1、解读 ACC/AHA 2005 心衰指南 代文在高血压及心衰治疗中地位,Heart Failure in the United States, 145%, 260%,1979 n=35,051,1999 50,624,1979 377,000,1999 962,000,Deaths,Hospitalization Discharges,AHA Statistical Update 2002,慢性心衰发病率,WHO Statistics 1996,心衰预后,心衰患者死亡率高，平均寿命低于多种常见类型肿瘤; (Ho et al. 1993) HF 高死亡率： 25% 新发患者在1年内死亡 (ESC
2、 1999 1979 年至 1999年间, 心衰引起的死亡增加 145% (AHA 2005) HF 中位生存时间约为诊断后 1.73.2 年 (Kannel et al. 1988; Kannel 1991) 心衰反复入院治疗很常见，超过50% 患者半年内即再入院治疗 (Krumholz et al. 1997, Vinson et al. 1990, Burns et al. 1997),The Cardiovascular Continuum: Targeting Mechanisms and Mediators,Adapted from Dzau V et al. Am Heart J
3、. 1991.,Endothelial Dysfunction,Target Organ Damage,Risk Factors,Vascular Dysfunction,Vascular Disease,Tissue Injury (MI, Stroke),Pathological Remodeling,Target Organ Dysfunction (CHF, Renal),End-stage Organ Failure,Death,Angiotensin II,Stages of Renal and CV Disease,ESRD,CRI ( GFR),Albuminuria, Pro
4、teinuria,Elderly, DM, HTN,Chronic Renal Disease,CV Disease,Elderly, DM, HTN,CAD, LVH,ASCVD Events,CHF,End- stage,Progression,Initiation,“At-risk”,Natural History of CVD Progression,Elevated BP,Target Organ Damage,More Recent Paradigm,A Proposed Future Paradigm,Elevated BP,Target Organ Damage,Vascula
5、r Dysfunction,Elevated BP,Target Organ Damage,Vascular Dysfunction,Endothelial Dysfunction,Early Paradigm,Angina Pectoris,Stroke,MI,Renal Damage,LVH,?,Hypertension: The Disease Continuum,CAD Hyp CM Valv,LVD,重构,低EF,死亡,非心脏因素,症状,CHF,心律失常,泵衰竭,激活SNS,RAS,激活SNS,RAS,激活SNS,RAS,心血管事件链,“心脏疾病是一系列疾病延时间发展而成的统一体。它
6、以危险因子为开端，中间经过诸如急性心梗等独立的危险事件，这些事件或者引发猝死或者促进心功能衰竭，因此,我们必须停止将不同心血管疾病割裂开来对待.”Mandeep Mehra, M.D. Head of Cardiology University of Maryland Medical Center,“心力衰竭心脏病最后的大战场”E Braunwald ACC 2003,心衰危险因素,高血压是 心衰最主要的危险因子 使心衰危险增加3倍 (AHA 2005) 75% 的心衰患者曾患高血压 (AHA 2005) 约 65% 的心衰由冠状动脉疾病引起。 35% 由非缺血性疾病如瓣膜疾病、心脏毒性药物、
7、心肌炎或原发性心肌病引起 (Chobanian et al. 2003) 年龄和冠心病是心衰的主要决定因素，其他预测因子包括高血压、糖尿病、吸烟和肥胖,ACC/AHA Practice Guidelines Pyramid Approach to HF Stages,Hunt SA et al. J Am Coll Cardiol. 2001;38:2101-2113.,心衰的A阶段,对血压,血脂及代谢异常的干预 高血压阶段的主要组织结构的病变特点,Evolution of Cardiovascular Events: ACC/AHA Stage A Heart Failure,Adapted
8、 from HFSA. Pharmacotherapy. 2000;20:495.,Average Percent ReductionStroke incidence 35-40% Myocardial infarction 20-25% Heart failure 50%,JNC VII: Benefits of Lowering BP,Not at Goal Blood Pressure (140/90 mm Hg) (130/80 mm Hg for those with diabetes or chronic kidney disease),Initial Drug Choices,D
9、rug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed.,With Compelling Indications,Lifestyle Modifications,Stage 2 Hypertension (SBP160 or DBP100 mm Hg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB)
10、,Stage 1 Hypertension (SBP 140-159 or DBP 90-99 mm Hg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination.,Without Compelling Indications,Not at Goal Blood Pressure,Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation wi
