Clinical Research
Ceramide Is Upregulated and Associated With Mortality in Patients With Chronic Heart Failure

https://doi.org/10.1016/j.cjca.2014.12.007Get rights and content

Abstract

Background

Ceramide is involved in apoptosis, inflammation, and stress responses, which are among the pathogenic components of chronic heart failure (CHF). However, no one has documented the levels of ceramide itself in CHF or determined its potential prognostic value.

Methods

In this study we recruited patients with heart failure consecutively from the hospital, of whom 423 stable patients were eventually selected to participate in this study after an observation period of at least 3 months after hospital discharge. All patents were followed up for all-cause death to December 31, 2013.

Results

Plasma ceramide levels were increased stepwise with New York Heart Association functional class (I, 5.32 ± 1.98; II, 5.81 ± 1.63; III, 6.14 ± 2.14; IV, 6.66 ± 2.61 ng/mL). During a mean follow-up of 4.4 years (interquartile range: 3.5-5.3 years), a total of 200 CHF patients died. The optimal threshold value of ceramide was 6.05 ng/mL. Ceramide levels as continuous and as dichotomous variables are risk factors for mortality in CHF (adjusted hazard ratio, 1.31; 95% confidence interval, 1.16-1.47; P < 0.001 and adjusted hazard ratio, 2.07, 95% confidence interval, 1.53-2.81; P < 0.001, respectively). When ceramide levels were combined with conventional CHF risk factors, the area under the curve increased from 0.68 (0.63-0.72) to 0.72 (0.68-0.76); P = 0.047. The continuous net reclassification index and integrated discrimination improvement index were 17.2% (5.0-29.9%; P = 0.027) and 0.04 (0.01-0.08; P = 0.020), respectively.

Conclusions

Plasma ceramide levels were increased and correlated with the severity of CHF, and were an independent risk factor of mortality in patients with CHF and reduced left ventricular systolic function. Ceramide levels might provide additional predictive value after conventional risk assessment.

Résumé

Introduction

Le céramide est impliqué dans l'apoptose, l'inflammation et la réponse au stress, qui sont parmi les composantes pathogènes de l'insuffisance cardiaque chronique (ICC). Cependant, personne n'a documenté les niveaux de céramide en soi dans l'ICC, ni déterminé valeur pronostique potentielle.

Méthodes

Dans cette étude nous avons recruté des patients consécutivement à une hospitalisation pour insuffisance cardiaque, dont 423 patients stables ont finalement été sélectionnés pour participer à cette étude, après une période d'observation d'au moins 3 mois après la sortie de l'hôpital. Chaque patient a été examiné pour toutes causes de décès confondues au 31 décembre 2013.

Résultats

Les niveaux de céramide plasmatique ont été augmentés progressivement selon la classification fonctionnelle de la New York Heart Association (I, 5,32 ± 1,98; II, 5,81 ± 1,63; III, 6,14 ± 2,14; IV, 6,66 ± 2,61 ng/ml). Au cours d'un suivi moyen de 4,4 ans (écart interquartile: 3,5-5,3 ans), un total de 200 patients atteints d'ICC sont décédés. La valeur du seuil de céramide optimal est de 6,05 ng/ml. Les niveaux de céramide en tant que variable continue ou dichotomique sont des facteurs de risque de mortalité en ICC (rapport de risques ajustés, 1,31; intervalle de confiance à 95 %, 1,16-1,47; P <0,001 et rapport de risques ajustés, 2,07, intervalle de confiance à 95 %, 1,53-2,81; P <0,001, respectivement). Lorsque les niveaux de céramide ont été combinés avec des facteurs de risque classiques d’ICC, l'aire sous la courbe est passée de 0,68 (0,63-0,72) à 0,72 (0,68-0,76); P = 0,047. L'indice continu « Net Reclassification » et l’indice « Integrated Discrimination Improvement » étaient de 17,2 % (5,0-29,9 %; P = 0,027) et de 0,04 (0,01-0,08; P = 0,020), respectivement.

Conclusions

Les niveaux de céramide plasmatique ont été augmentés et corrélés avec la gravité de l’ICC, et ont été un facteur de risque indépendant de la mortalité chez les patients avec ICC et une réduction de la fonction systolique ventriculaire gauche. Les niveaux de céramide pourraient apporter une valeur prédictive supplémentaire à l’évaluation des facteurs de risque conventionnels.

Section snippets

Study subjects and data collection

The study was carried out between 2008 and 2013, and we consecutively recruited patients from the Department of Cardiovascular Medicine of Xiangya Hospital, Changsha, China with symptoms of heart failure (HF), aged ≥18 years, and with a left ventricular ejection fraction (LVEF) of ≤50%. During the next observation period of at least 3 months after hospital discharge, patients were excluded from the present study if they clinically deteriorated and needed to change medication regimens. Finally,

Results

One hundred four healthy individuals and 423 patients with CHF and reduced left ventricular systolic function were enrolled. All patients in this study were receiving standard medical treatment during a mean follow-up period of 4.4 years (interquartile range, 3.5-5.3 years).

Discussion

To our knowledge, this study shows for the first time, that ceramide levels are increased and associated with NYHA functional classes in patients with CHF and reduced left ventricular function. Furthermore, this study revealed the prognostic value of plasma ceramide levels as a predictor of mortality in patients with CHF, and the potential use of ceramide to improve prognostic discrimination and risk reclassification beyond other parameters.

Several studies have revealed the relationship between

Conclusions

Plasma ceramide was upregulated and correlated with severity in a large cohort of Chinese patients with CHF and reduced left ventricular function. Ceramide level in plasma is an independent risk factor of mortality in patients with CHF, and can provide additional predictive value after conventional risk assessment.

Acknowledgements

Jingjia Yu and Wei Pan contributed equally to this work.

The authors thank the staff of the Department of Cardiovascular Disease of Xiangya Hospital for their assistance with enrolling patients and sample collection.

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