rôle de la néprilysine et du sraa dans l’insuffisance

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


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


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



Pharmacotherapy 2002;22:27–42 Kemp & Conte. Cardiovascular Pathology 2012;365–71


SNS

RAAS



Fibrosis

Ang II AT1R

HFrEF

SYMPTOMS &

PROGRESSION

Epinephrine


receptors



Contractility

RAAS inhibitors

(ACEI, ARB, MRA)

β-blockers

Natriuretic peptide

system


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:


hospitalization

CHARM-Added4 (2003) 2,548 patients

Key benefits of

candesartan (ARB) vs

placebo:


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


SNS

RAAS



Fibrosis

Ang II AT1R

HF SYMPTOMS &

PROGRESSION

INACTIVE

FRAGMENTS

NP system


NPRs NPs

Epinephrine


receptors



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;


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


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;


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


Sympathetic

nervous system

Renin-angiotensin-

aldosterone system



Fibrosis

Ang II AT1R

SYMPTOMeS &

PROGRESSION

Natriuretic peptide

system


NPRs NPs

Epinephrine


receptors



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;


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


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




• Venodilation1

• Antifibrosis1

32

Les Natriuretic peptides sont éliminés via NPR-C et

dégradés par une protease: la néprilysine


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




• Myocardial relaxation1

• Diuresis, natriuresis1,2

• Antiapoptosis1

• Anti-aldosterone1

• Renin secretion inhibition1,3

• Reduced sympathetic tone4

• Lipolysis1

NPR-B

Endothelial cells1

GTP cGMP

• Vasodilation1,2




• 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


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


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


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;


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



Ang II

Vasoconstriction



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




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


Pharmacotherapy 2002;22:27–42; Kemp & Conte. Cardiovascular Pathology

2012;365–71; Schrier & Abraham N Engl J Med 2009;341:577–85

SNS

RAAS



Fibrosis

Ang II AT1R

HF SYMPTOMS &

PROGRESSION

INACTIVE

FRAGMENTS

NP system


NPRs NPs

Epinephrine


receptors



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



Ang II

Vasoconstriction



NPR-C

Inactivation

of NPs

Receptor


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;


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


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




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



Vasoconstriction



NPR-C

Inactivation

of NPs

Receptor


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


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)


0

16

32

40

24

8

Enalapril (n=4212)

360 720 1080 0 180 540 900 1260


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


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


Vasoconstriction

Hypertrophy Na+/H2O retention

Aldosterone release

Hypertrophy

Fibrosis

Signaling

cascade

rôle de la néprilysine et du sraa dans l’insuffisance

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