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New paradigm of Heart Failure

Patophysiology and Diagnosis

Hasanah Mumpuni
KSM Jantung /Departemen Kardiologi dan Kedokteran Vaskular
RSUP Dr. Sardjito / FK-KMK UGM
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Gagal
Leukemia
jantung

2
HF is deadlier than many cancers

5-YEAR DEATH RATES 48%2

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 2016: HF is a clinical syndrome


characterized by typical symptoms
that may be accompanied by signs
caused by a structural and/or
functional cardiac abnormality, Left
resulting in a reduced cardiac output atrium

and/ or elevated intracardiac Right


atrium
pressures at rest or during stress1 Left
ventricle

ACCF/AHA 2013: HF is a complex Right


ventricle
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 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
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HFrEF and HFpEF
Heart failure definition

Systolic dysfunction Diastolic dysfunction

HFrEF HFmr EF HFpEF


LVEF≤ 40% LVEF 40-49% LVEF ≥ 50%

Echocardiography is a useful method for evaluating left ventricular ejection fraction

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

These changes lead to systemic neurohormonal


imbalance

This may lead to fibrosis, apoptosis, hypertension,


hypertrophy, cellular and molecular alterations, myotoxicity

Remodeling and Hemodynamic


progressive worsening of alterations, salt and water
LV function retention

Morbidity and mortality HF symptoms


arrhythmias, pump failure 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
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

Normal LV structure Subclinical


and function LV remodeling LV dysfunction Clinical HF
Years Years/months

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;362:147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 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

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 Release of NPs in


response to cardiac
Short-term effects are beneficial in early HF1 stress2
Long-term activation exerts unfavourable effects1,3
Opposes the actions of
the RAAS2 and SNS4,5

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

Floras, JACC, 2009, 34: 375-85.


Ach=acetylcholine; AngII= angiotensin II; CV=cardiovascular; E=epinephrine; Lymperopoulos et al. Circ Res 2013;113:739–53.
HF=heart failure; NE=norepinephrine; SNS=sympathetic nervous system
RAAS: Initially compensatory and
subsequently pathological in HF
Angiotensinoge
n Renin
Ang I
ACE
Ang II

AT1 receptor

Signalling
cascade
Biological
actions

Hypertrophy Vasoconstriction Aldosterone Na+/H2O ADH Norepinephrine release


Fibrosis hypertrophy secretion retention Secretion Sympathetic tone

Cardiac remodeling Blood Blood volume Heart rate


Myocyte necrosis Pressure Contractility

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

Cardiac structure/function abnormality


Activation of compensatory mechanisms to
maintain cardiac output and organ perfusion1

SNS RAAS NP system

β blocker RAAS blocker


bisoprolol, carvedilol, ACEi : captopril, Lisinopril
nebifolol ARB : valsartan, candesartan
MRA : spironolactone

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
Mortality Remain High Despite
of The Standard HFREF Management
 Survival rates in chronic HF have improved with the pharmacological therapies1

ACEI* β-blocker* MRA* ARB*


Reduction in relative risk of
mortality vs placebo

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%

ACEI=angiotensin-converting-enzyme inhibitor; ARB=angiotensin receptor


 1. McMurray et al. Eur Heart J 2012;33:1787–847; 2. SOLVD Investigators. N Engl J Med
blocker; HF=heart failure; ARR=absolute risk reduction; HFrEF=heart failure with
1991;325:293–302; 3. CIBIS-II Investigators. Lancet 1999;353:9–13; 4. Pitt et al. N Engl J Med
reduced ejection fraction; LVEF=left ventricular ejection fraction;
1999;341:709-17; 5. Granger et al. Lancet 2003;362:772–66. 6. Yancy et al. Circulation 2013;128:e240–
MRA=mineralocorticoid receptor antagonist 327; 7. Levy et al. N Engl J Med 2002;347:1397–402
Pharmacological Treatment was Developed
to Counter 2 Core Pathophysiology Pathway

Cardiac structure/function abnormality

Activation of compensatory mechanisms to maintain


cardiac output and organ perfusion1

SNS RAAS NP system

β blocker RAAS blocker


What can we
ACEi : captopril, Lisinopril
bisoprolol, carvedilol, nebifolol ARB : valsartan, candesartan do?
MRA : spironolactone
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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
Discovery of Nps: Factors Involved in Homeostatic
Balance of Electrolyte and Body Fluid1,2

ANP BNP CNP


H2N
H2N H2N

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:

Vasodilation3–5 Sympathetic outflow3 Fibroblast proliferation5–7


Diuresis3 Vasopressin3 Hypertrophy3,8–10
Aldosterone3 Systemic vascular resistance5,3 Arterial stiffness5
Renin3 Pulmonary artery pressure5 Right atrial pressure11

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

Relaxation;  arterial stiffness4

 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;57:1418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
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

Inactive LBQ657 Ang II


(NEP inhibitor) Valsartan
fragments
O O
AT1 receptor
Enhancing N OH

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

Physical mixture of individual agents or


Sacubitril valsartan – salt complex1 their salts2
Formed from a chemical reaction No chemical reaction involved
One melting point (138°C) Melting point range
Can deliver sacubitril and valsartan Physical mixtures of two agents are prepared by
only in a 1:1 molar ratio individually weighing each component – there is
variation in the ratio of the two agents from batch
to batch (i.e. not always 1:1)

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

Breathlessness Pumping action Coughing


Orthopnea of the heart
grows weaker Fluid retention
Paroxysmal Nocturnal Dyspnea
Reduced exercise tolerance
Fatigue Pleural effusion
Ankle swelling

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

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 Clear relationship between
breathlessness, fatigue, or palpitations. severity of symptoms and
survival
Class II Slight limitation of physical activity.
Poor relationship between
Comfortable at rest, but ordinary physical
activity results in undue breathlessness,
severity of symptoms and
fatigue, or palpitations. ventricular function
Patients with mild symptoms
Class III Marked limitation of physical activity. may still have a relatively high
Comfortable at rest, but less than
absolute risk of hospitalization
ordinary physical activity results in undue
breathlessness, fatigue, or palpitations. and death

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. 27

McMurray et al. Eur Heart J 2012;33:1787–847


Summary
 HF has a complex pathophysiology involving activation of three
neurohormonal systems:
 Renin–angiotensin–aldosterone system
 Sympathetic nervous system
 Natriuretic peptide
 Natriuretic peptides counteract the detrimental effects of RAAS and SNS
activation.
 Although beta blocker and RAAS blocker has been widely used, HFrEF
treatment outcome is still poor, 50% of HF patient died in 5 years.
 Natriuretic peptide enhancement has been the approach of novel
therapeutic approach:
 Neprilysin inhibition alone failed to show benefit
 Combination with ACEi induce major adverse event
 ARNI (angiotensin receptor neprilysin inhibitor) is the first NP system agent
that shows significant benefit in HF treatment
 Sakubitril Valsartan (LCZ696) is the first ARNI and the first salt complex that
shows two action both in NP system enhancement and RAAS inhibition
 Clinical history, physical examination, ECG, and echocardiography is still the
28
fundamental tools for diagnosing HF