兴奋收缩耦联和心力衰竭的治疗.ppt

田野 教授 哈医大二院心内科,兴奋收缩耦联和心力衰竭的治疗,TOPICS,Excitation-contraction (EC) coupling Excitation Calcium Cycling Contraction Alterations of E-C coupling in HF Inotropic agents for HF,Excitation-contraction coupling,“The power of locomotion is that which contracts and relaxes the muscles whereby the members and joints are moved, extended or flexed. This power reaches the limbs by way of the nerves and there are as many forms of power as there are of movement. Each muscle has its own peculiar purpose and it obeys the decree of the composite sense.“,Avicenna(11671248),William Harvey (1578 1657),He was an English medical doctor /physician, who is credited with being the first to correctly describe, in exact detail, the systemic circulation and properties of blood being pumped around the body by the heart.,We shall designate the entire seque-nce of reactions: excitation, inward acting link, and activation of contra-ction by the term excitation-contraction coupling.,ALEXANDER SANDOW,1952 (New York University),Sandow A.Yale J Biol Med . 1952.25 (3): 176201,Cardiac excitationcontraction coupling is the process from electrical excitation of the myocyte to contraction of the heart (which propels blood out). The ubiquitous second messenger Ca2+ is essential in cardiac electrical activity and is the direct activator of the myofilaments, which cause contraction.,Bers DM. Nature, 2002, 415(6868): 198-205.,Excitation,The cardiac action potential,A notable difference between skeletal and cardiac myocytes is how each elevates the myoplasmic Ca2+ to induce contraction. In cardiac myocytes, the release of Ca2+ from the sarcoplasmic reticulum is induced by Ca2+ influx into the cell through voltage-gated calcium channels.,Calcium Cycling,Pictorial OF Calcium Cycling,Ca+,Ca+,Ca+,Ca+,Plb,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Na+,Na+,Na+,Ca+,SERCA,SR,RyR,L-Type Ca+ Channel,Na+/Ca+ Exchanger,Ca+,Sarcolemma,Ca+,Cardiac tissue and cells,Conduct electrical waves Contract in response to an electrical stimulus,(Guinea-pig ventricular cell),Cardiac tissue,Function,B,Sarcoplasmic Reticulum(SR),PLN and SERCA,the sites of interaction between PLN and SERCA,Sodium-calcium exchanger(NCX),Two-way transporter “forward”mode “reverse”mode Na:Ca=3:1,Ca release Coincides with activation of the contractile machinery,Contraction,Sliding Filament Theory,A.F. Huxley 1954,EM evidence for sliding filament theory,The micrograph shows myosin bound to actin,The molecular basis for myocardial contraction,Thin filament (Actin ,Tropom- yosin, Troponin) Thick filament (Myosin) Other proteins,Chien, K.R., 1999,Z,Z,Titin,28,000 amino acids (3MDa) the largest protein known in mammals.,MYOSIN MW 480 kDa Forms thick filaments Hydrolyses ATP Interacts with F-actin 300-400 myosin molecules per 1 filament,S1,150 nm,Thick Filament Proteins,RLC,ELC,ATP Binding Site,Actin Binding Site,ATP （Myosin） ADP + Pi + Energy,Myosin Head (S1) molecular motor of muscle contraction,G-Actin F-Actin,G to F actin MW 42 kDa The blue and grey molecules are actin monomers (MW 42.000),Ken C. Holmes: Max-Planck-Institute,Takeda, S. et al. Nature 424, 35 41, 2003,Crystal Structure of Human Cardiac Troponin,Gordon et al. 2001,Regulation of thin filament in contraction,Muscle Contraction,Alterations in E-C coupling in HF,RyR2 channel leak,Heart Failure,PDE4D levels loss of FKBP12.6,RyR2 channel leak,Arrhythmia and progression of heart failure.,Jeffery D Molkentin. Nature Medicine 11, 1284 - 1285 (2005),PLNSERCA2a interactions in physiological and diseased cardiac function,Steven R. Houser. J Mol Cell Cardiol 32, 15951607 (2000),Inotropic Agents for HF,Inotropic Agents and -blocker,Digitalis Phosphodiesterase inhibitor - adrenoceptor blocker,Digitalis (200 years),Digilis purpurea Purple foxglove,William Withering (1741 1799),Mechanism of Action,Digitalis,Other study,Some evidence suggests that the benefits of digitalis may be related in part to enzyme inhibition in noncardiac tissues. Inhibition of Na-K ATPase in vagal afferent fibers acts to sensitize cardiac baroreceptors, which in turn reduces sympathetic outflow from the central nervous system. In addition, by inhibiting Na-K ATPase in the kidney, digitalis reduces the renal tubular reabsorption of sodium; the resulting increase in the delivery of sodium to the distal tubules leads to the suppression of renin secretion from the kidneys.,Thames MD. Circ Res. 1979;44:8 15. Ferguson DW et al. Circulation. 