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INTRODUCTION TOHEART 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
ESC: European Society of Cardiology; AHA: American Heart Association; ACCF: American College of Cardiology Foundation1. McMurray et al. Eur Heart J 2012;33:1787–847; 2. Yancy et al. JACC 2013;62:e147–239
Leftatrium
Rightatrium
Rightventricle
Leftventricle
LV=left ventricularMcMurray. 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
The pathophysiology of chronic HF
HF symptomsdyspnea, edema, fatigue
Remodeling and progressive worsening of LV
function
Morbidity and mortality arrhythmias, pump failure
Hemodynamic alterations, salt and water retention
These changes lead to systemic neurohormonal imbalance
Damage to cardiac myocytes and extracellular matrix leads to changes in the size, shape and function of the heart (remodeling)
and cardiac wall stress
This may lead to fibrosis, apoptosis, hypertension, hypertrophy, cellular and molecular alterations, myotoxicity
Heart failure definition
Terminology related to left ventricularejection fraction
McMurray et al. Eur Heart J 2012;33:1787–847; Dickstein et al. Eur Heart J 2008;29:2388–442
Systoleventricles contracting
Diastoleventricles relaxing
Amount of bloodpumped out ofthe ventricle
Total amount ofblood in
the ventricle
= Ejection fraction (%)
Heart failure definitionHFrEF and HFpEF
HFrEFEF≤35–40%
HFpEF EF>40–50%
HFpEF: heart failure with preserved ejection fractionMcMurray et al. Eur Heart J 2012;33:1787–847; Dickstein et al. Eur Heart J 2008;29:2388–442
Diastolic dysfunction
Systolic dysfunction
HFrEF
EF≤35–40%
HFpEF
EF>40–50%
Echocardiography is a useful method for evaluating left ventricular ejection fraction
Heart failure definitionAn abnormality of cardiac structure or function
Acute infarction
Infarct zone thinning and elongation
Fibrous scar Myocyte hypertrophy
Spherical ventricular dilation
Increased interstitial collagen
Konstam MA, et al. J Am Coll Cardiol Img 2011;4:98–108
From myocardial infarction (MI) to HF: Ventricular Remodeling after MI
Contents
Heart failure definition
Etiology
Pathophysiology
Clinical manifestations
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
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)
Most common causes of Heart Failure
• Congenital heart disease
• Pericardial disease
• Hyperkinetic states
• Anemia
• Arterio-venous fistula
• Beriberi
*Others: Including hypertension, diabetes, exposure to cardiotoxic agents, peripartum cardiomyopathy, etc.
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
AgeSmokingObesity
HypertensionCoronary artery diseaseDiabetesDyslipidemia
Normal LV structure and function LV remodeling
Subclinical LV dysfunction Clinical HF
Years/months
MI
LVhypertrophy
HFrEFHFpEF
Systolicdysfunction
Diastolicdysfunction
Years
‡ 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 infarction1. Krum, Gilbert. Lancet 2003;362:14758; 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
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 Hypertrophyand Failure. Vol 7. Edited by Alpert NR. New York: Raven Press; 1993:1–15. Copyright © 1993 Wolters Kluwer Health
−
Volumeoverload
Increaseddiastolic pressure
Increaseddiastolic wall stress
Series addition of new sarcomeres
Chamberenlargement
Eccentrichypertrophy
HFrEF
−
Increasedsystolic pressure
Increasedsystolic wall stress
Parallel additionof new myofibrils
Wallthickening
Concentrichypertrophy
Pressureoverload
HFpEF
Left ventriclevolume
overload
Left ventriclepressureoverload
Left ventriclenormal
HFrEF – a condition of volume overload
• characterized by eccentric hypertrophy
• results in thinning of the LV walls, decreased systolic function and enlarged LV volume
HFpEF – a condition of pressure overload
• characterized by concentric hypertrophic growth
• results in normal sized LV cavity with thickened walls and preserved systolic function
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
Activated in response to reduced cardiac output1
Short-term effects are beneficial in early HF1
Long-term activation exerts unfavourable effects1,3
NP=natriuretic peptide; RAAS=renin angiotensin aldosterone system;SNS=sympathetic nervous system1. 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
Release of NPs in response to cardiac stress2
Opposes the actions of the RAAS2 and SNS4,5
SNS RAAS NP system
The SNS and RAAS are overactivated in heart failure and are responsible for many of the pathophysiological responses that contribute to disease progression
ANG=angiotensin; AT1R=angiotensin type 1 receptor; NP=natriuretic peptide; NPRs=natriuretic peptide receptors; RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous systemLevin 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;57:141825; Schrier & Abraham N Engl J Med 2009;341:577–85
RAASAng II AT1R
HF SYMPTOMS& PROGRESSION
EpinephrineNorepinephrine
α1, β1, β2
