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. 2023 May 9;81(18):1780-1792.
doi: 10.1016/j.jacc.2023.02.050.

Lipoprotein(a), Oxidized Phospholipids, and Coronary Artery Disease Severity and Outcomes

Thomas C Gilliland  1 , Yuxi Liu  2 , Reza Mohebi  2 , Hannah Miksenas  2 , Sara Haidermota  3 , Megan Wong  3 , Xingdi Hu  4 , Joaquim Rosado Cristino  4 , Auris Browne  4 , Jorge Plutzky  5 , Sotirios Tsimikas  6 , James L Januzzi Jr  7 , Pradeep Natarajan  8
Affiliations

Lipoprotein(a), Oxidized Phospholipids, and Coronary Artery Disease Severity and Outcomes

Thomas C Gilliland et al. J Am Coll Cardiol. .

Abstract

Background: Lipoprotein(a) (Lp[a]) and oxidized phospholipids (OxPLs) are each independent risk factors for atherosclerotic cardiovascular disease. The extent to which Lp(a) and OxPLs predict coronary artery disease (CAD) severity and outcomes in a contemporary, statin-treated cohort is not well established.

Objectives: This study sought to evaluate the relationships between Lp(a) particle concentration and OxPLs associated with apolipoprotein B (OxPL-apoB) or apolipoprotein(a) (OxPL-apo[a]) with angiographic CAD and cardiovascular outcomes.

Methods: Among 1,098 participants referred for coronary angiography in the CASABLANCA (Catheter Sampled Blood Archive in Cardiovascular Diseases) study, Lp(a), OxPL-apoB, and OxPL-apo(a) were measured. Logistic regression estimated the risk of multivessel coronary stenoses by Lp(a)-related biomarker level. Cox proportional hazards regression estimated the risk of major adverse cardiovascular events (MACEs) (coronary revascularization, nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) in follow-up.

Results: Median Lp(a) was 26.45 nmol/L (IQR: 11.39-89.49 nmol/L). Lp(a), OxPL-apoB, and OxPL-apo(a) were highly correlated (Spearman R ≥0.91 for all pairwise combinations). Lp(a) and OxPL-apoB were associated with multivessel CAD. Odds of multivessel CAD per doubling of Lp(a), OxPL-apoB, and OxPL-apo(a) were 1.10 (95% CI: 1.03-1.18; P = 0.006), 1.18 (95% CI: 1.03-1.34; P = 0.01), and 1.07 (95% CI: 0.99-1.16; P = 0.07), respectively. All biomarkers were associated with cardiovascular events. HRs for MACE per doubling of Lp(a), OxPL-apoB, and OxPL-apo(a) were 1.08 (95% CI: 1.03-1.14; P = 0.001), 1.15 (95% CI: 1.05-1.26; P = 0.004), and 1.07 (95% CI: 1.01-1.14; P = 0.02), respectively.

Conclusions: In patients undergoing coronary angiography, Lp(a) and OxPL-apoB are associated with multivessel CAD. Lp(a), OxPL-apoB, and OxPL-apo(a) are associated with incident cardiovascular events. (Catheter Sampled Blood Archive in Cardiovascular Diseases [CASABLANCA]; NCT00842868).

Keywords: atherosclerosis; coronary artery disease; lipids and lipoproteins; lipoprotein(a).

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Conflict of interest statement

Funding Support and Author Disclosures This study was sponsored by Novartis. The sponsor provided feedback on the study design but not data interpretation. Dr Gilliland has received partial supported from the National Heart, Lung, and Blood Institute (NHLBI) (T32 grant 5T32HL125232). Dr Mohebi has received support from the Dennis and Marilyn Barry fellowship. Dr Hu is an employee of Novartis. Mr Cristino was an employee of Novartis at the time of manuscript preparation. Dr Browne is an employee of Novartis. Dr Tsimikas has received support from the NHLBI (grant R01HL159156), Fondation Leducq, and Novartis (research grant for the measurement of Lp[a] and OxPL levels); is a co-inventor and has received royalties from patents owned by the University of California San Diego (UCSD); is a co-founder and has an equity interest in Oxitope and its affiliates, Kleanthi Diagnostics, and Covicept Therapeutics; and has a dual appointment at UCSD and Ionis Pharmaceuticals. Dr Januzzi has received partial support from the Hutter Family Professorship; has served as a trustee of the American College of Cardiology; has served as a board member of Imbria Pharmaceuticals; has received grant support from Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Abbott Diagnostics; has received consulting income from Abbott, Janssen, Jana Care, Novartis, Prevencio, and Roche Diagnostics; and has participated in clinical endpoint committees or data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, MyoKardia, and Takeda. Dr Natarajan has received support from the NHLBI (grants R01HL142711, R01HL127564, R01HL148050, R01HL151283, R01HL148565, R01HL135242, and R01HL151152), the National Institute of Diabetes and Digestive and Kidney Diseases (grant R01DK125782), Fondation Leducq (grant TNE-18CVD04), and Massachusetts General Hospital (Paul and Phyllis Fireman Endowed Chair in Vascular Medicine); has received personal consulting fees from Amgen, Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Genentech, Novartis, and TenSixteen Bio; has received investigator-initiated grants from Apple, AstraZeneca, and Boston Scientific; is a co-founder of TenSixteen Bio; has equity in TenSixteen Bio, geneXwell, and Vertex; and has spousal employment at Vertex, all unrelated to the present work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

