Background.: Outcomes in heart transplantation are affected by a variety of variables and patient factors. However, the impact of circadian rhythms, gene expression, and transcription remain underexplored. We thus evaluated the potential role of donor heart cross-clamp times on short-term and long-term outcomes after heart transplantation. Methods.: A total of 31 713 heart transplants were identified from the United Network for Organ Sharing Database. Patients were first stratified on the basis of time of donor procurement: 12 am to 12 pm or 12 pm to 12 am. To evaluate a possible effect of circadian rhythms, donor time was further divided into 5 groups based on preclinical data: 4 am to 8 am; 8 am to 11 am; 11 am to 5 pm; 5 pm to 10 pm; 10 pm to 4 am. Groups were assessed with comparative statistics. Long-term survival was evaluated using Kaplan-Meier methods and a multivariate Cox proportional hazard model. Results.: Patients who received hearts recovered between 12 am and 12 pm had significantly higher survival than those who received hearts recovered between 12 pm and 12 am. This survival difference was observed in both unadjusted (P = 0.002) and adjusted analyses (hazard ratio [HR]: 0.93; 95% confidence interval [CI], 0.89-0.97; P < 0.001). On unadjusted analysis, the survival difference among the 5 groups was insignificant (P = 0.07). Following adjustment, the periods of 11 am to 5 pm (HR: 1.09, 95% CI, 1.02-1.17; P = 0.012), 5 pm to 10 pm (HR: 1.11; 95% CI, 1.04-1.19; P = 0.002), and 10 pm to 4 am (HR: 1.07; 95% CI, 1.01-1.15; P = 0.034), were all independently associated with increased long-term mortality. Notably, the time of 8 am to 11 am was not associated with a change in survival (HR: 1.04; 95% CI, 0.96-1.14; P = 0.3). Conclusions.: Given the independent association of donor timing and survival after adjustment in a large national cohort, further investigation into the role of donor circadian rhythm and donor procurement time is warranted in preclinical and clinical studies. Understanding the underlying mechanisms of this observation could potentially lead to the development of effective treatments and donor procurement processes that prepare the organs for transplantation in a better condition.

To clarify the mechanism of myocardial injury associated with lipid peroxidation and the role of fatty acid binding proteins FABP3/4 during Static cold storage (SCS) of donor hearts. Multi-omics analysis included mouse myocardial metabolomics and transcriptomics, proteomics of cardiac preservation solution in SCS injury. Lipid peroxidation was detected by malondialdehyde, transmission electron microscopy (TEM), and fluorescent probes. Lipid peroxidation antagonist MitoQ was examined by TEM. FABP3/4 were analyzed by combining the proteomic data of first perfusion serum from human donor hearts with those of mouse myocardial SCS solution. Overexpressing FABP3/4 were evaluated by detecting ROS and apoptosis via flow cytometry. snRNA-seq revealed the cellular landscape of SCS injury in pig cardiomyocytes. Multi-omics analysis of the SCS injury model revealed significant changes in lipid metabolism. Disturbed lipid metabolism and peroxidation were demonstrated in mouse SCS injury model and cell model. MitoQ attenuated lipid peroxidation and antagonized cardiac SCS injury. FABP3/4 were released during SCS and promoted injury in cardiomyocytes. In SCS solution, FABP3/4 expression were improved in both short-term and long-term SCS. In myocardial tissue, FABP3 expression decreased during short-term SCS and then gradually increased after long-term SCS. FABP4 expression were first upregulated and then decreased, remaining stable during long-term SCS. Pig cardiomyocytes showed low FABP3 and high FABP4 expression during short-term SCS. Disturbed lipid metabolism and peroxidation occur during SCS of hearts. FABP3/4 promote lipid uptake and aggravate SCS damage. FABP3/4 should be further investigated as potential therapeutic targets for SCS injury during heart transplantation.