receptors
SNS
VasoconstrictionBlood pressure
Sympathetic tone
Aldosterone
Hypertrophy
Fibrosis
Sodium and water retention
VasoconstrictionRAAS activity
Vasopressin
Heart rate
Contractility
Secretion of natriuretic peptides results in a number of responses that act to reduce the symptoms and progression of heart failure
NP=natriuretic peptide; NPRs=natriuretic peptide receptorsLevin 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;57:141825; 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
Inactivefragments
NP system
Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy
NPRs NPsNeprilysin
RAASAng II AT1R
HF SYMPTOMS& PROGRESSION
Inactivefragments
NP system
Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy
NPRs NPsNeprilysin
EpinephrineNorepinephrine
α1, β1, β2
receptors
As heart failure advances, the RAAS and SNS become the predominantly activated neurohormonal systems
ANG=angiotensin; AT1R=angiotensin type 1 receptor; NP=natriuretic peptide; NPRs=natriuretic peptide receptors; RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous systemLevin 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;57:141825; 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
SNS
VasoconstrictionBlood pressure
Sympathetic tone
Aldosterone
Hypertrophy
Fibrosis
VasoconstrictionRAAS activity
Vasopressin
Heart rate
Contractility
Aldosterone suppression
Natriuretic peptides have potential for protection of the heart, vessels and kidneys
Enhanced endothelial functionEndothelin inhibition
Vasodilation
Sympatho-inhibitory
LusitropicAttenuation of cardiac remodeling (LVH) and fibrosis
Antiproliferative effect:reverse vascular remodeling
(arterial stiffness)
ANP
BNP
Renin inhibitionImproved renal hemodynamicsIncreased natriuresis and diuresisAttenuation of renal fibrosis
Inhibition of RAAS
ANP=atrial natriuretic peptide; BNP=brain natriuretic peptide; LVH=left ventricular hypertrophy; NPs=natriuretic peptides; RAAS=renin-angiotensin-aldosterone systemFigure 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
NPs are released in response to cardiac wall stress and act in the brain, adrenal gland, kidney, vasculature and heart
ANP
Inhibition of renin secretion Decrease in SNS outflow
Decrease in BP
Modulation of arterial and cardiopulmonary baroreceptors
ANP interacts with baroreflex controlof the circulation to inhibit the
activity of the SNS2
ANP and BNP inhibit the RAASvia actions in the kidneysand the adrenal glands1
ANP/BNP
Inhibition of aldosterone secretion
Decrease in BP
Natriuretic peptides inhibit the activity of the RAAS and counterbalance the sympathetic nervous system
ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide; BP=blood pressure; NPs=natriuretic peptides; RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous system1. Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; 2. Rubattu et al. Am J Hypertens 2008;21:733–41
NPs=natriuretic peptides; RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous system
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
Contents
Heart failure definition
Etiology
Pathophysiology
Clinical manifestations
Fluid retention
Pumping action of the heart
grows weaker
Swelling of feet, ankles, abdomen and lower back area
Coughing
TirednessShortness of breath
Pulmonary edema
Pleural effusion
Clinical manifestations
• 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
Symptoms and Signs
McMurray et al. Eur Heart J 2012;33:1787–847
Goldberg et al. Clin Cardiol 2010;33:e73–80
Dyspn
eaEde
ma
Cough
Orthop
nea
Angina
l/che
st p
ainW
eakn
ess
Noctu
rnal
paro
xysm
s
Nause
a/vo
mitin
gFat
igue
Ascite
s
Men
tal o
btun
datio
nW
eight
gain
Palpita
tions
Abdom
inal p
ain
Clinical manifestationsFrequency of signs and symptoms
Signs and symptoms in 4,537 residents of Worcester, Massachusetts, USA, hospitalized for acute HF between 1995 and 2000
Pat
ient
s (%
)
100
80
60
40
20
0
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.
New York Heart Association functional classification based on severity of symptoms and physical activity
McMurray et al. Eur Heart J 2012;33:1787–847
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
Symptomatic severity of heart failure
NYHA: New York Heart AssociationMuntwyler et al. Eur Heart J 2002;23:1861–6
Clinical manifestationsNYHA class is related to prognosis in chronic HF
1.0
0.9
0.8
0.7
Time (months)
0.6
P<0.001
NYHA II
Sur
viva
l pro
bab
ility
acco
rdin
g t
o N
YH
A c
lass
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
0 3 6 9 12 15
NYHA IV
NYHA III
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
A progressive condition with high mortality
LV: left ventricularGheorghiade et al. Am J Cardiol 2005;96:11G–17G; Gheorghiade & Pang. J Am Coll Cardiol 2009;53:557–73
Chronic decline
Mortality
Acute episodes
Disease progression
Function& quality
of life (QoL)
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