System Maintenance Notice

Please note that maintenance work is scheduled between 4 AM and 5 AM - CET. During this time, you may experience reduced performance. Thanks for your patience.

Publications

Journal Article Epublish

PubMed: 42846201 DOI: 10.3389/fphar.2026.1934998

Circulating serotonin is associated with calcific aortic valve stenosis: a two-phase metabolomics study.

Front Pharmacol 17:1934998

Authors: Wei Gao, Chenghu Guo, Nizal Sarrafzadegan, Haowei Zhang, Zeyuan Mei, Jiaqi Li, Lin Chen, Junkang Cheng, Jocelyn Gao, Chaoyu Liu, Yue You, Zhiyi Wang, Mei Dong, Mei Ni, Xiaolin Liu, Xiaoling Liu, Guipeng An

Affiliations

  • State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
  • Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran.
  • The Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States.

Abstract

BACKGROUND

Calcific aortic valve stenosis (CAVS) is the most prevalent valvular heart disease in the elderly, yet no pharmacological therapy can halt its progression, partly due to incomplete understanding of disease-associated metabolic alterations and the lack of circulating biomarkers for disease detection.

OBJECTIVE

We aimed to characterize metabolic alterations associated with CAVS and evaluate a candidate circulating marker for CAVS detection.

METHODS

In the discovery cohort, patients with severe CAVS and matched controls without aortic valve disease were enrolled. Untargeted serum metabolomics was performed to characterize metabolic profiles. Differential metabolites, pathway enrichment analysis, and machine-learning-based feature prioritization were conducted. Based on pathway-level metabolic annotation, biological evidence, and feasibility of targeted measurement, serotonin was selected as a biologically prioritized, hypothesis-generating candidate and evaluated by ELISA in an independent targeted assessment cohort including controls, non-severe CAVS, and severe CAVS. Associations between serum serotonin levels and CAVS were assessed using multivariable logistic regression, smooth curve analysis, subgroup analyses, and ROC analysis.

RESULTS

The discovery cohort included 58 participants [29 with severe CAVS (69.7 ± 7.5 years; 44.8% male) and 29 matched controls (66.8 ± 5.1 years; 58.6% male)]. Untargeted metabolomics identified 70 differential metabolites. KEGG pathway enrichment analysis revealed serotonin-related metabolic annotations, while Random Forest analysis prioritized indoleacrylic acid as a discriminatory metabolite feature. Serotonin was not selected based on individual metabolite ranking but was evaluated based on pathway-level evidence, biological plausibility, and feasibility of targeted measurement. In the independent targeted assessment cohort of 303 individuals (101 controls, 101 non-severe CAVS, and 101 severe CAVS), serum serotonin levels were significantly lower in both non-severe and severe CAVS groups compared with controls, but did not differ between disease severity groups. Multivariable logistic regression adjusted for confounders confirmed its independent inverse association with CAVS. Incorporation of serum serotonin into the clinical model improved discrimination (AUC increased from 0.752 to 0.865), whereas serotonin alone showed moderate diagnostic performance.

CONCLUSION

Reduced circulating serotonin is associated with the presence of CAVS and may represent a biologically plausible candidate adjunct biomarker for disease detection. Further multicenter prospective and mechanistic studies are required to determine its clinical utility and biological significance.

MeSH

Research Design, Constriction, Pathologic, Aortic Valve Stenosis, Serum, Biomarkers, Serotonin, Aortic Valve, Metabolomics