Exercise Exercise training is recommended to all chronic stable HF patients. Twenty years ago, exercise was strongly discouraged in patients with HF as it was considered to be harmful. Nowadays, numerous studies have demonstrated the opposite. Rehabilitation programs have shown to increase exercise capacity and health related quality of life, and decrease hospitalization rates and symptoms. (Class I recommendation, level of evidence A) Other Other non-pharmacological treatment recommendations include immunization of HF patients (pneumococcal- and influenza vaccination should be considered), the consulting of a physician around pregnancy, the screening for depression and sleep disorders that require additional medical attention. Pharmacological treatment A flowchart for the treatment of patients presenting with systolic HF is depicted in Figure 5. Medications with a class I indication in patients with systolic heart failure are summarized in Table 5. Indications, mode of action, contraindications of the medication, and possible side effects of drugs included in this algorithm are discussed below. https://www.textbookofcardiology.org/wiki/Heart_Failure 16/30 7/3/23, 11:59 PM Heart Failure - Textbook of Cardiology Figure 5. Treatment options for patients with chronic systolic HF https://www.textbookofcardiology.org/wiki/Heart_Failure 17/30 7/3/23, 11:59 PM Heart Failure - Textbook of Cardiology NYHA I & EF <40% NYHA II NYHA III NYHA IV Diuretic ACE-inhib AT-II antagonist Alternative Alternative Alternative Post infarction Betablocker Aldosteron antagonist EF < 35% EF < 35% EF < 35% Nitrate / Hydralazine Afro-American Afro-American Afro-American SR>75/min & EF<35% SR>75/min & EF<35% SR>75/min & EF<35% Ivabradine Digoxin Table 5. Medication with a class I indication in patients with systolic heart failure. Note that AT-II antagonists are alternative medicine for ACE inhibitors in case of intolerance (coughing, allergy). Nitrates and Hydralazine are added therapy for patients of Afro-American descent, and alternative therapy for patients that cannot tolerate ACE-inhibitors and AT-II antagonists). Digoxin can also be seen as symptomatic (instead of added preventive) treatment, not always necessary in NYHA III or even IV. Angiotensin-converting enzyme (ACE) inhibitors An ACE inhibitor is indicated for every patient with symptomatic systolic HF and an EF 40 % (NYHA class II-IV). (Class I recommendation, level of evidence A) Contraindications for the use of ACE inhibitors are: History of angioedema Bilateral renal artery stenosis Serum potassium concentration >5.0 mmol/L Serum creatinine >220 mol/L Severe aortic stenosis ACE inhibitors relieve the heart by decreasing the preload and afterload. This is achieved through two mechanisms. Firstly, conversion of angiotensin-I to angiotensin II is inhibited, which reduces vasoconstriction and lowers BP. Secondly, production of aldosterone is decreased, as angiotensin II induces this production. Aldosterone stimulates sodium- and water retention. Possible side effects are symptomatic hypotension (dizziness), hyperkalemia, worsening renal function and cough. In patients with congestive HF, total mortality and hospitalization are significantly reduced by ACE inhibitors.[8] Beta Blockers Beta blockade (in addition to an ACE inhibitor or ARB when ACE inhibitor is not tolerated) is indicated for every patient with symptomatic systolic HF and an EF 40 % (NYHA class II-IV) and in asymptomatic patients with a LVEF 40% after a MI. (Class I recommendation, level of evidence A).[9] https://www.textbookofcardiology.org/wiki/Heart_Failure 18/30 7/3/23, 11:59 PM Heart Failure - Textbook of Cardiology Contraindications are: Bronchial asthma Second - or third degree heart block, sick sinus syndrome, sinus bradycardia Beta blockers mainly exert their effect by reducing the toxic effects of the sympathetic nervous stimulation on the heart and by deactivating the renin-angiotensin system. Possible side effects include (symptomatic) hypotension, worsening of HF and bradycardia. The recommendation is start low, go slow , i.e. start with a low dose, and titrate every two weeks. In patients with persistent symptoms after treatment with