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Heart Failure _ZhangQing,Heart Failure,上海交通大学医学院 附属仁济医院心内科 张 清 副教授,Heart failure is the pathophysiological state in which the heart is unable to pump sufficient blood to satisfy the metabolic demands of the body with enough preload.,The Progressive Development of Cardiovascular Disease,Endstage Heart Disease,Congestive Heart Failure,Ventricular Dilation,Remodeling,Arrhythmia & Loss of Muscle,Myocardial Infarction,Myocardial Ischemia,CAD,Atherosclerosis,Endothelial Dysfunction,Risk Factors,Coronary Thrombosis,For progressive duration,Congestive heart failure is classified into acute and chronic heart failure,Congestive heart failure is classified into left side, right side and biventricular heart failure,For anatomical type,Heart Failure _ZhangQing,Chronic heart failure,Causes,Fundamental causes: impairment of myocardium, such as AMI,cardiomyopathy,myocarditis overloading of the heart, such as hypertension, aortic stenosis, mitral stenosis,emphysema,aortic insufficiency,mitral insufficiency,VSD,PDA,ASD. diminished LV compliance, such as ventricular hypertrophy,Precipitating factors infection,especially pulmonary infection, fever physical,environmental,or emotional stress increased sodium load arrhythmia, pulmonary emboli pregnancy and delivery anemia,bleeding,excessive transfusion,Pathophysiology of heart failure,Impaired myocardium Cardiac output , heart failure Neurohumoral stimulation RAS and sympathetic-adrenergic Vasoconstriction increased heart rate Salt and water retention increased energy (augments preload) expenditure Hypertrophy Leads to deterioration and death of cardiac cell,Effects of Neurohormonal Stimulation in Heart Failure,Heart Heart rate Contractility Stroke volume Cardiac output Conduction velocity Myocardial oxygen consumption,Peripheral Circulation Arterial vasoconstriction Venoconstriction Systemic vascular resistance Redistribution of blood flow Renal vasoconstriction,Heart Failure _ZhangQing,Pathophysiology of Heart Failure: Left Ventricular Remodeling,Left-ventricular (LV) remodeling is defined as a change in LV geometry, mass and volume that occurs over a period of time,Ventricular Remodeling: Compensatory Mechanism,Dilation Hypertrophy Globular shape Short term: Compensatory Long term: Harmful,DETERMINANTS OF VENTRICULAR FUNCTION,STROKE VOLUME,PRELOAD,CONTRACTILITY,CARDIAC OUTPUT,HEART RATE,AFTERLOAD,Vicious Cycle of Heart Failure,Myocardial dysfunction,Diminished Cardiac output,Diminished renal blood flow,Renin release,Angiotensin II,Aldosterone,Increased Sympathetic Activity,Vasoconstriction,Increased force and rate of myocardial contraction,Increased cardiac workload,Renal retention of sodium and water,Increased venous return,Edema,Pathophysiology and Therapeutic Approaches to Heart Failure,LV Function,Cardiac Output,Neurohormonal Activation,Salt and Water Retention,Peripheral vasoconstriction Blood flow,Vasodialtors ACE Inhibitors,Diuretics,ACE Inhibitors Blockers,Digoxin,Common Symptoms of Heart Failure,Dyspnea on exertion Paroxysmal nocturnal dyspnea Orthopnea Fatigue Lower extremity edema Cough, usually worse at night Nausea, vomiting, anorexia, RUQ pain, ascites Nocturia Sleep disorders Increased abdominal