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

2. Contents
Heart failure definition
Etiology
Pathophysiology
Clinical manifestations

3. 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

4. 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

5. Terminology related to left ventricular ejection fraction
Heart failure definition
Diastole ventricles relaxing
Systole ventricles contracting
Image adapted from:
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

6. Diastolic dysfunction
HFrEF and HFpEF
Heart failure definition
Systolic dysfunction
Diastolic dysfunction
Image adapted from:
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

7. 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

8. Contents
Heart failure definition
Etiology
Pathophysiology
Clinical manifestations

9. 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: 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

10. Contents
Heart failure definition
Etiology
Pathophysiology
Clinical manifestations

11. 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

12. 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

13. 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– Luchner & Schunkert. Cardiovasc Res 2004;63:443–9; 5. Thysgesen et al. Eur Heart J 2012;33:2001–6

14. 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

15. 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

16. 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 
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

17. 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 © Informa Healthcare; Rubattu et al. Am J Hypertens 2008;21:733–41

18. 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

19. 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

20. Contents
Heart failure definition
Etiology
Pathophysiology
Clinical manifestations

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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