a combination of beta blocker and ACE inhibitor or ARB, a mineralocorticoid/aldosterone receptor antagonist (MRA) is recommended. (Class I recommendation, level of evidence A) Diuretics (Loop of Henle diuretics, Thiazides, Aldosterone antagonists) Diuretics reduce preload by venous vasodilatation and by increasing diuresis. As a result, filling pressures of the heart lung vasculature decrease. the and Although the effects of diuretics on mortality and morbidity have not been studied in patients with HF (irrespective of EF), it is recommended in patients with signs and symptoms of congestion as diuretics relieve dyspnea and edema. Figure 6 depicts the nephron and the sites where different diuretics work. Loop of Henle diuretics Figure 6. Diuretics and site of action in the nephron. Loop of Henle diuretics act on ascending loop of Henle in the kidney tubules to inhibit sodium and chloride (and indirectly calcium and magnesium) reabsorption. This will ultimately result in increased urine production of sodium and water. Compared to thiazides, loop diuretics produce a more intense and shorter diuresis. the Thiazides Thiazide increases urine production by decreasing reabsorption of sodium in the distal tubule. This type of diuretic is often used in combination with loop diuretics to enhance their effects, but may be less effective in patients with a severely reduced kidney function. Aldosterone antagonists Adding this drug is suggested for patients with moderate to severe symptomatic HF (NYHA class II to IV, refer to Table 2) and an LVEF < 35%. (Class I recommendation, level of evidence A) Contraindications: https://www.textbookofcardiology.org/wiki/Heart_Failure 19/30 7/3/23, 11:59 PM Heart Failure - Textbook of Cardiology Serum potassium concentration > 5.0 mmol/L Serum creatinine > 220 mol/L Concomitant potassium sparing diuretic or potassium supplements Combination of an ACEI and ARB Aldosterone antagonists reduce sodium retention by the kidney, and inhibit fibrosis formation in the heart. Possible side effects include hyperkalemia, hyponatremia, worsening renal function, and breast tenderness and/or enlargement. Eplerenon has less mastopathy side effects and is an alternative to spironolacton. In patients with severe heart failure, spironolactone in addition to standard therapy, reduces morbidity and mortality. [10] Choice and combination of diuretics Patients with heart failure may be treated with a thiazide diuretic, which should be switched to a loop diuretic if a suboptimal response occurs. In patients with a decreased renal function, a loop diuretic is the mainstay of treatment. Addition of a thiazide diuretic to a loop diuretic can be considered in case of a suboptimal response of loop diuretic alone, when given in sufficient doses (furosemide 250 mg twice daily), suggesting that diuretic resistance is due to distal tubular increased activity of retaining sodium. In all patients with NYHA II or more, except in those with a creatinine clearance < 20 ml/min (creatinine > 220 micromol/L), addition of an aldosterone antagonist should be considered. In special cases in which hypercapnia plays a role, metabolic alkalosis can result from diuretics, and acetazolamide, a reversible carbonic anhydrase inhibitor, is then prescribed as an alternative diuretic. Angiotensin receptor blockers (ARBs) ARBs are recommended in patients who do not tolerate an ACE inhibitor. Until recently, the addition of ARBs was the first choice recommendation in patients with HF and EF 40% who remained symptomatic despite optimal treatment with ACE inhibitor and beta blocker. As aldosterone antagonists have also proven their effects in NYHA class II patients, aldosterone antagonists have become first choice additional therapy after an ACE inhibitor and beta blocker. Whether ARBs may still be recommended in this patient group as added therapy after the addition of aldosterone antagonist is not known. Contraindications are: Bilateral renal artery stenosis Serum potassium concentration > 5.0 mmol/L Serum creatine > 220 mol/L Severe aortic stenosis Possible side effects include symptomatic hypotension (dizziness), hyperkalemia, and a worsening renal function. Digoxin