girth,Common Physical Findings of Heart Failure,Elevated jugular venous pressure Hepatojugular reflux Displaced apical impulse S3 gallop Pulmonary rales Hepatomegaly Peripheral edema Ascites,Clinical manifestation,Left heart failure:SOB,cough,rales,gallop Right heart failure:gastrointestinal congestion,anorexia,nausea,a sense of fullness after meals,hepato-jugular reflux,swelling of feet or ankles Low cardiac output:fatigue and weakness,oliguria Biventricular heart failure:both clinical manifestation of left and right heart failure,one of which maybe predominant.,Functional Classification,A classification of patients with heart disease based on the relation between symptoms and the amount of effort required to provoke them has been developed by the New York Heart Association.,Class 1-No limitation Ordinary physical activity does not cause undue fatigue,dyspnea,or palpitation Class 2-Slight limitation of physical activity Such patients are comfortable at rest.Ordinary physical activity results in fatigue,palpitation,dyspnea,or angina,Class 3-Marked limitation of physical activity Although patients are comfortable at rest,less than ordinary activity will lead to symptoms. Class 4-Inability to carry on any physical activity Symptoms of congestive failure are present even at rest.With any physical activity,increased discomfort is experienced.,Complication,Pulmonary embolism, Congestive hepatomegaly, Ascites, Hepatic sclerosis, Imbalance of electrolytes,Laboratory Finding,Venous pressure:elevated Chest roentgenogram:cardiothoracic ratio,pulmonary edemaKerleys lines,perivascular and subpleural edema (butterfly and pleural effusion) Invasive assessment of cardiac function: ventricular pressure,PCWP, Echo and radionuclide,Diagnosis and differential diagnosis,Left heart failure: Symptoms: orthopnea and paroxysmal nocturnal dyspnea Signs: moist and fine crepitant rales, PCWP25mmHg Right heart failure: Symptoms: anorexia ,nausea,a sense of fullness after meals and constipation Signs: peripheral edema,congestive heptomegaly,hepatojugular reflux,ascites,Differential diagnosis,Differentiation between cardiac and pulmonary dyspnea: Chronic obstructive lung disease is usually associated with sputum production,the dyspnea is relieved after patients rid themselves of secretions by coughing rather than specifically by sitting up Acute cardiac asthma (paroxysmal nocturnal dyspnea with prominent wheezing) usually occurs in patients who have obvious clinical evidence of heart disease Airway obstruction and dyspnea that respond to bronchodilators or smoking cessation favor a pulmonary origin of the dyspnea, while the response of these manifestations to diuretics supports heart failure as the cause of dyspnea,Therapy,To get rid of induction factors and complication Uses of inotropic agents:digitalis,dobutamine Uses of diuretics Uses of vasodilators Other treatment: sedative drug and oxygen supply,Survival Morbidity Exercise capacity Quality of life Neurohormonal changes Progression of CHF Symptoms,TREATMENT OBJECTIVES,TREATMENT Correction of aggravating factors,MEDICATIONS,TREATMENT PHARMACOLOGIC THERAPY,DIURETICS INOTROPES VASODILATORS NEUROHORMONAL ANTAGONISTS OTHERS (Anticoagulants, antiarrhythmics, etc),PHARMACOLOGIC THERAPY,DIURETICS,Improved symptoms,Decreased mortality,Prevention of CHF,yes,?,?,Vasodil.