BACKGROUND: Oxidized phospholipids (OxPLs) are carried by apolipoprotein B-100-containing lipoproteins (OxPL-apoB) including lipoprotein(a) (Lp[a]). Both OxPL-apoB and Lp(a) have been associated with calcific aortic valve disease (CAVD).
OBJECTIVES: This study aimed to evaluate the associations between OxPL-apoB, Lp(a) and the prevalence, incidence, and progression of CAVD.
METHODS: OxPL-apoB and Lp(a) were evaluated in MESA (Multi-Ethnic Study of Atherosclerosis) and a participant-level meta-analysis of 4 randomized trials of participants with established aortic stenosis (AS). In MESA, the association of OxPL-apoB and Lp(a) with aortic valve calcium (AVC) at baseline and 9.5 years was evaluated using multivariable ordinal regression models. In the meta-analysis, the association between OxPL-apoB and Lp(a) with AS progression (annualized change in peak aortic valve jet velocity) was evaluated using multivariable linear regression models.
RESULTS: In MESA, both OxPL-apoB and Lp(a) were associated with prevalent AVC (OR per SD: 1.19 [95% CI: 1.07-1.32] and 1.13 [95% CI: 1.01-1.27], respectively) with a significant interaction between the two (P < 0.01). Both OxPL-apoB and Lp(a) were associated with incident AVC at 9.5 years when evaluated individually (interaction P < 0.01). The OxPLapoB* Lp(a) interaction demonstrated higher odds of prevalent and incident AVC for OxPL-apoB with increasing Lp(a) levels. In the meta-analysis, when analyzed separately, both OxPL-apoB and Lp(a) were associated with faster increase in peak aortic valve jet velocity, but when evaluated together, only OxPL-apoB remained significant (ß: 0.07; 95% CI: 0.01-0.12).
CONCLUSIONS: OxPL-apoB is a predictor of the presence, incidence, and progression of AVC and established AS, particularly in the setting of elevated Lp(a) levels, and may represent a novel therapeutic target for CAVD.
Oxidized phospholipids (OxPLs) are generated in vivo by nonenzymatic and enzymatic pro-oxidant pathways that involve lipid peroxidation, cell membrane oxidation, and microparticle generation. Unlike native phospholipids, OxPLs are characterized by altered chemical modifications that are recognized as dangerassociated molecular patterns by the immune system. The interaction of OxPLs with specific receptors on a variety of vascular cells associated with the immune system results in acute and chronic inflammatory responses that lead to protein degradation, cellular dysfunction, apoptosis, cell necrosis, tissue fibrosis, and may also regulate cellular calcification pathways. OxPLs further mediate and amplify prooxidant and proinflammatory effects in a wide range of tissues, including atherosclerotic lesions and valvular interstitial cells. OxPLs are generated in tissues where excessive oxidation and inflammation occur, such as the liver and arterial walls, and their proinflammatory effects can be inhibited by murine monoclonal antibody E06 targeting OxPL. OxPLs are carried in the circulation by lipoproteins, particularly lipoprotein(a) (Lp[a]), and can be released into the circulation by disruption of atherosclerotic lesions. Circulating OxPLs can be measured on apolipoprotein B-100 as OxPL-apoB, which includes OxPL on Lp(a). Elevated levels of OxPL-apoB are associated with higher risk of adverse cardiovascular anatomical and clinical phenotypes, such as first and recurrent myocardial infarction and stroke.
Lp(a) levels in plasma are 80% to 90% genetically determined and are causally associated with calcific aortic valve disease (CAVD). Lp(a) has been associated with aortic valve calcium (AVC) in multiple imaging studies and with risk for aortic stenosis (AS) in epidemiologic and genetic studies. In addition, Lp(a) is associated with more rapid progression of AS and AVC. As such, Lp(a) represents a target for medical treatment for CAVD, and a clinical trial of Lp(a)-lowering therapy with the antisense oligonucleotide pelacarsen in individuals with mild-moderate AS, Lp(a) FRONTIERS CAVS (A Randomized Double-blind, Placebo-controlled, Multicenter Trial Assessing the Impact of Lipoprotein(a) Lowering With Pelacarsen [TQJ230] on the Progression of Calcific Aortic Valve Stenosis; NCT05646381). has recently been initiated.
Oxidized phospholipids can be measured on all apolipoprotein B-100 containing lipoproteins, including low-density lipoprotein (LDL), very low-density lipoprotein, intermediatedensity lipoprotein, and Lp(a), with the measurement described as OxPL-apoB. The methodology uses microtiter well plates in which a fixed and similar amount of apolipoprotein B-100 is captured from each plasma sample and the amount of OxPL is quantitated by the biotinylated monoclonal antibody E06 that recognizes OxPL. Because the amount of apolipoprotein B-100 on which OxPL is measured is the same from each plasma sample, this method reflects the OxPL carrying capacity of individual apolipoprotein B-100 particles and is independent of plasma apolipoprotein B-100 or low-density lipoprotein cholesterol (LDL-C) levels. Elevated OxPL-apoB levels are associated with the presence and progression of AVC and faster progression of AS, including in genome-wide association studies and post hoc analyses of several randomized clinical trials. However, the interaction between Lp(a) and OxPLapoB for the development and progression of CAVD in clinical studies, and thereby the primacy of each to the development of CAVD, has not been well studied primarily because of lack of power to analyze both in the same models. In the current study, we investigated whether OxPL-apoB levels, indicative of OxPL content across all apolipoprotein B100 lipoproteins, including Lp(a), are associated with the presence and progression of AVC and the progression of established AS, irrespective of Lp(a) concentration.