By Ellen Feldman, MD
Synopsis: In a 30-year prospective study of nearly 28,000 initially healthy U.S. women, baseline levels of high-sensitivity C-reactive protein, low-density lipoprotein cholesterol or lipoprotein(a) independently and additively predicted major cardiovascular events.
Source: Ridker PM, Moorthy MV, Cook NR, et al. Inflammation, Cholesterol, lipoprotein(a), and 30-year cardiovascular outcomes in women. N Engl J Med. 2024;391(22):2087-2097.
This landmark prospective cohort study from the Women’s Health Study investigated the long-term predictive utility of three key biomarkers in 27,939 initially healthy U.S. women followed over 30 years.1 The selected biomarkers of each represent distinct and clinically relevant pathways contributing to atherosclerotic cardiovascular disease. High-sensitivity C-reactive protein (hs-CRP) serves as a marker of vascular inflammation, low-density lipoprotein (LDL) cholesterol remains the primary modifiable target for risk reduction, and lipoprotein(a) reflects a genetically mediated, lifelong atherosclerotic burden.2-4
The primary endpoint was the first major cardiovascular event (MACE), including myocardial infarction, stroke, coronary revascularization, or cardiovascular death. The study found that elevated baseline levels of each biomarker independently predicted long-term cardiovascular risk. Women in the highest quintile of hs-CRP (≥ 5.18 mg/L) had an adjusted hazard ratio (HR) of 1.70 (95% confidence interval [CI], 1.52-1.90) for a first cardiovascular event compared to those in the lowest quintile. The corresponding HRs were 1.36 (95% CI, 1.23-1.52) for LDL cholesterol (≥ 150.7 mg/dL) and 1.33 (95% CI, 1.21-1.47) for lipoprotein(a) (≥ 44.1 mg/dL). Risk increased progressively across quintiles for hs-CRP and LDL cholesterol, whereas for lipoprotein(a), risk elevation was most pronounced in the highest quintile.
Notably, when the biomarkers were examined together using clinically relevant thresholds — hs-CRP ≥ 2 mg/L, LDL cholesterol ≥ 130 mg/dL, and lipoprotein(a) ≥ 40 mg/dL — risk was markedly highest among patients with elevations in all three. Women with all three biomarkers above these thresholds had an HR of 2.63 (95% CI, 2.16-3.19) for a first cardiovascular event compared to women with all three biomarkers below the thresholds. The joint risk was similarly elevated for stroke and coronary heart disease.
Sensitivity analysis accounting for statin use — which increased significantly over time, with 57.5% of participants having received a statin prescription by year 30 — demonstrated that the predictive value of baseline biomarkers remained robust during the pre-statin period. When follow-up was censored at the time of statin initiation, the risk gradients by biomarker quintiles remained consistent, suggesting that elevated levels of hs-CPR, LDL cholesterol, and lipoprotein(a) predicted cardiovascular events before treatment began.
However, because the analysis excluded events and measurements of biomarkers after statin initiation, the study does not address whether or how statin therapy modified the relative risk associated with these biomarkers.
Commentary
This study provides primary care providers (PCPs) with compelling evidence to reassess how cardiovascular risk is evaluated in women. Traditional models often emphasize short-term (10-year) risk, yet this 30-year prospective analysis illustrates that a single baseline measurement of hs-CPR, LDL cholesterol, and lipoprotein(a) yields strong and additive predictive power for long-term cardiovascular outcomes.
Critically, this study evaluated not just statistical associations across quintiles but also used clinically meaningful thresholds: hs-CRP ≥ 2 mg/L (a widely used marker of inflammation), LDL cholesterol ≥ 130 mg/dL (an established treatment threshold), and lipoprotein(a) ≥ 40 mf/dL (a level associated with increased atherosclerotic risk). When women had elevations in all three biomarkers above these thresholds, the 30-year HR for a first major cardiovascular event was more than 2.5 times higher than those with all three measures below their thresholds.
For clinical practice, these thresholds are especially useful. They allow the PCP to go beyond population-based risk scoring and instead implement individualized risk discussions — particularly with women in midlife who may not qualify for statins or other therapies based on standard algorithms. The fact that even a single elevated biomarker increased risk (HR, 1.27 for one elevated marker and HR, 1.66 for two) suggests that intermediate levels of risk warrant closer monitoring and lifestyle counseling.