1989;80:6577. Torretti J et al. Am J Physiol. 1972;222:1398405.,Placebo n=3403,Digoxin n=3397,48,0,12,24,36,Mortality %,N Engl J Med 1997;336:525,Months,p = 0.8,N=6800 NYHA II-III,DIG trail (1997),ACC/AHA HF guideline 2009,Long-term use of an infusion of a positive inotropic drug may be harmful and is not recommended for patients with current or prior symptoms of HF and reduced LVEF, except as palliation for patients with end-stage disease who cannot be stabilized with standard medical treatment (Stage D). (Class III, Level of Evidence: C),Continuous intravenous infusion of a positive inotropic agent may be considered for palliation of symptoms in patients with refractory end-stage HF(Stage D). (Class IIb, Level of Evidence: C),Phosphodiesterase inhibitor,The different forms or subtypes of phosphodiesterase were initially isolated from rat brains by Uzunov and Weiss in 1972 and were soon afterwards shown to be selectively inhibited in the brain and in other tissues by a variety of drugs The potential for selective phosphodisterase inhibitors as therapeutic agents was predicted as early as 1977 by Weiss and Hait. This prediction meanwhile has proved to be true in a variety of fields.,Uzunov, P. and Weiss, B Biochim. Biophys. Acta 284:220-226, 1972,Weiss, B. and Hait, W.N.: Ann. Rev. Pharmacol. Toxicol. 17:441-477, 1977.,Phosphodiesterase-3 inhibitor,PDEI,cAMP,AMP,PDE3,Yuan James Rao,(2009),Mechanism of action,As a result of its high expression in both the vasculature and the airways, PDE3 was identified as a potential therapeutic target in cardiovascular disease and asthma. Augment myocardial contractility Relax vascular and airway smooth muscle Inhibit platelet aggregation Induce lipolysis,BARNES P.J.et al. Pharmacol. Rev. 1988;40:4984. MANGANIELLO V.C.,et al. Cell Signal. 1995;7:445455.,“I wish I had my beta-blockers handy“,His landmark invention of propranolol in 1964 and the H2-receptor antagonist, cimetidine, in 1972 earned him the Nobel Prize in Medicine in 1988.,James W. Black,- adrenoceptor Receptor Blockers,Mechanism of action,Density of 1 receptors Inhibit cardiotoxicity of catecholamines Neurohormonal activation HR Antiischemic Antihypertensive Antiarrhythmic Antioxidant, Antiproliferative,100,90,80,60,70,50,24,0,20,16,12,8,4,28,Placebo,Carvedilol,Months,N = 2289 III-IV NYHA,NEJM 2001;344:1651,Survival%,p=0.00014 35% RR,COPERNICUS Study(2001),ACC/AHA HF guideline 2009,Use of 1 of the 3 beta blockers proven to reduce mortality (i.e., bisoprolol, carvedilol, and sustained release metoprolol succinate) is recommended for all stable patients with current or prior symptoms of HF and reduced LVEF, unless contraindicated . (Class I, Level of Evidence: A),When to start ?,Patient stable No physical evidence of fluid retention No need for I.V. inotropic drugs Start ACE-I / diuretic first Start Low, Increase Slowly Increase the dose every 2 - 4 weeks,Risks of treatment,Fluid Retention And Worsening HF(intensification of conventional therapy) Fatigure Bradycardia And Heart Block Hypotension (block alpha-1receptors),Review treatment (+/-diuretics, other drugs) Reduce dose Consider cardiac pacing Discontinue beta blocker only in severe cases,How should clinical deterioration be managed in patients who have been taking a beta blocker for long periods of time (more than 3 months)? if patients develop fluid retention, with or without mild symptoms, it is reasonable to continue the beta blocker while the dose of diuretic is increased. If the deterioration in cli