For decades, doctors have searched for simple signals that can whisper the future of the heart long before illness appears. In a large and patient study led by investigators at Brigham and Women’s Hospital, one such signal emerges from the blood of healthy women, measured once and then followed for thirty years. The signal is lipoprotein(a), a particle whose levels are largely written into our genes and settle into place within the first two years of life.
Unlike many familiar cholesterol measures that shift with diet, exercise, or medication, lipoprotein(a) tends to stay where it starts. That early stability means lifelong exposure, turning a single baseline measurement into a quiet companion across decades. The new findings suggest that when this number rises to extreme levels, it carries a meaningful warning about the long-term risk of serious cardiovascular events.
The Uneasy Place of Lipoprotein(a) in Prevention
For clinicians, lipoprotein(a) has long been both intriguing and frustrating. Its genetic control makes testing attractive, because the result reflects a person’s usual level across life. At the same time, lifestyle changes and standard drugs do little to move the needle once it is high, leaving few clear options for intervention.
Earlier research connected elevated lipoprotein(a) to atherosclerotic cardiovascular disease, aortic valve stenosis, and cardiovascular death. Yet those studies also raised an uncomfortable question. If only a modest portion of people have levels high enough to matter, where should the line be drawn? Mild to moderately elevated values may not add much risk, and evidence remains unclear on whether lowering lipoprotein(a) alone actually reduces cardiovascular events. As a result, screening guidelines have struggled to find firm ground.
The new study set out to clarify that uncertainty by stretching observation far into the future and asking a simple but powerful question: at what point does lipoprotein(a) truly begin to matter?
Thirty Years of Watching Healthy Hearts
The research, titled “Thirty-Year Risk of Cardiovascular Disease Among Healthy Women According to Clinical Thresholds of Lipoprotein(a),” was published in JAMA Cardiology. It followed participants from the Women’s Health Study, beginning in 1993 and continuing through January 2023. At enrollment, the women had no history of cardiovascular disease, cancer, or other major chronic illness. They provided blood samples for biochemical testing and DNA analysis, along with detailed lifestyle and demographic information.
Among 27,748 women, with a median age of 53 years, baseline lipoprotein(a) was measured and later compared with outcomes recorded over three decades. The researchers tracked major cardiovascular events, coronary heart disease, ischemic stroke, and cardiovascular death. To understand risk with precision, they used advanced statistical models, including cause-specific Cox proportional hazards models and spline modeling, treating lipoprotein(a) as a continuous exposure rather than a blunt category.
A genetic dimension added depth to the analysis. Among women with genetically verified European ancestry, researchers examined the LPA rs3798220 variant, known to be linked with higher lipoprotein(a) levels. This genotype analysis included at least 23,179 women, offering a window into how inherited differences translate into long-term outcomes.
When Risk Finally Breaks the Surface
Over thirty years of follow-up, a clear pattern emerged. Risk did not creep up gently with every small increase in lipoprotein(a). Instead, it gathered force at the extremes.
Women with very high lipoprotein(a) levels faced a 54% to 74% higher relative risk of major cardiovascular events compared with those at the low end. When translated into everyday terms, that relative increase became an approximately 10% higher absolute risk of cardiovascular disease over thirty years.
The data revealed a stepwise rise in cumulative risk once lipoprotein(a) reached 30 mg/dL or more. From there, the curve continued upward, with risk climbing further across higher groups and peaking at 120 mg/dL or more. This was not a subtle shift. Hazard ratios showed that major cardiovascular events increased sharply for women with lipoprotein(a) 120 mg/dL or higher compared with those below 10 mg/dL, and again for levels 131 mg/dL or higher compared with values below 11 mg/dL.
The Heart’s Arteries Tell the Same Story
The pattern was especially striking for coronary heart disease. Risk began to rise once lipoprotein(a) crossed 30 mg/dL, then intensified at 120 mg/dL or higher, and remained elevated at 131 mg/dL or higher compared with the lowest reference groups. In women with the highest values, researchers observed an abrupt increase in the cumulative incidence of coronary heart disease as early as five years into follow-up, hinting that extreme levels may accelerate disease sooner than expected.
Not every outcome behaved the same way. Ischemic stroke and cardiovascular death increases were concentrated at the most extreme end of lipoprotein(a). For levels 131 mg/dL or higher, risk rose compared with women below 11 mg/dL. At 120 mg/dL or higher, ischemic stroke showed a strong upward trend but did not reach statistical significance, with a hazard ratio of 1.41 and a 95% confidence interval of 0.93 to 2.15. The direction was consistent, even if certainty fell just short.
A Genetic Echo Across Decades
Genetics reinforced what the blood measurements suggested. Women who carried one copy of the LPA rs3798220 minor allele had a higher thirty-year risk of major cardiovascular events than those with two major alleles, with a hazard ratio of 1.27. This genetic signal aligned with elevated lipoprotein(a) levels, strengthening the idea that lifelong exposure, set early in life, plays a central role.
Only 13 women in the study were minor allele homozygotes, too few to define a reliable risk estimate. Even so, the presence of genetic confirmation added confidence that the observed associations were not fleeting correlations but reflections of long-term biological reality.
Why the Extremes Matter Most
One of the most important messages from this research is what it does not show. Mild to moderate elevations in lipoprotein(a) did not consistently translate into large increases in long-term risk. The danger gathered where values became very high, suggesting that prevention efforts should focus on identifying those extremes rather than casting an overly wide net.
This matters because lifestyle interventions and currently available pharmacological treatments only modestly affect lipoprotein(a). For most people, there is little that can be done today to meaningfully lower it. But for those with very high levels, even limited preventive strategies may offer benefit, especially when combined with careful monitoring and attention to other cardiovascular risk factors.
Why This Research Matters
This study reshapes how lipoprotein(a) can be understood in clinical practice. By following healthy women for three decades, it shows that the true signal lies not in small elevations, but in the extremes where risk rises sharply and meaningfully. A single blood test, reflecting a value set early in life, can help identify women who carry a substantially higher long-term risk of major cardiovascular events.
The findings offer a clearer rationale for screening for very elevated lipoprotein(a) in the general population. They also provide a crucial foundation for future therapies aimed specifically at lowering lipoprotein(a), helping to define who might benefit most once such treatments become available.
In the long arc of prevention, this research reminds us that some numbers are more than snapshots. They are stories written early, unfolding quietly over decades, and finally revealing their meaning when time is given long enough to listen.
Study Details
Ask Tybjærg Nordestgaard et al, Thirty-Year Risk of Cardiovascular Disease Among Healthy Women According to Clinical Thresholds of Lipoprotein(a), JAMA Cardiology (2026). DOI: 10.1001/jamacardio.2025.5043
