INTRODUCTION TO HEART FAILURE © 2015 Novartis Pharma AG, May 2015, GLCM/HTF/0027b

Contents Heart failure definition Etiology Pathophysiology Clinical manifestations

Heart failure definition ESC 2012: Heart failure (HF) is an abnormality of cardiac structure or function leading to failure of the heart to deliver oxygen at a rate commensurate with the requirements of the metabolizing tissues1 ACCF/AHA 2013: HF is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood2 Left atrium Right atrium Left ventricle Right ventricle ESC: European Society of Cardiology; AHA: American Heart Association; ACCF: American College of Cardiology Foundation 1. McMurray et al. Eur Heart J 2012;33:1787–847; 2. Yancy et al. JACC 2013;62:e147–239

The pathophysiology of chronic HF Damage to cardiac myocytes and extracellular matrix leads to changes in the size, shape and function of the heart (remodeling) and cardiac wall stress These changes lead to systemic neurohormonal imbalance This may lead to fibrosis, apoptosis, hypertension, hypertrophy, cellular and molecular alterations, myotoxicity Remodeling and progressive worsening of LV function Hemodynamic alterations, salt and water retention Morbidity and mortality arrhythmias, pump failure HF symptoms dyspnea, edema, fatigue LV=left ventricular McMurray. N Engl J Med 2010;362:228–38; Francis et al. Ann Intern Med 1984;101:370–7; Krum, Abraham. Lancet 2009;373:941–55

Terminology related to left ventricular ejection fraction Heart failure definition Diastole ventricles relaxing Systole ventricles contracting Image adapted from: http://www.cardiachealth.org/heart-information/heart-failure Amount of blood pumped out of the ventricle = Ejection fraction (%) Total amount of blood in the ventricle McMurray et al. Eur Heart J 2012;33:1787–847; Dickstein et al. Eur Heart J 2008;29:2388–442

Diastolic dysfunction HFrEF and HFpEF Heart failure definition Systolic dysfunction Diastolic dysfunction Image adapted from: http://www.merckmanuals.com/home/heart_and_blood_vessel_disorders/heart_failure/heart_failure.html HFrEF EF≤35–40% HFrEF EF≤35–40% HFpEF EF>40–50% HFpEF EF>40–50% Echocardiography is a useful method for evaluating left ventricular ejection fraction HFpEF: heart failure with preserved ejection fraction McMurray et al. Eur Heart J 2012;33:1787–847; Dickstein et al. Eur Heart J 2008;29:2388–442

An abnormality of cardiac structure or function Heart failure definition From myocardial infarction (MI) to HF: Ventricular Remodeling after MI Fibrous scar Myocyte hypertrophy Acute infarction Increased interstitial collagen Image adapted from: Konstam MA, et al. J Am Coll Cardiol Img 2011;4:98–108 Infarct zone thinning and elongation Spherical ventricular dilation Konstam MA, et al. J Am Coll Cardiol Img 2011;4:98–108

Contents Heart failure definition Etiology Pathophysiology Clinical manifestations

Most common causes of Heart Failure Etiology Coronary heart disease Hypertension Valvular disease Cardiomyopathy Idiopathic cardiomyopathy Alcoholic cardiomyopathy Toxin-related cardiomyopathy e.g. adriamycin Post-partum cardiomyopathy Hypertrophic obstructive cardiomyopathy Tachyarrhythmia-induced cardiomyopathy Infiltrative disorders (e.g. amyloidosis) Congenital heart disease Pericardial disease Hyperkinetic states Anemia Arterio-venous fistula Beriberi Image of enlarged failing heart from: http://www.cardiachealth.org/heart- information/heart-failure *Others: Including hypertension, diabetes, exposure to cardiotoxic agents, peripartum cardiomyopathy, etc. Krum and Gilbert. Lancet 2003;362:147–58; Colucci (Ed.). Atlas of Heart Failure, 5th ed. Springer 2008; Dickstein et al. Eur Heart J 2008;29:2388–442

Contents Heart failure definition Etiology Pathophysiology Clinical manifestations

