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1
Rôle de la néprilysine et du SRAA
dans l’insuffisance cardiaque
Chérif Abdelkhirane, MD, PhD
Cardiologie Maarif – Clinique Maarif
Casablanca
Amcar, Agadir, 20 mai 2016
2
L’insuffisance cardiaque
Anormalies structurelles et/ou fonctionnelles
Anomalies de la structure et de fonction du muscle cardiaque entrainant une inadéquation
de perfusion des organes1
Ces anomalies du myocarde aboutissent à une défaillance de la fonction pompe avec une
souffrance par insuffisance de perfusion2
HF=heart failure
1. McMurray et al. Eur Heart J 2012;33:1787–847
2. Harrison’s ‘Principles of Internal Medicine’, Seventeenth Edition p1442–55
Images from: Wilde and Behr. Nat Rev Cardiol 2013;10:571–83
Normal heart HF
Weakened heart muscle
3
L’insuffisance cardiaque
Une condition chronique parsemée d’épisodes aigus
HF=heart failure
1. Ahmed et al. Am Heart J 2006;151:444–50; 2. Gheorghiade et al. Am J Cardiol 2005;96:11G–17G
3. Gheorghiade, Pang. J Am Coll Cardiol 2009;53:557–73; 4. Holland et al. J Card Fail 2010;16:150–6
5. Muntwyler et al. Eur Heart J 2002;23:1861–6
Déclin chronique
Fonction
cardiaque
et
qualité de vie
Progression de la maladie
Hospitalisations pour
décompensation aiguë
Adapted from Gheorghiade et al. 20052
L’augmentation de la fréquence des évenements aigus avec progression de la maladie
entraîne la multiplication des hospitalisations et l’augmentation du risque de mortalité.1–5
4
Characteristic
HF with preserved ejection fraction
(HFpEF)1–4
HF with reduced ejection
fraction (HFrEF)1–4
Dysfunction Diastolic Systolic-diastolic
LVEF >40–50% ≤35–40%
LV remodeling Concentric Eccentric
• Normal end-diastolic volume
• ↑ wall thickness and mass
• High ratio of mass:volume
• ↑ end-diastolic volume
• ↓ wall thickness
• Low ratio of mass:volume
Prognostic improvement with
current HF therapy
No Yes, but morbidity and mortality
remain high
L’insuffisance cardiaque chronique peut être classée avec
une FE réduite ou préservée
1. Aurigemma. Circulation 2006;113;296–304
2. Paulus et al. Eur Heart J 2007;28:2539–50
3. Colucci (Ed.). Atlas of Heart Failure, 5th ed. Springer 2008
4. McMurray et al. Eur Heart J 2012;33:1787–847
HF=heart failure; LV=left ventricular;
LVEF=left ventricular ejection fraction
5
Un peu d’histoire…....
Effets des drogues IV sur les performances
VG, in Basics of HF, Jaski, KAP, 2000
L’approche hémodynamique : la courbe Pression-Volume
Effets des drogues IV sur les performances
VG, in Basics of HF, Jaski, KAP, 2000
L’approche hémodynamique : les drogues actives
Les résultats de l’approche hémodynamique :
Mortalité sous inotropes
Inotropes positifs Majoration de la mortalité vs placebo
136%
51%
28%
1.Dies, Circulation, 1998
2.Packer, Profile, Circulation, 1993
3.Packer,Promise, NEJM, 1991
Collins Berry, EHJ, 2000
L’approche moléculaire et hormonale
Physiopathologie : le double orage
Activation
SRAA
Activation
sympathique
Progression
de l’IC
Mort subite
et TdR
IC
Application clinique du concept
SRAA S
Catabolisme
Mortalité
IC
b1,b2
a1
ECA
AT1
AT2
12
Evolution du traitement
de l’insuffisance cardiaque
13
La sur-activation du SRAA et du SNS est cruciale dans l’IC
et met en exergue la base du traitement
See notes for abbreviation definitions
1. McMurray et al. Eur Heart J 2012;33:1787–847
Figure references: Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert.
Pharmacotherapy 2002;22:27–42 Kemp & Conte. Cardiovascular Pathology 2012;365–71
Schrier & Abraham. N Engl J Med 1999;341:577–85
SNS
RAAS
Vasoconstriction Blood pressure
Sympathetic tone Aldosterone Hypertrophy
Fibrosis
Ang II AT1R
HFrEF
SYMPTOMS &
PROGRESSION
Epinephrine
Norepinephrine α1, β1, β2
receptors
Vasoconstriction RAAS activity
Vasopressin Heart rate
Contractility
RAAS inhibitors
(ACEI, ARB, MRA)
β-blockers
Natriuretic peptide
system
Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy
NPRs NPs
The crucial importance of the RAAS is supported by the beneficial effects of ACEIs, ARBs and MRAs1
Benefits of β-blockers indicate that the SNS also plays a key role1
14
La sur-activation du SRAA et du SNS est cruciale dans l’IC
et met en exergue la base du traitement
See notes for abbreviation definitions
1. McMurray et al. Eur Heart J 2012;33:1787–847
Figure references: Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert.
