Blood Test of Three Factors Predicts 30-Year Risk of Heart Attack, Stroke and Cardiovascular Death in American Women

A study led by Brigham researchers finds that measuring three modifiable factors together provided greater information on risk compared to any marker used alone; inflammation shown to be at least as important as cholesterol, yet rarely measured

Key Takeaways

• Brigham researchers assessed data from more than 27,000 participants in the Women’s Health Study who were followed for 30 years.
• An initial, one-time measure of three biological markers—hsCRP, LDL-cholesterol and lipoprotein(a)—in their blood predicted their risk of major cardiovascular events over the following decades.
• The findings support universal screening for inflammation and lipoprotein(a) in addition to cholesterol, as well as earlier, aggressive use of targeted interventions, particularly among women for whom cardiovascular disease remains underdiagnosed and undertreated.

Investigators from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, shared new insights about women’s health and cardiovascular risk, finding that measurement of three independent biological markers in a blood sample can better predict risk of major cardiovascular events over the next three decades than measuring only one. In a landmark study of 27,939 initially healthy American women presented at the European Society of Cardiology (ESC) Congress in London and published simultaneously in the New England Journal of Medicine, a single measure of high-sensitivity C-reactive protein (hsCRP, a marker of vascular inflammation), low density lipoprotein cholesterol (LDL-C or “bad cholesterol”), and lipoprotein(a) (Lp(a), a genetically determined lipid fraction), strongly predicted cardiovascular risk over an unprecedented 30-year follow-up period.

“Doctors cannot treat what they don’t measure,” said lead author Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, who presented the findings at ESC Congress 2024. “To provide the best care for our patients, we need universal screening for inflammation, cholesterol, and lipoprotein(a), and we need it now. By so doing, we can target our treatments to the specific biologic need of individual patients, fulfilling our longstanding hope to provide truly personalized preventive care.”

The research team analyzed data from the Women’s Health Study (WHS), funded by the U.S. National Institutes of Health (NIH) through research grants to preventive cardiology investigators in the Division of Preventive Medicine at the Brigham. The landmark trial began in 1993 and has followed female health professionals aged 45 years and older ever since. Women had their hsCRP, LDL-C and Lp(a) levels tested in a blood sample obtained when they enrolled in the WHS. The primary endpoint of the study was a first major adverse cardiovascular event—heart attack, coronary revascularization, stroke, or death from cardiovascular causes.

A Wake-Up Call for Women

To assess each marker as well as the combined effect of having elevated levels of two or all three, the research team divided participants into five quintiles, ranging from those with the highest to the lowest levels of the markers. Researchers found that, compared to women with the lowest levels of individual markers:

• Women with the highest levels of hsCRP had a 70% greater risk of a major cardiovascular event;
• Women with the highest levels of LDL-C had a 36% greater risk;
• Women with the highest levels of Lp(a) had a 33% greater risk.

While hsCRP was the strongest of the three biomarkers, all mattered greatly. Women who had elevated levels of all three markers were 2.6 times more likely to have a major adverse cardiovascular event. This association was even stronger for stroke—women with the most elevated levels were 3.7 times more likely to have a stroke over the next 30 years.

“These data should be a wake-up call for women,” said co-author Julie Buring, ScD, principal investigator of the WHS and an epidemiologist in the Brigham’s Division of Preventive Medicine. “Waiting until women are in their 60s and 70s to initiate heart attack and stroke prevention is a prescription for failure.”

Reducing Risk

Each of the three risk factors is modifiable with a combination of lifestyle changes and drug therapy. Multiple randomized trials have demonstrated that lowering cholesterol and lowering inflammation both significantly reduce risks of heart attack and stroke. Further, several new drugs that markedly reduce Lp(a) as well as second-generation anti-inflammatory agents are being tested to see if they too can lower rates of clinical events.

The new data strongly support earlier and more aggressive use of targeted preventive interventions, particularly among women for whom cardiovascular disease remains underdiagnosed and undertreated.

“While we still need to focus on lifestyle essentials like diet, exercise, and smoking cessation, the future of prevention is clearly going to include combination therapies that target inflammation and Lp(a) in addition to cholesterol,” said Ridker.

Authorship: In addition to Ridker, BWH authors include epidemiologists Julie Buring and I-Min Lee, data analyst Vinayaga Moorthy, and biostatistician Nancy Cook. Additional authors include Nader Rifai.

Disclosures: Ridker has received research grant support to the Brigham and Women’s Hospital and/or served as a consultant to entities developing preventive strategies and treatments that target inflammation, cholesterol, and lipoprotein(a), including support from Novo Nordisk, Novartis, Pfizer, Agepha, and Kowa. Full disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Funding: Supported by grants (HL043851, HL080467, and HL099355) from the National Heart, Lung, and Blood Institute and grants (CA047988 and CA182913) from the National Cancer Institute, National Institutes of Health. Paper cited: Ridker PM et al. “Inflammation, Cholesterol, Lipoprotein(a), and 30-Year Cardiovascular Outcomes in Women” NEJM DOI: 10.1056/NEJMoa2405182