Multi-omics profiling of circulating proteins and metabolites in persistent atrial fibrillation: VDAC1 identified as a candidate circulating protein

Background Atrial fibrillation (AF) is the most common heart rhythm disorder worldwide. Changes in metabolism and damage to mitochondria affect left atrial structure and electrical function. Few studies have applied multi-omics to plasma from AF patients. Methods We enrolled 37 patients with persistent AF and 36 with supraventricular tachycardia (SVT). Blood samples were drawn from the coronary sinus in all patients. Ten subjects from each group were randomly selected for 4D-DIA proteomics and untargeted metabolomics. ELISA validation was done on 35 patients per group. Four GEO atrial tissue datasets and one single-nucleus RNA-seq dataset were used for external support. Differentially expressed proteins (DEPs) were defined by |fold change| ≥ 1.5 and Benjamini-Hochberg adjusted P < 0.05. Protein-protein interaction networks were built with STRING and Cytoscape. Results We quantified 3268 plasma proteins and identified 217 DEPs in AF. Network analysis showed voltage-dependent anion channel 1 (VDAC1) as a central mitochondrial hub. It connected respiratory chain subunits and autophagy regulators. ELISA confirmed higher plasma VDAC1, citrate synthase(CS) and secreted frizzled-related protein 2(SFRP2) in AF patients (all P < 0.001). Metabolomics identified 505 differentially abundant compounds. Glycerophospholipid and fatty acid pathways were disrupted. Integrated analysis revealed eight shared dysregulated pathways linked to energy metabolism. Four GEO datasets showed higher atrial VDAC1 transcripts in AF ( P < 0.05). Single-nucleus RNA-seq localized VDAC1 to cardiomyocytes. Conclusions Plasma protein and metabolite profiles differ between persistent AF and SVT. Mitochondrial and lipid pathways are both affected. VDAC1 is elevated in plasma, atrial tissue. These findings are supported across multiple cohorts.