Pharmacotherapy 2002;22:27–42 Kemp & Conte. Cardiovascular Pathology 2012;365–71
Schrier & Abraham. N Engl J Med 1999;341:577–85
SNS
RAAS
Vasoconstriction Blood pressure
Sympathetic tone Aldosterone Hypertrophy
Fibrosis
Ang II AT1R
HFrEF
SYMPTOMS &
PROGRESSION
Epinephrine
Norepinephrine α1, β1, β2
receptors
Vasoconstriction RAAS activity
Vasopressin Heart rate
Contractility
RAAS inhibitors
(ACEI, ARB, MRA)
β-blockers
Natriuretic peptide
system
Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy
NPRs NPs
The crucial importance of the RAAS is supported by the beneficial effects of ACEIs, ARBs and MRAs1
Benefits of β-blockers indicate that the SNS also plays a key role1
15
Essais repères chez les patients en IC à FE altérée
Percentages are relative risk reductions vs comparator
ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker;
ARNI=angiotensin receptor neprilysin inhibitor; BB=beta blocker; CV=cardiovascular;
HF=heart failure; HFrEF=heart failure with reduced ejection fraction;
MRA=mineralocorticoid receptor antagonist. See notes for definitions of study names
1. SOLVD Investigators. N Engl J Med 1991;325:293–302
2. CIBIS-II Investigators. Lancet 1999;353:9–13; 3. Granger et al. Lancet 2003;362:772−6
4. McMurray et al. Lancet 2003;362:767–771; 5. Swedberg et al. Lancet 2010;376:875–85
6. Zannad et al. N Engl J Med 2011;364:11–21; 7. McMurray et al. N Engl J Med 2014;371:993–1004
CIBIS-II2 (1999) 2,647 patients
Key benefits of bisoprolol (BB)
vs placebo:
• 34% all-cause mortality
EMPHASIS-HF6 (2011) 2,737 patients
Key benefits of eplerenone
(MRA) vs placebo:
• 37% CV mortality or HF
hospitalization
SHIFT5 (2010) 6,558 patients
Key benefits of ivabradine
(If inhibitor) vs placebo:
• 18% CV death or HF
hospitalization
PARADIGM-HF7 (2014) 8,442 patients
Key benefits of LCZ696
(ARNI) vs enalapril:
• 20% CV mortality or
HF hospitalization
SOLVD-T1 (1991) 2,569 patients
Key benefits of enalapril (ACEI)
vs placebo:
• 16% all-cause mortality
CHARM-Alternative3 (2003) 2,028 patients
Key benefits of candesartan
(ARB) vs placebo:
• 23% CV mortality or HF
hospitalization
CHARM-Added4 (2003) 2,548 patients
Key benefits of
candesartan (ARB) vs
placebo:
• 15% CV mortality or HF
hospitalization
1990s 2000s 2010s
16
La mortalité demeure élevée malgré l’introduction des
nouvelles thérapies améliorant la survie
ACEI=angiotensin-converting-enzyme inhibitor; ARB=angiotensin receptor blocker;
HF=heart failure; ARR=absolute risk reduction; HFrEF=heart failure with reduced
ejection fraction; LVEF=left ventricular ejection fraction;
MRA=mineralocorticoid receptor antagonist
1. McMurray et al. Eur Heart J 2012;33:1787–847; 2. SOLVD Investigators. N Engl J Med
1991;325:293–302; 3. CIBIS-II Investigators. Lancet 1999;353:9–13; 4. Pitt et al. N Engl J Med
1999;341:709-17; 5. Granger et al. Lancet 2003;362:772–66. 6. Go et al. Circulation 2014;129:e28-e292;
7. Yancy et al. Circulation 2013;128:e240–327; 8. Levy et al. N Engl J Med 2002;347:1397–402
Survival rates in chronic HF have improved with the introduction of new therapies1
*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 and Morbidity)
enrolled chronic HF patients with LVEF≤40%
However, significant mortality remains – ~50% of patients die within 5 years of diagnosis6–8
16% (4.5% ARR;
mean follow up
of 41.4 months)
SOLVD1,2
34% (5.5% ARR;
mean follow up
of 1.3 years)
CIBIS-II3
Red
uctio
n in r
ela
tive
ris
k o
f
mo
rtalit
y v
s p
lace
bo
30% (11.0% ARR;
mean follow up
of 24 months)
RALES4
17% (3.0% ARR;
median follow up
of 33.7 months)
CHARM-
Alternative5
ACEI* β-blocker* MRA* ARB*
17
LCZ696: enhancement of natriuretic and other vasoactive peptides, with simultaneous RAAS suppression
Evolution des approches pharmacologiques dans
l’insuffisance cardiaque: LCZ696 : une nouvelle alternative dans l’IC à FE basse
ACEI=angiotensin-converting enzyme inhibitor; Ang=angiotensin; ARB=angiotensin
receptor blocker; AT1R=angiotensin II type 1 receptor; HF=heart failure; HFrEF=heart
failure with reduced ejection fraction; MRA=mineralocorticoid receptor antagonist;
NP=natriuretic peptide; NPRs=natriuretic peptide receptors; RAAS=renin-angiotensin-
aldosterone system; SNS=sympathetic nervous system
1. McMurray et al. Eur J Heart Fail 2013;15:1062–73
Figure references: Levin et al. N Engl J Med 1998;339:321–8 Nathisuwan & Talbert.
