Prognostic Value of Circulating NETosis Biomarkers in ST-Elevation Myocardial Infarction: Citrullinated Histone H3 Outperforms Cell-Free DNA and Nucleosomes.

BACKGROUND

Even after successful primary percutaneous coronary intervention (PPCI), a substantial proportion of ST-elevation myocardial infarction (STEMI) patients develop major adverse cardiovascular events (MACE). Neutrophil extracellular trap formation (NETosis) contributes to atherothrombosis and coronary microvascular injury, but the prognostic value of circulating NETosis biomarkers in STEMI has not been systematically compared.

METHODS

We studied 420 STEMI patients who survived index hospitalisation after PPCI. Plasma citrullinated histone H3 (H3Cit), cell-free DNA (cfDNA) and nucleosomes were measured at admission. The primary endpoint was MACE; all-cause death was secondary. Incremental prognostic value over a conventional model was assessed by ΔC-index, net reclassification improvement (NRI) and integrated discrimination improvement (IDI).

RESULTS

Over a median 545-day follow-up, 81 patients (19.3%) experienced MACE and 36 (8.6%) died. In fully adjusted Cox models, each 100ng/mL increase in H3Cit was independently associated with MACE (HR 1.511, 95% CI 1.155-1.977, P=0.003) and death (HR 1.752, 95% CI 1.203-2.552, P=0.003). Q4 vs Q1-Q3 H3Cit independently predicted MACE (HR 2.139, P=0.002) and death (HR 2.836, P=0.004). cfDNA was associated with death but not MACE after adjustment; nucleosomes lost significance after full adjustment. Adding H3Cit improved discrimination for MACE (ΔC-index 0.042; NRI 0.417; IDI 0.022) and death (ΔC-index 0.055). The prognostic association of H3Cit was directionally consistent across prespecified subgroups.

CONCLUSION

Among three circulating NET biomarkers, H3Cit provides the strongest and most consistent prognostic information for MACE and death after STEMI and offers meaningful incremental value beyond established clinical risk factors, supporting NETosis as a potentially actionable pathway for post-STEMI risk stratification.