Methods: A CAD cohort (n=105) of a consecutive clinical study of which 66.7% of patients received statin treatment was characterized regarding the platelet lipidome. Lipid extracts of isolated platelets were comprehensively analyzed by untargeted lipidomics using liquid chromatography/high-resolution mass spectrometry which allowed identification of 928 lipids across 20 lipid classes. Multi-variate statistics was employed to test for confounding effects (comorbidities and co-medication).

Results: Volcano plots indicate that triglyceride (TGs) with fatty acyl (FA) carbon number between 46 and 53 containing monounsaturated FA 18:1 (MUFA) or FA 18:2, were significantly upregulated in the statin-group. These enhanced levels of MUFA-TGs could serve as a pool for MUFA-PCs which have shown beneficial antiferroptotic effects e.g. in cancer cells. Likewise, elevated 18:2-TGs can serve as pool for 18:2-PCs which upon release of 18:2 and 12-LOX activation can be metabolized to 13-HODE that was shown to inhibit thromboxane A₂ synthesis in human platelets. On contrary, a number of TGs with very-long chain FAs (FA 20:0) are down-regulated in the statin-treated group. These TGs can be regarded as a pool of the FA precursor of FA 20:4 which can be converted into prothrombotic and proinflammatory lipids (e.g. TXA2). Furthermore, CE 22:6, which represents a pool for PUFA-phospholipids, was higher in the statin-treated group. PUFA-PCs, in particular FA22:6-PCs, were found significantly downregulated in a recent study in acute coronary syndrom (ACS) as compared to chronic CS (CCS). It was further striking that ceramides (Cer) were significantly downregulated in the statin-group. Mitochondrial Cer levels are increased during apoptosis and elevated plasma Cer levels have been associated with significant CAD risk. It turns out that statin-lowers the Cer levels with possible consequence of antiapoptotic effects. Volcano plots further indicate that phospholipids with polyunsaturated FAs, e.g. FA 20:3, 20:4, 22:4, 22:5, (PUFA-PLs) (in particular PUFA-PEs and PUFA-PCs) are down-regulated in the statin-group vs statin-naïve. They may serve as substrates for oxidized PLs, amongst others leading to PC 18:0/HpETE and PC 16:0/HpETE. These PUFA-PL hydroperoxides are usually reduced by Glutathione peroxidases (e.g. GPx4) to the corresponding PUFA-PL hydroxides (e.g. PC 18:0/HETE and PC 16:0/HETE). The latter two lipids were elevated in the statin-treated group. It may indicate consolidated GPx bioactivity due to statin-treatment with favorable effect on the platelet redox state. In contrast, PUFA-PL hydroxides, such as PC 18:0/HETE, were found downregulated in ACS vs CCS, which could be due to GPx insufficiency in the more severe disease group. Thus, it can be hypothesized that statins have a beneficial effect on the cellular redox state of platelets.

Conclusion: Our data show that statin-treatment has a favorable effect on the platelet lipidome shifting the lipid metabolism towards lipids that are associated with reduced platelet reactivity.