(Nitrates),yes,yes,?,DIGOXIN,yes,=,minimal,INOTROPES,yes,mort.,?,Other neurohormonal control drugs,yes,+ / -,?,ACEI,yes,YES,yes,Neurohumoral Control,NO,yes,no,no,YES,YES,TREATMENT,Normal,Asymptomatic LV dysfunction EF 40%,Symptomatic CHF NYHA II,Inotropes Specialized therapy Transplant,Symptomatic CHF NYHA - IV,Symptomatic CHF NYHA - III,Secondary prevention Modification of physical activity,ACEI,Diuretics mild Neurohormonal inhibitors Digoxin?,Loop Diuretics,Cortex,Medulla,Thiazides Inhibit active exchange of Cl-Na in the cortical diluting segment of the ascending loop of Henle,K-sparing Inhibit reabsorption of Na in the distal convoluted and collecting tubule,Loop diuretics Inhibit exchange of Cl-Na-K in the thick segment of the ascending loop of Henle,Loop of Henle,Collecting tubule,DIURETICS,THIAZIDES MECHANISM OF ACTION,Excrete 5 - 10% of filtered Na+ Elimination of K Inhibit carbonic anhydrase: increase elimination of HCO3 Excretion of uric acid, Ca and Mg No dose - effect relationship,LOOP DIURETICS MECHANISM OF ACTION,Excrete 15 - 20% of filtered Na+ Elimination of K+, Ca+ and Mg+ Resistance of afferent arterioles - Cortical flow and GFR - Release renal PGs - NSAIDs may antagonize diuresis,K-SPARING DIURETICS MECHANISM OF ACTION,Volume and preload Improve symptoms of congestion No direct effect on CO, but excessive preload reduction may Improves arterial distensibility Neurohormonal activatio Levels of NA, Ang II and ARP Exception: with spironolactone,DIURETIC EFFECTS,DIURETICS ADVERSE REACTIONS Thiazide and Loop Diuretics,Changes in electrolytes: Volume Na+, K+, Ca+, Mg+ metabolic alkalosis Metabolic changes: glycemia, uremia, gout LDL-C and TG Cutaneous allergic reactions,DIURETICS ADVERSE REACTIONS K-SPARING DIURETICS,Changes in electrolytes Na+, K+, acidosis Musculoskeletal: Cramps, weakness Cutaneous allergic reactions :,Na+,K+,K+,Na+,Na+,Ca+,Ca+,Na-K ATPase,Na-Ca Exchange,Myofilaments,DIGOXIN,CONTRACTILITY,DIGOXIN PHARMACOKINETIC PROPERTIES,Oral absorption (%) Protein binding (%) Volume of distribution (l/Kg) Half life Elimination Onset (min) i.v. oral Maximal effect (h) i.v. oral Duration Therapeutic level (ng/ml),60 - 75 25 6 (3-9) 36 (26-46) h Renal 5 - 30 30 - 90 2 - 4 3 - 6 2 - 6 days 0.5 - 2,DIGOXIN DIGITALIZATION STRATEGIES,(mg) 0.125-0.5 / d 0.25 / d,i.v 0.5 + 0.25 / 4 h ILD: 0.75-1,oral 12-24 h 0.75 + 0.25 / 6 h 1.25-1.5,oral 2-5 d 0.25 / 6-12 h 1.5-1.75,Loading dose (mg),Maintenance Dose,ILD = average INITIAL dose required for digoxin loading,DIGOXIN HEMODYNAMIC EFFECTS,Cardiac output LV ejection fraction LVEDP Exercise tolerance Natriuresis Neurohormonal activation,DIGOXIN NEUROHORMONAL EFFECTS,Plasma Noradrenaline Peripheral nervous system activity RAAS activity Vagal tone,WORSENING OF CHF %,p = 0.001,DIGOXIN: 0.125 - 0.5 mg /d (0.7 - 2.0 ng/ml) EF 35% Class I-III (digoxin+diuretic+ACEI) Also significantly decreased exercise time and LVEF.,DIGOXIN EFFECT ON CHF PROGRESSION,RADIANCE N Engl J Med 1993;329:1,Placebo n=93 DIGOXIN Withdrawal,DIGOXIN n=85,30,10,0,20,100,80,20,0,40,60,Days,Placebo n=3403,DIGOXIN n=3397,48,0,12,24,36,OVERALL MORTALITY,%,DIG N Engl J Med 