https://www.textbookofcardiology.org/wiki/Heart_Failure 20/30 7/3/23, 11:59 PM Heart Failure - Textbook of Cardiology In the past, digoxin was the standard treatment in HF. Digoxin inhibits sodium-potassium ATPase in the cell membrane of the myocytes, and, by decreasing the sodium extrusion, also inhibits the exchange of calcium out of the cell for sodium into the cell. More calcium remains in the myocyte and increases the contractility of the heart. In contrast to other inotropics, digoxin does not increase mortality. In patients with symptomatic HF and atrial fibrillation (AF) with a ventricular rate at rest of >80 beats per minute, use of digoxin may be considered to slow the ventricular rate. (Class I recommendation, level of evidence C) Digoxin may be considered to reduce HF hospitalization in patients with symptomatic (NYHA class II- IV) systolic HF in sinus rhythm with an EF 45%. These patients should also use an ACE inhibitor (or ARB) and an MRA (or ARB) and preferably a beta blocker. (Class IIb recommendation, level of evidence B) This may also be considered in patients with an EF 45% and persisting symptoms despite treatment with an ACE inhibitor (or ARB) and an MRA (or ARB). (Class IIb recommendation, level of evidence B) Contraindications for the use of digoxin are: Second- or third degree heart block without a permanent pacemaker, sick sinus syndrome Pre-excitation syndromes Possible side effects include sinoatrial or atrioventricular block, arrhythmias or signs of toxicity (nausea and visual effects as halos). Ivabradine Ivabradine lowers the heart rate through inhibition of the If channel in the sinus node. This drug can be used in patients who are still in NYHA class II-IV after treatment with ACE inhibitor (or ARB), beta blocker and an MRA (or ARB), who have a LVEF 35%, are in sinus rhythm and have a heart rate 75 beats/min. Ivabradine may also be used in patients who do not tolerate, or have contraindications for the use of beta blockers. Hydralazine and isosorbide dinitrate (H-ISDN) H-ISDN can be used as an alternative treatment when both ACEI and ARBs are not tolerated by symptomatic HF patients with a LVEF 45% and dilated LV (or EF 35%). These patients should also receive a beta blocker and MRA. (Class IIb recommendation, level of evidence B). H-ISDN can be used in addition to the standard HF treatments (ACEI, beta blocker and MRA) in patients of Afro-American descent (Class IIb recommendation). H-ISDN may reduce risk of HF hospitalization and risk of premature death in patients with a LVEF 45% and dilated LV (or EF 35%) with persistent symptoms despite treatment with beta blocker, ACEI (or ARB), and an MRA (or ARB). (Class IIb recommendation, level of evidence B) Contraindications for the use of H-ISDN are: Symptomatic hypotension Lupus syndrome Severe renal failure The H-ISDN combination acts by decreasing peripheral vascular resistance. https://www.textbookofcardiology.org/wiki/Heart_Failure 21/30 7/3/23, 11:59 PM Heart Failure - Textbook of Cardiology Possible side effects include symptomatic hypotension or drug-induced lupus-like syndrome. Other Anticoagulants Anti platelet agents Statins Anti arrhythmic medication Calcium antagonists Therapy of acute heart failure When severe symptoms of heart failure quickly develop over time, it is termed acute heart failure. In Table 6, common their acute HF medications recommended doses are summarized. In Figure 7, a flowchart for the treatment of acute HF is depicted. The mainstay of acute heart includes inotropics and diuretics, vasodilators, vasopressors. Moreover, oxygen and morphine can be added. and failure therapy Figure 7. Flowchart acute HF. https://www.textbookofcardiology.org/wiki/Heart_Failure 22/30 7/3/23, 11:59 PM Heart Failure - Textbook of Cardiology Table 6. Medication in acute heart failure Medication Condition Dose Diuretics Adequate blood pressure and signs of overfilling 40 mg Furosemide i.v. Renal failure 125 mg max 1000 mg 1 mg Bumetanide i.v. Renal failure 3 mg max 25 mg Vasodilators Adequate blood pressure and signs of severe overfilling 20 g/min max 200 g/min (guided by blood pressure) Nitroglycerine i.v. Hypertensive crisis or in combination with inotropic in