Large-scale lipidomics profiling reveals characteristic lipid signatures associated with an increased cardiovascular risk

Abstract

Abstract Background Patients with cardiovascular disease (CVD) are at high risk to develop adverse events.1 The distinct risk of developing recurring adverse cardiovascular events is not solely explained by traditional risk factors.2-4 Platelets are essentially involved in progression of CVD including coronary artery disease (CAD) and platelet hyperreactivity leads to development of adverse cardiovascular (CV) events.5-7 Alterations in the platelet lipidome are associated with disease severity in CAD and lead to platelet hyperresponsiveness and thus might alter the individual risk profile.8,9 Objective In this study we investigate the platelet lipidome of CAD patients by untargeted lipidomics and elucidate alterations in the lipid composition of patients with recurring adverse cardiovascular events. Methods We characterized the platelet lipidome in a large consecutive CAD cohort (n=1057) by an untargeted lipidomics approach using liquid chromatography coupled to mass spectrometry. Results The platelet lipidome in this study covered 767 lipids and characteristic changes occurred in patients with adverse cardiovascular events. The most prominent upregulated lipids in patients with cardiovascular events primarily belong to the class of phospholipids (lysophosphatidylethanolamines (LPE)) and fatty acyls (acylcarnitines (CAR) and unsaturated fatty acids (FA)). It was striking that patients with ischemic events exclusively showed upregulation of LPE whereas mainly CAR and FA were upregulated in patients with major bleeding events in contrast to patients without CV events (Figure 1 A, B). PCA revealed a major separation of patients with adverse CV events when compared to patients free from any events during follow-up indicating a substantial change in the platelet lipidome of patients with adverse CV events (Figure 1C). Further, upregulated platelet lipids are associated with an increased cardiovascular or bleeding risk and independently predict upcoming adverse events (Figure 2 A, B). Stratification of an increased CV risk in patients with CAD including platelet lipids outperformed conventional risk assessment utilizing conventional lipids measurements (e.g. plasma lipoproteins) (Figure 2 C). In addition, specific alterations of the platelet lipidome, including LPE and CAR are associated with modulation of in vitro platelet functions and thus, might contribute to the development of adverse CV events by promotion or inhibition of platelet functions (Figure 2D, E). Conclusions Our results reveal that the composition of the platelet lipidome is altered in CVD patients with an increased cardiovascular risk and distinct platelet lipids may indicate adverse events. Results of this study may contribute to improved risk discrimination and classification for cardiovascular events in patients with CVD. Further, altered lipid signatures might modulate platelet function and contribute to disease progression and development of adverse CV events in patients with CVD.Figure 1Figure 2