1997;336:525,Months,p = 0.8,DIGOXIN LONG TERM EFFECTS,Survival similar to placebo Fewer hospital admissions More serious arrhythmias More myocardial infarctions,DIGOXIN CLINICAL USES,AF with rapid ventricular response CHF refractory to other drugs Other indications? Can be combined with other drugs,DIGOXIN CONTRAINDICATIONS,ABSOLUTE: - Digoxin toxicity RELATIVE - Advanced A-V block without pacemaker - Bradycardia or sick sinus without PM - PVCs and TV - Marked hypokalemia - W-P-W with atrial fibrillation,DIGOXIN TOXICITY CARDIAC MANIFESTATIONS,ARRHYTHMIAS : - Ventricular (PVCs, TV, VF) - Supraventricular (PACs, SVT) BLOCKS: - S-A and A-V blocks CHF EXACERBATION,DIGOXIN TOXICITY EXTRACARDIAC MANIFESTATIONS,GASTROINTESTINAL: - Nausea, vomiting, diarrhea NERVOUS: - Depression, disorientation, paresthesias VISUAL: - Blurred vision, scotomas and yellow-green vision,CARDIAC GLYCOSIDES SYMPATHOMIMETICS Catecholamines -adrenergic agonists PHOSPHODIESTERASE INHIBITORS Amrinone Enoximone Others,Milrinone Piroximone,POSITIVE INOTROPES,-ADRENERGIC STIMULANTS CLASSIFICATION,B1 Stimulants Increase contractility Dobutamine Doxaminol Xamoterol Butopamine Prenalterol Tazolol,Mixed,Dopamine,DOPAMINE AND DOBUTAMINE EFFECTS,Receptors,Contractility,Heart Rate,Arterial Press.,Renal perfusion,Arrhythmia,DA (g / Kg / min),Dobutamine, 2,DA1 / DA2,+,-,2 - 5,1,+,+,+,+, 5,1 + a,+,+,+,+,1,+,+,+,POSITIVE INOTROPES CONCLUSIONS,May increase mortality Safer in lower doses Use only in refractory CHF NOT for use as chronic therapy,Venous Vasodilatation,MIXED Calcium antagonists a-adrenergic Blockers ACEI Angiotensin II inhibitors K+ channel activators Nitroprusside,VENOUS Nitrates Molsidomine,ARTERIAL Minoxidil Hydralazine,VASODILATORS CLASSIFICATION,Arterial Vasodilatation,1- VENOUS VASODILATATION Preload 2- Coronary vasodilatation Myocardial perfusion 3- Arterial vasodilatation Afterload 4- Others,Pulmonary congestion Ventricular size Vent. Wall stress MVO2,NITRATES HEMODYNAMIC EFFECTS,0.6,PROBABILITY OF DEATH,0,Placebo (273) Prazosin (183) Hz + ISDN (186),MONTHS,0.7,0.5,0.3,0.4,0.2,0.1,VHefT-1 N Engl J Med 1986;314:1547,NITRATES SURVIVAL,0,6,12,18,24,30,36,42,NITRATES TOLERANCE,Can be avoided or minimized - Intermittent administration - Use the lowest possible dose,NITRATES CONTRAINDICATIONS,Previous hypersensitivity Hypotension ( 80 mmHg) AMI with low ventricular filling pressure 1st trimester of pregnancy,WITH CAUTION:,Constrictive pericarditis Intracranial hypertension Hypertrophic cardiomyopathy,NITRATES CLINICAL USES,Pulmonary congestion Orthopnea and paroxysmal nocturnal dyspnea CHF with myocardial ischemia In acute CHF and pulmonary edema: NTG s.l. or i.v.,VASOCONSTRICTION,VASODILATATION,Kininogen,Kallikrein,Inactive Fragments,Angiotensinogen,Angiotensin I,RENIN,Kininase II,Inhibitor,ALDOSTERONE,SYMPATHETIC,VASOPRESSIN,PROSTAGLANDINS,tPA,ANGIOTENSIN II,BRADYKININ,ACE-i. Mechanism of Action,A.C.E.,ACEI HEMODYNAMIC EFFECTS,Arteriovenous Vasodilatation - PAD, PCWP and LVEDP - SVR and BP - CO and exercise tolerance No change in HR / contractility Renal, coronary and cerebral flow,75,95,No Additional Treatment Necessary (%),Quinapril Heart Failure Trial JACC 1993;22:1557,ACEI FUNCTIONAL CAPACITY,Quinapril continued