hsCRP and lipoprotein(a) may enhance ischemic stroke risk prediction in women

medwireNews: Early screening for plasma concentrations of high-sensitivity C-reactive protein (hsCRP) and lipoprotein(a) in addition to low-density lipoprotein (LDL) cholesterol may help identify healthy women at risk for ischemic stroke, suggests an analysis of the Women’s Health Study.

While screening for elevated LDL cholesterol is already recommended in primary prevention guidelines for people over the age of 40 years, Ask Nordestgaard (Brigham and Women’s Hospital, Boston, Massachusetts, USA) and team sought to clarify guideline ambiguity on screening for hsCRP and lipoprotein(a).

To this end, they analyzed data on 27,939 participants of the Women’s Health Study who were aged 45 years and older at enrolment between 1992 and 1995 and had baseline blood measurements of hsCRP, lipoprotein(a), and LDL cholesterol.

The participants were a median of 53 years old and 12% were current smokers. The women had a median BMI of 25 kg/m², 25% had hypertension, and 2% a history of diabetes.

Over a median follow-up of 27.7 years, a total of 1345 stroke events occurred, of which 966 were ischemic, 206 hemorrhagic, and 173 unclassified.

For hsCRP, the researchers found stepwise significant increases in the risk for any stroke and ischemic stroke from the lowest to the highest quintile. In all, there were 194 incidences of any stroke among women in the first quintile for hsCRP (<0.7 mg/dL), compared with 344 among women in the highest quintile (≥5.2 mg/dL), giving a significant hazard ratio (HR) of 1.32 after taking into account a variety of factors such as age, blood pressure, BMI, diabetes, smoking, physical activity, history of migraine, and use of hormone replacement therapy.

Similarly, the adjusted HR for ischemic stroke was a significant 1.56 for women in the highest versus the lowest quintile, with 264 and 126 incidences, respectively.

For lipoprotein(a), the risks for any stroke and ischemic stroke were only significant for those in the highest (≥44.1 mg/dL) compared with the lowest (<3.6 mg/dL) quintile, with 308 versus 255 stroke events (adjusted HR=1.23) and 228 versus 184 ischemic stroke events (adjusted HR=1.27), respectively.

In the case of LDL cholesterol, there was a trend for any stroke and ischemic stroke to be higher for women who had levels in the fourth (3.4–3.8 mmol/L) and fifth (≥3.9 mmol/L) quintiles compared with the first quintile (<2.5 mmol/L). There were 328 versus 226 occurrences of any stroke among in women in the fifth (≥3.9 mmol/L) compared with the first quintile (<2.5 mmol/L), and 244 versus 150 ischemic stroke events.

However, the respective adjusted HRs did not reach statistical significance. This was only seen after the 15,694 statin-treated women had been removed from the analysis, when the adjusted HRs for women in the fifth versus the first quintile were 1.34 for any stroke and 1.50 for ischemic stroke.

The researchers note in The Lancet Neurology that “none of the biomarkers correlated with hemorrhagic stroke.”

Nordestgaard and team found that combining the biomarkers had an additive effect on the risk for any stroke and ischemic stroke. For women who had all three biomarkers in the highest quintile the HR for any stroke was a significant 1.60, compared with those with no biomarkers in the highest quintile, and a significant 1.79 for ischemic stroke.

In a related comment, Jukka Putaala (Helsinki University Hospital, Finland) highlights “[t]he large cohort size, extended follow-up period, and robust adjustment for multiple baseline clinical factors” as strengths of the study. However, he cautions that “[w]ithout distinguishing between the main ischaemic stroke mechanisms—large artery atherosclerosis, cerebral small-vessel disease, or cardioembolism—it remains unclear which subtypes are most accurately predicted by the studied biomarkers.”

The commentator says that the study “highlights the potential for earlier, more inclusive screening strategies that could improve primary prevention for women.”

He adds that as the risk for stroke in young people is “increasingly shaped by non-traditional factors,” a “crucial next step” will be “developing prediction algorithms that span the entire lifespan and incorporate these risk factors as well as sex-specific risk factors.”

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2025 Springer Healthcare Ltd, part of Springer Nature

Lancet Neurol 2025; doi:10.1016/S1474-4422(25)00306-0
Lancet Neurol 2025; doi:10.1016/S1474-4422(25)00347-3