Low-density lipoprotein electronegativity and risk of death after acute coronary syndromes: A case-cohort analysis

The identification of novel cardiovascular risk factors is limited by tradeoffs between statistical power, resource availability (e.g., complexity of sample preparation and analysis), and costs. Case-cohort studies have emerged as an attractive epidemiological approach to study the association between exposures and disease outcomes [1,2], particularly when a full-cohort design is not feasible due to resource constraints [3]. The case-cohort design, first proposed by Prentice [4], delineates the framework of an observational study in which a random subset of the full cohort is selected, while all newly occurring cases within the original cohort are concurrently included. This study design provides high efficiency and flexibility enabling the cost-effective investigation of multiple exposures while minimizing the risk of selection bias owing to outcome-dependent sampling, as it may occur in nested case-control studies, providing precise estimates of exposure-outcome associations of the full-cohort [3,5].

Low-density lipoprotein (LDL) indubitably promotes the initiation and progression of atherosclerotic cardiovascular disease (ASCVD), with alterations in LDL quality representing an important but understudied determinant of ASCVD risk [[6], [7], [8]]. In patients with a recent acute coronary syndrome (ACS) or established ASCVD, interventions that lower levels of LDL-cholesterol (LDL-C) improve cardiovascular outcomes, but the residual risk remains high [9,10]. Observational studies examining the relationship between baseline LDL-C levels and mortality in patients with ACS have yielded discordant outcomes: one study has reported a counterintuitive inverse relationship [11], while others did not establish any association [12,13], potentially due to other factors influencing short-to-mid-term outcomes post-ACS. Whilst traditional cardiovascular risk factors, such as those informing the Framingham risk score [14], are undeniably linked to long-term risk of cardiovascular events, biomarkers other than cholesterol levels have been shown to determine 1-year outcomes after the index ACS [12,15,16].

LDL particles ship their water-insoluble lipid cargo in a polar shell of apolipoproteins which serve as a molecular fingerprint to direct them to specific cell types. A single apolipoprotein (apo) B100 molecule encircles the LDL particle and stabilizes the outer unilamelar layer consisting of amphiphilic phospholipids, sphingolipids and unesterified cholesterols, with its hydrophobic core containing a conglomerate of cholesteryl esters and triacylglycerols [17]. Beyond the presence of additional proteins (e.g., apoC-III) and the degree of sialylation, lipid composition represents a major determinant of LDL charge [18], with electronegative properties of LDL particles impinging on their pro-atherogenic and pro-thrombotic effects [19,20], the latter being particularly relevant in patients with a recent ACS. However, the association of altered LDL electronegativity and mortality in these patients is uncertain, and data on corresponding changes in the LDL particles’ lipidome remain limited.

To address this knowledge gap, we aimed (1) to determine the associations of LDL electronegativity with all-cause and cardiovascular mortality, (2) to test its predictive utility beyond and above established risk scores, and (3) to study the lipidome of least (L1) and most electronegative (L5) LDL particles in patients with ACS who were prospectively recruited at four university hospitals in Switzerland.

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