Different co-morbidities and pathophysiological processes can lead to different types of heart failure A range of risk factors and co-morbidities contribute to the development of HF1 Age Smoking Obesity Hypertension Coronary artery disease Diabetes Dyslipidemia MI Systolic dysfunction HFrEF HFpEF Diastolic dysfunction LV hypertrophy Normal LV structure and function Subclinical LV dysfunction LV remodeling Clinical HF Years Years/months ‡ Patients with an LV ejection fraction of 35–50% represent a ‘gray area’ and may have primarily mild systolic dysfunction2 HF=heart failure; LV=left ventricular; LVEF=left ventricular ejection fraction;MI=myocardial infarction Krum, Gilbert. Lancet 2003;362:14758; Figure reproduced with permission from Krum, Gilbert. Lancet 2003;362:147–58 Copyright © 2003 Elsevier

Patterns of ventricular remodeling are different for HFrEF and HFpEF Left ventricle normal HFrEF HFpEF HFrEF – a condition of volume overload characterized by eccentric hypertrophy results in thinning of the LV walls, decreased systolic function and enlarged LV volume Volume overload Pressure overload HFpEF – a condition of pressure overload characterized by concentric hypertrophic growth results in normal sized LV cavity with thickened walls and preserved systolic function Increased diastolic pressure Increased systolic pressure Increased diastolic wall stress Increased systolic wall stress − Series addition of new sarcomeres Parallel addition of new myofibrils − Chamber enlargement Wall thickening Left ventricle volume overload Eccentric hypertrophy Concentric hypertrophy Left ventricle pressure overload LV=left ventricular; HFpEF=heart failure with preserved ejection fraction; HFrEF=heart failure with reduced ejection fraction Adapted from Colucci (Ed.). Atlas of Heart Failure, 5th ed. Springer 2008; Figure reproduced with permission from Grossman W, et al. In: Perspectives in Cardiovascular Research; Myocardial Hypertrophy and Failure. Vol 7. Edited by Alpert NR. New York: Raven Press; 1993:1–15. Copyright © 1993 Wolters Kluwer Health

Cardiac dysfunction triggers the activation of three compensatory neurohormonal systems Cardiac structure/function abnormality Activation of compensatory mechanisms to maintain cardiac output and organ perfusion1 SNS RAAS NP system Activated in response to reduced cardiac output1 Short-term effects are beneficial in early HF1 Long-term activation exerts unfavourable effects1,3 Release of NPs in response to cardiac stress2 Opposes the actions of the RAAS2 and SNS4,5 NP=natriuretic peptide; RAAS=renin angiotensin aldosterone system;SNS=sympathetic nervous system 1. Francis et al. Ann Intern Med 1984;101:370–7; 2. Clerico et al. Am J Physiol Heart Circ Physiol 2011;301:H12–H20; 3. Von Lueder et al. Circ Heart Fail 2013;6:594–605 4. Luchner & Schunkert. Cardiovasc Res 2004;63:443–9; 5. Thysgesen et al. Eur Heart J 2012;33:2001–6

HF SYMPTOMS & PROGRESSION The SNS and RAAS are overactivated in heart failure and are responsible for many of the pathophysiological responses that contribute to disease progression SNS Epinephrine Norepinephrine α1, β1, β2 receptors Vasoconstriction RAAS activity  Vasopressin  Heart rate  Contractility  HF SYMPTOMS & PROGRESSION RAAS Ang II AT1R Vasoconstriction Blood pressure  Sympathetic tone  Aldosterone  Hypertrophy  Fibrosis  Sodium and water retention  ANG=angiotensin; AT1R=angiotensin type 1 receptor; NP=natriuretic peptide; NPRs=natriuretic peptide receptors; RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous system Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; Kemp & Conte. Cardiovascular Pathology 2012;365–371; Schrier et al. Kidney Int 2000;57:141825; Schrier & Abraham N Engl J Med 2009;341:577–85

