、泽泻、香加皮葶苈子、泽泻、香加皮标标本本兼治兼治强心、利尿、扩血管强心、利尿、扩血管缓解心慌气短、缓解心慌气短、不能平卧、尿少水肿症状不能平卧、尿少水肿症状抑制抑制RASSRASS与交感神经与交感神经减少心室重构减少心室重构 与与RASSRASS、交感神经系统激活导致心室重构为慢性心衰病机新概念相吻合、交感神经系统激活导致心室重构为慢性心衰病机新概念相吻合 脉络学说指导脉络学说指导慢性心衰病机、有效组方及作用研究慢性心衰病机、有效组方及作用研究Cellular Immunology 2009, 260:52-55ResultsThe effect of Qiliqiangxin on the echocardiographic and hemodynamic parameters in the infarcted hearts. 4 g/kg/day for 4 weeks for RatsThe ratio of TNF-a/IL-10 in infarcted myocardial tissue was reversed by Qiliqiangxin.Conclusion:Qiliqiangxin improves cardiac function of rats with MI through regulation the balance between TNF-a and IL-10.J Cardiovasc Pharmacol, 2012, 59(3): 268-280Conclusion:1.QL inhibits myocardial inflammation and cardiomyocyte death and promotes cardiomyocyte proliferation, leading to an ameliorated cardiac remodeling and function in a mouse model of pressure overload. 2.The possible mechanisms may involve inhibition of angiotensin II type 1 receptor and activation of ErbB receptors.American journal of hypertension, 2012, 25, 250-260QL:0.6mg/kg/day for 4 weeks for miceConclusion:1. QLQX improves both systolic and diastolic cardiac function in SHRs.2. QLQX downregulate the cardiac chymase signaling pathway and chymase-mediated ang II production.临床试验注册临床试验注册Li X, Zhang J, Huang J, Ma A, Yang J, Li W, Wu Z, Yao C, Zhang Y, Yao W, Zhang B, Gao R. A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study of the Effects of Qili Qiangxin Capsules in Patients With Chronic Heart Failure. J Am Coll Cardiol. 2013;62(12):1065-1072. 临床研究简介临床研究简介Li X, Zhang J, Huang J, Ma A, Yang J, Li W, Wu Z, Yao C, Zhang Y, Yao W, Zhang B, Gao R. A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study of the Effects of Qili Qiangxin Capsules in Patients With Chronic Heart Failure. J Am Coll Cardiol. 2013;62(12):1065-1072. BNP/NT-proBNPBNP/NT-proBNP可用于指导可用于指导心衰的治疗心衰的治疗 心衰患者治疗后心衰患者治疗后BNP/NT-proBNPBNP/NT-proBNP与基线相比下降与基线相比下降达到或超过达到或超过30%30%，表明治疗奏效，表明治疗奏效 如未下降或下降未达标甚至继续走高，则表明治如未下降或下降未达标甚至继续走高，则表明治疗效果不佳，应继续增强治疗的力度。疗效果不佳，应继续增强治疗的力度。中国心力衰竭诊断和治疗指南中国心力衰竭诊断和治疗指南2014 中华心血管病杂志中华心血管病杂志 2014(42):22014(42):2生物标志物及应用生物标志物及应用情情 况况推荐类推荐类 别别证据水证据水 平平利钠肽利钠肽 HFHF的诊断或排除的诊断或排除非卧床，急性非卧床，急性 I I A AHFHF的预后的预后非卧床，急性非卧床，急性 I I A A达到达到GDMTGDMT目标目标非卧床非卧床IIa IIa B B指导急性失代偿性指导急性失代偿性HFHF治疗治疗急性急性IIb IIb C C心肌损伤标志物心肌损伤标志物附加危险分层附加危险分层急性，非卧床急性，非卧床 I I A A心肌纤维化标志物心肌纤维化标志物附加危险分层附加危险分层非卧床非卧床IIb IIb B B急性急性IIb IIb A A 2013 ACCF/AHA HF Guideline 2013 ACCF/AHA HF Guideline 生物生物标志物测定建议标志物测定建议GDMT, Guideline-Directed Medical Therapy; 指南导向药物治疗指南导向药物治疗2013 ACCF/AHA Guideline for the