11、th hypertension specialist.,JNC 7 高血压治疗流程,大量临床试验证明了ARB卓越的治疗作用 ARB不仅在应用ACEI发生咳嗽时推荐使用无咳嗽时仍可以使用 确立了ARB在高血压伴有某些特殊疾病时的治疗地位,对ARB治疗地位的肯定,2004年高血压治疗指南,ARB在特殊疾病时的 治疗地位,糖尿病高血压 要求将血压降至130/80mmHg以下，常须联合用药 ARB对2型糖尿病防止肾损害有益 慢性肾病 ACEI、ARB有利于防止肾病进展，重度病人须合用袢利尿剂 心力衰竭 在症状多的将ACEI、阻滞剂、ARB和醛固酮拮抗剂与袢利尿剂合用,2004年高血压治疗指南,代文降压
12、疗效与氨氯地平相同,4周时血压平均下降值 (mmHg),Palatini et al. J Hypertens 2001; 19: 1-6,舒张压,收缩压,-9.1,-10.3,代文80mg,氨氯地平5mg,代文80mg,氨氯地平5mg,-19.5,-20.2,P=NS,P=NS,双倍剂量代文降压疗效 优于双倍剂量依那普利,Fogari et al. Eur J Clin Pharmacol 2004; 59: 863-868,P0.01,P0.01,16周时血压较基线值的改变 (mmHg),舒张压,收缩压,代文 160mg,依那普利 20mg,代文 160mg,依那普利 20mg,不同 AR
13、B治疗后的血压下降值(mmHg),舒张压,-9.8,-6.9,收缩压,-14.1,-9.9,代文 80mg,氯沙坦 50mg,厄贝沙坦 150mg,代文 80mg,氯沙坦 50mg,厄贝沙坦 150mg,-13.8,-9.9,-7.9,-10.8,坎地沙坦 8mg,坎地沙坦 8mg,拉丁方试验证实 ARB降压的疗效有了充分体现,Fogari et al. Curr Ther Res 2000; 61 (10): 669-679,P0.05,P=NS,P0.05,P=NS,心肌缺血发生的时间与分钟,0-2 3-5 6-8 9-11 12-14 15-17 18-20 21:-24,n=11816
14、,180 160 140 120 100 80 60 40 20 0,脑梗死发作的时间及%,ARB降压的长效与平稳可以减少心脑血管事件发生,Time-Dependent Effects of Valsartan on ABP: Double-Digit 24-h BP Reductions With Morning or Evening Dosing,*P 0.001 vs baseline. Hermida RC et al. Hypertension. 2003;42:283-290.,Systolic,Diastolic,17.0*,11.3*,24-h Mean in BP (mm H
15、g),14.6*,11.4*,Valsartan 160 mg at awakening (n = 46),Valsartan 160 mg at bedtime (n = 44),Treatment With Valsartan Reduces Percent of Nocturnal Non-dippers,Hermida RC et al. Hypertension. 2003;42:283-290.,Percent of Nocturnal Non-dippers,0,20,40,60,80,100,59.1,15.9,Awakening,Bedtime,RRR = 73.1%,RRR
16、 = 12.5%,Relative risk reduction of 73.1% with bedtime administration,心衰A期的组织结构的的主要变化ARB在心衰A期的干预作用,血管主要的结构病变特性,Vascular Remodeling: Clinical Implications,Myocardial Infarction,Renal Failure,Hypertension,Stroke,Tissue Ischemia,Coronary reserve in hypertension and LVH,0 20 40 60 80 100 120 140 160,100
17、,200,300,400,500,Flow (ml/min),Coronary Flow Reserve,Maximal Vasodilation,NT,HT,LVH,Arterial Pressure (mmHg),LV 功能不全,RAAS 激活, 阻力,LV 重构,Ang II and Vascular Remodeling,Ang II,Vascular Hypertrophy, Vascular Compliance, Afterload, M/L Ratio,Vascular Fibrosis,M,L,M,L,Influence of Angiotensin II on the Bl
18、ood Vessel,Weir MR, Dzau VJ. Am J Hypertens. 1999;12:205S213S.,Induction of Angiotensin II Pathways at the Tissue Level, Local Angiotensin II production,Vascular remodeling,Blood Pressure,Vascular Injury,6%,Media-lumen ratio,ACEI ARB,CCB,Hypertensive,8.5%*, 7%,8.5%*,Atenolol,No change,Improve,Normot
19、ensive,* p 0.01 vs normotensive p 0.05 vs hypertensive and atenolol,*,*P 0.05 vs baseline.,250,0,50,100,150,200,Valsartan,Baseline,Week 8,300,350,% Change in Forearm Blood Flow in Response to ACh,Valsartan Improves Endothelial Function,Tzemos N et al. Am J Hypertens. 2001;14:66A67A. Abstract P-111.,