HF SYMPTOMS & PROGRESSION Secretion of natriuretic peptides results in a number of responses that act to reduce the symptoms and progression of heart failure NP system HF SYMPTOMS & PROGRESSION NPRs NPs Vasodilation  Blood pressure  Sympathetic tone  Natriuresis/diuresis  Vasopressin  Aldosterone  Fibrosis  Hypertrophy Neprilysin Inactive fragments NP=natriuretic peptide; NPRs=natriuretic peptide receptors Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; Kemp & Conte. Cardiovascular Pathology 2012;365–371; Schrier et al. Kidney Int 2000;57:141825; Schrier & Abraham N Engl J Med 2009;341:577–85; Boerrigter, Burnett. Expert Opin Invest Drugs 2004;13:643–52; Ferro et al. Circulation 1998;97:2323–30; Brewster et al. Am J Med Sci 2003;326:15–24

HF SYMPTOMS & PROGRESSION As heart failure advances, the RAAS and SNS become the predominantly activated neurohormonal systems SNS Epinephrine Norepinephrine α1, β1, β2 receptors Vasoconstriction RAAS activity  Vasopressin  Heart rate  Contractility  NP system HF SYMPTOMS & PROGRESSION NPRs NPs Vasodilation  Blood pressure  Sympathetic tone  Natriuresis/diuresis  Vasopressin  Aldosterone  Fibrosis  Hypertrophy Neprilysin RAAS Ang II AT1R Inactive fragments Vasoconstriction Blood pressure  Sympathetic tone  Aldosterone  Hypertrophy  Fibrosis  Sodium and water retention  ANG=angiotensin; AT1R=angiotensin type 1 receptor; NP=natriuretic peptide; NPRs=natriuretic peptide receptors; RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous system Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; Kemp & Conte. Cardiovascular Pathology 2012;365–371; Schrier et al. Kidney Int 2000;57:141825; Schrier & Abraham N Engl J Med 2009;341:577–85; Boerrigter, Burnett. Expert Opin Invest Drugs 2004;13:643–52; Ferro et al. Circulation 1998;97:2323–30; Brewster et al. Am J Med Sci 2003;326:15–24

Natriuretic peptides have potential for protection of the heart, vessels and kidneys NPs are released in response to cardiac wall stress and act in the brain, adrenal gland, kidney, vasculature and heart Sympatho-inhibitory Inhibition of RAAS ANP Lusitropic Attenuation of cardiac remodeling (LVH) and fibrosis Enhanced endothelial function Endothelin inhibition Vasodilation BNP Aldosterone suppression Antiproliferative effect: reverse vascular remodeling (arterial stiffness) Renin inhibition Improved renal hemodynamics Increased natriuresis and diuresis Attenuation of renal fibrosis ANP=atrial natriuretic peptide; BNP=brain natriuretic peptide; LVH=left ventricular hypertrophy; NPs=natriuretic peptides; RAAS=renin-angiotensin-aldosterone system Figure reproduced with permission from Boerrigter G, Burnett JC Jr. Expert Opin Investig Drugs 2004;13(6):643–52. Copyright © 2004. Informa Healthcare; Rubattu et al. Am J Hypertens 2008;21:733–41

Natriuretic peptides inhibit the activity of the RAAS and counterbalance the sympathetic nervous system ANP and BNP inhibit the RAAS via actions in the kidneys and the adrenal glands1 ANP interacts with baroreflex control of the circulation to inhibit the activity of the SNS2 ANP/BNP ANP Modulation of arterial and cardiopulmonary baroreceptors Inhibition of renin secretion Inhibition of aldosterone secretion Decrease in SNS outflow Decrease in BP Decrease in BP ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide; BP=blood pressure; NPs=natriuretic peptides; RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous system 1. Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; 2. Rubattu et al. Am J Hypertens 2008;21:733–41

Summary Hypertension and myocardial infarction are major contributors to the development of heart failure The RAAS and SNS are activated in response to reduced cardiac output and are responsible for many of the pathophysiological responses that contribute to disease progression in HF Secretion of NPs results in a number of physiological responses that act to reduce the symptoms and progression of HF via inhibition of the RAAS and counterbalance SNS activation As HF advances, excessive activation of the SNS and the RAAS occurs leading to cardiac stress and overcomes any benefits of NPs, leading to a neurohormonal imbalance NPs=natriuretic peptides; RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous system

