1. 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 _ZhangQing

2. 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.

3. The Progressive Development of Cardiovascular Disease Risk Factors Endothelial Dysfunction Atherosclerosis CAD Myocardial Ischemia Coronary Thrombosis Myocardial Infarction Arrhythmia & Loss of Muscle Remodeling Ventricular Dilation Congestive Heart Failure Endstage Heart Disease

4. 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 progressive duration For anatomical type

6. Chronic heart failure Heart Failure _ZhangQing

7. 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

8. 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

9. 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 Effects of Neurohormonal Stimulation in Heart Failure

10. 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 Heart Failure _ZhangQing

12. Ventricular Remodeling: Compensatory Mechanism Dilation Hypertrophy • Globular shape Short term: Compensatory Long term: Harmful

13. - Synergistic LV contraction - LV wall integrity - Valvular competence DETERMINANTS OF VENTRICULAR FUNCTION CONTRACTILITY PRELOAD AFTERLOAD STROKE VOLUME HEART RATE CARDIAC OUTPUT

14. Vicious Cycle of Heart Failure Diminished renal blood flow Myocardial dysfunction Diminished Cardiac output Increased cardiac workload Increased Sympathetic Activity Increased force and rate of myocardial contraction Renin release Vasoconstriction Increased venous return Renal retention of sodium and water Angiotensin II Aldosterone Edema

15. Pathophysiology and Therapeutic Approaches to Heart Failure • LV Function Digoxin Vasodialtors ACE Inhibitors • Cardiac Output • Peripheral vasoconstriction • Blood flow • ACE Inhibitors • Blockers Neurohormonal Activation Salt and Water Retention Diuretics

16. 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

17. Common Physical Findings of Heart Failure • Elevated jugular venous pressure • Hepatojugular reflux • Displaced apical impulse • S3 gallop • Pulmonary rales • Hepatomegaly • Peripheral edema • Ascites

18. 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.

19. 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.

20. 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

21. 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.

23. Complication • Pulmonary embolism, • Congestive hepatomegaly, • Ascites, • Hepatic sclerosis, • Imbalance of electrolytes

24. Laboratory Finding • Venous pressure:elevated • Chest roentgenogram:cardiothoracic ratio,pulmonary edema—Kerley’s lines,perivascular and subpleural edema (butterfly and pleural effusion) • Invasive assessment of cardiac function: ventricular pressure,PCWP, • Echo and radionuclide

27. Diagnosis and differential diagnosis • Left heart failure: Symptoms: orthopnea and paroxysmal nocturnal dyspnea Signs: moist and fine crepitant rales, PCWP>25mmHg • Right heart failure: Symptoms: anorexia ,nausea,a sense of fullness after meals and constipation Signs: peripheral edema,congestive heptomegaly,hepatojugular reflux,ascites

28. 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

30. 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

31. TREATMENT OBJECTIVES Survival Morbidity Exercise capacity Quality of life Neurohormonal changes Progression of CHF Symptoms

32. Pregnancy Arrhythmias (AF) Infections Hyperthyroidism Thromboembolism Endocarditis Obesity Hypertension Physical activity Dietary excess TREATMENT Correction of aggravating factors MEDICATIONS

33. TREATMENT PHARMACOLOGIC THERAPY DIURETICS INOTROPES VASODILATORS NEUROHORMONAL ANTAGONISTS OTHERS (Anticoagulants, antiarrhythmics, etc)

34. PHARMACOLOGIC THERAPY Neurohumoral Control Improved symptoms Decreasedmortality Prevention of CHF yes ? DIURETICS NO ? yes = yes DIGOXIN minimal yes mort. no INOTROPES ? yes yes no Vasodil.(Nitrates) ? yes ACEI YES yes YES Other neurohormonal control drugs + / - yes YES ?

35. TREATMENT Normal AsymptomaticLV dysfunction EF <40% Symptomatic CHF NYHA II ACEI Symptomatic CHF NYHA - III Diuretics mild Neurohormonal inhibitors Digoxin? Symptomatic CHF NYHA - IV Loop Diuretics Inotropes Specialized therapy Transplant Secondary prevention Modification of physical activity

36. DIURETICS Thiazides Inhibit active exchange of Cl-Na in the cortical diluting segment of the ascending loop of Henle Cortex K-sparing Inhibit reabsorption of Na in the distal convoluted and collecting tubule Medulla Loop diuretics Inhibit exchange of Cl-Na-K in the thick segment of the ascending loop of Henle Loop of Henle Collecting tubule

37. THIAZIDESMECHANISM 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

38. LOOP DIURETICSMECHANISM 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

39. Eliminate < 5% of filtered Na+ Inhibit exchange of Na+ for K+ or H+ Spironolactone = competitive antagonist for the aldosterone receptor Amiloride and triamterene block Na+ channels controlled by aldosterone K-SPARING DIURETICSMECHANISM OF ACTION

40. DIURETIC EFFECTS Volume and preload Improve symptoms of congestion No direct effect on CO, butexcessive preload reduction may Improves arterial distensibility Neurohormonal activatio Levels of NA, Ang II and ARP Exception: with spironolactone

41. DIURETICSADVERSE REACTIONSThiazide 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

42. DIURETICSADVERSE REACTIONS K-SPARING DIURETICS Changes in electrolytes Na+, K+, acidosis Musculoskeletal: Cramps, weakness Cutaneous allergic reactions :

43. DIGOXIN Na-K ATPase Na-Ca Exchange Na+ K+ Na+ Ca++ Ca++ Myofilaments K+ Na+ CONTRACTILITY

44. DIGOXINPHARMACOKINETICPROPERTIES • 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

45. DIGOXINDIGITALIZATION STRATEGIES Maintenance Dose Loading dose (mg) (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 ILD = average INITIAL dose required for digoxin loading

46. DIGOXINHEMODYNAMIC EFFECTS Cardiac output LVejection fraction LVEDP Exercisetolerance Natriuresis Neurohormonalactivation

47. DIGOXINNEUROHORMONALEFFECTS PlasmaNoradrenaline Peripheral nervous system activity RAAS activity Vagaltone

48. DIGOXIN EFFECT ON CHF PROGRESSION 30 Placebo n=93 DIGOXIN Withdrawal WORSENING OF CHF % 20 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. 10 DIGOXIN n=85 0 RADIANCE N Engl J Med 1993;329:1 60 0 20 40 80 100 Days

49. 50 40 30 20 10 0 OVERALL MORTALITY Placebo n=3403 % p = 0.8 DIGOXIN n=3397 Months 0 12 24 36 48 DIG N Engl J Med 1997;336:525

50. DIGOXIN LONG TERM EFFECTS Survival similar to placebo Fewer hospital admissions More serious arrhythmias More myocardial infarctions