Figure 1.
Figure 1.. Correlation heatmap between Lp(a) biomarkers and traditional lipid parameters.
Spearman correlations between log2-transformed Lp(a), OxPL-apo(a), and OxPL-apoB, and between each Lp(a)-related biomarker and traditional lipid parameters. Cells are highlighted with ‘*’ when meeting P-value threshold of P<0.05. ApoB = apolipoprotein B; HDL-C = high density lipoprotein cholesterol; LDL-C = low density lipoprotein cholesterol; Lp(a) = lipoprotein(a); OxPL = oxidized phospholipid; TG = triglycerides; total-C = total cholesterol.
Figure 2.
Figure 2.. Association between Lp(a), OxPL-apo(a), and OxPL-apoB and angiographic CAD.
A) Logistic regression estimated the odds of one or more coronary stenoses (‘Any CAD’) or two or more coronary stenoses (‘Multi-vessel CAD’) per doubling of Lp(a), OxPL-apo(a), and OxPL-apoB in both unadjusted models and models adjusted for age, body-mass index, diabetes mellitus, high density lipoprotein cholesterol, hypertension, low density lipoprotein cholesterol, sex, systolic blood pressure, smoking status, and statin use. Results are plotted as odds ratio with 95% confidence interval. (B) Prevalence of ‘Multi-vessel CAD’ for quintiles of Lp(a), OxPL-apoB, and OxPL-apo(a). CAD = coronary artery disease; Lp(a) = lipoprotein(a); OxPL-apo(a) = oxidized phospholipid on apo(a); OxPL-apoB = oxidized phospholipid on apoB.
Figure 3.
Figure 3.. Association between Lp(a), OxPL-apoB, and OxPL-apo(a) and MACE.
Cox proportional hazards regression estimated the hazard of MACE in follow-up per doubling of Lp(a), OxPL-apo(a), and OxPL-apoB in both unadjusted models and models adjusted for age, body-mass index, diabetes mellitus, high density lipoprotein cholesterol, hypertension, low density lipoprotein cholesterol, sex, systolic blood pressure, smoking status, and statin use. Results are plotted as hazard ratio with 95% confidence interval. CI = confidence interval; Lp(a) = lipoprotein(a); MACE = major adverse cardiovascular events; OxPL-apo(a) = oxidized phospholipid on apo(a); OxPL-apoB = oxidized phospholipid on apoB.
Central illustration.
Central illustration.. Lp(a)-related Biomarkers and Coronary Artery Disease Burden and Cardiovascular Outcomes.
Lipoprotein(a) [Lp(a)] and oxidized phospholipids associated with apolipoprotein B (OxPL-apoB) and apolipoprotein(a) [OxPL-apo(a)] were measured among CASABLANCA participants undergoing coronary angiography at baseline. Top left panel: histograms demonstrating population distribution of Lp(a), OxPL-apoB, and OxPL-apo(a) among 1098 individuals. Bottom left panel: pairwise correlations between Lp(a), OxPL-apoB, and OxPL-apo(a) within the cohort. Blue line is the linear relationship. Top right panel: Prevalence of angiographic ‘Multi-Vessel CAD’ (≥ 2 severe coronary stenoses) at baseline angiography according to quintile of Lp(a), OxPL-apo(a), or OxPL-apoB. Bottom right panel: Cox proportional hazards regression estimated the risk of major adverse cardiovascular events in follow-up per doubling of Lp(a), OxPL-apoB, or OxPL-apo(a) in unadjusted models and models adjusted for the study covariates. CAD = coronary artery disease; CI = confidence interval; Lp(a) = lipoprotein(a); OxPL-apo(a) = oxidized phospholipids on apo(a); OxPL-apoB = oxidized phospholipids on apoB.
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