Contents Heart failure definition Etiology Pathophysiology Clinical manifestations

Symptoms and Signs Clinical manifestations Main symptoms Main signs Fluid retention Pumping action of the heart grows weaker Swelling of feet, ankles, abdomen and lower back area Coughing Tiredness Shortness of breath Pulmonary edema Pleural effusion Main symptoms Breathlessness Orthopnea Paroxysmal Nocturnal Dyspnea Reduced exercise tolerance Fatigue Ankle swelling Main signs Elevated jugular venous pressure Hepato-jugular reflux Third heart sound Laterally displaced apical impulse Cardiac murmur McMurray et al. Eur Heart J 2012;33:1787–847

Frequency of signs and symptoms Clinical manifestations Signs and symptoms in 4,537 residents of Worcester, Massachusetts, USA, hospitalized for acute HF between 1995 and 2000 100 80 60 Patients (%) 40 20 Cough Dyspnea Edema Fatigue Ascites Orthopnea Weakness Weight gain Palpitations Abdominal pain Anginal/chest pain Nausea/vomiting Nocturnal paroxysms Mental obtundation Goldberg et al. Clin Cardiol 2010;33:e73–80

Symptomatic severity of heart failure Clinical manifestations Clear relationship between severity of symptoms and survival Poor relationship between severity of symptoms and ventricular function Patients with mild symptoms may still have a relatively high absolute risk of hospitalization and death New York Heart Association functional classification based on severity of symptoms and physical activity Class I No limitation of physical activity. Ordinary physical activity does not cause undue breathlessness, fatigue, or palpitations. Class II Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in undue breathlessness, fatigue, or palpitations. Class III Marked limitation of physical activity. Comfortable at rest, but less than ordinary physical activity results in undue breathlessness, fatigue, or palpitations. Class IV Unable to carry on any physical activity without discomfort. Symptoms at rest can be present. If any physical activity is undertaken, discomfort is increased. McMurray et al. Eur Heart J 2012;33:1787–847

NYHA class is related to prognosis in chronic HF Clinical manifestations Among 411 outpatients with NYHA class II, III or IV HF, total mortality was 7.1%, 15.0% and 28.0%, respectively during a mean follow-up period of 1.4 years 1.0 NYHA II 0.9 NYHA III Survival probability according to NYHA class 0.8 NYHA IV 0.7 P<0.001 0.6 3 6 9 12 15 Time (months) NYHA: New York Heart Association Muntwyler et al. Eur Heart J 2002;23:1861–6 24

A progressive condition with high mortality Clinical manifestations Increasing frequency of acute events with disease progression leads to high rates of hospitalization and increased risk of mortality With each acute event, myocardial injury may contribute to progressive LV dysfunction Chronic decline Function & quality of life (QoL) Mortality Acute episodes Disease progression LV: left ventricular Gheorghiade et al. Am J Cardiol 2005;96:11G–17G; Gheorghiade & Pang. J Am Coll Cardiol 2009;53:557–73

Summary Heart Failure is an abnormality of cardiac structure or function leading to failure of the heart to deliver sufficient oxygen to metabolizing tissues1 The most common cause of HF is coronary artery disease2 The most frequently reported signs and symptoms of HF are dyspnea, edema and cough3 HF has a complex pathophysiology involving activation of two key neurohormonal systems:4 Renin–angiotensin–aldosterone system Sympathetic nervous system Natriuretic peptides counteract the detrimental effects of RAAS and SNS activation5 RAAS: renin-angiotensin-aldosterone system; SNS: sympathetic nervous system 1. McMurray et al. Eur Heart J 2012;33:1787–847; 2. Lam et al. Eur J Heart Fail 2011;13:18–28; 2. Dickstein et al. Eur Heart J 2008;29:2388–442; 3. Goldberg et al. Clin Cardiol 2010;33:e73–80; 4. McMurray et al. Eur Heart J 2012;33:1787–847; 5. Levin et al. N Engl J Med 1998;339;321–8