case of a cardiogenic shock 0.3 g/kg/min max 5 g/kg/min (guided by blood pressure) Nitroprusside i.v. Inotropes Low blood pressure and/or renal failure with or without overfilling Dobutamine i.v. 2-3 g/kg/min max 20 g/kg/min Low blood pressure and/or renal failure with or without overfilling 2-3 g/kg/min max 20 g/kg/min Dopamine i.v. Signs of peripheral hypoperfusion with or without overfilling, and adequate blood pressure 0.25 0.75 mg/kg in 10 minutes; subsequently 1.25 7.5 g/kg/min Enoximone i.v. 0.1 g/kg/min, If beta-blockade is thought to be contributing to hypoperfusion can be decreased to 0.05 or increased to 0.2 g/kg/min Levosimendan i.v. Vasopressors Restore circulation in cardiogenic shock Adrenalin i.v. Noradrenalin i.v. Septic shock Patient presents at first aid or emergency room with signs of acute HF. https://www.textbookofcardiology.org/wiki/Heart_Failure 23/30 7/3/23, 11:59 PM Heart Failure - Textbook of Cardiology Table 7. Medication in chronic heart failure Medication Condition Dose Adequate blood pressure and signs of overfilling Loop diuretic 40 mg Furosemide Renal failure 80 mg max 1000 mg 1 mg Bumetanide Renal failure 2 mg max 25 mg ACE inhibitors Start 6.25mg Captopril 1st week 6.25mg three times daily. 3-5 weeks 12.5mg three times daily. >7 weeks 25mg three times daily. Start 2.5-5mg Lisinopril 1st week 2.5-5mg twice daily. 3-5 weeks 5-10mg twice daily. >7 weeks 10-20mg twice daily. Beta blockers EF >30-45% and NYHA II-III Start 25mg Metoprolol zoc (succinate) 1st week 50mg once daily. 3-5 weeks 100mg once daily. >7 weeks 100-200mg once daily. EF <30% and NYHA IV Start 12.5mg 1st week 25mg once daily. 3-5 weeks 50mg once daily. https://www.textbookofcardiology.org/wiki/Heart_Failure 24/30 7/3/23, 11:59 PM Heart Failure - Textbook of Cardiology >7 weeks 100-200mg once daily. EF >30-45% and NYHA II-III Start 2.5mg Bisoprolol 1st week 3.75mg once daily. 3-5 weeks 5mg once daily. >7 weeks 7.5-10mg once daily. EF <30% and NYHA IV Start 1.25mg 1st week 2.5mg once daily. 3-5 weeks 3.75mg once daily. >7 weeks 5-7.5-10mg once daily. EF >30-45% and NYHA II-III Start 6.25mg Carvedilol 1st week 6.25mg twice daily. 3-5 weeks 12.5mg twice daily. >7 weeks 25mg twice daily. EF <30% and NYHA IV Start 3.125mg 1st week 3.125mg twice daily. 3-5 weeks 6.25mg twice daily. >7 weeks 12.5-25mg daily. twice EF >30-45% and NYHA II-III Start 1.25mg Nebivolol 1st week 2.5mg once daily. 3-5 weeks 5mg once daily. >7 weeks 10mg once daily. EF <30% and NYHA IV Start 1.25mg 1st week 2.5mg once daily. 3-5 weeks 5mg once daily. https://www.textbookofcardiology.org/wiki/Heart_Failure 25/30 7/3/23, 11:59 PM Heart Failure - Textbook of Cardiology >7 weeks 10mg once daily. Aldosterone antagonist Start 25mg s.i.d. Spironolactone/eplerenone 1st week potassium <5.0: 25mg once daily. potassium 5.0-5.5: 12.5mg once daily. potassium >5.5: stop 3rd week potassium <5.0: 25mg once daily. potassium 5.0-5.5: 12.5mg once daily. potassium >5.5: stop Start 0.5mg, 0.25mg and 0,25 mg, each with 6 hours in between Digoxin Continue with 0.25mg once daily. Half dose with age above 70 or creatinin above 110 or with amiodarone use AT II blockers Start 4mg Candesartan 3-5 weeks 8mg once daily. >7 weeks 16mg once daily. Start 40mg twice daily Valsartan 3-5 weeks 80mg twice daily. >7 weeks 160mg twice daily. Hydralazine and isosorbide dinitrate (H-ISDN) Start 25mg three times daily. Hydralazine 3-5 weeks 50mg three times daily. https://www.textbookofcardiology.org/wiki/Heart_Failure 26/30 7/3/23, 11:59 PM Heart Failure - Textbook of Cardiology >7 weeks 75-100mg times daily. three Start 20mg twice daily ISDN 3-5 weeks 40mg twice daily >7 weeks 80mg twice daily Management of HF beyond medication Device treatment is an Prevention of because important approximately half of the deaths occur suddenly, and many of these are related to ventricular Implantable arrhythmias. cardioverter-defibrillator (ICD) therapy is in survivors of cardiac recommended life arrest I is >1 expectancy recommendation, level of evidence A). sudden death in HF goal , irrespective of EF, when (Class year. In symptomatic HF patients (NYHA class II-III) with an EF 35% after more than 3 months of pharmacological treatment