2. Low-Output Heart Failure • Systolic Heart Failure (HFREF): • Decreased Left ventricular ejection fraction • Diastolic Heart Failure (HFPEF): • Elevated Left and Right ventricular end-diastolic pressures • Normal LVEF • High-Output Heart Failure • Seen with peripheral shunting, low-systemic vascular resistance, hyperthryoidism, beri-beri, carcinoid, anemia • Often have normal cardiac output • Right-Ventricular Failure • Seen with pulmonary hypertension, large RV infarctions.

3. Causes of Low-Output Heart Failure • Systolic Dysfunction • Coronary Artery Disease • Idiopathic dilated cardiomyopathy (DCM) • 50% idiopathic (at least 25% familial) • 9 % myocarditis (viral) • tachycardia, peripartum, hypertension, HIV, connective tissue disease, substance abuse (alcohol), doxorubicin/herceptin • Hypertension • Valvular Heart Disease • Diastolic Dysfunction • Hypertension • Coronary artery disease • Hypertrophic obstructive cardiomyopathy (HCM) • Restrictive cardiomyopathy

4. (Mal)adaptation-hemodynamic

5. (Mal) adaptation-neurohormonal • Activation of the sympathetic nervous system • Vasoconstriction/increased afterload • Tolerance • Arhythmogenic

6. Activation of renin-angiotensin system • Na resorption • Vasoconstriction • Apoptosis/fibrosis

7. Antidiuretic hormone • Proinflammatory cytokines • TNFalpha • IL-6

8. Clinical Presentation of Heart Failure • Due to excess fluid accumulation: • Dyspnea (most sensitive symptom) • Edema • Hepatic congestion • Ascites • Orthopnea, Paroxysmal Nocturnal Dyspnea (PND) • Due to reduction in cardiac ouput: • Fatigue (especially with exertion) • Weakness

9. S3 gallop • Low sensitivity, but highly specific • Cool, pale, cyanotic extremities • Have sinus tachycardia, diaphoresis and peripheral vasoconstriction • Crackles or decreased breath sounds at bases (effusions) on lung exam • Elevated jugular venous pressure • Lower extremity edema • Ascites • Hepatomegaly • Splenomegaly • Displaced PMI • Apical impulse that is laterally displaced past the midclavicular line is usually indicative of left ventricular enlargement>

10. Lab Analysis in Heart Failure • CBC • Since anemia can exacerbate heart failure • Serum electrolytes and creatinine • before starting high dose diuretics • Fasting Blood glucose • To evaluate for possible diabetes mellitus • Thyroid function tests • Since thyrotoxicosis can result in A. Fib, and hypothyroidism can results in HF. • Iron studies • To screen for hereditary hemochromatosis as cause of heart failure. • ANA • To evaluate for possible lupus • Viral studies • If viral mycocarditis suspected

11. Laboratory Analysis (cont.) • BNP • With chronic heart failure, atrial mycotes secrete increase amounts of atrial natriuretic peptide (ANP) and brain natriuretic pepetide (BNP) in response to high atrial and ventricular filling pressures • Usually is > 400 pg/mL in patients with dyspnea due to heart failure.

12. Chest X-ray in Heart Failure • Cardiomegaly • Cephalization of the pulmonary vessels • Kerley B-lines • Pleural effusions

13. Cardiomegaly

14. Pulmonary Edema due to Heart Failure

15. Kerley B lines

16. Cardiac Testing in Heart Failure • Electrocardiogram: • May show specific cause of heart failure: • Ischemic heart disease • Dilated cardiomyopathy: first degree AV block, LBBB, Left anterior fascicular block • Amyloidosis: pseudo-infarction pattern • Idiopathic dilated cardiomyopathy: LVH • Echocardiogram: • Left ventricular ejection fraction • Structural/valvular abnormalities

17. Further Cardiac Testing in Heart Failure • Coronary arteriography • Should be performed in patients presenting with heart failure who have angina or significant ischemia • Reasonable in patients who have chest pain that may or may not be cardiac in origin, in whom cardiac anatomy is not known, and in patients with known or suspected coronary artery disease who do not have angina. • Measure cardiac output, degree of left ventricular dysfunction, and left ventricular end-diastolic pressure.

