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

doi:10.1016/j.jacc.2023.02.050

Journal of the American College of Cardiology

Volume 81, Issue 18, 9 May 2023, Pages 1780-1792

https://doi.org/10.1016/j.jacc.2023.02.050 Get rights and content

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)

Central Illustration

Section snippets

Methods

Study procedures were approved by the Mass General Brigham Institutional Review Board (IRB 2008P001076, IRB 2021P002474) and were conducted in accordance with the Declaration of Helsinki.

The rationale and design of the CASABLANCA study have been published.²⁹ The study was designed to identify circulating biomarkers predictive of short and long-term adverse events in individuals undergoing coronary or peripheral angiography. This is a convenience sample of patients who underwent angiography at

Baseline characteristics

Baseline characteristics of the 1,098 study participants are displayed in Table 1. Their mean age was 66.3 ± 11.4 years, 778 (70.9%) were male, and 1,022 (93.1%) were White. A minority of individuals (n = 214; 19.5%) underwent coronary angiography for an acute coronary syndrome (acute MI or unstable angina). The most common indication for catheterization was an abnormal stress test result (n = 421; 38.3%) (Supplemental Table 1). Prevalent CAD was present in 565 (51.5%) participants: 302 (27.5%)

Discussion

In a contemporary cohort of patients undergoing coronary angiography for both urgent and nonurgent indications, elevated Lp(a) and OxPLs increased the risks of both multiple coronary stenoses at baseline and cardiovascular events in follow-up. In contrast, LDL-C and apoB were negatively associated with all outcomes, a finding that likely reflects indication bias from higher-risk patients being prescribed more intense LDL-C–lowering regimens. These findings also highlight challenges in using

Conclusions

In a high-risk coronary angiography cohort, isoform-independent Lp(a) particle number and OxPLs associated with apoB and apo(a) were highly correlated and associated with the presence of severe coronary atherosclerosis at baseline and adverse cardiovascular outcomes in follow-up. Clinical trials of Lp(a)-lowering therapies will ultimately determine the extent to which Lp(a)-related residual risk can be mitigated.

COMPETENCY IN MEDICAL KNOWLEDGE: Lp(a) is a risk factor for atherosclerotic

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

Acknowledgments

The authors acknowledge and thank the participants of the CASABLANCA study.

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: Listen to this manuscript's audio summary by Editor-in-Chief Dr Valentin Fuster on www.jacc.org/journal/jacc.

: Anum Saeed, MD, served as Guest Associate Editor for this paper. Athena Poppas, MD, served as Guest Editor-in-Chief for this paper.

: The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.

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

Abstract

Background

Objectives

Methods

Results

Conclusions

Central Illustration

Section snippets

Methods

Baseline characteristics

Discussion

Conclusions

Funding Support and Author Disclosures

Acknowledgments

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

J Lipid Res

J Lipid Res

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

J Lipid Res

IJC Metab Endocr

J Am Coll Cardiol

Atherosclerosis

Metabolism

J Clin Lipidol

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol Intv

J Clin Lipidol

Heart disease and stroke statistics—2021 update

Circulation

Lipoprotein(a) and cardiovascular diseases

JAMA

Clinical utility of lipoprotein(a) and LPA genetic risk score in risk prediction of incident atherosclerotic cardiovascular disease

JAMA Cardiol

Deep-coverage whole genome sequences and blood lipids among 16,324 individuals

Nat Commun

Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease

Nat Genet

Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations

J Clin Invest

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