and a life expectancy >1 year, prophylactic ICD implantation is recommended in patients with I recommendation, level of evidence A) and non-ischemic I (Class etiology recommendation, level of evidence B). ischemic etiology (Class Cardiac resynchronization therapy (CRT) is indicated in patients with symptomatic heart failure with one type and severity of ventricular conduction delay (LBBB, QRS 120 msec), and preferably in patients with sinus rhythm. The responder rate (improvement of at least 5% EF) is about 70%. Recommendation for use of this therapy differs according to heart rhythm, NYHA class, QRS duration and morphology, and LVEF. This is depicted in the Figure 8. Figure 8. flowchart CRT Timing of ICD implantation Figure 5 offers recommendations to which patients should receive ICD treatment. In this flowchart, the timing of the placement has not been defined completely. In most patients, it should be safe to wait for their ICD whilst receiving (pharmacological) treatment as events typically occur after 6-12 months.[11] https://www.textbookofcardiology.org/wiki/Heart_Failure 27/30 7/3/23, 11:59 PM Heart Failure - Textbook of Cardiology An exception to this rule is the group of high risk patients (i.e. patients with major myocardial infarction (MI), who have extensive fibrosis on the MRI or NSVT despite optimal pharmacological treatment); an ICD implantation should not be postponed too long in these patients. Early (within 40 days after event) ICD placement after an acute myocardial infarction has not been shown to reduce mortality, because the patients most at risk of sudden death are also the patients most at risk of death due to heart failure.[12] [13][14] For this reason, prophylactic ICD treatment is recommended only after 40 days in post-infarct patients who have an EF < 35%. For non-ischemic heart failure patients, three months is considered a safe waiting time for an ICD. There are, however, also higher risk patients among this group, and a decision should be made for each patient on an individual basis.[15] Heart transplantation and Left Ventricular Assist Devices When a patient has severe and progressive HF, his or her prognosis is grim. Considering the paucity of donor hearts, the waiting list for heart transplantation may be long and early consideration of heart transplantation is part of the treatment strategy in HF. Average 2-year survival rates after cardiac transplantation are approximately 80%. A patient in NYHA class III should be evaluated with an exercise test for maximal oxygen uptake, in order to consider further steps. Indication for heart transplantation includes a VO2max < 14 ml/min/kg.[16] Exclusion pulmonary hypertension (risk of immediate RV donor failure), severe comorbidity, and diabetes mellitus with organ damage. Left Ventricular Assist Devices are more commonly to transplantation, when the patient in on a waiting list. They have evolved from pulsatile to continuous flow pumps, with less complications and a longer durability. Often Left Ventricular Assist Devices become destination therapy. criteria are used as a bridge Management of HF patients with preserved LVEF (HFPEF) Figure 9. Two-year mortality in landmark contemporary clinical heart failure trials (from Cleland et al) To date, no evidence exists of any treatment reducing morbidity or mortality in this patient group. With the aim of controlling water and sodium retention and to decrease breathlessness and edema, diuretics are prescribed to HFPEF patients. Furthermore, ACE-I, Angiotensin II blockers and/or beta blockers may be considered. The CHARM trial including 3023 HF patients with preserved EF, showed angiotensin II blockade (candesartan) to have a moderate effect on hospital admission but showed no effect on the risk of cardiovascular death.[17] Prognosis The life expectancy of a patient with heart failure is determined by age, NYHA class, LVEF, normal level of sodium, systolic blood pressure, use of medication and use of ICD or CRT-D (Seattle Heart failure is score (http://depts.washington.edu/shfm/app.php)). The mean yearly annual mortality https://www.textbookofcardiology.org/wiki/Heart_Failure 28/30 7/3/23, 11:59 PM Heart Failure - Textbook of Cardiology approximately 10%, varying from <6% per year when a normal LVEF is identified, to > 14% per year with an EF of <15%. Trials with medication illustrate that the (short term) benefit of medication is highest when the NYHA class is higher (Figure 9).