How neutrophil calprotectin unmasks future atherosclerotic heart disease risk

Accumulating evidence suggests that the immune system plays a crucial role in the emergence of atherosclerotic cardiovascular disease—a condition where fatty deposits, also known as plaque, gradually build up in the arteries.

This narrowing of blood vessels restricts blood flow to the heart and other organs, increasing the risk of heart attacks and strokes.

When the artery lining starts to be damaged, and cholesterol accumulates, the immune system responds.

Neutrophils, along with other immune cells, rush to the site.

While this is a natural defense mechanism, the inflammation associated with excessive neutrophil activity can accelerate plaque growth and worsen disease progression.

These harmful processes often occur silently, with no noticeable symptoms for years.

This makes early detection difficult, as reliable biomarkers to measure immune activity and inflammation remain relatively scarce. 

However, a promising candidate is calprotectin—a key marker of neutrophil activation and the formation of neutrophil extracellular traps, harmful structures that promote inflammation and plaque buildup also known as NETs.

The University of Michigan research team leading the study previously characterized calprotectin’s utility as a biomarker in overtly inflammatory disorders like antiphospholipid syndrome and COVID-19, but this is the first time it has been considered as a potential marker for the general population.

SEE ALSO: Antiphospholipid antibodies may increase heart disease risk in healthy people 

Given the strong link between neutrophil activation and ASCVD, calprotectin may serve as an early warning signal for cardiovascular disease risk.

Ray Zuo, M.D., Edward T. and Ellen K. Dryer Early Career professor of rheumatology and assistant professor of medicine in the Division of Rheumatology at University of Michigan, investigated calprotectin’s role in ASCVD.

In collaboration with James de Lemos, M.D., and colleagues at UT Southwestern Medical Center, Zuo’s team utilized samples and data from the Dallas Heart Study, a large population-based research project, to explore the relationship between calprotectin and ASCVD, including whether calprotectin can help predict future heart disease risk.

The results of the study published confirm that higher calprotectin levels can predict future ASCVD, even in people who appear healthy.

Using blood samples from the Dallas Heart Study, a diverse population cohort where two-thirds of the participants are either Black or Hispanic, Zuo’s team measured calprotectin levels in 2,412 individuals.

Over the next eight years, 114 people developed new ASCVD.

People with higher calprotectin levels were more likely to develop heart disease, even after accounting for common risk factors like age, sex, race, weight, smoking, blood pressure, diabetes, cholesterol, and kidney function.

People with more calprotectin in their blood also had higher coronary artery calcium scores, which indicate early plaque buildup in the arteries.

To understand how calprotectin may contribute to heart disease, Zuo’s team conducted lab experiments, led by Somanathapura K. Naveen Kumar, Ph.D., a senior postdoctoral fellow in the Zuo Lab.

SEE ALSO: Novel anti-NET antibodies in a multinational cohort 

The team’s work showed that calprotectin negatively impacts blood vessel cell health, reducing the production of nitric oxide (which keeps arteries flexible) and likely promoting scarring and damage in coronary arteries.

These findings suggest that calprotectin could serve as an early warning sign for heart disease, helping to identify people at risk long before symptoms appear.

This research could lead to better early detection and prevention strategies, potentially helping more people avoid heart attacks and strokes.

“These findings highlight calprotectin as a potential early warning signal for heart disease, long before symptoms first appear,” said Zuo.

“And, since calprotectin appears to damage blood vessel cells, one wonders if it could eventually be targeted therapeutically.”

“By understanding how immune activation contributes to artery damage, we hope to open new doors for earlier detection and better prevention strategies. In the future, measuring calprotectin levels could help identify at-risk individuals sooner, allowing for timely interventions that could ultimately save lives.”

The Dallas Heart Study is a population-based cohort study that, since 2000, has tracked the health of thousands of people of various races and ethnicities to improve the diagnosis, prevention, and treatment of heart disease.

“Heart disease is the number one cause of death in the United States,” said Zuo.

“Our collaboration with UT Southwestern using the Dallas Heart Study resource is a testament to the ways scientific collaboration can contribute to the advancement of life-saving medicine.”

Additional authors: Somanathapura K. Naveen Kumar, Ph.D., Sherwin Navaz, B.S., Wenying Liang, Ph.D., Katarina Kmetova, Ph.D., Lyndsay Kluge, Emily Chong and Jason S. Knight, M.D., Ph.D., from the Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. Colby R. Ayers, M.D., Amil M. Shah, M.D., M.P.H., and James A. de Lemos, M.D., from the Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. Jarett D. Berry, M.D., from the Department of Internal Medicine, University of Texas at Tyler, Tyler, Texas.

Paper Cited: “Epidemiological and Translational Study of Calprotectin and Antherosclerotic Cardiovascular Disease,” JAMA Cardiology. DOI: 10.1001/jamacardio.2025.0945

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