Pharmacotherapy 2002;22:27–42
Kemp & Conte. Cardiovascular Pathology 2012;365–71
Schrier & Abraham. N Engl J Med 2009;341:577–85
SNS
RAAS
Vasoconstriction Blood pressure
Sympathetic tone Aldosterone Hypertrophy
Fibrosis
Ang II AT1R
HF SYMPTOMS &
PROGRESSION
INACTIVE
FRAGMENTS
NP system
Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy
NPRs NPs
Epinephrine
Norepinephrine α1, β1, β2
receptors
Vasoconstriction RAAS activity
Vasopressin Heart rate
Contractility
Neprilysin
inhibitors
RAAS inhibitors
(ACEI, ARB, MRA)
β-blockers
LCZ696
18
Inhibiteur de
la néprilysine
seul
Omapatrilat
(Inhibiteur de
la néprilysine et
IEC)
LCZ696
(Inhibiteur de
la néprilysine et
AT1 bloqueur)
Omapatrilat developed to both inhibit neprilysin and suppress the RAAS,
via ACE inhibition4,5
Demonstrated a trend towards reduced morbidity and mortality in HFrEF5
Development was halted due to increased frequency of angioedema1,5
LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI)
Alternative approach to simultaneously suppressing the RAAS via AT1
receptor blockade and enhancing NP system1,6
PARADIGM-HF is the first study to test the effect of LCZ696 on morbidity
and mortality in patients with HFrEF1,7
Augmentation des NPs comme stratégie thérapeutique
dans l’IC et l’émergence du LCZ696
ACE=angiotensin-converting enzyme; ARNI=angiotensin receptor neprilysin inhibitor;
AT1=angiotensin II type 1; HF=heart failure; HFrEF=heart failure with reduced ejection
fraction; NP=natriuretic peptide; PARADIGM-HF=Prospective comparison of ARNI with
ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure;
RAAS=renin-angiotensin-aldosterone system
1. McMurray et al. Eur J Heart Fail. 2013;15:1062–73;
2. Northridge et al. Am Heart J. 1999;138:114957
3. Eberlin et al. Front Pharmacol. 2013;3:93; 4. Rouleau et al. Lancet 2000;356:615–20
5. Packer et al. Circulation 2002;106:920–6; 6. Gu et al. J Clin Pharmacol 2010;50:401–14
7. McMurray et al. Eur J Heart Fail. 2014;16:817–25
Tested enhancing the effects of NPs by reducing their breakdown through
neprilysin inhibition1
• e.g. candoxatril2, thiorphan3
Ultimately not developed for clinical use in HF1
19
ACE=angiotensin-converting enzyme; ACEI=angiotensin-converting enzyme inhibitor; Ang=angiotensin;
ANP=atrial natriuretic peptide; ARNI=angiotensin receptor neprilysin inhibitor; AT1R=angiotensin II type 1
receptor; HF=heart failure; HFpEF=heart failure with preserved ejection fraction; HFrEF=heart failure with
reduced ejection fraction; NEP=neprilysin; NEPi=neprilysin inhibition; NP=natriuretic peptide; NT-
proBNP=N-terminal pro-B-type natriuretic peptide; PARADIGM-HF=Prospective comparison of ARNI with
ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure; PARAMOUNT=Prospective
comparison of ARNI with ARB on Management of heart failure with preserved ejection fraction
1. de Bold et al. Life Sci 1981;28:89–94;
2. Sonnenberg et al. Peptides 1988;9:173–80;
3. Von Lueder et al. Pharmacol Ther 2014;144:41–9; 4. Packer et al.
Circulation 2002;106:920–6; 5. McMurray et al. Eur J Heart Fail 2013;15:1062–73;
6. Solomon et al. Lancet 2012;380:1387–95;
7. McMurray et al. N Engl J Med 2014;371:993–1004
2010 2011 2012 2013 2014 2015 2009
1981 Discovery
of ANP1
1980s
1988 NEP identified as
the primary
enzyme
responsible for
degrading ANP2
1990s
1990s NEPi
NEP inhibition alone fails to
demonstrate efficacy in patients
with chronic HF, mainly due to
the ‘promiscuity’ of NEP
towards other substrates such
as Ang II3
2009 LCZ696 (ARNI)
Phase III PARADIGM-HF
(HFrEF) and
Phase II PARAMOUNT
(HFpEF) studies
initiated5,6
2000s
2002 Omapatrilat (NEPi+ACEI)
Combined NEP and ACE inhibition
with omapatrilat indicates trends
towards efficacy in chronic HF, but
raises significant safety
concerns3,4
2010s
2012 LCZ696 (ARNI)
PARAMOUNT study
NEP inhibition and AT1R blockade
with LCZ696 significantly reduced
NT-proBNP levels compared with
valsartan in patients with HFpEF6
2014 LCZ696 (ARNI)
PARADIGM-HF study
LCZ696 was superior to
enalapril in reducing the
risks of death and HF
hospitalization in
patients with HFrEF7
LCZ696, le 1er agent démontrant un bénéfice clinique significatif par
implication du système des NP dans l’IC.
