The Present and Future
JACC Review Topic of the Week
Targeting Cyclic Guanosine Monophosphate to Treat Heart Failure: JACC Review Topic of the Week

https://doi.org/10.1016/j.jacc.2020.08.031Get rights and content
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Highlights

  • Levels of cGMP are often reduced in patients with HF.

  • Several drugs modulating NO-GMP-PDE pathways have been evaluated as potential therapeutic avenues for HF.

  • Sacubitril/valsartan and vericiguat are associated with beneficial effects on prognosis in patients with HF.

Abstract

The significant morbidity and mortality associated with heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF) justify the search for novel therapeutic agents. Reduced cyclic guanosine monophosphate levels contribute to HF progression. Among molecules modulating the nitric oxide (NO)–GMP–phosphodiesterase (PDE) pathway, the evaluation of nitrates, synthetic natriuretic peptides (NP), and NP analogs has yielded mixed results. Conversely, sacubitril/valsartan, combining NP degradation inhibition through neprilysin and angiotensin receptor blockade, has led to groundbreaking findings in HFrEF. Other strategies to increase tissue cyclic guanosine monophosphate have been attempted, such as PDE-3 or PDE-5 inhibition (with negative or neutral results), NO-independent soluble guanylate cyclase (sGC) activation, or enhancement of sGC sensitivity to endogenous NO. Following the positive results of the phase 3 VICTORIA (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction) trial on the sGC stimulator vericiguat in HFrEF, the main open questions are the efficacy of the sacubitril/valsartan-vericiguat combination in HFrEF and of vericiguat in HFpEF.

Key Words

cGMP
heart failure
natriuretic peptides
sGC
vericiguat

Abbreviations and Acronyms

ACE
angiotensin-converting enzyme
AE
adverse event
AHF
acute heart failure
ANP
atrial natriuretic peptide
ARB
angiotensin receptor blocker
ARNI
angiotensin receptor neprilysin inhibitor
BNP
B-type natriuretic peptide
cAMP
cyclic adenylate monophosphate
cGMP
cyclic guanosine monophosphate
CI
confidence interval
GC
guanylate cyclase
HF
heart failure
HFpEF
heart failure with preserved ejection fraction
HFrEF
heart failure with reduced ejection fraction
HR
hazard ratio
ISDN
isosorbide dinitrate
LV
left ventricle
MRA
mineralocorticoid receptor antagonist
NEP
neprilysin
NO
nitric oxide
NP
natriuretic peptide
NTG
nitroglycerin
NT-proBNP
N-terminal fraction of pro–B-type natriuretic peptide
NYHA
New York Heart Association
PCWP
pulmonary capillary wedge pressure
PDE
phosphodiesterase
pGC
particulate guanylate cyclase
PKG
protein kinase G
QoL
quality of life
RAAS
renin-angiotensin-aldosterone system
RR
rate ratio
sGC
soluble guanylate cyclase
SNS
sympathetic nervous system

Cited by (0)

Dr. Emdin has received consulting fees from Merck; and serves as an Italian national leader investigator of VICTORIA. Dr. Metra has received consulting fees from Bayer, Fresenius, Novartis, and Windtree Therapeutics for participation on Advisory Boards or Executive Committees of clinical trials. Dr. Senni has received consulting fees from Bayer, Merck, Novartis, Vifor Pharma, Abbott, Boehringer Ingelheim, AstraZeneca, BioVentrix, and Servier; and serves as an Italian national leader investigator of VICTORIA. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC author instructions page.

Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.

Drs. Emdin and Aimo contributed equally to this work.