Combined analysis of three blood tests enhances heart attack risk prediction

A combined analysis of blood tests to measure three biomarkers linked to higher risk of cardiovascular disease-lipoprotein a (Lp(a)), remnant cholesterol and high-sensitivity C-reactive protein (hsCRP)-may help identify high-risk individuals earlier and guide more personalized prevention strategies, according to a preliminary study to be presented at the American Heart Association's Scientific Sessions 2025. The meeting, Nov. 7-10, in New Orleans, is a premier global exchange of the latest scientific advancements, research and evidence-based clinical practice updates in cardiovascular science.

In the analysis, adults with elevated levels of all three biomarkers of heart disease had nearly three times the risk of a heart attack compared to participants with normal levels. The three blood tests examine different pathways that can lead to cardiovascular disease. Lipoprotein(a) is a type of cholesterol that is largely inherited and can cause plaque buildup in arteries. Remnant cholesterol refers to harmful fat particles in the blood that standard cholesterol tests can miss but can also clog arteries. High-sensitivity C-reactive protein (hsCRP) measures inflammation in the body. Elevated levels of hsCRP may signal that the body is under stress and may indicate risk of damage to the arteries.

Each of the blood tests on its own indicate only a modest increase in heart attack risk, however, when we found elevated levels for all three, the risk of heart attack was nearly three times higher."

Richard Kazibwe, M.D., M.S., lead researcher and assistant professor of internal medicine at Wake Forest University School of Medicine in Winston-Salem, North Carolina

"These biomarkers work together like pieces of a puzzle. One piece cannot show the full picture, yet when combined, we can see a much clearer and more complete depiction of heart attack risks," he added.

Researchers reviewed health data from the UK Biobank, one of the world's largest health databases, for more than 300,000 participants who were free of heart disease when they were first enrolled. Scientists tracked heart attack rates for these participants over a median follow-up of 15 years and calculated how many participants had each of the three blood test results in the highest 20% of values. The analysis found a clear stepwise pattern:

• Participants with all three test results in the highest ranges had nearly triple the risk of heart attack;
• Those with two elevated results had more than double the risk; and
• Participants with one elevated test result had about a 45% higher heart attack risk.

"A clear pattern confirmed that these biomarkers are related and together they reveal a 3-fold increase in heart attack risk. Evaluating the combined results of all three blood tests may help health care professionals act more quickly and provide tailored care for people with the highest risk. In addition, guidance that encourages healthy lifestyle changes or initiating treatment, such as medication to lower cholesterol and/or blood pressure, are keys to reducing risk and preventing heart attacks," Kazibwe said.

Although these blood tests are not yet part of routine screening guidelines, Kazibwe notes this combination approach may be more accessible than it initially appears. Lp(a) and hsCRP tests are available at most labs upon request, and health care professionals can calculate remnant cholesterol from standard cholesterol panels already performed during many routine checkups. Remnant cholesterol is calculated as total cholesterol minus LDL cholesterol and HDL cholesterol.

"Even if traditional risk factors like cholesterol and blood pressure are under control, these simple blood tests can identify hidden inflammation, genetic risk and cholesterol abnormalities. The results could help health care professionals detect heart disease risk earlier and guide steps to keep your heart healthy before symptoms appear or a cardiac event occurs," Kazibwe said.

The 2025 AHA/ACC High Blood Pressure Guideline recommends that health care professionals use the Predicting Risk of cardiovascular disease EVENTs (PREVENT™) equation to help assess cardiovascular disease risk and optimize primary prevention of cardiovascular disease. Developed by the American Heart Association in 2023, the PREVENT^TM risk calculator uses cardiovascular, kidney and metabolic health factors to more precisely estimate a person's cardiovascular disease risk, which can help guide treatment decisions personalized for each individual. Kazibwe emphasized that people with a family history of heart disease, Type 2 diabetes, high blood pressure or other cardiovascular risk factors may particularly benefit from discussing these additional biomarker tests with their health care team.

"Advances in the accuracy and precision of risk for atherosclerotic cardiovascular disease (caused by plaque buildup in arterial walls) mean that clinicians can now more precisely identify individuals who are likely to benefit from preventive therapies," said Pamela Morris, M.D., FAHA, an American Heart Association volunteer expert and a professor of cardiology, Paul V. Palmer Endowed Chair in cardiovascular disease prevention and director of the Seinsheimer Cardiovascular Health Program at the Medical University of South Carolina.

"However, risk estimation remains the starting point. This study supports recommendations that consideration of risk enhancers including Lp(a), hsCRP and remnant cholesterol can play an important role in personalizing risk estimates. The findings indicate that these biomarkers can aid in clinical decision making, particularly for those patients in whom treatment decisions are uncertain," said Morris, who was not involved in the study.

Kazibwe acknowledges some health care professionals may initially be cautious about adding more tests due to cost and insurance coverage considerations, however, growing research and new treatments are making these tests increasingly relevant in preventive cardiology care.

"The three biomarker tests represent part of a larger toolkit for assessing heart attack risks that also include genetic risk scores and coronary artery calcium scans. The future challenge will be learning how to combine all this information to help health care professionals make personalized decisions for each patient," he said.

Study details, background and design:

• Researchers examined health data from 306,183 adults in the UK Biobank who were free from cardiovascular disease at enrollment and had available blood test measures for lipoprotein(a), remnant cholesterol and high-sensitivity C-reactive protein.
• The average age at enrollment was 56.4 years, and about 55% of participants were women.
• Participants were followed for a median of 15 years, during which 10,824 (3.5%) of them had a heart attack.
• All three biomarkers were measured simultaneously for each participant at the beginning of the study period. The analysis examined the cumulative effect of having multiple elevated blood test results, defined as the number of biomarkers in the top 20% of values, adjusted for conventional cardiovascular risk factors and other biomarkers.

The research has important limitations. As an observational study, the findings show patterns in the data but cannot prove elevated levels of these biomarkers directly caused the heart attacks. Research is needed to determine if using these tests to guide treatment decisions leads to improved patient outcomes or saves lives. The findings also come from the UK Biobank, with approximately 95% of participants identifying as white. Additional research would be needed to confirm whether the results apply broadly to diverse populations in the U.S. and other countries.