1、Heart Failure,Department of pathophysiology Xiangrong Sun,Fundamental knowledge,Heart is one of the most important organs in body. The main function of heart is to providing impetus for circulation of blood.,volume：like left fist weight：500g Ejection of blood：70ml/SV70/min 60min24h7056 L/d 10.8万次/天,
2、Histology of myocardium,Intercalated disc,2018/9/2,mitochondrion,Ca2+,Ca2+ 10-7mol/L,Ca2+ 10-5mol/L,Release of Ca2+,tropomyosin,contraction,（粗）myosin,（细）actin,troponin,Ca2+,Ca2+ 10-5mol/L,SR,mitochondrion,Ca2+,Ca2+ 10-7mol/L,Reuptake of Ca2+,relaxation,tropomyosin,（粗）myosin,（细）actin,troponin,Ca2+,20
3、18/9/2,AP and contraction of cardiac myocyte,冠心病 (CHD) 高血压(Hypertension) 心肌病(Cardiomyopathy)瓣膜疾病 (Valvular heart disease),What causes heart failure?,In addition to those causes above, the following factors also can play a role in determining if heart failure will affect you:family history of heart d
4、isease(家族史） diabetes（糖尿病） marked obesity（肥胖） heavy consumption of alcohol, or tobacco（酗酒、 吸烟） 5.large salt intake in diet （高盐饮食）,Other factors,heart failure is the pathological process in which the systolic or/and diastolic function of the heart impaired, and as result , cardiac output decrease and
5、is unable to meet the metabolic demands of body,Concept of heart failure,the systolic or/and diastolic function of the heart impaired,heart failure,2018/9/2,Determinants of cardiac function,Etiology,Decreased myocyte contractility,pressure overload (afterload),Overload for myocardium,volume overload
6、 （preload ）,etiology of heart failure,2018/9/2,Restriction of filling,output,low-output heart failurehigh-output heart failure (*compared with healthy adult),Classification,Low output heart failure,before high output heart failure,high output heart failure,Normal output,health adult,onset,acute hear
7、t failurechronic heart failure,Location,left-sided heart failure right-sided heart failure whole heart failure,2018/9/2,法洛氏四联征,Compensatory responses,increased heart rate,cardiac dilation,myocardial hypertrophy,Cardiac compensation,(一) Increased heart rate,Mechanism,pressure receptor volume receptor
8、,advantage,This adaptation may increase the cardiac output And maintain the perfusion of heart and brain,disadvantage,If heart rate 180times/min, it will:Increase the consumption of oxygen of heart Reduce the duration for ventricular filling Inadequate flow of the coronary artery (squeeze, lumen, na
9、rrow),(二) cardiac dilatation,Frank-Starling law: The more a myocyte or ventricular chamber is stretched ,the more it will contract,2018/9/2,tonicity dilation: the volume of ventricle increases due to the sarcomere dilation, accompanying the increased cardiac contractility and stoke volume,myocardiog
10、enic dilation: the stretch of sarcomere does not accompany the increasedcardiac contractility.,(三) Myocardial hypertrophy,concentric hypertrophy,eccentric hypertrophy,2018/9/2,Concentric hypertrophy: is the response to pressure overload. It is associated with increased number of sarcomere arranged i
11、n parallel. The increase in wall thickness reduces wall tension and cardiac compliance without increasing the internal chamber size.,eccentric hypertrophy: the response to volume overload is characterized by dilation of chamber size, as well as relative decreased wall thickness. It is thought to res