20、The clinical significance of these effects is unknown.,Valsartan Improves Vessel Elasticity*, in Augmentation Index,*BP reductions similar for valsartan and HCTZ. P 0.01 vs HCTZ and vs placebo. Adapted with permission from Klingbeil AU et al. J Hypertens. 2002;20:2423-2428.,Valsartan,Placebo,HCTZ,Va
21、lsartan improves arterial compliance in patients with hypertension. Effects are independent of BP reduction.,-21.7 (n = 20),-3.2 (n = 20),-0.3 (n = 20),*P 0.005 vs placebo. Adapted with permission from Peters S et al. J Invasive Cardiol. 2001;13:93-97.,Val-PREST: In-Stent Restenosis and Reinterventi
22、on Rates at 6 Months,Patients With Restenosis, %,50% reduction with valsartan vs placebo,*,0,10,20,30,40,50,Restenosis,Reintervention,*,58% reduction with valsartan vs placebo,心衰 - 心血管事件链的最后阶段,危险因素 糖尿病 高血压,动脉粥样硬化 左室肥厚,心肌梗死,左室重构,心室扩张,终末期心脏病死亡,充血性 心力衰竭,心血管事件链是一系列以病生理为主线， 将心血管危险因子和临床疾病连接而成的链条,Sympathet
23、ic Nervous System, CNS sympathetic outflow, Cardiac sympathetic activity, Renal sympathetic activity,Sodium retention,Myocyte hypertrophy Myocyte injury Increased arrhythmias,Disease progression,1,b1,b1,b2,1, Vascular sympathetic activity,Vasoconstriction,1,Activation of RAS,异常的血管收缩,激活SNS, 血管加压素,肌细胞
24、增生,血管 平滑肌增生, 胶原,心肌血管重构, PAI-1/ 血栓形成,血小板聚集,超氧化产物, 内皮素,Ang II,血管紧张素 II的在心肌及血管重构的有害作用,Adapted from Burnier M, Brunner HR. Lancet. 2000;355:637645. Brown NJ, Vaughan DE. Adv Intern Med. 2000;45:419429., 醛固酮,Pathophysiologic Effects of Ang II,Adapted from Burnier M et al. Lancet. 2000;355:637645.,Abnorma
25、l Vasoconstriction,Activate SNS,Aldosterone, Vasopressin,Collagen,Contractility,PAI-1/ Thrombosis,Platelet Aggregation,Superoxide Production,Endothelin,Vascular Smooth Muscle Growth,Myocyte Growth,Ang II,Sympathetic FibersAngiotensinogenNE b Reninreceptors (kidney,heart,vessels)Presynaptic Angiotens
26、in IAT1 receptor ACE Angiotensin II,Sun Ning ling,Levels,Adapted from Cohn JN. Cardiology. 1997;88:26.,血浆 去甲肾上腺素 (pg/mL),NL,HF,血浆 肾素激活 (ng/mL/h),NL,HF,精氨酸 血管加压素 (pg/mL),NL,HF,心房钠尿肽 (pg/mL),NL,HF,内皮素-1 (pg/mL),NL,HF,心衰神经激素激活,BNP (pg/ml),41,4197,98238,238,BNP,随机化后时间 (月),生存率,9.7,14.3,20.7,32.4,% 死亡率,NE
27、,572,274,274394,395572,NE (pg/mL),24.2,% 死亡率,13.8,16.5,23.0,Val-HeFT: BNP和NE基线四分法全因死亡率亚组分析,20,10,30,0,40,Anand IS. Circulation. 2003;107:12781283.,随机化后时间 (月),传统的心衰常规治疗-强心、利尿、扩血管已被以神经内分泌拮抗剂为主的新的“常规治疗”或“标准治疗”所取代：ACEI/ARB、受体阻滞剂、利尿剂、有时加用地高辛,2001 ACC/AHA Practice Guidelines Pyramid Approach to HF Therapy
28、,High Risk for Developing HF,Asymptomatic HF,Symptomatic HF,End-StageHF,A,B,C,D,Neurohormonal Activation in Heart Failure,Hypertrophy, apoptosis, ischemia, arrhythmias, remodeling, fibrosis,Angiotensin II,Norepinephrine,Morbidity and Mortality,ACE-I,CONSENSUS* NYHA Class IV,SOLVD Treatment NYHA Clas
