Abstract
Background
Heart failure with midrange ejection fraction (HFmrEF) has been recently acknowledged
as a separate phenotype, but metabolomics evaluation of this subtype remains largely
unexamined.
Methods
A quantitative metabolomics study on amino acids and acylcarnitines was performed
to characterize different states of heart failure (HF) in 628 participants. Both multivariate
orthogonal partial least squares- discriminant analysis and univariate Mann-Whitney
U test were used to explore reliable metabolic profiles associated with different HF
states. The resulting metabolites were further refined to obtain diagnostic metabolite
scores (DMSs) with the use of ordinal logistic regression. Lasso-penalized regression
was applied to produce a survival-associated prognostic metabolite score (PMS). The
Cox proportional hazards model, Kaplan-Meier curves, and time-dependent receiver operating
characteristics were used for a comprehensive assessment of prognostic value using
PMS versus traditional clinical biomarkers.
Results
The optimized models identified a panel of 15 differential metabolites that were shared
across different HF states, whereas some metabolites were associated with a specific
state. PMS consisting of 9 metabolites demonstrated an appreciably better prognostic
value (hazard ratio [HR] 1.62, 95% confidence interval [CI] 1.25-2.1) vs the natural
logarithm of N-terminal pro–B-type natriuretic peptide (Ln[NT-proBNP]; HR 1.23, 95%
CI 0.94-1.61; P < 0.001). The overall area under the receiver operating characteristic curve value
of PMS was superior to that of Ln(NT-proBNP) in risk prediction for patients with
HFmrEF and HF with reduced ejection fraction (HFrEF) subtypes (P < 0.001).
Conclusions
Targeted metabolomics has provided a novel understanding of the molecular mechanism
underlying HF. Both DMS and PMS clearly demonstrated HFmrEF as a distinct phenotype
between a mild HF with preserved ejection fraction state and a severe HFrEF state.
PMS exhibited superior prognostic value than Ln(NT-proBNP). Further investigation
is needed with independent large-scale validation.
Résumé
Contexte
L’insuffisance cardiaque à fraction d’éjection intermédiaire (ICFEI) est depuis peu
reconnue comme étant un phénotype distinct, mais l’évaluation métabolomique de ce
sous-type n’a pas beaucoup été explorée.
Méthodologie
Nous avons mené une étude métabolomique quantitative des acides aminés et des acylcarnitines
chez 628 sujets afin de caractériser les différents états d’insuffisance cardiaque.
Nous avons eu recours à une régression des moindres carrés partiels orthogonale multivariée
et au test U de Mann-Whitney univarié pour établir les profils métaboliques fiables associés à
différents états d’insuffisance cardiaque. Les résultats relatifs aux métabolites
produits ont ensuite été affinés à l’aide d’une régression logistique ordinale afin
d’obtenir des scores pour les métabolites diagnostiques (SMD). Nous avons utilisé
une régression LASSO pour établir un score pour les métabolites pronostiques (SMP)
associés à la survie. L’évaluation exhaustive de la valeur pronostique du SMP par
rapport à celle des biomarqueurs cliniques conventionnels reposait sur un modèle à
risques proportionnels de Cox, sur des courbes de Kaplan-Meier et sur les courbes
caractéristiques de la performance d’un test tributaires du temps.
Résultats
Les modèles optimisés ont permis de recenser 15 métabolites différentiels présents
dans plusieurs des états d’insuffisance cardiaque étudiés, tandis que certains autres
métabolites étaient associés à un état particulier. Le SMP tenant compte de 9 métabolites
s’est révélé avoir une valeur pronostique sensiblement supérieure (rapport des risques
instantanés [RRI] de 1,62; intervalle de confiance [IC] à 95 % : de 1,25 à 2,1) à
celle du logarithme naturel du taux de propeptide natriurétique de type B N-terminal
(ln[NT-proBNP]; RRI de 1,23; IC à 95 % : de 0,94 à 1,61; p < 0,001). La valeur globale de l’aire sous la courbe caractéristique de la performance
d’un test correspondant au SMP était supérieure à celle du ln(NT-proBNP) pour prédire
le risque chez les patients présentant une ICFEI ou une insuffisance cardiaque à fraction
d’éjection réduite (ICFER) (p < 0,001).
Conclusions
L’évaluation métabolomique ciblée nous a permis d’acquérir une nouvelle compréhension
des mécanismes moléculaires qui sous-tendent l’insuffisance cardiaque. Le SMD et le
SMP ont tous deux nettement démontré le caractère distinct du phénotype de l’ICFEI,
situé à mi-chemin entre celui de l’insuffisance cardiaque légère à fraction d’éjection
préservée et celui de l’ICFER grave. Le SMP s’est révélé avoir un pouvoir pronostique
supérieur à celui du ln(NT-proBNP). Une investigation plus approfondie et une validation
indépendante à grande échelle s’imposent.
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Article info
Publication history
Published online: March 28, 2020
Accepted:
March 18,
2020
Received:
June 22,
2019
Footnotes
See page 308 for disclosure information.
Identification
Copyright
© 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