20
Dosages des BNP et NT-proBNP est utile dans le
diagnostic de l’IC à FE altérée (HFrEF)
BNP=B-type natriuretic peptide; ECG=electrocardiograph;
HF=heart failure; HFrEF=heart failure with reduced ejection fraction;
NT-proBNP=N-terminal pro-B-type natriuretic peptide
Dickstein et al. Eur Heart J 2008;29:2388–442
Melanson, Lewandrowski. Am J Clin PathoI 2005;124:S122–8
Clinical examination, ECG,
chest X-ray, echocardiography
Chronic HF unlikely Chronic HF likely Uncertain diagnosis
Natriuretic peptides
BNP >400 pg/mL
NT-proBNP >2,000 pg/mL
BNP 100–400 pg/mL
NT-proBNP 400–2,000 pg/mL
BNP <100 pg/mL
NT-proBNP <400 pg/mL
Clinical usefulness of BNP and NT-proBNP testing in patients with chronic HF:
• diagnosis of chronic HF in patients with dyspnea
• prognosis and risk stratification
• screening for chronic HF in high-risk populations
• monitoring and guiding treatment
• treatment with recombinant BNP
21
Les guidelines recommandent plusieurs thérapies pour les
patients insuffsants cardiaques à FE basse (HFrEF)
*Patients in NYHA classes II, III or IV have mild, moderate or severe symptoms of HF,
respectively. ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin-receptor blocker;
HF=heart failure; LVEF=left ventricular ejection fraction; NYHA=New York Heart Association;
RAAS=renin-angiotensin-aldosterone system McMurray et al. Eur Heart J 2012;33:1787–847
Therapy Recommendation
IEC FEVG ≤40% pour réduire le risque de mortalité et les hospitalisation pour IC (sauf
si intolérance)
β-bloqueurs FEVG ≤40% pour réduire le risque de mortalité et les hospitalisation pour IC
Anti-Aldosterone
Si persistence des symptômes (NYHA class II–IV*) et FE ≤35%, malgré un
traitement avec un IEC (ou un ARA2 en cas d’intolérance) et un β-bloqueur, pour
réduire le risque de mortalité et d’hospitalisation
ARA2
FE ≤40% avec intolérance des IEC pour réduire le risque de mortalité et des
hospitalisations
Si persistence des symptômes (NYHA class II–IV*) et FE ≤35%, malgré un
traitement avec un IEC et un β-bloqueur, avec intolérance des anti-aldostérones
Diurétiques A la demande pour soulager les sympôomes decongestion (aucun bénéfice
démontré sur la mortalité et les hospitalisation)
La majorité des patients aqvec IC chronique devraient systématiquement
être géré avec l’association d’un bloqueur du SRAA, d’un β-bloqueur et
d’un diurétique
22
LCZ696, mécanisme d’action:
Physiopathologie de l’insuffisance cardiaque
23
Morbidity and mortality:
arrhythmias, pump failure
HF symptoms:
dyspnea, edema, fatigue
La physiopathologie de l’IC à FE basse
HF=heart failure; HFrEF=heart failure with reduced ejection fraction;
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
Maladaptive remodeling and
progressive worsening
of LV function
Hemodynamic alterations,
salt and water retention
Systemic neurohormonal overactivation
Damage to cardiac myocytes and extracellular matrix leads to
changes in the size, shape and function of the
heart and cardiac wall stress
Vasoconstriction, fibrosis, apoptosis, hypertrophy,
cellular and molecular alterations, myotoxicity
L’inhibition de la néprilysine potentialise les actions des peptides endogènes vasoactifs qui limitent
les mécanismes maladapatatifs de l’IC
Peptides endogènes vasoactifs
(peptides natriurétiques, adrenomedulline,
bradykinin, substance P,
calcitonin gene-related peptide)
Métabolites Inactifs
Activation neurohormonale
Tonus vasculaire
Fibrose cardiac., hypertrophie
Retention sodée
Néprilysine Inhibition
Néprilysine
Stress ou lésion myocardique ou
vasculaire
Evolution et progression de l’IC
Mécanismes de la progression dans l’IC
Activité exagérée ou réponse maldadaptée
Activité réduite ou réponse maldadaptée
Mécanismes de la progression dans l’IC
Bloqueurs du SRA Inhibition de la
néprilysine
Stress ou lésion myocardique ou
vasculaire
Activité exagérée ou réponse maldadaptée
Activité réduite ou réponse maldadaptée
Evolution et progression de l’IC
27
Le déclin de la fonction contractile entraîne l’activation des
3 systèmes neurohormonaux majeurs
Ang=angiotensin; AT1R=angiotensin II type 1 receptor;
HF=heart failure; NPs=natriuretic peptides; NPRs=natriuretic peptide receptors;
RAAS=renin-angiotensin-aldosterone system
Levin et al. N Engl J Med 1998;339:321–8
Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42
Kemp & Conte. Cardiovascular Pathology 2012;365–71
Schrier & Abraham. N Engl J Med 2009;341:577–85
Sympathetic
nervous system
Renin-angiotensin-
aldosterone system
Vasoconstriction Blood pressure
Sympathetic tone Aldosterone Hypertrophy
Fibrosis
Ang II AT1R
SYMPTOMeS &
PROGRESSION
Natriuretic peptide
system
Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy
NPRs NPs
Epinephrine