18. Further testing in Heart Failure • Endomyocardial biopsy • Not frequently used • Amyloidosis, giant-cell myocarditis

19. Classification of Heart Failure

20. Aggravating Factors • Medications • New heart disease • Myocardial ischemia • Pregnancy • Arrhythmias (AF) • Infections • Thromboembolism • Hyper/hypothyroidism • Endocarditis • Obesity • Hypertension • Physical activity • Dietary excess

21. Heart Failure and Myocardial Ischemia • Coronary HD is the cause of 2/3 of HF • Segmental wall motion abnormalities are not specific if ischemia • Angina coronary angio and revascularization • No angina • Search for ischemia and viability in all ? • Coronary angiography in all ?

22. ACE-i. Mechanism of Action VASOCONSTRICTION VASODILATATION ALDOSTERONE PROSTAGLANDINS VASOPRESSIN tPA Kininogen SYMPATHETIC Kallikrein Angiotensinogen RENIN BRADYKININ Angiotensin I A.C.E. Kininase II Inhibitor ANGIOTENSIN II Inactive Fragments

23. ACE-I. Clinical Effects • Improve symptoms • Reduce remodelling / progression • Reduce hospitalization • Improve survival

24. Mortality Reduction with ACE-i Study ACE-i Clinical Seting CONSENSUS Enalapril CHF SOLVD treatment Enalapril CHF AIRE Ramipril CHF Vheft-II Enalapril CHF TRACE Trandolapril CHF / LVD SAVE Captopril LVD SMILE Zofenopril High risk HOPE Ramipril High risk

25. ACE-i 0.8 0.7 Placebo 0.6 Probabiilityof Death p< 0.001 0.5 0.4 p< 0.002 0.3 Enalapril 0.2 0.1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 CONSENSUS N Engl J Med 1987;316:1429 Months

26. ACE-i 30 Asymptomatic ventricular dysfunction post MI Placebo n=1116 20 Mortality, % Captopril n=1115 10 n = 2231 3 - 16 days post AMI EF < 40 12.5 --- 150 mg / day ² -19% p=0.019 0 SAVE N Engl J Med 1992;327:669 0 3 4 1 2 Years

27. ACE-i. Indications • Symptomatic heart failure • Asymptomatic ventricular dysfunction - LVEF < 35 - 40 % • Selected high risk subgroups AHA / ACC HF guidelines 2001 ESC HF guidelines 2001

28. ACE-i. Practical Use • Start with very low dose • Increase dose if well tolerated • Renal function & serum K+ after 1-2 w • Avoid fluid retention / hypovolemia (diuretic use) • Dose NOT determined by symptoms

29. ACE-i. Dose (mg) Initial Maximum Captopril 6.25 / 8h 50 / 8h Enalapril 2.5 / 12 h 10 to 20 / 12h Fosinopril 5 to 10 / day 40 / day Lisinopril 2.5 to 5.0 / day 20 to 40 / day Quinapril 10 / 12 h 40 / 12 h Ramipril 1.25 to 2.5 / day 10 / day AHA / ACC HF guidelines 2001

30. ACE-I. Adverse Effects • Hypotension (1st dose effect) • Worsening renal function • Hyperkalemia • Cough • Angioedema • Rash, ageusia, neutropenia, …

31. ACE-I. Contraindications • Intolerance (angioedema, anuric renal fail.) • Bilateral renal artery stenosis • Pregnancy • Renal insufficiency (creatinine > 3 mg/dl) • Hyperkalemia (> 5,5 mmol/l) • Severe hypotension

32. ß-Adrenergic Blockers Mechanism of action • Density of ß1 receptors • Inhibit cardiotoxicity of catecholamines • Neurohormonalactivation • HR • Antiischemic • Antihypertensive • Antiarrhythmic • Antioxidant, Antiproliferative

33. ß-Adrenergic Blockers 100 90 80 Survival % Carvedilol 70 p=0.00014 35% RR 60 Placebo N = 2289 III-IV NYHA 50 0 4 8 12 16 20 24 28 Months COPERNICUS NEJM 2001;344:1651

34. ß-Adrenergic Blockers When to start • Patient stable • No physical evidence of fluid retention • No need for i.v. inotropic drugs • No contraindications • In hospital or not

