Highlights
Elevated levels of Lipoprotein(a) [Lp(a)] serve as a robust, independent predictor of major cardiovascular events (MACE) and ischemic stroke over a 30-year period in initially healthy women.
While Lp(a) levels above 30 mg/dL significantly increase the risk for coronary heart disease, much higher levels—exceeding 120 mg/dL—are required to significantly predict long-term ischemic stroke and cardiovascular mortality.
The risk of stroke is compounded when elevated Lp(a) is present alongside high-sensitivity C-reactive protein (hsCRP) and LDL cholesterol, with women possessing elevations in all three biomarkers facing a 79% higher risk of ischemic stroke.
Genetic evidence confirms that carriers of the LPA rs3798220 minor allele are at a higher risk of major cardiovascular events, reinforcing the causal role of Lp(a) in atherosclerotic disease.
Introduction: Beyond the 10-Year Risk Model
In the traditional framework of cardiovascular risk assessment, clinicians have long relied on 10-year risk calculators to guide primary prevention. However, this short-term focus may significantly underestimate the lifetime burden of atherosclerotic cardiovascular disease (ASCVD), particularly in women who often present with lower short-term risk scores despite underlying genetic predispositions. Among the emerging biomarkers, Lipoprotein(a) has gained prominence as a genetically determined, independent risk factor that remains largely unaffected by standard lifestyle modifications or traditional statin therapy.
Lipoprotein(a) consists of an LDL-like particle covalently bound to apolipoprotein(a). Its structure confers both pro-atherogenic and pro-thrombotic properties. Despite its known clinical significance, screening guidelines have remained conservative, often limiting testing to those with a strong family history. New evidence from the Women’s Health Study (WHS) now challenges this approach, providing a compelling look at how baseline Lp(a) levels dictate health outcomes over three decades of a woman’s life.
Study Design: The Legacy of the Women’s Health Study
The insights presented here are derived from two pivotal analyses of the Women’s Health Study, a prospective, longitudinal cohort of female health professionals in the United States. The first study, published in JAMA Cardiology, focused on 27,748 women followed from 1993 to 2023 to examine the relationship between Lp(a) thresholds and MACE, coronary heart disease (CHD), and ischemic stroke. The second study, published in Lancet Neurology, expanded this scope to examine the interplay between Lp(a), LDL cholesterol, and hsCRP in predicting stroke risk among 28,345 participants.
Participants were initially healthy women aged 45 years or older, free of cardiovascular disease and cancer at baseline. The long-term follow-up—median 27.8 years—allowed researchers to capture the slow, cumulative progression of ASCVD, providing a unique window into the natural history of risk associated with these biomarkers.
Lipoprotein(a) Thresholds and 30-Year Cardiovascular Outcomes
The JAMA Cardiology study utilized spline models and specific clinical thresholds to determine at what level Lp(a) becomes a significant hazard. The findings suggest that the risk associated with Lp(a) is continuous, but specific clinical inflection points are noteworthy:
Coronary Heart Disease and MACE
For major cardiovascular events and coronary heart disease, a threshold of 30 mg/dL (roughly the 75th percentile) marked the beginning of increased risk. Women with Lp(a) levels above 120 mg/dL (the 99th percentile) compared to those below 10 mg/dL showed a hazard ratio (HR) of 1.54 (95% CI, 1.24-1.92) for MACE and 1.80 (95% CI, 1.36-2.37) for CHD. When using percentiles, those above the 99th percentile had a more than two-fold increased risk of CHD (HR 2.06) compared to those below the 50th percentile.
Stroke and Cardiovascular Death
Interestingly, the threshold for stroke prediction appears higher than that for coronary events. Lp(a) levels above 120 mg/dL or the 99th percentile were associated with a significant increase in ischemic stroke (HR 1.85) and cardiovascular death (HR 1.63). This suggests that while moderate elevations in Lp(a) are hazardous for the coronary arteries, the cerebrovascular system may be more resilient, requiring extreme elevations in Lp(a) to manifest clinical stroke events over time.