Norepinephrine α1, β1, β2
receptors
Vasoconstriction RAAS activity
Vasopressin Heart rate
Contractility
28
La sur-activation soutenue du SRAA a un effet délétère sur
l’IC
ACE=angiotensin-converting enzyme; ACEI=angiotensin-converting-enzyme
inhibitor; ARB=angiotensin receptor blocker; Ang=angiotensin;
HF=heart failure; MRA=mineralocorticoid receptor antagonist;
RAAS=renin-angiotensin-aldosterone system
Zaman et al. Nat Rev Drug Discov 2002;1:621–36
Schrier, Abraham. N Engl J Med 1999;341:577–85;
Brewster et al. Am J Med Sci 2003;326:15–24; Schmeider. Am J Hypertens 2005;18:
720–30; McMurray et al. Eur Heart J 2012;33:1787–847
Angiotensinogen
↑ Sympathetic tone
Renin
Vasopressin
Pituitary gland
Water absorption
Ang I Ang II
Vasoconstriction
Hypertrophy
Sodium and water retention
Aldosterone
ACE ↑ Blood volume
Adrenal gland
↑ Blood pressure
↑ Hypertrophy
↑ Fibrosis Cardiac remodeling
Myocyte necrosis
↑ Heart rate
↑ Contractility
↑ Blood volume
La dysfonction VG entraîne une activation du SRAA… …sur-activation soutenue engendre des
contraintes, créant un cercle vicieux
La suppression du SRAA est donc
une stratégie efficace dans l’IC
*Studies ongoing; not approved for treatment of HF
Direct renin inhibitors*
ACEIs ARBs MRAs
29
BNP est moins dégradé par la néprilysine que les ANP et
CNP
ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide;
CNP=C-type natriuretic peptide; HPLC=high performance liquid
chromatography . Further abbreviation definitions provided in the notes. Watanabe et al. Biochem Mol Med 1997;61:47–51
ANP and CNP are degraded by neprilysin with similar levels of enzymatic
efficiency
BNP is also degraded by neprilysin, but at a slower rate than ANP and CNP
Values calculated from the disappearance of substrate peak after HPLC. Time of incubation=60 minutes; substrate
concentration range=0.01–0.125 mM, respectively. Kcat calculated based on a molecular weight of 92,000
In vitro kinetics of natriuretic peptide hydrolysis by human neprilysin
Substrate
(human)
Km
(mM)
Vmax
(pmol/min)
Kcat
(min-1)
Kcat/Km
(min-1 mM-1)
ANP-28 28.3 38.5 145 5.12
BNP-32 102 43.2 54.3 0.532
CNP-22 12.4 66.1 97.4 7.85
30
t½ in circulation4 = ~120 mins t½ in circulation3 = ~3 mins t½ in circulation3 = ~20 mins t½ in circulation3 = ~2 mins
La néprilysine hydrolyse : ANP, BNP and CNP, mais
pas le NT-proBNP
ANP=atrial natriuretic peptide;
BNP=B-type natriuretic peptide;
CNP=C-type natriuretic peptide; NT-proBNP=N-
terminal pro-B-type natriuretic peptide; t1/2=half-life
1. Von Lueder et al. Circ Heart Fail 2013;6:594–605; 2. McKie & Burnett. Mayo Clin
Proc 2005;80:1029–36; 3. Potter. FEBS J 2011;278:1808–17; 4. Kim & Januzzi.
Circulation 2011;123:2015–19; 5. Langenickel & Dole. Drug Discovery Today: Ther
Strateg 2012;9:e131–9; 6. Levin et al. N Engl J Med 1998;339;321–8
Atrial natriuretic peptide
(ANP)1
H2N
HOOC-
Neprilysin does not
hydrolyze NT-proBNP5
NT-proBNP remains a
useful biomarker of
therapeutic effect and
prognosis during
neprilysin inhibition5
C-type natriuretic peptide
(CNP)1
HOOC-
H2N
B-type natriuretic peptide
(BNP)1
HOOC-
H2N
N-terminal-proBNP
(NT-proBNP)2
H2N -COOH His Pro Leu Gly Ser Pro Gly Ser Ala Ser Tyr Thr Leu Arg Ala Pro Arg
Neprilysin hydrolyzes ANP, BNP and CNP1,3
Neprilysin inhibition predominantly enhances the effects of ANP, BNP and CNP,1 leading to:
– Vasorelaxation5
– ↑ Diuresis/natriuresis5
– ↓ Proliferation6
– ↓ Hypertrophy5
– ↓ Aldosterone5
– ↓ Sympathetic tone5
– ↓ Cardiac preload5
– ↑ Venous capacitance5
31
Les Natriuretic peptides médient une large game d’effects
via leurs récepteurs
ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide;
cGMP=cyclic guanosine monophosphate; CNP=C-type
natriuretic peptide; GTP=guanosine triphosphate; NP=natriuretic
peptide; NPR=natriuretic peptide receptor
1. Mangiafico et al. Eur Heart J 2013;34:886–93; 2. Gardner et al.
Hypertension 2007;49:419–26; 3. Pandey. J Am Soc Hypertens
2008;2:210–26; 4. Levin et al. N Engl J Med 1998;339;321–8
5. Von Lueder et al. Pharmacol Ther 2014;144:41–9
NPR-A
GTP
ANP and BNP
NPR-C
Endocytosis
Inactivation
of NPs1,2,5
Receptor
recycling
Cardiomyocytes1
cGMP
• Vasodilation1,2
• Antihypertrophy1,2
• Antiproliferation2
• Vascular regeneration1
• Myocardial relaxation1
• Diuresis, natriuresis1,2
• Antiapoptosis1
• Anti-aldosterone1
• Renin secretion inhibition1,3
• Reduced sympathetic tone4
• Lipolysis1
NPR-B
CNP
Endothelial cells1
GTP
cGMP
• Vasodilation1,2
• Antihypertrophy1,2
• Antiproliferation2
• Vascular regeneration1
• Venodilation1
• Antifibrosis1
32
Les Natriuretic peptides sont éliminés via NPR-C et
dégradés par une protease: la néprilysine
ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide;