Management of Heart Failure. E-Published on June 5, 2013, available at: http:/content.onlinejacc.org/article.aspx?doi=10.1016/j.jacc.2013.05.019 aStudy DesignNT-proBNPNT-proBNP的水平变化及下降超过的水平变化及下降超过30%30%的比例的比例 两组两组NYHANYHA心功能分级描述和比较心功能分级描述和比较LVEFLVEF、LVEDLVED、6MWD6MWD基线与第基线与第1212周随访变化趋势周随访变化趋势 明尼苏达生活质量量表评分变化趋势明尼苏达生活质量量表评分变化趋势心血管复合事件心血管复合事件药物不良事件药物不良事件 EDITORIAL COMMENT EDITORIAL COMMENT CARDIOTONIC MODULATION IN HEART FAILURE: CARDIOTONIC MODULATION IN HEART FAILURE: INSIGHTS FROM TRADITIONAL CHINESE MEDICINEINSIGHTS FROM TRADITIONAL CHINESE MEDICINE 让衰竭的心脏更加强劲让衰竭的心脏更加强劲- -中国传统医学给我们的启示中国传统医学给我们的启示Tang WH, Huang Y. Cardiotonic Modulation in Heart Failure: Insights from Traditional Chinese Medicine. J Am Coll Cardiol. 2013;62(12):1073-1074.Editorial Comment （述评述评） -by Tang WHW, Huang YIt is conceivable that in the future if qili qiangxin proves to provide morbidity and mortality benefits in rigorous clinical trials, it will fundamentally challenge the existing foundation of scientific inquiry based upon the precise understanding of pharmacodynamics of drug therapies.可以想象的是，如果芪苈强心胶囊在未来高质量的临床研究中提供更多可以想象的是，如果芪苈强心胶囊在未来高质量的临床研究中提供更多关于其对受试者发病率、死亡率益处的证据，那么关于其对受试者发病率、死亡率益处的证据，那么它将从根本上挑战现它将从根本上挑战现有的关于药物效应动力学研究的科学观念。有的关于药物效应动力学研究的科学观念。Tang WH, Huang Y. Cardiotonic Modulation in Heart Failure: Insights from Traditional Chinese Medicine. J Am Coll Cardiol. 2013;62(12):1073-1074.Editorial Comment （述评述评） -by Tang WHW, Huang YYet even at present, the promising results reported by Li and colleagues may have already opened the opportunity to explore with the latest technologies how synergistic interactions among active TCM ingredients can benefit the syndrome of heart failure. This is a challenge that we should all warmly embrace.现如今，这项富有前景的研究表明李及他的研究同事们已经打开了一扇现如今，这项富有前景的研究表明李及他的研究同事们已经打开了一扇如何利用最新科技研究传统中药活性成分在心力衰竭治疗中协同作用的如何利用最新科技研究传统中药活性成分在心力衰竭治疗中协同作用的大门。大门。这是一个挑战，对此我们应该热烈拥抱。这是一个挑战，对此我们应该热烈拥抱。Tang WH, Huang Y. Cardiotonic Modulation in Heart Failure: Insights from Traditional Chinese Medicine. J Am Coll Cardiol. 2013;62(12):1073-1074.临床研究证据级别：由高到低临床研究证据级别：由高到低1. 随机对照研究随机对照研究2. 2. 前瞻性非随机对照研究前瞻性非随机对照研究3. 3. 回顾性对照研究回顾性对照研究4. 4. 非对照研究或历史对照研究非对照研究或历史对照研究5. 5. 荟萃分析荟萃分析6. 6. 病例报道病例报道 7. 7. 