Clinical Research
Association of Soluble ST2 Serum Levels With Outcomes in Pediatric Dilated Cardiomyopathy

https://doi.org/10.1016/j.cjca.2019.02.016Get rights and content

Abstract

Background

Prognosis in patients with pediatric dilated cardiomyopathy (PDCM) is urgently required to identify high-risk patients. Elevated soluble ST2 (sST2) is associated with prognosis in adult patients with heart failure. This study aimed to assess the prognostic value of sST2 in PDCM.

Methods

Ninety-four patients with PDCM were enrolled after admission from 2 centres in China and followed up for adverse events (death, cardiac transplantation, and heart-failure–related rehospitalization). B-type natriuretic peptide (BNP) and sST2 levels were measured.

Results

Over a median of 678 (interquartile range [IQR]: 533-785) days, 28 (29.8%) adverse events occurred. Patients in the highest tertile of sST2 levels had increased risk of short-term (< 6 months) (adjusted hazard ratio [HR]: 8.36, 95% confidence interval [CI], 1.02-73.52; P < 0.05) and long-term adverse events (2 years) (adjusted HR: 4.23; 95% CI, 1.32-13.60; P < 0.01) than those in lower tertiles. The C-statistic was increased with addition of sST2 to BNP from 0.697 (95% CI, 0.541-0.852) to 0.812 (95% CI, 0.697-0.939) for short-term and from 0.712 (95% CI, 0.604-0.819) to 0.798 (95% CI, 0.697-0.899) for prediction of long-term adverse events. An intermediate-risk subgroup was identified, and 24% had adverse events. When serial measurements were taken in a nested case-control subgroup, sST2 levels were constantly high in patients with late adverse events (> 6 months) but gradually decreased in nonadverse-event controls compared with 3-month and 6-month baseline levels.

Conclusions

In patients with PDCM, serum sST2 levels are associated with adverse events and have robust prognostic value. Serial measurements of sST2 could help in managing patients for monitoring outcomes of treatment.

Résumé

Contexte

Il est urgent de pouvoir disposer de facteurs pronostiques de la cardiomyopathie dilatée chez l’enfant (CDE) afin de pouvoir repérer les patients à haut risque. Un taux élevé de ST2 soluble (ST2s) est associé au pronostic chez les patients adultes atteints d’insuffisance cardiaque. Cette étude avait pour but d’évaluer la valeur pronostique du ST2s dans la CDE.

Méthodologie

Quatre-vingt-quatorze patients atteints de CDE ont été recrutés après leur admission dans deux établissements situés en Chine et ont fait l’objet d’un suivi visant à consigner les éventuels événements indésirables (décès, transplantations cardiaques et réhospitalisations imputables à l’insuffisance cardiaque). Les taux de peptide natriurétique de type B (BNP) et de ST2s ont été mesurés.

Résultats

Sur une période médiane de 678 jours (écart interquartile [EIQ], de 533 à 785), 28 (29,8 %) événements indésirables sont survenus. Les patients se situant dans le tertile supérieur des taux de ST2s présentaient un risque accru d’événement indésirable à court terme (< 6 mois) (rapport des risques instantanés [RRI] ajustés 8,36, intervalle de confiance [IC] à 95 %, de 1,02 à 73,52; p < 0,05) et à long terme (2 ans) (RRI ajusté, 4,23; IC à 95 %, de 1,32 à 13,60; p < 0,01) par rapport à ceux des tertiles inférieurs. La discrimination évaluée par analyse de statistique C augmentait avec l’ajout de ST2s au BNP de 0,697 (IC à 95 %, de 0,541 à 0,852) à 0,812 (IC à 95 %, de 0,697 à 0,939) pour la prédiction des événements indésirables à court terme, et de 0,712 (IC à 95 %, de 0,604 à 0,819) à 0,798 (IC à 95 %, de 0,697 à 0,899) pour celle des événements indésirables à long terme. Un sous-groupe à risque intermédiaire a été constitué, dans lequel 24 % des participants ont présenté des événements indésirables. Lorsque des mesures sérielles ont été prises dans un sous-groupe cas-témoin emboîté, les taux de ST2s étaient systématiquement élevés chez les patients ayant eu des événements indésirables tardifs (> 6 mois), mais diminuaient graduellement chez les témoins sans événement indésirable comparativement aux taux à 3 mois et à 6 mois par rapport à leur valeur au début de l’étude.

Conclusions

Chez les patients atteints de CDE, le taux sérique de ST2s est associé à la survenue d’événements indésirables et possède une valeur pronostique robuste. Les mesures sérielles du taux de ST2s pourraient faciliter la prise en charge des patients en permettant de suivre les résultats du traitement.

Section snippets

Study population

An Integrative-Omics Study of Cardiomyopathy Patients for Diagnosis and Prognosis in China (AOCC) is a double-centre, observational, prospective, integrative omics study, which aimed to determine the diagnostic and prognostic value of novel biomarkers in cardiomyopathy. All children (< 18 years old), including patients and 47 healthy controls, were enrolled in Beijing Anzhen Hospital and Fuwai Hospital from September 2015 to March 2017. Figure 1 shows a flowchart of the study. All potential

Baseline characteristics of the study patients

A total of 146 eligible perspective pediatric patients with DCM were enrolled in the AOCC clinical cohort. Of them, 94 patients were eventually entered in our study after exclusion (Fig. 1). Overall, 60.2% were female; these patients’ median age was 22.0 months (IQR: 10.5-69.5 months), and median LVEF was 38% (IQR: 32%-44%). Serum sST2 levels of patients are shown in Supplemental Fig. S1, with a median level of 23.7 ng/mL. Levels of sST2 were significantly higher in 94 patients with DCM than in

Discussion

In this study, we showed that sST2 levels were associated with clinical outcome in pediatric patients with DCM. Elevated baseline sST2 levels were strongly associated with adverse events, especially in short-term follow-up. In addition, sST2 could significantly improve on BNP for predicting adverse events. Compared with a sex-, age-, and medical medication-matched subgroup, we found that constant high sST2 levels indicated worse prognoses.

Distinguishing patients at high risk for adverse events

Conclusion

This study is the first to show the association between circulating sST2 levels and adverse events in pediatric patients with DCM. Soluble ST2 is a specific biomarker that can distinguish patients at high risk of death from those who are likely to recover. Soluble ST2 has strong prognostic value in short-term and long-term adverse events. In addition, sST2 can improve on BNP for predicting adverse events. Repeated measurement of sST2 could be useful for monitoring disease.

Acknowledgements

We thank Ms Yanyan Zhao from Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College for helping in collection of clinical data and Dr Chunxiao Wu from Xiyuan Hospital, China Academy of Chinese Medical Sciences for technical assistance in data processing. We also thank Dr Xingguang Zhang and Ms Xueyu Han from the Department of Epidemiology, Beijing Anzhen Hospital, Capital Medical University, for assistance with statistical analysis and Ellen Knapp, PhD, from Liwen

Funding Sources

This study was supported by grants from the Program for Innovative Research Team (IRT_17R76), National Science Foundation of China (81870341), National Key R&D Program of China (2016YFC0903000), and Beijing Municipal Science and Technology Commission (Z171100000417002).

Disclosures

The authors report no conflicts of interest.

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    See page 734 for disclosure information.

    ∗

    These authors contributed equally.

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