cGMP=cyclic guanosine monophosphate; CNP=C-type
natriuretic peptide; GTP=guanosine triphosphate; NP=natriuretic
peptide; NPR=natriuretic peptide receptor
1. Mangiafico et al. Eur Heart J 2013;34:886–93; 2. Gardner et al.
Hypertension 2007;49:419–26; 3. Pandey. J Am Soc Hypertens
2008;2:210–26; 4. Levin et al. N Engl J Med 1998;339;321–8
5. Von Lueder et al. Pharmacol Ther 20142014;144:41–9
NPR-A
GTP
ANP and BNP
NPR-C
Endocytosis
Inactivation
of NPs1,2,5
Receptor
recycling
Cardiomyocytes1
cGMP
• Vasodilation1,2
• Antihypertrophy1,2
• Antiproliferation2
• Vascular regeneration1
• Myocardial relaxation1
• Diuresis, natriuresis1,2
• Antiapoptosis1
• Anti-aldosterone1
• Renin secretion inhibition1,3
• Reduced sympathetic tone4
• Lipolysis1
NPR-B
Endothelial cells1
GTP cGMP
• Vasodilation1,2
• Antihypertrophy1,2
• Antiproliferation2
• Vascular regeneration1
• Venodilation1
• Antifibrosis1
ANP
BNP
CNP Inactive
cleavage
products CNP
NP dégradation & élimination
NP signalisation et effects
NEP
Neprilysin
33
ANP/BNP2
Relaxation; arterial stiffness4
CNP (endothelium)3
Les Natriuretic peptides possèdent un bénéfice potentiel
dans le traitement de l’IC
ANP=atrial natriuretic peptide;
BNP=B-type natriuretic peptide;
CNP=C-type natriuretic peptide;
HF=heart failure; H20=water; NA=sodium
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 & Dole. Drug Discovery Today: Ther Strateg 2012;9:e131–9; 5. Gardner
et al. Hypertension 2007;49:419–26; 6. Tokudome et al. Circulation 2008;117;2329–39; 7. Horio et al. Hypertension
2000;35:19–24; 8. D'Souza et al. Pharmacol Ther 2004;101:113–29; 9. Cao & Gardner. Hypertension 1995;25:227–34
Sympathetic outflow2
Vasopressin2
Salt appetite and water intake2
Na+/H2O loss2
Aldosterone2
Renin2
Hypertrophy2,5–7
Fibroblast proliferation4,8,9
Largage des ANP & BNP dans le myocarde et les CNP dans les vaisseaux1,2
Vasodilation2,3,4
Systemic vascular resistance4
Pulmonary artery pressure4
Pulmonary capillary wedge pressure4
Right atrial pressure4
34
Les études pré-cliniques indiquent que les natriuretic peptides médient des
effets antihypertrophiques et antifibrotiques effects au delà du contrôle de la
pression artérielle et le volume1
ANP=atrial natriuretic peptide;
BP=blood pressure; BNP=B-type natriuretic peptide;
CNP=C-type natriuretic peptide
1. Zois et al. Nat Rev Cardiol 2014;11:403–12; 2. Cao & Gardner. Hypertension 1995;25:227–34
3. Tokudome et al. Circulation 2008;117;2329–39; 4. Horio et al. Hypertension 2000;35:19–24
5. Fujita et al. Heart Vessels 2013;28:646–57; 6. Hobbs et al. Circulation 2004;110:1231–5
7. Zhang et al. Vasc Endovascular Surg 2008;42:263–7; 8. Kousholt. Dan Med J 2012;59:B4469
Preclinical evidence
ANP BNP CNP Effects on cardiac remodeling
Inhibition of cardiac fibroblast proliferation
Inhibition of hypertrophy in cardiac myocytes and fibroblasts
Inhibition of macrophage infiltration, collagen synthesis, and
pro-inflammatory chemotactic factors
Relaxation of coronary arteries
Reduction of infarct size
2 2 2
3 4
5
6
7 6 8
35
AT1 receptor
Signaling
cascades
NPR-A NPR-B
GTP GTP
cGMP
ANP
BNP CNP
Vasodilation
Cardiac fibrosis/hypertrophy
Natriuresis/diuresis
Ang II
Vasoconstriction
Cardiac fibrosis/hypertrophy
Sodium/water retention
NP signaling and effects
RAAS
over-activation
in HF
NPR-C
Inactivation
of NPs
Endocytosis
ANP
BNP
CNP
Receptor
recycling
Les effets cardiovasculaires et rénaux du système des
natriuretic peptides s’opposent à ceux du SRAA
ANP=atrial natriuretic peptide; Ang=angiotensin; AT1=angiotensin II type 1;
BNP=B-type natriuretic peptide; cGMP=cyclic guanosine monophosphate;
CNP=C-type natriuretic peptide; GTP=guanosine triphosphate; HF=heart failure;
NP=natriuretic peptide; NPR=natriuretic peptide receptor;
RAAS=renin-angiotensin-aldosterone system
Levin et al. N Engl J Med 1998;339;321–8; Gardner et al. Hypertension 2007;49:419–26
Molkentin. J Clin Invest 2003;111:1275–77; Nishikimi et al. Cardiovasc Res 2006;69:318–28
Guo et al. Cell Res 2001;11:165–80; Von Lueder et al. Circ Heart Fail 2013;6:594–605
Yin et al. Int J Biochem Cell 2003;35:780–3; Mehta and Griendling. Am J Physiol Cell Physiol 2007;292:C82–97
36
AT1 receptor
Signaling
cascades
NPR-A NPR-B
GTP GTP
cGMP
ANP
BNP CNP
Vasodilation
Cardiac fibrosis/hypertrophy
Natriuresis/diuresis
Ang II
Vasoconstriction
Cardiac fibrosis/hypertrophy
Sodium/water retention
NP signaling and effects
RAAS
over-activation
in HF
ANP
BNP
CNP Inactive
cleavage
products
NP degradation and
clearance
NPR-C
Inactivation
of NPs
Receptor
recycling Endocytosis
ANP
BNP
CNP
Neprilysin
Les natriuretic peptides sont éliminés par le NPR-C et par la
néprilysine
ANP=atrial natriuretic peptide; Ang=angiotensin; AT1=angiotensin II type 1; BNP=B-type
natriuretic peptide; cGMP=cyclic guanosine monophosphate; CNP=C-type natriuretic
peptide; GTP=guanosine triphosphate; HF=heart failure; NP=natriuretic peptide;
NPR=natriuretic peptide receptor; RAAS=renin-angiotensin-aldosterone system
Levin et al. N Engl J Med 1998;339;321–8; Gardner et al. Hypertension 2007;49:419–26
Molkentin. J Clin Invest 2003;111:1275–77; Nishikimi et al. Cardiovasc Res 2006;69:318–28
Guo et al. Cell Res 2001;11:165–80; Von Lueder et al. Circ Heart Fail 2013;6:594–605
Yin et al. Int J Biochem Cell 2003;35:780–3; Mehta and Griendling. Am J Physiol Cell Physiol
2007;292:C82–97; Mangiafico et al. Eur Heart J 2013;34:886–93; Potter. FEBS J 2011;278:1808–17
37
Neprilysin inhibitors: natriuretic and other vasoactive peptides enhancement
Evolution des approches pharmacologiques dans l’IC :
Inhibition de la Néprilysien comme une nouvelle stratégie
therapeutique1
ACEI=angiotensin-converting enzyme inhibitor; Ang=angiotensin; ARB=angiotensin receptor
blocker; AT1R = angiotensin II type 1 receptor; HF=heart failure; MRA=mineralocorticoid
receptor antagonist; NP=natriuretic peptide; NPRs=natriuretic peptide receptors;
RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous system
1. McMurray et al. Eur J Heart Fail 2013;15:1062–73
Figure references: Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert.
