CARDIOTalks: La IC vuelve a escena 22/05/2015 17:45h - 19:30h Hotel Sevilla Center. Sala Giralda I, Sevilla (XII Reunión Anual de la Sección de Insuficiencia Cardiaca y Trasplante de la SEC) http://cardiotalks.secardiologia.es Péptidos natriuréticos, nuestra protección endógena frente a la IC Dr. Antonio Bayés-Genis, Badalona

1. Antoni Bayes-Genis MD, PhD, FESC

2. Elsistemarenina-angiotensina-aldosterona(RAAS):
inicialmentecompensatorioyposteriormentepatológico
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

3. El corazón como organo endocrino:
liberación de PNs como mecanismo de defensa
Levin et al. N Engl J Med 1998;339;321–8; Gardner et al. Hypertension 2007;49:419–26;
Pandey. J Am Soc Hypertens 2008;2:210–6; Von Lueder et al. Pharmacol Ther 2014 [Epub ahead of print]; Potter. FEBS J
2011;278:1808–17; Lumsden et al. Curr Pharm Des 2010;16:4080–8; Mangiafico et al. Eur Heart J 2013;34:886–93

4. Péptidos natriuréticos, síntesis

5. El sistema de los Péptidos Natriuréticos
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
NPR-A
GTP
ANP and BNP
NPR-C
Internalization
Degradation of
NPs
Receptor
recycling
cGMP
• Diuresis, natriuresis
• Vasodilation
• Antihypertrophy
• Antiproliferation
• Antiapoptosis
• Anti-aldosterone
• Renin secretion inhibition
• Reduced sympathetic tone
NPR-B
CNP
GTP cGMP
• Vasodilation
• Antihypertrophy
• Antiproliferation
• Vascular regeneration
• Venodilation
• Antifibrosis

6. ANP/BNP
Relaxation;  arterial stiffness
CNP
(endothelium)
Acciones beneficiosas de los PN en la IC
 Sympathetic outflow
 Vasopressin
 Salt appetite and water intake
 Na+/H2O loss
 Aldosterone
 Renin
 Hypertrophy
 Fibroblast proliferation
Release of ANP and BNP from heart and CNP in vasculature
Vasodilation
 Systemic vascular resistance
 Pulmonary artery pressure
 Pulmonary capillary wedge pressure
 Right atrial pressure

7. LosPN contrarestanelsistemaRAAS
AT1 receptor
Neprilysin
(NEP)
Signaling
cascades
Gene expression; ↑ protein
synthesis; ↑ cell proliferation
NPR-A NPR-B
GTP GTP
cGMP
ANP
BNP CNP
ANP/CNP
BNP
Internalization
Inactive peptides
Receptor
recycling
Vasodilation
 Cardiac fibrosis/hypertrophy
Natriuresis/diuresis
Ang II
Inactive NP
fragments
ANP/CNP
BNP
Vasoconstriction
 Cardiac fibrosis/hypertrophy
Sodium/water retention
NPR-C

8. NEP: receptor transmembrana “promiscuo”
NEP: Membrane-anchored ReceptorPéptidos vasoactivos endógenos
Vasodilatadores: Péptidos
natriuréticos,adrenomedulina,Bradicinina
Vasoconstrictores: Angiotensina I y II,
endotelina-1
Metabolitos inactivos

9. NEP degrada múltiples péptidos con afinidad variable
Implications for NEP inhibition
 NEP substrates can have
opposing biological actions
 Overall effect is dependent upon
the net effect on NEP metabolism
of individual substrates
 Benefits in enhancing NP system
may be offset by increased Ang II
 Needs to be complemented by
simultaneous RAAS suppression
Relative
affinity
for NEP
ANP and CNP
Endothelin
Substance P
Bradykinin
Ang II
Adrenomedullin
Ang I
NEP
Inactive
fragments
or metabolites
BNP

10.  NEP inhibitors: natriuretic and other vasoactive peptides enhancement
Inhibición de NEP: una nueva estrategia la IC
SNS
RAAS
Vasoconstriction
Blood pressure
Sympathetic tone
Aldosterone
Hypertrophy
Fibrosis
Ang II AT1R
HFSYMPTOMS&
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

11. LCZ696 is a first-in-class
angiotensin receptor neprilysin inhibitor (ARNI)
 LCZ696 is a novel drug which delivers simultaneous
neprilysin inhibition and
AT1 receptor blockade
 LCZ696 is a salt complex that comprises
the two active moieties:
 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

12. LCZ696:estimulalosPNeinhibeelRAAS
AT1 receptor
NEP
Signaling
cascades
Gene expression; ↑ protein
synthesis; ↑ cell proliferation
NPR-A NPR-B NPR-C
GTP GTP
cGMP
ANP
BNP CNP
ANP/CNP/
BNP
Internalization
Inactive peptides
Vasodilation
 Cardiac fibrosis/hypertrophy
Natriuresis/diuresis
Vasoconstriction
 Cardiac fibrosis/hypertrophy
Sodium/water retention
Inactive NP
fragments ANP/CNP/
BNP
LCZ696
ValsartanSacubitril
Ang II
Enhancing
the natriuretic
peptide system
Supressing
the RAAS
Receptor
recycling
Signaling
cascades
Gene expression; ↑ protein synthesis; ↑
cell proliferation
Vasoconstriction
 Cardiac fibrosis/hypertrophy
Sodium/water retention

13. Packer M et al. Circulation. Online Nov 2014
PARADIGM-HF: perfil hormonal

14. Post Paradigm: PN como biomarcadores
• Diagnosis
• Prognosis and risk stratification
• Monitoring
• Guided-therapy
BNP NTproBNP

15. NEP puede encontrarse como péptido circulante
Dominio extracelular de NEP, Human 55-750
Dominio extracelular CT grande (55-750 aa)
con un átomo de Zn en el sitio activo

16. NEP soluble
Bayes-Genis A et al. J Am Coll Cardiol 2015;65:657

17. Take home message
1. Los PN son hormonas liberadas por el estiramiento de cardiomiocitos auriculares,
ventriculares (o endotelio) en IC
2. Los PN contrarestan (o lo intentan) los efectos deletéreos del sistema RAAS en IC.
3. NEP es la enzima principal en su degradación
4. LCZ696 bloquea NEP (Sacubitril) y el receptor de la AT-2 (Valsartan)
5. LCZ696 incrementa los niveles circulantes de PN
6. En la era post-PARADIGM, BNP deja de ser útil como biomarcador

18. HF Doc HF Patient
ACEi LCZ696