Beruflich Dokumente
Kultur Dokumente
Hasanah Mumpuni
KSM Jantung /Departemen Kardiologi dan Kedokteran Vaskular
RSUP Dr. Sardjito / FK-KMK UGM
Manakah yang paling berbahaya?
Gagal
Leukemia
jantung
2
HF is deadlier than many cancers
50
40%1
34%1
40
29%1
Percentage
30
14%1
20 10%1
10
0
Breast cancer Hodgkin's Non-Hodgkin's Colon and Leukemia Heart failure
lymphoma lymphoma rectum cancer
1. National Cancer Institute. Cancer stat fact sheets. Available at: http://seer.cancer.gov/statfacts. Accessed 31 May 2016;
2. Roger et al. JAMA 2004;292:344–50
Heart Failure Definition
ESC: European Society of Cardiology; AHA: American Heart Association; ACCF: American College of Cardiology Foundation
1. Ponikowski et al. Eur Heart J 2016; 37(27): 2129-2200; 2. Yancy et al. JACC 2013;62:e147–239
4
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
5
HFrEF and HFpEF
Heart failure definition
HFpEF: heart failure with preserved ejection fraction, HFmEF : heart failure with mid-range ejection frection
Ponikowski et al. Eur Heart J 2016; 37(27): 2129-2200; McMurray et al. Eur Heart J 2012;33:1787–847;
Dickstein et al. Eur Heart J 2008;29:2388–442
6
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
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
7
Most common causes of Heart Failure
Etiology
Coronary heart disease Congenital heart disease
Hypertension Pericardial disease
Valvular disease Hyperkinetic states
Cardiomyopathy :
Anemia
Idiopathic
Arterio-venous fistula
cardiomyopathy
Alcoholic cardiomyopathy Beriberi
Toxin-related
cardiomyopathy e.g.
adriamycin
Post-partum
cardiomyopathy
Hypertrophic obstructive
cardiomyopathy
Tachyarrhythmia-induced
cardiomyopathy
Infiltrative disorders
(e.g. amyloidosis)
8 *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
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 MI Systolic
Hypertension dysfunction
Coronary artery HFrEF
disease Diastolic HFpEF
Diabetes LV
dysfunction
Dyslipidemia hypertrophy
9
‡ 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;362:14758;
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
Left ventricle
normal
HFrEF HFpEF
HFrEF – a condition of Volume Pressure HFpEF – a condition of
volume overload overload overload pressure overload
• characterized by Increased Increased • characterized by
eccentric hypertrophy diastolic pressure systolic pressure concentric hypertrophic
• results in thinning of Increased Increased growth
diastolic wall stress systolic wall stress
the LV walls, • results in normal sized
−
decreased systolic Series addition of new Parallel addition LV cavity with
function and enlarged sarcomeres of new myofibrils − thickened walls and
LV volume Chamber Wall preserved systolic
enlargement thickening function
Eccentric Concentric
hypertrophy hypertrophy
Left ventricle Left ventricle
volume pressure
overload overload
10
entricular; HFpEF=heart failure with preserved ejection fraction; HFrEF=heart failure with reduced ejection fraction
from Colucci (Ed.). Atlas of Heart Failure, 5th ed. Springer 2008;
produced with permission from Grossman W, et al. In: Perspectives in Cardiovascular Research; Myocardial Hypertrophy
ure. 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
11
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
Sympathetic (or adrenergic) nervous system:
Role in pathophysiology of HF
HF is characterized by heightened
sympathetic tone
Imbalances in baroreceptor reflexes
and AngII- dependent SNS activation
play an important role in adverse
haemodynamic and cardiac responses
Stimulation of SNS in HF results in
Heart rate
Contractility
Na reabsorption
Renal and peripheral vascular
resistance
AT1 receptor
Signalling
cascade
Biological
actions
ACE=angiotensin-converting enzyme; ACEI=angiotensin-converting-enzyme inhibitor; Zaman et al. Nat Rev Drug Discov 2002;1:621–36; Schrier and Abraham.
