Smeets N J L, van Hoek I N, Jans J J M, Dalinghaus M, Laer S, Bajcetic M, Male C, de Wildt S N
Department of Pharmacology and Toxicology, Radboud Institute of Health Sciences, Radboud University Medical Center, Nijmegen, Netherlands.
Department of Genetics, Section Metabolic Diagnostics, University Medical Center Utrecht, Utrecht, Netherlands.
Front Pediatr. 2025 Apr 28;13:1530063. doi: 10.3389/fped.2025.1530063. eCollection 2025.
Enalapril is an angiotensin-converting enzyme (ACE) inhibitor (ACEi) which is widely used in the management of (paediatric) hypertension and heart failure (HF). There is a significant interindividual variability in the patient's response to enalapril that is not completely understood. Therefore, we aimed to examine the potential of metabolic profiling for stratifying paediatric patients with HF due to congenital heart disease (CHD) in terms of treatment response to enalapril. Additionally, we investigated metabolic profiles in CHD patients and healthy controls.
CHD patients aged 0-6 years of age who previously participated in a multi-centre and multinational pharmacokinetic safety bridging study of enalapril were included. Patients were defined as responder when aldosterone levels decreased after a single administration of enalapril. Non-responders were those with an increase in their aldosterone levels. We applied an untargeted mass spectrometry-based metabolomics approach on serum. By using both supervised and unsupervised learning algorithms, we compared metabolic profiles between responders and non-responders as well as between patients and age and sex matched healthy controls.
In total, 63 patients were included with a median age of 132 (IQR 54-211) days and 46 controls [97 (63-160) days]. 41 of 63 patients responded to enalapril therapy. Their baseline characteristics were similar to non-responders ( = 22). A total of 1,820 unique features were identified. Responders were distinguished from non-responders using a supervised learning algorithm based on 94 features ( = 0.05). Furthermore, metabolic profiles could distinguish between patients and controls based on an unsupervised learning algorithm which revealed 278 relevant features ( = 0.001).
These are the first data to demonstrate a clear metabolic signature in children with CHD using ACEi. We identified metabolites whose concentrations were both associated with ACEi response and HF. This indicates more severe HF in patients with more profound treatment response. Our results will therefore allow further studies aiming at disentangling variability in ACEi treatment response.
依那普利是一种血管紧张素转换酶（ACE）抑制剂（ACEi），广泛用于（儿科）高血压和心力衰竭（HF）的治疗。患者对依那普利的反应存在显著的个体差异，目前尚未完全明确。因此，我们旨在研究代谢谱分析在对先天性心脏病（CHD）所致儿科HF患者依那普利治疗反应进行分层方面的潜力。此外，我们还研究了CHD患者和健康对照者的代谢谱。
纳入先前参与依那普利多中心、多国药代动力学安全性桥接研究的0至6岁CHD患者。单次服用依那普利后醛固酮水平降低的患者被定义为反应者。醛固酮水平升高的患者为无反应者。我们对血清应用了基于非靶向质谱的代谢组学方法。通过使用监督学习和非监督学习算法，我们比较了反应者和无反应者之间以及患者与年龄和性别匹配的健康对照者之间的代谢谱。
共纳入63例患者，中位年龄为132（四分位间距54 - 211）天，46例对照者[97（63 - 160）天]。63例患者中有41例对依那普利治疗有反应。他们的基线特征与无反应者相似（n = 22）。共鉴定出1820个独特特征。使用基于94个特征的监督学习算法可将反应者与无反应者区分开（p = 0.05）。此外，基于非监督学习算法，代谢谱可区分患者和对照者，该算法揭示了278个相关特征（p = 0.001）。
这些是首批证明使用ACEi的CHD儿童存在明确代谢特征的数据。我们鉴定出了其浓度与ACEi反应和HF均相关的代谢物。这表明治疗反应越明显的患者HF越严重。因此，我们的结果将有助于进一步开展旨在阐明ACEi治疗反应变异性的研究。
