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Meta-Analysis
. 2024 Dec 17;84(25):2430-2441.
doi: 10.1016/j.jacc.2024.08.070. Epub 2024 Nov 15.

Oxidized Phospholipids and Calcific Aortic Valvular Disease

Harpreet S Bhatia  1 , Marc R Dweck  2 , Neil Craig  2 , Romain Capoulade  3 , Philippe Pibarot  4 , Patrick J Trainor  5 , Seamus P Whelton  6 , Rishi Rikhi  7 , Karita C F Lidani  8 , Wendy S Post  6 , Michael Y Tsai  9 , Michael H Criqui  10 , Michael D Shapiro  7 , Matthew J Budoff  11 , Andrew P DeFilippis  8 , George Thanassoulis  12 , Sotirios Tsimikas  13
Affiliations
Meta-Analysis

Oxidized Phospholipids and Calcific Aortic Valvular Disease

Harpreet S Bhatia et al. J Am Coll Cardiol. .

Abstract

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 OxPL-apoB∗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.

Keywords: aortic valve; calcification; computed tomography; lipoprotein(a); oxidized phospholipids; subclinical atherosclerosis.

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Conflict of interest statement

Funding Support and Author Disclosures Dr Bhatia is supported by National Institutes of Health (NIH) grants 1K08HL166962 and 1KL2TR001444. Dr Dweck is supported by the British Heart Foundation (FS/SCRF/21/32010) and is the recipient of the Sir Jules Thorn Award for Biomedical Research 2015 (15/JTA). Dr Craig is supported by the Medical Research Council (MR/Y009932/1). Dr Rikhi is supported by the National Heart, Lung, and Blood Institute (NHLBI) of NIH under Award Number T32HL076132. Dr Budoff was supported by R01 HL071739 and R01HL146666. Dr Thanassoulis was supported by NIH R01 HL128550-04 and is funded by the FRQS as a Senior Clinician Scientist. Dr Tsimikas is supported by NHLBI grants R01 HL159156 and HL170224. The MESA was supported by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from NHLBI, and by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences (NCATS). The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. Dr Bhatia has served on the scientific advisory boards for Novartis, Abbott, and Arrowhead; and has served as a consultant for Kaneka and Novartis. Dr Dweck has received speaker fees from Pfizer, Radcliffe Cardiology, Amarin, Bristol Myers Squibb, Edwards, and Novartis; and has received consultancy fees from Novartis, Jupiter Bioventures, AstraZeneca, Beren, and Silence therapeutics. Dr Capoulade has received an honorarium from Novartis. Dr Shapiro has received grants from Amgen, Boehringer Ingelheim, 89Bio, Esperion, Genentech, Novartis, Ionis, Merck, and New Amsterdam; has served on scientific advisory boards of Amgen, Agepha, Ionis, Novartis, Precision BioScience, and New Amsterdam; and has served as a consultant for Ionis, Novartis, Regeneron, Aidoc, Shanghai Pharma Biotherapeutics, Kaneka, and Novo Nordisk. Dr Budoff has received grant support from Amgen. Dr Tsimikas is a co-inventor and receives royalties from patents owned by the University of California-San Diego (UCSD); is a co-founder and has an equity interest in Oxitope and Kleanthi Diagnostics; is a consult to Novartis; and has a dual appointment at UCSD and Ionis Pharmaceuticals (the terms of this arrangement have been reviewed and approved by UCSD in accordance with its conflict-of-interest policies). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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