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BackgroundUsing human humoral metabolomic profiling, we can discover the diagnostic biomarkers and pathogenesis of disease. The specific characterization of atrial fibrillation (AF) subtypes with metabolomics may facilitate effective and targeted treatment, especially in early stages.ObjectivesBy investigating disturbed metabolic pathways, we could evaluate the diagnostic value of biomarkers based on metabolomics for different types of AF.MethodsA cohort of 363 patients was enrolled and divided into a discovery and validation set. Patients underwent an electrocardiogram (ECG) for suspected AF. Groups were divided as follows: healthy individuals (Control), suspected AF (Sus-AF), first diagnosed AF (Fir-AF), paroxysmal AF (Par-AF), persistent AF (Per-AF), and AF causing a cardiogenic ischemic stroke (Car-AF). Serum metabolomic profiles were determined by gas chromatography–mass spectrometry (GC-MS) and liquid chromatography–quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). Metabolomic variables were analyzed with clinical information to identify relevant diagnostic biomarkers.ResultsThe metabolic disorders were characterized by 16 cross-comparisons. We focused on comparing all of the types of AF (All-AFs) plus Car-AF vs. Control, All-AFs vs. Car-AF, Par-AF vs. Control, and Par-AF vs. Per-AF. Then, 117 and 94 metabolites were identified by GC/MS and LC-QTOF-MS, respectively. The essential altered metabolic pathways during AF progression included D-glutamine and D-glutamate metabolism, glycerophospholipid metabolism, etc. For differential diagnosis, the area under the curve (AUC) of specific metabolomic biomarkers ranged from 0.8237 to 0.9890 during the discovery phase, and the predictive values in the validation cohort were 78.8–90.2%.ConclusionsSerum metabolomics is a powerful way to identify metabolic disturbances. Differences in small–molecule metabolites may serve as biomarkers for AF onset, progression, and differential diagnosis.