Pharmacotherapy 2002;22:27–42; Kemp & Conte. Cardiovascular Pathology
2012;365–71; Schrier & Abraham N Engl J Med 2009;341:577–85
SNS
RAAS
Vasoconstriction Blood pressure
Sympathetic tone Aldosterone Hypertrophy
Fibrosis
Ang II AT1R
HF SYMPTOMS &
PROGRESSION
INACTIVE
FRAGMENTS
NP system
Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy
NPRs NPs
Epinephrine
Norepinephrine α1, β1, β2
receptors
Vasoconstriction RAAS activity
Vasopressin Heart rate
Contractility
Neprilysin
inhibitors
RAAS inhibitors
(ACEI, ARB, MRA)
β-blockers
38
AT1 receptor
Signaling
cascades
NPR-A NPR-B
GTP GTP
cGMP
ANP
BNP CNP
Vasodilation
Cardiac fibrosis/hypertrophy
Natriuresis/diuresis
Ang II
Vasoconstriction
Cardiac fibrosis/hypertrophy
Sodium/water retention
NPR-C
Inactivation
of NPs
Receptor
recycling Endocytosis
ANP
BNP
CNP
ANP
BNP
CNP
Inactive
cleavage
products
Neprilysin
La néprilysine dégrade d’autres substrats, comme Ang II et
des peptides vasoactifs incontournables dans la physiologie
cardiovasculaire
ANP=atrial natriuretic peptide; Ang=angiotensin; AT1=angiotensin II type 1;
BNP=B-type natriuretic peptide; cGMP=cyclic guanosine monophosphate;
CNP=C-type natriuretic peptide; ET-1=endothelin-1; GTP=guanosine
triphosphate; NP=natriuretic peptide; NPR=natriuretic peptide receptor;
RAAS=renin-angiotensin-aldosterone system
Levin et al. N Engl J Med 1998;339;321–8; Gardner et al. Hypertension 2007;49:419–26; Molkentin. J Clin Invest
2003;111:1275–77 Nishikimi et al. Cardiovasc Res 2006;69:318–28; Guo et al. Cell Res 2001;11:165–80; Von
Lueder et al. Circ Heart Fail 2013;6:594–605; Yin et al. Int J Biochem Cell 2003;35:780–3; Mehta and Griendling.
Am J Physiol Cell Physiol 2007;292:C82–97; Mangiafico et al. Eur Heart J 2013;34:886–93; Potter. FEBS J
2011;278:1808–17; Erdos, Skidgel. FASEB J 1989;3:145–51; Stephenson et al. Biochem J 1987;243:183–7; Abassi
et al. Metabolism 1992;41:683–5; Murphy et al. Br J Pharmacol 1994;113:137–42; Jiang et al. Hypertens Res
2004;27:109–17; Langenickel & Dole. Drug Discovery Today: Ther Strateg 2012;9:e131–9
Ang II
Ang I
Adrenomedullin
Bradykinin
ET-1
39
L’ inhibition de la Néprilysine DOIT ETRE associée à un
blocage simultané du SRAA
ACE=angiotensin-converting enzyme; AT1=angiotensin II type 1;
Ang=angiotensin; H20=water; Na=sodium;
RAAS=renin-angiotensin- aldosterone system
1. Von Lueder et al. Circ Heart Fail 2013;6:594–605
2. Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9
Angiotensinogen
Ang I
Ang II
AT1 receptor
Biological actions
Norepinephrine release
↑ Sympathetic tone
Vasoconstriction
Hypertrophy Na+/H2O retention
Aldosterone release
Hypertrophy
Fibrosis
Neprilysin metabolizes Ang I and Ang II via several
pathways1,2
Inhibition of neprilysin alone is insufficient as it
associated with an increase in Ang II levels,
counteracting the potential benefits of neprilysin
inhibition2
Neprilysin inhibition must be accompanied by
simultaneous RAAS blockade (e.g. AT1 receptor
blockade)2
Signaling
cascade
Ang-(1–7)
Renin
ACE
Inactive
fragments
Neprilysin inhibitor
Neprilysin inhibitor
Neprilysin
Neprilysin
40
LCZ696 met en exergue les bénéfices des effets du système NP en
bloquant ceux du SRAA
ANP=atrial natriuretic peptide; Ang=angiotensin; AT1 = angiotensin II type 1; BNP=B-type
natriuretic peptide; cGMP=cyclic guanosine monophosphate; CNP=C-type natriuretic
peptide; GTP=guanosine triphosphate; NEP=neprilysin; NP=natriuretic peptide;
NPR=natriuretic peptide receptor; RAAS=renin-angiotensin-aldosterone system
Levin et al. N Engl J Med 1998;339;321–8; Gardner et al. Hypertension 2007;49:419–26
Molkentin. J Clin Invest 2003;111:1275–77; Nishikimi et al. Cardiovasc Res 2006;69:318–28
Guo et al. Cell Res 2001;11:165–80; Von Lueder et al. Circ Heart Fail 2013;6:594–605
Yin et al. Int J Biochem Cell 2003;35:780–3; Mehta and Griendling. Am J Physiol Cell Physiol
2007;292:C82–97; Langenickel & Dole. Drug Discovery Today: Ther Strateg 2012;9:e131–9
AT1 receptor
Signaling
cascades
NPR-A NPR-B
GTP GTP
ANP
BNP CNP
Vasodilation
Cardiac fibrosis/hypertrophy
Natriuresis/diuresis
Vasoconstriction
Cardiac fibrosis/hypertrophy
Sodium/water retention
NPR-C
Inactivation
of NPs
Receptor
recycling Endocytosis
ANP
BNP
CNP
Signaling
cascades
Sacubitril
(pro-drug)
↑ANP
↑BNP ↑CNP
ANP
BNP
CNP
cGMP ↑ cGMP
LCZ696
NEP inhibitor (active metabolite
[LBQ657])
Valsartan
Neprilysin
41
Conclusion
42
Aucune physiopathologie, aussi belle soit-elle, ne vaut un
essai clinique bien fait…..
