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. 2026 Jan 7:e255043.
doi: 10.1001/jamacardio.2025.5043. Online ahead of print.

Thirty-Year Risk of Cardiovascular Disease Among Healthy Women According to Clinical Thresholds of Lipoprotein(a)

Ask Tybjærg Nordestgaard  1   2 , Daniel I Chasman  1   3 , Vinayaga Moorthy  1 , Jordan M Kraaijenhof  4 , Nancy R Cook  1   3 , I-Min Lee  1   3 , Julie E Buring  1   3 , Paul M Ridker  1   3   5
Affiliations

Thirty-Year Risk of Cardiovascular Disease Among Healthy Women According to Clinical Thresholds of Lipoprotein(a)

Ask Tybjærg Nordestgaard et al. JAMA Cardiol. .

Abstract

Importance: Elevated lipoprotein(a) predicts high risk of cardiovascular disease among a modest proportion of healthy individuals, an issue that complicates screening guidelines.

Objective: To examine spline models, clinical thresholds, and percentiles of baseline lipoprotein(a) levels as 30-year determinants of cardiovascular risk.

Design, setting, and participants: This cohort study was conducted among female health professionals participating in the Women's Health Study, who were followed up prospectively from 1993 to 2023. Women without cardiovascular disease, cancer, and other major chronic illnesses had blood samples taken at baseline. All individuals with lipoprotein(a) measurements and/or of European ancestry with genotype information for the LPA rs3798220 variation were included. Data analyses were performed from January through April 2025.

Exposures: Continuously valued baseline lipoprotein(a), lipoprotein(a) clinical thresholds and percentiles, and LPA rs3798220 genotypes known to predict lipoprotein(a) levels among individuals of European ancestry.

Main outcomes and measures: The primary outcomes were incident major cardiovascular events, coronary heart disease, ischemic stroke, and cardiovascular death. Age- and multivariable-adjusted cause-specific Cox models were used to calculated hazard ratios for the cardiovascular outcomes. The hypothesis was formulated after collection of the data.

Results: A total of 27 748 women with baseline lipoprotein(a) measurements and 23 279 women of European ancestry with rs3798220 genotype information were included (median [IQR] age, 53 [49-60] years), among whom 3707 and 3165 major cardiovascular events, respectively, accrued during a median (IQR) follow-up period of 27.8 (22.8-29.4) years. Among women with lipoprotein(a) measurements, lipoprotein(a) levels above 30 mg/dL or the 75th percentile (31 mg/dL) were associated with increased 30-year risk of major cardiovascular events and coronary heart disease. Levels above 120 mg/dL or the 99th percentile (131 mg/dL) were associated with increased risk of ischemic stroke and cardiovascular death. Multivariable adjusted hazard ratios for levels above 120 mg/dL vs below 10 mg/dL or above the 99th percentile vs below the 50th percentile (11 mg/dL) were 1.54 (95% CI, 1.24-1.92) and 1.74 (95% CI, 1.35-2.25) for major cardiovascular events, 1.80 (95% CI, 1.36-2.37) and 2.06 (95% CI, 1.49-2.84) for coronary heart disease, 1.41 (95% CI, 0.93-2.15) and 1.85 (95% CI, 1.17-2.93) for ischemic stroke, and 1.63 (95% CI, 1.16-2.28) and 1.86 (95% CI, 1.26-2.72) for cardiovascular death, respectively. Among women with genotype information, rs3798220 minor allele carriers had a higher risk of major cardiovascular events.

Conclusions and relevance: Per the results of this cohort study, very high lipoprotein(a) levels correlated with increased 30-year risk of cardiovascular disease among healthy women. Screening for elevated lipoprotein(a) in the general population may be warranted.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Nordestgaard reported grants from The Independent Research Fund Denmark during the conduct of the study. Dr Chasman reported a patent for LPA polymorphism (rs3798220) and aspirin use for CVD prevention, with royalties paid from Quest Diagnostics. Drs Lee and Buring reported grants from the US National Institutes of Health (NIH) during the conduct of the study. Dr Ridker reported institutional grants from Kowa, Novo Nordisk, Pfizer, the US National Cancer Institute, and the US National Heart, Lung, and Blood Institute and personal fees from Agepha, AstraZeneca, Cario Therapeutics, CSL Behring, Eli Lilly, New Amsterdam, NodThera, Novartis, Novo Nordisk, and Tourmaline Bio outside the submitted work. No other disclosures were reported.

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