Calprotectin Signals ASCVD Risk Beyond Traditional Markers

Calprotectin may represent a mechanistically informed biomarker for atherosclerotic cardiovascular disease (ASCVD), with high levels linked to an elevated risk of future cardiac events across 8 years in a new study.1

The diverse, population-based cohort identified the potential biomarker role of circulating calprotectin, irrespective of clinical cardiovascular risk factors, including high-sensitivity C-reactive protein (hs-CRP), N-terminal pro–brain natriuretic peptide (NT-proBNP), and high-sensitivity cardiac troponin T (hs-cTnT).

“Taken together, this research underscores the potential value of calprotectin as a mechanistically informed biomarker that is independently associated with future ASCVD events within a diverse, prospective population cohort beyond traditional and contemporary cardiovascular risk factors,” wrote the investigative team, led by Yu Zuo, MD, MSCS, University of Michigan.

Available evidence has pointed to the notable role of the immune system in the progression of ASCVD, particularly neutrophil activation, which are first responders to tissue damage and are critical in initiating inflammation and repair. Increased neutrophil production may be a key factor in atherosclerotic plaque development.2

Calprotectin, an abundant biomarker of neutrophil activation, may be mechanistically involved in ASCVD, with early data suggesting an association between higher levels of circulating calprotectin and an increased risk of cardiovascular events.3 In this study, Zuo and colleagues assessed the potential link between circulating calprotectin and ASCVD in more than 2000 patients from Phase 2 of the Dallas Heart Study (DHS-2).1

With a median follow-up of 8 years after plasma collection, investigators measured its link with ASCVD events, defined as first nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or death from a cardiovascular cause, using Cox proportional hazards models.

The study included 2412 participants from DHS-2, with a mean age of 50.6 years, 58% female, and 51% Black. Upon analysis, increased calprotectin was associated with older age, male sex, Black race, hypertension, diabetes, and smoking history. Those with higher levels also experienced a higher hemoglobin A1c (HbA1c), very low-density lipoprotein cholesterol (LDL-C), very low triglycerides, and lower high-density lipoprotein cholesterol (HDL-C).

Individuals who developed ASCVD had a larger mean calprotectin level (523.4 ng/mL; 95% CI, 454.2–610.6), compared with those who remained ASCVD-free (347.4 ng/mL; 95% CI, 333.8–361.2). Across 8 years, 114 participants experienced new ASCVD events.

Further unadjusted analysis identified a statistically significant association between log-transformed circulating calprotectin levels and future ASCVD events over 8 years (hazard ratio [HR], 1.98 per log unit change; 95% CI, 1.54–2.53). After adjusting for prior ASCVD, risk factors, body mass index (BMI), and estimated glomerular filtration rate (eGFR), investigators found the association remained statistically significant (HR, 1.61; 95% CI, 1.22–2.13).

Further adjustment for hs-CRP, NT-proBNP, and hs-cTnT revealed that circulating calprotectin remained associated, showing a nearly 1.5-fold increase in the risk of future ASCVD events (HR, 1.43; 95% CI, 1.04–1.96). Increased calprotectin was also linked to higher coronary artery calcium scores (P <.001).

Zuo and colleagues' analysis of calprotectin’s mechanistic contribution to ASCVD in vitro revealed calprotectin affected coronary endothelial integrity, lowered nitric oxide production, and allowed endothelial to mesenchymal transition, suggesting the potential mechanism of ASCVD progression.

“Calprotectin’s direct interaction with the coronary endothelium may contribute to pathophysiological changes relevant in the progression of ASCVD,” Zuo and colleagues wrote.1 “However, its true clinical utility remains uncertain and requires further investigation.”

References

1. Zuo Y, NaveenKumar SK, Navaz S, et al. Epidemiological and Translational Study of Calprotectin and Atherosclerotic Cardiovascular Disease. JAMA Cardiol. Published online May 07, 2025. doi:10.1001/jamacardio.2025.0945

2. Libby P. The changing landscape of atherosclerosis. Nature. 2021;592(7855):524-533. doi:10.1038/s41586-021-03392-8

3. Amaya-Garrido A, Brunet M, Buffin-Meyer B, et al. Calprotectin is a contributor to and potential therapeutic target for vascular calcification in chronic kidney disease. Sci Transl Med. 2023;15(712):eabn5939. doi:10.1126/scitranslmed.abn5939