A NET-associated immunothrombotic phenotype is associated with coronary no-reflow and myocardial injury after primary PCI in ST-segment elevation myocardial infarction: a real-world translational cohort

Background Coronary no-reflow after primary percutaneous coronary intervention (PCI) reflects failure of myocardial reperfusion despite treatment of the culprit epicardial lesion. Neutrophil extracellular traps (NETs) and immunothrombosis provide a plausible link between sterile inflammation, thrombus biology, and microvascular obstruction. We evaluated whether a clinically measurable NET-associated immunothrombotic phenotype (NET-IP) was associated with no-reflow and myocardial injury after primary PCI. Methods This single-center translational cohort included 742 patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI. NET-IP was calculated in 725 patients from five admission or pre-PCI variables—neutrophil count, D-dimer, fibrinogen, high-sensitivity C-reactive protein, and platelet-neutrophil product—by averaging log-transformed component z scores when at least four components were available, followed by standardization of the composite score. The primary endpoint was angiographic no-reflow, defined as final thrombolysis in myocardial infarction flow grade < 3 in the absence of mechanical epicardial obstruction. A case-enriched nested enzyme-linked immunosorbent assay (ELISA) biomarker subcohort was used to measure MPO-DNA, citrullinated histone H3 (H3Cit), and double-stranded DNA. Results Angiographic no-reflow occurred in 110 of 742 patients. NET-IP was calculable in 725 patients, and the fully adjusted complete-case models included 700 patients. Patients with no-reflow had higher admission NET-IP scores than those with normal reflow (0.73 [0.24, 1.25] vs. -0.06 [-0.77, 0.54]; P < 0.001). In the fully adjusted model, NET-IP remained associated with angiographic no-reflow (OR per SD, 1.96; 95% CI, 1.46–2.62; P < 0.001) and tissue-level reperfusion failure (OR per SD, 1.64; 95% CI, 1.32–2.02; P < 0.001). In the case-enriched ELISA subcohort, adjusted associations with no-reflow were observed for MPO-DNA (OR per SD log 2 , 1.88; 95% CI, 1.26–2.81; P = 0.002) and H3Cit (OR per SD log 2 , 2.01; 95% CI, 1.33–3.02; P < 0.001), whereas double-stranded DNA was weaker after adjustment ( P = 0.074). NET-IP was also associated with higher peak high-sensitivity cardiac troponin I, higher peak creatine kinase-MB, lower discharge left ventricular ejection fraction (LVEF), large myocardial injury, and discharge LVEF < 50%. Conclusion A NET-IP was linked to impaired coronary reperfusion and myocardial injury after primary PCI in STEMI. The findings support NET-associated immunothrombosis as a clinically measurable immune phenotype but do not establish direct NET burden, causal mediation, or immediate clinical treatment guidance.