[18] References 1. Withering W., Keys TE, An account of the foxglove and some of its medical uses, with practical remarks on dropsy, and other diseases, Classics of Cardiology. Volume I. New York, NY: Henry Schuman, Dover Publications; 1941: 231 252. 2. Kannel WB, Silbershatz H, Belanger AJ, Wilson PW, Levy D. Profile for Estimating Risk of Heart Failure, Arch Intern Med. 1999;159:1197-204 3. McMurray JJV et al., ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012, European Heart Journal (2012; 33;1787 1847) 4. McDonagh TA, Morrison CE, Lawrence A, Ford I, Tunstall-Pedoe H, McMurray JJ, Dargie HJ. Symptomatic and asymptomatic left-ventricular systolic dysfunction in an urban population. Lancet. 1997 Sep 20;350(9081):829-33 5. Wang TJ, Evans JC, Benjamin EJ, Levy D, LeRoy EC, Vasan RS. Natural history of asymptomatic left ventricular systolic dysfunction in the community. Circulation. 2003 Aug 26;108(8):977-82. Epub 2003 Aug 11. 6. Holubarsch C et al, Existence of the Frank-Starling Mechanism in the Failing Human Heart Investigations on the Organ, Tissue, and Sarcomere Levels. Circulation. 1996 Aug 15;94(4):683-9. 7. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. New England Journal of Medicine. 1971; 23;285(26):1441-6. 8. Garg R, Yusuf S, Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Journal of the American Medical Association. 1995;273:1450-6 9. Foody JM, Farrell MH, Krumholz MH. -Blocker Therapy in Heart Failure. Scientific Review. Journal of the American Medical Association. 2002;287(7):883-889. 10. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. New England Journal of Medicine .1999;341:709-17 https://www.textbookofcardiology.org/wiki/Heart_Failure 29/30 7/3/23, 11:59 PM Heart Failure - Textbook of Cardiology 11. Moss AJ, Zareba W, Hall J, Klein H, Wilbur DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML . Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. New England Journal of Medicine. 2002;346:877 883. 12. Hohnloser SH, Kuck KH, Dorian P, Roberts RS, Hampton JR, Hatala R, Fain E, Gent M, Connolly SJ. Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction. New England Journal of Medicine.2004;351:2481 2488 13. Steinbeck G, Andresen D, Seidl K, Brachmann J, Hoffmann E, WojciechowskiD, Kornacewich-Jach Z, Sredniawa B, Lupkovics G, Hofgartner F, Lubinski A, Rosenqvist M, Habets A, Wegscheider K, Senges J. Defibrillator implantation early after myocardial infarction. New England Journal of Medicine. 2009;361:1427 1436 14. Wilber DJ, Zareba W, Hall WJ, Brown MW, Lin AC, Andrews ML, Burke M, MossAJ . Time- dependence of mortality risk and defibrillator benefit after myocardial infarction. Circulation. 2004;109:1082 1084. 15. Kadish A, Dyer A, Daubert JP, Quigg R, Estes NA, Anderson KP, Calkins H, Hoch D, Goldberger J, Shalaby A, Sanders WE, Schaechter A, Levine JH. Prophylactic defibrillator implantation in patients with non-ischemic dilated cardiomyopathy. England Journal of Medicine. 2004;350:2151 2158 16. Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH, Wilson JR. Value of peak exercise consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation. 1991;83:778 786 17. Yusuf S. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. The Lancet. Sept 2003 362;9386:777-781 18. Cleland JGF, Andrew L, Clark AL. Delivering the cumulative benefits of triple therapy to improve outcomes in heart failure. Journal of the American College of Cardiology. 2003;42(7) 19. Mosterd A. Clinical epidemiology in heart failure. Heart 2007;93:1137-1146 20. McMurray JJ. Clinical practice. Systolic heart failure. New England Journal of Medicine. 2010;362: 228-238 Retrieved from "http://www.textbookofcardiology.org/index.php?title=Heart_Failure&oldid=2560" This page was last edited on 11 October 2015, at 16:00. Content is available under Attribution-NonCommercial-ShareAlike 3.0 Unported unless otherwise noted. https://www.textbookofcardiology.org/wiki/Heart_Failure 30/30