Transcript The new *Silently pressing* DAC, to address the false perception

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
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
Left
ventricle
Right
ventricle
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
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
HFrEF and HFpEF
Heart failure definition
Systolic
dysfunction
Diastolic
dysfunction
HFrEF
EF≤35–40%
EF≤35–40%
HFpEF
HFpEF
EF>40–50%
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
Acute
infarction
Increased
interstitial
collagen
Infarct zone thinning
and elongation
Konstam MA, et al. J Am Coll Cardiol Img 2011;4:98–108
Myocyte hypertrophy
Spherical ventricular
dilation
Contents
Heart failure definition
Etiology
Pathophysiology
Clinical manifestations
Most common causes of Heart Failure
Etiology
• Coronary heart disease
• Congenital heart disease
• Hypertension
• Pericardial disease
• Valvular disease
• Hyperkinetic states
• Cardiomyopathy
• Idiopathic cardiomyopathy
• Alcoholic cardiomyopathy
• Anemia
• Arterio-venous fistula
• Beriberi
• Toxin-related cardiomyopathy
e.g. adriamycin
• Post-partum cardiomyopathy
• Hypertrophic obstructive
cardiomyopathy
• Tachyarrhythmia-induced
cardiomyopathy
• Infiltrative disorders (e.g.
amyloidosis)
*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
Normal LV structure
and function
MI
LV
hypertrophy
LV remodeling
Years
Systolic
dysfunction
HFrEF
HFpEF
Diastolic
dysfunction
Subclinical
LV dysfunction
Clinical HF
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
1. 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
Volume
overload
Pressure
overload
• characterized by
eccentric hypertrophy
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
Eccentric
hypertrophy
Concentric
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
−
−
Left ventricle
volume
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
• results in normal sized
LV cavity with thickened
walls and preserved
systolic function
Left ventricle
pressure
overload
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
NP system
RAAS
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
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
HF SYMPTOMS
& PROGRESSION
α1, β1, β2
receptors
Vasoconstriction
RAAS activity 
Vasopressin 
Heart rate 
Contractility 
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
Secretion of natriuretic peptides results in a number of responses
that act to reduce the symptoms and progression of heart failure
NP system
NPRs
HF SYMPTOMS
& PROGRESSION
NPs
Vasodilation
 Blood pressure
 Sympathetic tone
 Natriuresis/diuresis
 Vasopressin
 Aldosterone
 Fibrosis
 Hypertrophy
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
As heart failure advances, the RAAS and SNS become the
predominantly activated neurohormonal systems
SNS
Epinephrine
Norepinephrine
NP system
NPRs
α1, β1, β2
receptors
Vasoconstriction
RAAS activity 
Vasopressin 
Heart rate 
Contractility 
HF SYMPTOMS
& PROGRESSION
NPs
Vasodilation
 Blood pressure
 Sympathetic tone
 Natriuresis/diuresis
 Vasopressin
 Aldosterone
 Fibrosis
 Hypertrophy
RAAS
Inactive
fragments
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;
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
Enhanced endothelial function
Endothelin inhibition
Vasodilation
BNP
Lusitropic
Attenuation of cardiac remodeling
(LVH) and fibrosis
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 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
Decrease in SNS outflow
Decrease in BP
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
Tiredness
Shortness of breath
• Main symptoms
• Breathlessness
• Orthopnea
Coughing
Pumping action
of the heart
grows weaker
Fluid retention
• Paroxysmal Nocturnal Dyspnea
• Reduced exercise tolerance
• Fatigue
Pleural effusion
• Ankle swelling
• Main signs
• Elevated jugular venous pressure
Swelling of feet,
ankles, abdomen
and lower back
area
• Hepato-jugular reflux
• Third heart sound
• Laterally displaced apical impulse
• Cardiac murmur
Pulmonary edema
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
Patients (%)
80
60
40
20
0
Goldberg et al. Clin Cardiol 2010;33:e73–80
Symptomatic severity of heart failure
Clinical manifestations
New York Heart Association functional classification
based on severity of symptoms and physical activity
Class I
Class II
No limitation of physical activity. Ordinary
physical activity does not cause undue
breathlessness, fatigue, or palpitations.
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
• 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
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
Survival probability
according to NYHA class
NYHA II
0.9
NYHA III
0.8
NYHA IV
0.7
P<0.001
0.6
0
3
6
9
Time (months)
NYHA: New York Heart Association
Muntwyler et al. Eur Heart J 2002;23:1861–6
12
15
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