12、ult from increased number of sarcomere arranged in series.,concept,GPCR,胞膜,Ca2+,离子通道,Ca2+,IP3,DAG,Gq,PLC,PKC,Biologic responses in hypertrophy,CA, Ang等,Gs,R,R,肌钙蛋白结合,兴奋-收缩偶联,心肌收缩,基因表达增加，心肌和血管平滑肌增生,cAMP,PKA,细胞内 Ca2+库,MAPK家族/NHE-1,CaM-K,2018/9/2,Significance of myocardial hypertrophyEnhancing the cont
13、ractility of heart Decreasing wall tension and oxygenconsumption,2018/9/2,Reduced in the concentration of NE and 1-adrenergic receptor (Tyrosine hydroxylase ),Decreased oxygen and blood supply,Altered of energy metabolism and utilization,Dysfunction of excitation-contraction coupling,Excessive cardi
14、ac hypertrophy,Decreased compliance (collagen),(四) Increased ability of cells to use oxygen,Systemic compensation,Increased blood volume,机制,1.肾小球滤过率（ CA ，AGII , PGE2 ,肾血流),2.肾小管对水钠的重吸收 肾内血流重分布：皮质髓质水钠的重吸收 肾小球滤过分数=肾小球滤过率/肾血流量. 促进水钠重吸收的激素（醛固酮ADH ）抑制水钠重吸收的激素（PGE2 利钠素）,交感肾上腺髓质系统激活(activation of sympathet
15、ic-adrenal medulla system),肾素-血管紧张素-醛固酮系统激活 (activation of renin-angiotensin-aldosterone system, RAAS),Neurohumoral compensation,血流重新分布,Renin-angiotensin system and concept of its inhibitory action,Angiotensinogen,Angiotensin ,Angiotensin ,Vascular contraction,Angiotension II Receptor antangonists,A
16、CE Inhibitors,Angiotensin converting enzyme (ACE),Renin,Renin inhibitors,etc.,etc.,etc.,Receptor,心力衰竭与机体的代偿模式图,心力衰竭,机体代偿,心脏,HR,心脏紧张源性扩张,心肌肥大,收缩力,舒缩功能,心外,血容量,血液重分配,红细胞、肌红蛋白,心血供,有效循环血量,供血供氧,利用氧能力,细胞线粒体数 、呼吸酶活性,SV,CO,心肌舒缩功能降低,R x SV = CO,组织细胞缺血缺氧,神经-体液,交感-肾上腺髓质系统,ARRS,血容量,血液重分配,收缩力,2018/9/2,infection (
17、 pulmonary infection),precipitating factors,Precipitating factors,2018/9/2,infection,2018/9/2,cardiac dysrhythmia,precipitating factors,2018/9/2,尤其是快速型心律失常心率舒张期缩短 心肌耗氧量 冠脉血流 心肌缺血、缺氧心室充盈 心泵功能心输出量,房室活动协调性紊乱,2018/9/2,water-electrolytes and acid-base disturbance,precipitating factors,Ca2+ inflow , SR re
18、leased Ca2+ binding to troponin activity of ATP enzyme sensitivity of Cap to CA ,myocardial conductibility,autorhythmicity,cardiac contractility,myocardial excitability,2018/9/2,pregnancy and delivery,precipitating factors,2018/9/2,妊娠期血容量（临产期） 分娩时疼痛、精神紧张、 稀释性贫血 交感一肾上腺髓质系统兴奋高动力循环状态 静脉回流 小血管收缩心脏前负荷（左室
19、）后负荷 心肌耗氧量和冠脉流量 心输出量,2018/9/2,Excessively labor and spiritual burden; infusion,precipitating factors,2018/9/2,(一) loss of cardiomyocyte,(二) metabolic dysfunction of myocardium,(三) dysfunction of excitation-contraction coupling,Pathogenesis,Decreased myocardial contractility,(一) loss of cardiomyocyte
20、,Decreased myocardial contractility,contractility decreased,myocardial cell apoptosis : apoptotic index 35.5%,(二) metabolic dysfunction of myocardium,impaired energy productionreduced energy reserveimpaired energy utilization,Decreased myocardial contractility,1.impaired energy production,myocardial
21、 ischemia hypoxia,Disorder of myocardial energy metabolism,2. reduced energy reserve,CP,Disorder of myocardial energy metabolism,3. impaired energy utilization,Disorder of myocardial energy metabolism,能量生成,能量利用,脂肪酸 乳酸 丙酮酸 葡萄糖 氨基酸,三羧酸循环,氧化磷酸化,ATP,ADP+Pi,Ca2+,与肌钙 蛋白结合,心肌收缩,心衰时的能量代谢障碍,CP,能量储存,ATPase,乙酰
22、 CoA,(三) dysfuncion of excitation-contraction coupling,Decreased myocardial contractility,1. Altered of Sarcoplasmic reticulum (SR) handling Ca2+,2. Reduced influx of extracellular Ca2+,3. Dysfunction of Ca2+ binding to troponin,1.Sarcoplasmic reticulum (SR) mishandling Ca2+,Impaired excitation-cont
23、raction coupling,SR mishandling Ca2+,Reduced Ca2+ released by SRRyanodin receptor (Ry-R) or Ry-R mRNA decreasedAcidosis reduced release of Ca2+ by SR,SR mishandling Ca2+,2. Reduced influx of extracellular Ca2+,Ca2+ inflow,voltage dependence,- receptor dependence,Na+/Ca2+ exchange,Impaired excitation
