Insights into Human Cardiac Lipid Dynamics Through Comprehensive Arteriovenous Lipidomics.

AIMS: Lipid metabolism is fundamental to cardiac function, with free fatty acids (FFAs) as the primary energy substrate in the adult heart. A comprehensive analysis of human cardiac lipid dynamics remains elusive. This study aimed to assess human cardiac lipid metabolism using arteriovenous lipidomics to explore lipid import and export dynamics within the heart. METHODS AND RESULTS: In this prospective observational study, 59 patients undergoing catheter ablation for atrial arrhythmias were enrolled. Arterial and coronary sinus venous blood samples were collected. Plasma underwent targeted lipidomics, detecting 1,464 lipid species spanning 20 classes; 851 species were analyzed. Paired comparisons used separate Benjamini-Hochberg corrections for classes and species. The heart exhibited a strong net uptake of FFAs (-122.4 μmol/L; 95% CI, -146.0 to -98.8; q=1.49×10-13) and a nonsignificant uptake of triglycerides. Lysophosphatidylcholine was released (+4.32 μmol/L; 95% CI, 2.45 to 6.19; q=2.12×10-4); no other class met q<0.05. Thirty-two species met q<0.05. Release from other classes offset FFA and triglyceride uptake on average, yielding a positive aggregate acyl-chain-equivalent difference (+28.2 μmol acyl-chain equivalents/L), although the confidence interval included both uptake and release (95% CI, -112.8 to 169.2; P=0.690). CONCLUSION: This comprehensive assessment of human cardiac lipid dynamics using arteriovenous lipidomics reveals a complex interplay of lipid import and export under fasting conditions. Further studies are warranted to elucidate the source of the released lipids and explore cardiac lipid handling in the fed state. TRANSLATIONAL PERSPECTIVE: This study delivers a comprehensive quantification of human cardiac lipid exchange by combining arterial and coronary sinus sampling with targeted lipidomics in 59 fasting patients. Distinct handling patterns emerged: the heart imports free fatty acids and releases selected lipids, with lysophosphatidylcholine release and 32 species-level differences surviving correction for multiple testing. Release from other classes offset free-fatty-acid and triglyceride uptake on average, although the aggregate estimate was imprecise. These findings refine our understanding of cardiac lipid handling and provide a basis for studies in heart failure and broader cardiometabolic disease.