Uncoupling of energy metabolism and myocardial function in early left atrial dysfunction: a metabolomics study.

Background: Left atrial (LA) dysfunction is a key preclinical phenotype of heart failure (HF), closely linked to HF progression, yet its molecular mechanisms remain unclear. Energy metabolic abnormalities may critically influence early LA dysfunction. This study aimed to explore the metabolic mechanisms underlying early LA dysfunction and develop a predictive model using metabolomics. Methods: We enrolled 315 participants, classified into early LA dysfunction and healthy control groups based on LA reservoir strain assessed via cardiovascular magnetic resonance (CMR). Targeted metabolomics was applied to detect plasma metabolites, and machine learning methods were used to construct predictive models. In addition, metabolic pathway and mediation analyses were also performed. Results: A total of 11 metabolites were significantly altered in early LA dysfunction, including elevated short-chain acylcarnitines (C4OH, C5:1) and proline, and decreased linoleic acid. C4OH and C5:1 correlated positively, while linoleic acid negatively correlated with LA reservoir strain. These metabolites distinguished early LA dysfunction from controls effectively (AUC=0.716; 95% CI: 0.616-0.817). Mediation analysis indicated that C5:1 and C5OH exacerbated LA dysfunction partly via obesity (BMI). Conclusions: Energy metabolic-mechanical function uncoupling may underlie early LA dysfunction. C4OH, C5:1, linoleic acid, and proline represent potential biomarkers and candidate metabolic pathways for future therapeutic investigation for early HF detection and intervention. Registration number: ChiCTR2200057991; Date of registration: 2022-03-25. URL: http://www.chictr.org.cn/showproj.aspx?proj=162316.