24、-contraction coupling,L型通道亚单位,胞外 Ca2+内流障碍,Na+/Ca2+ exchange：Depolarization Na+ outward Ca2+ inwardRepolarizationNa+ inward Ca2+ outward,Reduced influx of extracellular Ca2+,K+ impaired influx of Ca2+ (Hyperkalemia),Reduction of 1-receptor density,Norepinephrine depletion,H+ depress the sensitivity o
25、f receptor,Causes of Ca2+ influx decreased in heart failure:,Reduced influx of extracellular Ca2+,Acidosis decrease the m，L-Ca2+ cannel ,3. Dysfunction of Ca2+ binding to troponin,troponin,Impaired excitation-contraction coupling,Reduced in the concentration of NE and 1-adrenergic receptor,Decreased
26、 oxygen and blood supply,Altered of energy metabolism and utilization,Dysfunction of excitation-contraction coupling,Excessive cardiac hypertrophy,Decreased compliance,Delayed reposition of Ca2+Ca2+ 10-5 mol/L 10-7 mol/L,Diastolic dysfunction,Affinity of Ca2+ and Ca2+-Na+ Ca2+ excretion,Delayed repo
27、sition of Ca2+,Impaired dissociation of the actin-myosin complex,Impaired myocardial diastolic properties,ATP,Decreased ventricular diastolic potential,Impaired myocardial diastolic properties,Reduced ventricular compliancemyocardial hypertrophy; fibrosis; edemadv/dp,Impaired myocardial diastolic pr
28、operties,心室顺应性(ventricular compliance)：心室在单位压力变化下所引起的容积改变(Dv/dp),PV曲线左移,V稍有增加 P增加很多,2018/9/2,三、 Inconsistent behavior in systolic and diastolic function of the heart,Summary of the etiology of heart failure,Heart failure,Contractility,Loss of cardiomyocyte,Metabolic dysfunction,Dysfunction of excita
29、tion-contraction coupling,Altered of SR handling Ca2+,Reduced influx of extracellular Ca+,Dysfunction of Ca+ binding to troponin,Diastolic dysfunction,Delay of Ca+ reposition,Impaired dissociation of actin-myocin complex,Cardiac diastolic potential energy,Impaired ventricular compliance,Inconsistent
30、 behavior in systolic and diastolic function,Questions:,(一) 肺循环淤血 (Pulmonary congestion),当PCWP18 mmHg时，即出现肺循环淤血征，见于左心衰竭。,Clinical manifestations,左心衰竭能导致肺淤血、肺水肿；因此主要的 临床表现是呼吸困难,肺水肿,心力衰竭细胞,1、呼吸困难 (dyspnea),劳力性呼吸困难的发生机制:,回心血量增多，加重肺淤血 心率加快，舒张期缩短 机体活动时需氧量增加,睡眠时,1) 毛细血管压 左心衰左室舒张末期压力肺毛细血管压 超过其代偿能力肺水肿2) 毛细血
31、管通透性,肺循环淤血 肺泡通气血流失调缺氧 毛细血管通透性 肺水肿肺泡表面活性物质破坏肺泡表面张力 毛细血管通透性 肺水肿,2、肺 水 肿,(二) 体循环淤血 (Systemic congestion),当CVP16 cmH2O时，即出现体循环淤血征，见于右心衰竭及全心衰竭。,主要表现 颈静脉充盈或怒张 肝肿大及肝功能损害 胃肠道淤血所致的食欲不振等消化道症状 心性水肿,体循环淤血,体征：,肝大 水肿 颈静脉怒张,食欲不振、恶心、腹胀,肝颈静脉返流征,皮下水肿、腹水、胸水,全心 左心衰右心衰,槟榔肝,(三) 心输出量不足,(low cardiac output ),心输出量 (cardiac
32、output,CO)减少 心脏指数 (cardiac index,CI)降低 射血分数 (ejection fraction)降低心室充盈(ventricular filling)受损心率(heart rate)增快,亦称低排出量综合征 (syndrome of low output)或前向衰竭( forward failure) 特点为:,临床表现,疲乏无力、失眠、嗜睡,皮肤苍白或发绀,尿量减少,心源性休克,表现形式,防治基本病因、消除诱因,改善心脏舒缩功能,减轻心脏前、后负荷,控制水肿,增强心肌收缩功能,改善心脏舒张功能,降低心脏后负荷,调整心脏前负荷,防治的病理生理基础,Pathophy
33、siologic basis of prevention and treatment,着眼点 从传统的改善血流动力学，减轻症状“强心、利尿、扩血管” 到改善预后，降低总死亡率针对过度激活的神经、内分泌系统（交感神经、肾素-血管紧张素-醛固酮系统），进行“修复” 药物 强心甙地位 利尿剂、转化酶抑制剂、-阻滞剂地位,2003年在法国召开的以心衰为主题的国际会议上，欧洲心脏学会心衰指南委员会的主席之一K. Swedberg建议：应向医生们广泛宣传阻滞剂在心衰治疗中的效用 2006在西班牙召开的国际会议上再次被强调,病史：患风湿性心脏病10余年。近3月来出现心慌、闷气, 伴浮肿、腹胀，不能平卧。 体查：重病容, 半坐卧位, 颈静脉怒张, 呼吸36次/分, 两肺底可闻湿性罗音。心界向左右两侧扩大, 心率130次/分, 血压(110/80mmHg) 。,Clinical example,心尖部可闻IV级收缩期吹风样及舒张期雷鸣样杂音。肝脏在右肋下6cm可触及，有压痛，腹部有移动性浊音，骶部及下肢明显凹陷性水肿。试分析患者发生了哪些病理生理变化？其发生机制是什么?,111,掌握心力衰竭概念;心力衰竭发生机制;心力衰竭时心脏的代偿方式（包括几个重要概念） 熟悉心力衰竭原因及分类;心力衰竭时心外代偿反应；心力衰竭临床表现的病理生理基础 了解心力衰竭时神经-体液的代偿反应，防治原则,本章要求,