29、s IIIII,*危险降低 40% (P = 0.003) 危险降低 16% (P = 0.0036),安慰剂 (n = 126),依那普利 (n = 1285),60,80,40,20,0,安慰剂 (n = 1284),死亡率 (%),12,6,18,30,36,42,0,24,48,Months,Swedberg K et al. Circulation. 1990;82:17301736. The SOLVD Investigators. N Engl J Med. 1991;325:293302.,ACEI在 CONSENSUS和SOLVD试验中 对CHF的作用,依那普利 (n = 1
30、26),Beta-blocker Therapy in Heart Failure,Potential Beneficial Effects,Protection from Catecholamine Toxicity,Renin- Angiotensin System,Reversal of Remodeling,Up-regulation of b-adrenergic Receptors,Ancillary Factors,2P = 0.0002,LVES容积,mL/m,4,0, 4, 8,12, 12,8,2P = 0.0042,LVED容积,mL/m,4,0, 4, 8,12, 12
31、,8,ANZ 卡维地洛试验,Doughty RN et al. J Am Coll Cardiol. 1997;29:106066.,P = 0.019,LVES容积,mL,6 个月,基线,12 个月,4 个月,基线,12 个月,4,0, 4, 8,12, 12,8,P = 0.025,LVED 容积,mL,4,0, 4, 8,12, 12,8,SOLVD 试验,Greenberg B et al. Circulation. 1995;91:257381.,安慰剂,依那普利,安慰剂,依那普利l,安慰剂,卡维地洛,安慰剂,卡维地洛,ACEI 和受体阻滞剂对心室重构的作用,Neurohormona
32、l Activation in Heart Failure,Hypertrophy, apoptosis, ischemia, arrhythmias, remodeling, fibrosis,Angiotensin II,Norepinephrine,Morbidity and Mortality,ACEI (yes) BB (yes),15.5,1.1,7.2,Ang II (fmol/mL),(n = 11),ACEI (yes) BB (no),(n = 11),101,5,10,20,15,100,95,Ang I (fmol/mL),5,10,20,15,100,95,血管紧张素
33、 II,血管紧张素 I,105,105,ACEI + BB 在心衰患者中显著降低Ang II 水平,0,0,Campbell DJ et al. Lancet. 2001;358:16091610.,Aldosterones Role in Cardiovascular Disease,McMahon EG. Current Opinion Pharmacol. 2001;1:190-196.,Prothrombotic effects,Potassium and magnesium loss,Vascular inflammation and injury,Myocardial fibros
34、is,Central hypertensive effects,Endothelial dysfunction,Ventricular arrhythmias,Sodium retention,Catecholamine potentiation,Cardiovascular disease,Deleterious effects of aldosterone,Aldosterone Blockade in Heart Failure,RALES: Randomized Aldactone Evaluation Study,1663 pts NYHA II, III, and IV, aver
35、age age 65 and LVEF 0.35, on ACEI, loop diuretic, digoxin randomized to spironolactone 25 mg PO qd vs placebo. Pitt B et al. N Engl J Med. 1999;341:709-717.,Spironolactone,Placebo,Follow-up (months),100,80,60,40,20,0,0,10,20,30,36,RR 0.70 (0.60-0.82),P0.001,Probability of Survival (%),心肌梗死,ACE-I 醛固酮
36、受体拮抗剂,左室重构,危险因素高脂血症高血压糖尿病吸烟肥胖胰岛素抵抗,动脉粥样硬化 左室肥厚,血管内皮功能不全 微小血管病,冠状动脉疾病,心力衰竭,死亡,终末期微小血管 肾病,SAVE TRACE AIRE EPHESUS,CONSENSUS SOLVD RALES,HOPE,HOPE,HOPE,ACE-I及醛固酮拮抗剂在心血管事件链中的作用,ACEI长期治疗后的血管紧张素II逃逸现象,*p0.001 versus placebo.Biollaz J, et al. J Cardiovasc Pharmacol. 1982;4:966-972.,*,*,*,*,*,*,*,*,*,100,80
37、,60,40,20,0,血浆 ACE (nmol/mL/min),血浆血管紧张素 (pg/mL),安慰剂,4 h,24 h,1,2,3,4,5,6,月,住院,ARBs Prevent Angiotensin II Escape,Angiotensinogen,Angiotensin I,Angiotensin II,ACE-I,X,Angiotensin Receptor Blocker,X,Degradation Products,Renin,AT1 Receptor,AT2 Receptor,X,Non ACE-dependent pathways to ANG II production
38、,Bradykinin,Chymase-Dependent vs ACE-Dependent A II Formation in Hearts of Various Species,Reprinted with permission from Balcells E et al. Am J Physiol. 1997;273:H1769-H1774.,A II Formation (%),Mouse,Rabbit,Rat,Dog,Human,ACE-dependent Chymase-dependent,A II Formation in Normal and Dysfunctional Ves
