Combined Biomarker Analysis Reveals Triple Heart Attack Risk in High-Risk Individuals

Adults with elevated levels of three biomarkers for heart disease had nearly triple the risk of heart attack compared to those without elevated levels, according to research to be presented at the American Heart Association's Scientific Sessions 2025. The study analyzed lipoprotein(a), remnant cholesterol, and high-sensitivity C-reactive protein (hsCRP) as combined indicators of cardiovascular risk. Participants with elevated levels of only one biomarker showed a 45% increased risk, while those with two elevated biomarkers had double the risk of heart attack.

The three biomarkers measure different pathways to cardiovascular disease: genetics through lipoprotein(a), cholesterol metabolism through remnant cholesterol, and inflammation through hsCRP. 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 that standard cholesterol tests can miss but can also clog arteries. High-sensitivity C-reactive protein measures inflammation in the body, with elevated levels potentially signaling risk of arterial damage.

"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," said Richard Kazibwe, M.D., M.S., lead researcher and an assistant professor of internal medicine at Wake Forest University School of Medicine. "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."

Researchers examined 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 at enrollment. The analysis tracked heart attack rates over a median follow-up of 15 years, calculating how many participants had each biomarker in the highest 20% of values. The study revealed a clear stepwise pattern where risk increased with each additional elevated biomarker.

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. Lipoprotein(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. The 2025 AHA/ACC High Blood Pressure Guidelines recommend that health care professionals use the Predicting Risk of cardiovascular disease EVENTs (PREVENT™) equation to help assess cardiovascular disease risk and optimize primary prevention.

"Advances in the accuracy and precision of risk for atherosclerotic cardiovascular disease 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. "This study supports recommendations that consideration of risk enhancers including lipoprotein(a), hsCRP and remnant cholesterol can play an important role in personalizing risk estimates."

The research has important limitations as an observational study from the UK Biobank, with approximately 95% of participants identifying as white. Additional research is needed to determine if using these tests to guide treatment decisions leads to improved patient outcomes and to confirm whether the results apply broadly to diverse populations. The findings are considered preliminary until published as a full manuscript in a peer-reviewed scientific journal.