评论，教授或其他专家意见评论，教授或其他专家意见 Professor Joseph S. Alpert Editor-in-Chief, American Journal of Medicine 2013.7.19 Nanjing中国心力衰竭诊断和治疗指南中国心力衰竭诊断和治疗指南2014（中华心血管病杂志中华心血管病杂志 2014(42):22014(42):2）对芪苈强心临床试验结果进行了描述（参考文献对芪苈强心临床试验结果进行了描述（参考文献58）dayMISacrifice071421QL21 dWorking model : AMI remodelingOur work:（我们的研究我们的研究）Project1: Traditional Chinese Medication Qiliqiangxin attenuates cardiac remodeling after acute myocardial infarction in miceUnpublished dataSaline + shamSaline + MIQL + MIQL + ShamResultsUnpublished dataRemoteRemoteRemoteRemoteBorderInfarctBorderInfarctBorderBorder Saline + MIQL+ MISaline + MIQL + MIUnpublished dataSaline+ShamSaline+MIQL+MIPPARg1PGC1aGAPDHPPARaUnpublished data Reversal experiments- PPARa a PPARg gUnpublished dataMI+QL+PPARg InhibitorMI+QL+PPARg ActivatorMI+QLUnpublished dataPGC1aCb-ActinPPARaQM QM+PPARg InhibitorPPARgDUnpublished dataMISacrifice071421QL31 2418 dday0123dayMISacrificeQL3 dFuture workAcute phaseRemodeling phaseUnpublished dataSaline + MIQL + MIUnpublished dataAcute phase (TTC Staining)NMQMMISacrifice071421QL31 2418 dFigure 11ABBPPARaPPARg1PGC-1ab-actinMI+SalineQL+SalineCProject2: The matabolic effects of QLQX on H9C2 (in vitro) Unpublished dataBasal Oxidative MetabolismPeak Oxidative MetabolismFigure1: Oxidative Metabolism indicated by oxygen consumption of H9C2 myocytes treated with QL at different time and doseAMitochondrial UncouplingMetabolic RelianceBCBasal GlycolysisPeak GlycolysisFigure2: Glycolysis Metabolism indicated by oxygen consumption of H9C2 myocytes treated with QL at different time and doseABFigure3: Mitochondrial Content measured by microscopy and flow cytometryControllQL (48hr)MitotrackerMitotrackerMergeMergeMitochondrial contentAB待发表文章待发表文章:Traditional Chinese Medication Qiliqiangxin attenuates cardiac remodeling after acute myocardial infarction targeting PPARR已于3月31号向哈佛大学医学院附院心内科主任、新英格兰副主编托尼教授汇报过研究结果受到好评。临床意义临床意义 作为作为预防预防心肌梗死后心室重构导致心心肌梗死后心室重构导致心衰的治疗策略之一？（衰的治疗策略之一？（B阶段）（阶段）（RAS/BB）Qiliqiangxin in Heart FailUre：AssESsment of Reduction in MorTality Prof Xinli LiThe First Affiliated Hospital with Nanjing Medical Universityon behalf of the InvestigatorsStudy DesignTherapeutic regimen : enrolled patients with HF are given oral medication treatment according to Diagnosis and Treatment Guidelines of HF(version 2014).Treatment group and control group add Qiliqiangxin capsule / placebo (4 capsules Tid) respectively on the basis of original medication.screening12345678910randomizationVisitTime(Month)-0.503691218243036 SHF case（n=1840 1:1） DHF case（ n=1840 1:1 ）Mid-term evaluation of the follow-up in 36 months is made by statisticians unconnected with the trial. If the endpoint indicator is positive, the trial would be terminated.Enrollment42481112observation period:3-4 years The primary endpoint: composite endpoint of cardiovascular death and re-hospitalization for worsening heart failure谢谢 谢！谢！