39、sels,A II Formed (nmol/min/mg protein),Others (non-ACE, non-chymase dependent) ACE-dependent Chymase-dependent,Normal aorta (n = 9),0,1,2,3,4,5,6,Atherosclerotic lesions (n = 8),Aneurysm (n = 6),*,*,*P 0.01 vs normal aorta. P 0.01 vs chymase-dependent A II-forming activity in the normal aorta. Repri
40、nted with permission from Ihara M et al. Hypertension. 1999;33:1399-1405.,药物对肾素血管紧张素系统的作用,血管紧张素原,肾素,Ang I,AT1 受体,Ang II,Renin-Angiotensin-Aldosterone System,Angiotensinogen,Angiotensin I,Angiotensin II,Bradykinin,Inactive Fragments,ACE,AT2,AT1,B2, NO,Renin,Vasodilation Antiproliferation (kinins),Non
41、-ACE Pathways (tonin, chymase, CAGE),VasoconstrictionCell growthNa/H20 retentionSympathetic activation,Aldosterone,cough vasodilation platelet agg ischemia + inotropic,NE,BB,ARB在心衰A,B,C期的干预作用,“心脏重构可定义为基因表达，分子、细胞以及间质性的显著改变，在临床上表现为心脏受损后心脏大小、形状和功能的改变。 ”,Cohn JN et al. J Am Coll Cardiol. 2000;35:569582.
42、,心脏重构,“Cardiac remodeling may be defined as genome expression, molecular, cellular and interstitial changes that are manifested clinically as changes in size, shape and function of the heart after cardiac injury.”,SV 100 EF 60,SV 100 EF 40,SV 100 EF 25,左室重构,月,1.0,0.9,0.8,0.7,0.6,Q1,Q2,Q3,Q4,LVIDd,EF
43、,生存概率,月,1.0,0.9,0.8,0.7,0.6,Q1,Q2,Q3,Q4,Val-HeFT: Kaplan-Meier 死亡率曲线 LVIDd 和 EF四分法与基线,Wong M et al. J Am Coll Cardiol. 2002;40:970975.,P 0.00001,P 0.00001,Clinical Significance of AT1 Receptor Blockade,A II,AT2,BP,Atherosclerosis,Endothelial Function,Neuroendocrine,LVH,Cardioprotection Vasculoprotec
44、tion Renoprotection,AT1 receptor blockade,A II binding at the AT2 receptor,ARB,LVH=left ventricular hypertrophy.,AT1,ARB对血管紧张素II和缓激肽的作用,ARBs 在心血管事件链中的作用,心肌梗死,左室重构,危险因素高脂血症高血压糖尿病吸烟肥胖胰岛素抵抗,动脉粥样硬化 左室肥厚,血管内皮功能不全 微小血管病,冠状动脉疾病,心力衰竭,死亡,终末期微血管 心肾疾病,OPTIMAAL VALIANT,RENAAL IDNT IRMA-2 MARVAL,Elite II Val-HeF
45、T CHARM,NAVIGATOR,ONTARGET TRANSCEND,LIFE Value,卒中,Beta Blocker,ACE inhibitor or ARB ? or ACE inhibitor and ARB?,Aldosterone Receptor Antagonist,+,+,CIBIS-2 MERIT-HF COPERNICUS,CONSENSUS SOLVD-T,ELITE-2,Val-HeFT CHARM,RALES,CAPRICORN,SAVE AIRE TRACE,OPTIMAAL VALIANT,VALIANT,EPHESUS,CHRONIC HEART FAI
46、LURE,AMI LVSD/HF,ELITE II:,Pitt B, et al. Lancet. 2000;355:1582-1587.,氯沙坦在降低总死亡率或心源性 猝死方面的疗效并不优于卡托普利,VALSARTAN HEART FAILURE TRIAL 缬沙坦治疗心力衰竭试验,心衰治疗的里程碑,在主要心衰试验中生存率最高,National Vital Statistics Report. 1999; Cohn et al. NEJM 2001;345:1667; SOLVD Investigators. NEJM 1991;325:293; Cohn et al. NEJM 1986;12; Packer M, et al. NEJM 1996; Consensus Study Group NEJM 1987; Packer M, et al. NEJM 1991;325:1468,研究回顾,代文 降低所有原因病死率与病残率联合终点13.2%,Cohn JN. Circulation. 2000;102:2672-2676.,0,65,70,75,80,85,90,95,缬沙坦,安慰剂,100,* p=0.009,月,无事件概率 (%),代文 降低心力衰竭住院*27.5%,0,65,70,75,80,85,90,
