LAUSR

Novel biomarkers that accurately report the risk of cardiovascular events such as myocardial infarction have long been sought after. This is driven by the need to inform clinical diagnostic pathways and to optimize therapeutic approaches with the ultimate aim of reducing cardiovascular mortality and morbidity. Technical advances in the sensitivity, precision, and throughput of analytical instruments have recently facilitated unprecedented profiling approaches to identify specific mRNA, microRNA, genetic, proteomic, metabolomic, and, most recently, lipidomic profiles associated with cardiovascular risk. Plasma has been the major compartment utilised in such profiling studies, while urine has also attracted interest, particularly for proteomic profiling. In this issue of the journal, Chatterjee et al. go a step further and perform lipidomic profiling in patients with coronary artery disease in a specific cellular compartment of the blood—the platelet. Platelets are central players in orchestrating thrombotic and inflammatory responses. They promote vascular inflammation, and hence the initiation and progression of atherosclerosis, in addition to accumulating with remarkable alacrity upon plaque rupture or erosion to form the nidus of occlusive arterial thrombi. Platelets contain abundant quantities of lipids, which play fundamental roles in regulating platelet structure, signalling, and, ultimately, function, including platelet activation. Chatterjee et al. establish platelets as a separate compartment of lipid metabolism, including oxidation/peroxidation that can accrue specific lipid species (Figure 1A). Notably, platelets provide a specific, potentially shielded environment, less accessible to enzymes such as the phopholipases that can metabolize oxidized phospholipids in plasma. This is emphasized by the finding that increased oxidized LDL (oxLDL) in platelets was found to be associated with stable coronary artery disease and ST-segment elevation myocardial infarction (STEMI), which stands in contrast to data demonstrating a lack of correlation between plasma oxLDL levels and cardiovascular risk. Platelets may provide a unique window to view intracellular lipid metabolism, potentially reflective of the lipidome in unstable atherosclerotic plaques. This raises the intriguing prospect that the platelet lipidome may report on the atherothrombotic risk in patients. Furthermore, via platelet adhesion to atherosclerotic plaques and consequent deposition of ‘pathological’ lipids, the platelet lipidome indeed may not only report on, but may also directly contribute to plaque instability (Figure 1B). Furthermore, the platelet lipidome may also serve as a tool to monitor the efficacy of riskreducing therapeutic approaches. The continued development of liquid chromatography and mass spectrometry systems has driven the field of lipidomics over recent years. Current lipidomic strategies typically rely on either shotgunbased approaches (i.e. direct infusion into the mass spectrometer, without the use of chromatography) or chromatography-based approaches, typically using high-pressure liquid chromatography. Both these approaches have their advantages and limitations, which have been discussed in recent reviews. A second distinction in lipidomic strategies relates to the use of targeted or untargeted approaches. Targeted analysis relates to the foreknowledge of the lipid species to be analysed and is typically performed using liquid chromatography coupled to a triple quadrupole mass spectrometer with multiple reaction monitoring (MRM) experiments tuned to a specific set of lipid species. Untargeted analyses (as applied by Chatterjee et al.) is typically performed on a high-resolution instrument, with or without chromatography, and relies on scanning experiments to capture information on all lipid species within the detection capabilities of the instrument. Subsequent statistical analyses can identify those features of interest, which can then be identified by a combination of exact mass measurement, fragmentation analysis, and database searching. While an untargeted approach provides greater potential for discovery, targeted lipidomics is more