ADH=antidiuretic hormone; ARB=angiotensin receptor blocker; N Engl J Med 1999;341:577–85; Brewster et al. Am J Med Sci
MRA=mineralocorticoid receptor antagonist; RAAS=renin-angiotensin-aldosterone 2003;326:15–24; Schmieder. Am J Hypertens 2005;18:720–30;
McMurray et al. Eur Heart J 2012;33:1787–847 Francis et al. Ann Intern
system Med 1984;101:370–7;
Pharmacological Treatment was Developed to
Counter 2 Core Pathophysiology Pathway
16% 17%
(4.5% ARR; (3.0% ARR;
mean follow up median follow up
of 41.4 months)
30% of 33.7 months)
SOLVD1,2 34% (11.0% ARR; CHARM-
(5.5% ARR; mean mean follow up
follow up of 24 months) Alternative
5
of 1.3 years) RALES4
CIBIS-II3
However, significant mortality remains – ~50% of patients die within 5 years of diagnosis6–7
*On top of standard therapy at the time of study (except in CHARM-Alternative where background ACEI therapy was excluded). Patient populations varied between trials and as such relative risk
reductions cannot be directly compared. SOLVD (Studies of Left Ventricular Dysfunction), CIBIS-II (Cardiac Insufficiency Bisoprolol Study II) and RALES (Randomized Aldactone Evaluation Study) enrolled
chronic HF patients with LVEF≤35%. CHARM-Alternative (Candesartan in Heart failure: Assessment of Reduction in Mortality 15and Morbidity) enrolled chronic HF patients with LVEF≤40%
199014
19811
19882
HOOC- HOOC-
HOOC-
Discovered in the porcine brain,2 and
Discovered in the central nervous system14
Discovered in rat atria1 subsequently found to be expressed in
and also expressed in vascular endothelial
atrial and ventricular tissue3,12
cells12
In addition to natriuretic effects,3 natriuretic peptides have other potential actions in HF:
Release of NPs is thought to be a compensatory physiological mechanism that opposes the effects of the RAAS and SNS in patients with HF5
Scientists hypothesized that HF is an ‘NP-deficient’ state,12 although subsequent efforts to increase NP levels via exogenous application were unsuccessful13
ANP=atrial natriuretic peptide; 1. de Bold et al. Life Sci 1981;28:89–94; 2. Maekawa et al. Bioch Biophys Res Commum1988;157:410–16; 3. Levin et al. N Engl J Med 1998;339;321–8; 4. Lumsden
BNP=B-type natriuretic peptide; et al. Curr Pharm Des 2010;16:4080–8; 5. Langenickel and Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9; 6. D'Souza et al. Pharmacol Ther 2004;101:113–
CNP=C-type natriuretic peptide; 29; 7. Cao and Gardner. Hypertension 1995;25:227–34; 8. Gardner et al. Hypertension 2007;49:419–26; 9. Tokudome et al. Circulation 2008;117;2329–39; 10.
HF=heart failure; NP=natriuretic Horio et al. Hypertension 2000;35:19–24; 11. Marcus et al., Circulation 1996; 94: 3184-89. 12. Mangiafico et al. Eur Heart J. 2013;34:886–93c; 13. O’Connor et al. N
peptide; RAAS=renin-angiotensin- Engl J Med 2011;365:32–43; 14. Sudoh et al. Biochem Biophys Res Commun 1990;168:863–70
Natriuretic Peptides have Potential Beneficial
Actions in HF
Release of ANP and BNP from heart and CNP in vasculature1,2
Sympathetic outflow2
Vasopressin2
ANP/BNP2
Salt appetite and water intake2
CNP
(endothelium)3
Hypertrophy2, 4
Fibroblast proliferation4,
Na+/H2O loss2 Vasodilation2,3,4
Aldosterone2 Systemic vascular resistance4
Renin2 Pulmonary artery pressure4
ANP=atrial natriuretic peptide; Pulmonary capillary wedge pressure4
BNP=B-type natriuretic peptide; Right atrial pressure5
CNP=C-type natriuretic peptide; HF=heart failure
1. Mangiafico et al. Eur Heart J 2013;34:886–93; 2. Levin et al. N Engl J Med 1998;339;321–8;
3. Lumsden et al. Curr Pharm Des 2010;16:4080–8; 4. Langenickel and Dole. Drug Discov
Today: 5. Marcus et al., Circulation 1996; 94: 3184-89.