The Triple Threat: Lp(a), LDL-C, and hsCRP in Stroke Risk
The Lancet Neurology analysis provided a more nuanced view of stroke risk by integrating inflammatory and lipid markers. While LDL cholesterol is a cornerstone of stroke prevention, this study found that in a multivariable-adjusted model, the highest quintile of LDL-C (≥3.4 mmol/L) had a relatively modest association with total stroke (HR 1.05). In contrast, both hsCRP and Lp(a) remained significant independent predictors.
Synergistic Effects
The study highlighted a cumulative risk model. Women who were in the highest quintiles for all three biomarkers—hsCRP (≥5.2 mg/L), LDL cholesterol (≥3.4 mmol/L), and Lp(a) (≥44.1 mg/dL)—faced a substantially higher risk of total stroke (HR 1.60) and ischemic stroke (HR 1.79) compared to women who had no biomarkers in the highest quintile. This suggests that the risk of stroke is not driven by a single pathway but is a result of the combined forces of cholesterol-mediated plaque formation, Lp(a)-mediated thrombosis/atherogenesis, and systemic inflammation.
Genetic Evidence: The Role of the LPA rs3798220 Variation
To address potential confounding factors, the researchers examined the rs3798220 genotype, a known predictor of high Lp(a) levels in individuals of European ancestry. Among 23,279 women with genotype information, carriers of the minor allele—who genetically produce more Lp(a)—consistently showed a higher risk of major cardiovascular events. This Mendelian randomization-style evidence strengthens the argument that Lp(a) is a causal agent in the development of cardiovascular disease, rather than a mere bystander or marker of other pathologies.
Expert Commentary: Clinical Implications and Screening
The findings from these 30-year follow-up studies have profound implications for clinical practice and public health policy. Current guidelines from organizations like the European Society of Cardiology (ESC) suggest that Lp(a) should be measured at least once in every adult’s lifetime. However, adoption in the United States and other regions has been slower, often reserved for high-risk cases.
The data argue that a single measurement of Lp(a) in mid-life can accurately predict a woman’s cardiovascular trajectory for the next three decades. Because Lp(a) levels are approximately 90% genetically determined and remain stable throughout life, early screening could identify high-risk individuals decades before their first event occurs. This “early warning system” allows for more aggressive management of modifiable risk factors, such as blood pressure and LDL cholesterol, to offset the innate risk posed by Lp(a).
Furthermore, the emergence of targeted Lp(a)-lowering therapies, such as antisense oligonucleotides and small interfering RNA (siRNA) currently in Phase 3 clinical trials (e.g., pelacarsen, olpasiran), makes identification of these patients even more critical. If these therapies prove successful in reducing clinical events, universal screening for Lp(a) will likely become a standard of care.
Conclusion
The 30-year data from the Women’s Health Study provide a definitive link between elevated Lipoprotein(a) and long-term cardiovascular and cerebrovascular morbidity. The evidence suggests that even moderate elevations increase coronary risk, while extreme elevations significantly raise the risk of ischemic stroke and death. When combined with inflammation (hsCRP) and LDL cholesterol, the risk of stroke becomes particularly pronounced. Clinicians should consider Lp(a) screening as a vital component of a comprehensive risk assessment, moving beyond 10-year models to protect the long-term health of women.
Funding and References
This research was supported by the US National Heart, Lung, and Blood Institute, the National Cancer Institute, and the Independent Research Fund Denmark.
References
1. Nordestgaard AT, Chasman DI, Moorthy V, et al. Thirty-Year Risk of Cardiovascular Disease Among Healthy Women According to Clinical Thresholds of Lipoprotein(a). JAMA Cardiol. 2026; doi:10.1001/jamacardio.2025.5043.
2. Nordestgaard AT, Moorthy MV, Cook NR, et al. High-sensitivity C-reactive protein, LDL cholesterol, lipoprotein(a) and 30-year risk of stroke in healthy women: a prospective, longitudinal cohort study. Lancet Neurol. 2025;24(11):920-930. doi:10.1016/S1474-4422(25)00306-0.