Circulating Organic Acid Profiles in Non-Ischaemic Cardiomyopathy: A Case-Control Study

Metabolic remodeling is increasingly recognized as a key component of cardiomyopathy, yet the circulating organic acid profile associated with this condition remains incompletely characterized. In this case-control study, we investigated differences in circulating organic acid profiles between patients with cardiomyopathy and control participants using targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 160 participants were enrolled, including 80 patients with cardiomyopathy and 80 age- and sex-comparable control participants. Circulating organic acids were quantitatively analyzed, and between-group differences were assessed using the two-sided Mann-Whitney U test with Benjamini-Hochberg false discovery rate correction; effect sizes were estimated using Cliff's delta. Detection rates were also examined because several metabolites included values below the assay limit of detection. Sixteen metabolites remained significant after correction. Among these, 3-hydroxyisovaleric acid demonstrated the largest increase, followed by 2-oxoglutaric acid and 2-methylcitric acid. Additional elevations were observed in citric acid, malic acid, N-acetylaspartic acid, fumaric acid, and suberic acid, whereas 2-oxoadipic acid was reduced. These alterations are consistent with perturbations in mitochondrial intermediary metabolism, branched-chain amino acid catabolism, ketone body metabolism, and tricarboxylic acid cycle-related pathways. However, because comorbidities, renal function, glycemic status, and medication use differed between groups, the findings should be interpreted as phenotype-associated metabolic signals rather than cardiomyopathy-specific causal effects or validated diagnostic biomarkers. In conclusion, targeted LC-MS/MS-based organic acid profiling reveals an altered circulating metabolic pattern in cardiomyopathy, although further prospective studies with individual-level adjustment and external validation are required to determine its clinical relevance.