Natriuretic Peptides Inhibit The Activity of The RAAS
and Counterbalance The Sympathetic Nervous System
ANP and BNP inhibit the RAAS ANP interacts with baroreflex control
via actions in the kidneys of the circulation to inhibit the
and the adrenal glands1 activity of the SNS2
ANP/BNP ANP
Modulation of
arterial and
cardiopulmonary
baroreceptors
Inhibition of renin Inhibition of
secretion aldosterone secretion Decrease in SNS outflow
Decrease in BP Decrease in BP
19
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
NP system counter balance the unfavourable prolonged
effect of SNS and RAS, but quickly degraded by Neprilysin
SNS
Epinephrine α1, β 1, β 2
Norepinephrine receptors
Vasoconstriction
RAAS activity
NP system HF SYMPTOMS
Vasopressin
& PROGRESSION Heart rate
NPRs NPs Contractility
Vasodilation
Blood pressure
Sympathetic tone RAAS
Natriuresis/diuresis
Vasopressin Inactive Ang II AT1R
Aldosterone fragments Vasoconstriction
Fibrosis Blood pressure
Hypertrophy Sympathetic tone
Aldosterone
Hypertrophy
Fibrosis
ANG=angiotensin; AT1R=angiotensin type 1 receptor; NP=natriuretic peptide; NPRs=natriuretic peptide receptors; Sodium and water retention
RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous system 20
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;57:141825; 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
Evolution of pharmacologic approaches in HF:
ARNI is a new agent in HFrEF treatment1
SNS
Epinephrine α1, β1, β2
Norepinephrine receptors
Vasoconstriction
RAAS activity
Vasopressin
NP system HF SYMPTOMS & Heart rate
PROGRESSION Contractility
NPRs NPs
Vasodilation
Blood pressure
Sympathetic tone RAAS
Natriuresis/diuresis
Vasopressin Ang II AT1R
Aldosterone INACTIVE
Fibrosis FRAGMENTS Vasoconstriction
Hypertrophy Blood pressure
Sympathetic tone
ARNI Aldosterone
Hypertrophy
Fibrosis
ARNI: enhancement of natriuretic and other vasoactive peptides, with simultaneous RAAS suppression
ACEI=angiotensin-converting enzyme inhibitor; Ang=angiotensin; ARB=angiotensin 1. McMurray et al. Eur J Heart Fail 2013;15:1062–73
receptor blocker; AT1R=angiotensin II type 1 receptor; HF=heart failure; HFrEF=heart failure with reduced Figure references: Levin et al. N Engl J Med 1998;339:321–8 Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42
ejection fraction; MRA=mineralocorticoid receptor antagonist; NP=natriuretic peptide; NPRs=natriuretic Kemp & Conte. Cardiovascular Pathology 2012;365–71
Schrier & Abraham. N Engl J Med 2009;341:577–85
peptide receptors; RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous system
ARNI (Sacubitril Valsartan) :
simultaneously inhibits neprilysin and blocks AT1 receptors
Sakubitril
Valsartan
ANP, BNP, CNP, other
vasoactive peptides*
RAAS
Angiotensinogen
(liver secretion)
Sacubitril
(AHU377; pro-drug)
Ang I
Vasorelaxation HN
O
Inhibiting
Blood pressure O
OH
N
N
Vasoconstriction
HO N NH
Sympathetic tone O Blood pressure
Aldosterone levels Sympathetic tone
Fibrosis Aldosterone
Hypertrophy Fibrosis
Natriuresis/diuresis Hypertrophy
Levin et al. N Engl J Med 1998;339:321–8
• *Neprilysin substrates listed in order of relative affinity for neprilysin: ANP, CNP, Ang II, Ang I,
Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42
adrenomedullin, substance P, bradykinin, endothelin-1, BNP Schrier & Abraham. N Engl J Med 2009;341:577–85
Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9
• Ang=angiotensin; ANP=atrial natriuretic peptide; AT1=angiotensin II type 1; BNP=B-type natriuretic Feng et al. Tetrahedron Letters 2012;53:275–6
peptide; CNP=C-type natriuretic peptide; NEP=neprilysin; RAAS=renin-angiotensin-aldosterone system
Sacubitril Valsartan is a Salt Complex, Not a Physical
Mixture of Individual Agents
Sacubitril valsartan is the first example of a dual-acting pharmaceutical built as a
supramolecular complex delivering two pharmacologic effects—angiotensin receptor 1
(AT1) blockage and neprilysin (NEP) inhibition
1. Feng et al. Tetrahedron Lett 2012;53:275–6; 2. Jayasheel. Perspect Clin Resm 2010;1:120–3
Symptoms and Signs
Clinical manifestations
Tiredness
Main symptoms: Shortness of breath
Main signs :
Elevated jugular venous pressure
Hepato-jugular reflux
Third heart sound Swelling of feet,
ankles, abdomen
Laterally displaced apical impulse and lower back
Cardiac murmur area
24
Pulmonary edema
Ponikowski et al. Eur Heart J 2016; 37(27): 2129-2200 McMurray et al. Eur Heart J 2012;33:1787–847
Diagnosis Algoritm
ESC 2016 guideline
25
Diagnosis Algoritm
ESC 2016 guideline
26
Symptomatic Severity of Heart Failure
Clinical manifestations