The finding that hs-CRP alone had predictive value comparable to LDL cholesterol over 30 years challenges the notion that inflammation markers are too variable to be clinically actionable. The data suggest that a single hs-CRP ≥ 2 mg/L has durable prognostic value and reasonably could be included in midlife screening — especially given that several anti-inflammatory agents (e.g., colchicine, sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists) have demonstrated cardiovascular benefits in recent trials.5-7
Lipoprotein(a), often overlooked in clinical practice, showed a threshold effect: risk was notably elevated only in the top quintile (≥ 44.1 mg/dL, close to the 40 mg/dL used in the joint-effect analysis.) Because lipoprotein(a) is genetically determined, a one-time measurement already recommended in American College of Cardiology/American Heart Association guidelines for patients with a family history of premature cardiovascular disease could identify women who may benefit from aggressive LDL-lowering or novel therapies as they become available.
Although this study did not examine or document any specific interventions, the findings underscore the importance of identifying cardiovascular risk early, even in patients who appear healthy, so that clinicians can engage patients in timely, meaningful conversations about lifestyle change. Adopting strategies to improve lifestyle behaviors and manage risk factors, such as smoking cessation, healthy eating, weight management, blood pressure control, and regular physical activity, have the greatest long-term payoff when initiated in midlife or earlier, before subclinical disease progresses. By linking biomarker findings to long-term risk trajectory, PCPs can personalize prevention efforts and motivate patients to act while risk is still modifiable.
However, while the findings are robust, generalizability of this study is limited by the homogeneity of its cohort, which consisted primarily of white female health professionals. As a result, the applicability of these results to more diverse populations, including not only men but also different racial, ethnic, socioeconomic, and occupational groups, remains uncertain. Further studies in broader populations are needed to determine whether these biomarker-based risk associations hold true across varied patient groups.
Additionally, the study lacked repeated biomarker measurements, although it is notable that the consistency of associations over the 30 years suggests strong baseline signal strength. More than half of the participants eventually initiated statins during follow-up, but it is worth repeating that the study did not evaluate changes in biomarker levels or outcomes after statin use. Still, the strong predictive value of baseline hs-CRP, LDL cholesterol, and lipoprotein(a) highlights the need for prevention strategies that address multiple risk pathways, not just LDL cholesterol-lowering.
This study makes a powerful case for broader integration of hs-CRP and lipoprotein(a) into cardiovascular risk assessments, especially in women. PCPs can use these biomarkers, anchored to practical thresholds, to stratify lifetime risk, initiate earlier prevention strategies, and consider tailored pharmacologic therapies. In the era of individualized medicine and prevention-focused care, these findings mark a pivotal shift in how we think about cardiovascular risk in midlife women.
Rather than relying solely on short-term risk calculators, clinicians are now equipped to identify silent risk earlier, even in patients who might not meet traditional treatment thresholds. This approach can help close the longstanding treatment gap in cardiovascular prevention for women, who often are underrecognized and undertreated despite significant long-term risk.8 By incorporating these biomarkers into routine midlife evaluations, the PCP can better align prevention with the patient’s risk trajectory, helping to reduce cardiovascular morbidity and mortality through more proactive, personalized care.
Ellen Feldman, MD, works for Altru Health System, Grand Forks, ND.
References
- Women’s Health Study. Harvard Medical School. https://whs.bwh.harvard.edu
- Mehta A, Blumenthal R, Gluckman TJ, et al. High-sensitivity C-reactive protein in atherosclerotic cardiovascular disease: To measure or not to measure? US Cardiol. 2025;19:e06.
- Stanciulescu LA, Scafa-Udriste A, Dorobantu M. Exploring the association between low-density lipoprotein subfractions and major adverse cardiovascular outcomes — a comprehensive review. Int J Mol Sci. 2023;24(7):6669.
- Kamstrup PR, R Dermot G Neely, Nissen S, et al. Lipoprotein(a) and cardiovascular disease: Sifting the evidence to guide future research. Eur J Prev Cardiol. 2024;31(7):903-914.
- Gasparyan AY, Ayvazyan L, Yessirkepovet M, Kitas GD. Colchicine as an anti-inflammatory and cardioprotective agent. Expert Opin Drug Metab Toxicol. 2015;11(11):1781-1794.
- Scisciola L, Cataldo V, Taktaz F, et al. Anti-inflammatory role of SGLT2 inhibitors as part of their anti-atherosclerotic activity: Data from basic science and clinical trials. Front Cardiovasc Med. 2022;9:1008922.
- Alharbi SH. Anti-inflammatory role of glucagon-like peptide 1 receptor agonists and its clinical implications. Ther Adv Endocrinol Metab. 2024;15:20420188231222367.
- Mahowald MK, Esmail K, Ezzeddineet FM, et al. Sex disparities in cardiovascular disease. Methodist Debakey Cardiovasc J. 2024;20(2):107-119.
In a 30-year prospective study of nearly 28,000 initially healthy U.S. women, baseline levels of high-sensitivity C-reactive protein, low-density lipoprotein cholesterol or lipoprotein(a) independently and additively predicted major cardiovascular events.
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