n=114,Quinapril stopped Placebo n=110,p0.001,100,90,85,80,Weeks,Class II-III,16,ACEI ADVANTAGES,Inhibit LV remodeling post-MI Modify the progression of chronic CHF - Survival - Hospitalizations - Improve the quality of life In contrast to others vasodilators, do not produce neurohormonal activation or reflex tachycardia,Placebo,Enalapril,12,11,10,9,8,7,6,5,PROBABILITY OF DEATH,MONTHS,0.1,0.8,0,0.2,0.3,0.7,0.4,0.5,0.6,p 0.001,p 0.002,CONSENSUS N Engl J Med 1987;316:1429,ACEI SURVIVAL,4,3,2,1,0,50,40,30,20,10,0,Months,0,6,12,p = 0.30,24,18,30,36,42,48,Enalapril n=2111,Placebo n=2117,SOLVD (Prevention) N Engl J Med 1992;327:685,MORTALITY %,ACEI SURVIVAL,n = 4228 No CHF symptoms EF 35,Months,0,6,12,p = 0.0036,MORTALITY %,24,18,30,36,42,48,Enalapril n=1285,Placebo n=1284,SOLVD (Treatment) N Engl J M 1991;325:293,ACEI SURVIVAL,n = 2589 CHF - NYHA II-III - EF 35,Mortality %,4,SAVE N Engl J Med 1992;327:669,Years,30,20,10,0,1,2,3,Placebo,Captopril,0,n=1115,n=1116,p=0.019, -19%,ACEI SURVIVAL,n = 2231 3 - 16 days post AMI EF 40 12.5 - 150 mg / day,Asymptomatic ventricular dysfunction post MI,ISIS-4,GISSI-3,SAVE,SMILE,AIRE,ACEI,Benefit,Pt Selection,Captopril,Lisinopril,Captopril,Zofenopril,Ramipril,0.5 / 5 wk,0.8 / 6 wk,4.2 / 3.5 yr,4.1 / 1 yr,6 / 1 yr,All with AMI,All with AMI,EF 40 asymptomatic,Ant. AMI, No TRL,Clinical CHF,TRACE,Trandolapril,7.6 / 3 yr,Vent Dysfx / Clinical CHF EF 35,ACEI SURVIVAL POST MI,ACEI INDICATIONS,Clinical cardiac insufficiency - All patients Asymptomatic ventricular dysfunction - LVEF 35 %,ACEI UNDESIRABLE EFFECTS,Inherent in their mechanism of action - Hypotension - Hyperkalemia - Angioneurotic edema,- Dry cough - Renal Insuff.,ACEI CONTRAINDICATIONS,Renal artery stenosis Renal insufficiency Hyperkalemia Arterial hypotension Intolerance (due to side effects),ANGIOTENSIN II INHIBITORS （ARB) MECHANISM OF ACTION,RENIN,Angiotensinogen,Angiotensin I ANGIOTENSIN II,ACE,Other paths,Vasoconstriction,Proliferative Action,Vasodilatation,Antiproliferative Action,AT1,AT2,AT1 RECEPTOR BLOCKERS,RECEPTORS,AT1 RECEPTOR BLOCKERS DRUGS,Losartan Valsartan Irbersartan Candersartan,Competitive and selective blocking of AT1 receptors,ALDOSTERONE,Retention Na+ Retention H2O Excretion K+ Excretion Mg2+,Collagen deposition Fibrosis - myocardium - vessels,Spironolactone,Edema,Arrhythmias,Competitive antagonist of the aldosterone receptor (myocardium, arterial walls, kidney),ALDOSTERONE INHIBITORS,ALDOSTERONE INHIBITORS INDICATIONS,FOR DIURETIC EFFECT Pulmonary congestion (dyspnea) Systemic congestion (edema) FOR ELECTROLYTE EFFECTS Hypo K+, Hypo Mg+ Arrhythmias Better than K+ supplements FOR NEUROHORMONAL EFFECTS Please see RALES results, N Engl J Med 1999:341:709-717, Hyperkalemia Severe renal insufficiency Metabolic acidosis,ALDOSTERONE INHIBITORS CONTRAINDICATIONS,-ADRENERGIC BLOCKERS POSSIBLE BENEFICIAL EFFECTS,Density of 1 receptors Inhibit cardiotoxicity of catecholamines Neurohormonal activation HR Antihypertensive and antianginal Antiarrhythmic Antioxidant Antiproliferative, BLOCKERS CARVEDILOL,4 studies in U.S.; 1 in Australia/New Zealand U.S. studies with control group Mortality with Placebo 8.2% Mortality with Carvedilol 2.9% Initial low doses, progressive,p 0.0001,-ADRENERGIC BLOCKERS INDIC