35. ß-Adrenergic Blockers Dose (mg) Initial Target Bisoprolol 1.25 / 24h 10 / 24h Carvedilol 3.125 / 12h 25 / 12h Metoprolol succinnate12,5-25 / 24h 200 / 24h • Start Low, Increase Slowly • Increase the dose every 2 - 4 weeks

36. ß-Adrenergic Blockers Adverse Effects • Hypotension • Fluid retention / worsening heart failure • Fatigue • Bradycardia / heart block

37. Aldosterone Inhibitors ALDOSTERONE Spironolactone - Competitive antagonist of the aldosterone receptor (myocardium, arterial walls, kidney) • Retention Na+ • Retention H2O • Excretion K+ • Excretion Mg2+ • Collagen • deposition • Fibrosis • - myocardium • - vessels Edema Arrhythmias

38. 1.0 0.9 0.8 0.7 0.6 0.5 0 6 12 24 30 36 18 Spironolactone Annual Mortality Aldactone 18%; Placebo 23% Survival Aldactone N = 1663 NYHA III-IV Mean follow-up 2 y p < 0.0001 RALES NEJM 1999;341:709 Placebo months

39. Spironolactone.Indications • Recent or current symptoms despite ACE-i, diuretics, dig. and b-blockers • AHA / ACC HF guidelines 2001 • Recommended in advanced heart failure (III-IV), in addition to ACE-i and diuretics • Hypokalemia • ESC HF guidelines 2001

40. Spironolactone.Practical use • Do not use if hyperkalemia, renal insuf. • Monitor serum K+ at “frequent intervals” • Start ACE-i first • Start with 25 mg / 24h • If K+ >5.5 mmol/L, reduce to 25 mg / 48h • If K+ is low or stable consider 50 mg / day • New studies in progress

41. Angiotensin II Receptor Blockers (ARB) RENIN Angiotensin IANGIOTENSIN II Angiotensinogen ACE Other pathways AT1 Receptor Blockers RECEPTORS AT1 AT2 Vasoconstriction Proliferative Action Vasodilatation Antiproliferative Action

42. Angiotensin II Receptor Blockers (ARB) • Candesartan, Eprosartan, Irbesartan Losartan, Telmisartan, Valsartan • Not indicated with beta blockers • Indicated in patients intolerant to ACE-I AHA / ACC HF guidelines 2001 ESC HF guidelines 2001

43. Positive Inotropes • Digitalis • Sympathomimetics • Catecholamines • B-adrenergic agonists • Phosphodiesterase inhibitors • Amrinone, Milrinone, Enoximone • Calcium sensitizers • Levosimendan, Pimobendan

44. Positive Inotropic Therapy • May increase mortality Exception: Digoxin, Levosimendan • Use only in refractory CHF • NOT for use as chronic therapy

45. - PlasmaNoradrenaline - Peripheral nervous system activity - RAAS activity - Vagaltone - Normalizes arterial baroreceptors Digitalis. Mechanism of Action Blocks Na+ / K+ ATPase => Ca+ + •Inotropic effect •Natriuresis •Neurohormonal control NEJM 1988;318:358

46. Digitalis. Clinical Effects • Improve symptoms • Modest reduction in hospitalization • Does not improve survival

47. Digitalis. Indications • When no adequate response to ACE-i + diuretics + beta-blockers AHA / ACC Guidelines 2001 • In combination with ACE-i + diuretics if persisting symptoms ESC Guidelines 2001 • AF, to slow AV conduction Dose 0.125 to 0.250 mg / day

48. 50 40 30 20 10 0 Digitalis Mortality % Placebo n=3403 p = 0.8 N=6800 NYHA II-III Digoxin n=3397 0 12 24 36 48 DIG N Engl J Med 1997;336:525 Months

49. Diuretics. Indications • 1. Symptomatic HF, with fluid retention • Edema • Dyspnea • Lung Rales • Jugular distension • Hepatomegaly • Pulmonary edema (Xray) AHA / ACC HF guidelines 2001 ESC HF guidelines 2001

50. Loop Diuretics / Thiazides. Practical Use • Start with variable dose. Titrate to achieve dry weight • Monitor serum K+ at “frequent intervals” • Reduce dose when fluid retention is controlled • Teach the patient when, how to change dose • Combine to overcome “resistance” • Do not use alone