(all comparisons are versus
enalapril 20 mg daily, not versus placebo)
0
16
32
40
24
8
Enalapril (n=4212)
360 720 1080 0 180 540 900 1260
Days After Randomization
PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint)
4187
4212
3922
3883
3663
3579
3018
2922
2257
2123
1544
1488
896
853
249
236
LCZ696
Enalapril
Patients at Risk
1117
Kap
lan
-Meie
r E
sti
mate
of
Cu
mu
lati
ve
Rate
s (
%)
0
16
32
40
24
8
Enalapril (n=4212)
360 720 1080 0 180 540 900 1260
Days After Randomization
4187
4212
3922
3883
3663
3579
3018
2922
2257
2123
1544
1488
896
853
249
236
LCZ696
Enalapril
Patients at Risk
1117
Kap
lan
-Meie
r E
sti
mate
of
Cu
mu
lati
ve
Rate
s (
%)
914
LCZ696 (n=4187)
PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint)
0
16
32
40
24
8
Enalapril (n=4212)
360 720 1080 0 180 540 900 1260
Days After Randomization
4187
4212
3922
3883
3663
3579
3018
2922
2257
2123
1544
1488
896
853
249
236
LCZ696
Enalapril
Patients at Risk
1117
Kap
lan
-Meie
r E
sti
mate
of
Cu
mu
lati
ve
Rate
s (
%)
914
LCZ696 (n=4187)
HR = 0.80 (0.73-0.87)
P = 0.0000002
Number needed to treat = 21
PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint)
10%
Angiotensin Neprilysin Inhibition With LCZ696 Doubles Effect on Cardiovascular Death of Current
Inhibitors of the Renin-Angiotensin System
20%
30%
40%
ACE inhibitor
Angiotensin receptor blocker
0%
% D
ec
rea
se
in
Mo
rta
lity
18%
20%
Effect of ARB vs placebo derived from CHARM-Alternative trial
Effect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial
Effect of LCZ696 vs ACE inhibitor derived from PARADIGM-HF trial
Angiotensin neprilysin inhibition
15%
48
Merci
49
LCZ696 mechanism of action:
LCZ696 introduction
50
LCZ696 is a first-in-class angiotensin receptor neprilysin
inhibitor (ARNI)
ARNI=angiotensin receptor neprilysin inhibitor;
AT1=angiotensin II type 1
1. Bloch & Basile. J Clin Hypertens 2010;12:809–12
2. Gu et al. J Clin Pharmacol 2010;50:401–14
3. Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9
LCZ696 is a novel drug which delivers
simultaneous neprilysin inhibition and
AT1 receptor blockade1–3
LCZ696 is a salt complex that comprises
the two active components:2,3
– sacubitril (AHU377) – a pro-drug; further
metabolized to the neprilysin inhibitor
LBQ657, and
– valsartan – an AT1 receptor blocker
in a 1:1 molar ratio 3D LCZ696 structure2
51
LCZ696 is a novel crystalline salt complex comprising sacubitril and valsartan
in their anionic forms, sodium cations and water molecules
LCZ696 2D scheme and 3D structure
LCZ696 is a first-in-class angiotensin receptor neprilysin
inhibitor (ARNI)
ARNI=angiotensin receptor neprilysin inhibitor;
H20=water; Na=sodium
Bloch, Basile. J Clin Hypertens 2010;12:809–12
Gu et al. J Clin Pharmacol 2010;50:401–14
Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9
6
Alternative to slide 100
62
Le SRAA est sur-activé dans l’IC – la compensation initiale
évolue vers la décompensation pathologique
ACE=angiotensin-converting enzyme; Ang=angiotensin;
AT1=angiotensin II type 1; HF=heart failure; H20=water;
Na=sodium; RAAS=renin-angiotensin-aldosterone system
Francis et al. Ann Intern Med 1984;101:370–7
Von Lueder et al. Circ Heart Fail 2013;6:594–605
Angiotensinogen
Ang I
Ang II
ACE
Renin
AT1 receptor
Biological actions
Norepinephrine release
↑ Sympathetic tone
Vasoconstriction
Hypertrophy Na+/H2O retention
Aldosterone release
Hypertrophy
Fibrosis
Signaling
cascade