Cardiovascular

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.

Sun Z, Zhang Z, Qiao G, Jia F • Frontiers in immunology • 2026

PubMed 42870905 DOI 10.3389/fimmu.2026.1926100

TL;DR

A NET-associated immunothrombotic phenotype (NET-IP), calculated from five admission variables, was independently associated with angiographic no-reflow, tissue-level reperfusion failure, and myocardial injury after primary PCI in STEMI, supporting NET-associated immunothrombosis as a clinically measurable immune phenotype.

Key Findings

Results

Angiographic no-reflow occurred in 110 of 742 STEMI patients undergoing primary PCI.

Single-center translational cohort of 742 patients with ST-segment elevation myocardial infarction (STEMI).
No-reflow was defined as final TIMI flow grade < 3 in the absence of mechanical epicardial obstruction.
NET-IP was calculable in 725 patients; fully adjusted complete-case models included 700 patients.

Results

Patients with no-reflow had significantly higher admission NET-IP scores than those with normal reflow.

Median NET-IP score in no-reflow group: 0.73 [IQR 0.24, 1.25] vs. -0.06 [IQR -0.77, 0.54] in normal reflow group.
Difference was statistically significant: P < 0.001.
NET-IP was calculated from five variables: neutrophil count, D-dimer, fibrinogen, high-sensitivity C-reactive protein, and platelet-neutrophil product.
The composite score was derived by averaging log-transformed component z scores when at least four components were available, then standardizing the composite.

Results

NET-IP remained independently associated with angiographic no-reflow in fully adjusted models.

OR per SD increase in NET-IP: 1.96 (95% CI, 1.46–2.62; P < 0.001).
NET-IP was also associated with tissue-level reperfusion failure: OR per SD, 1.64 (95% CI, 1.32–2.02; P < 0.001).
Associations persisted after full adjustment for covariates in complete-case models including 700 patients.

Results

Direct NET biomarkers MPO-DNA and citrullinated histone H3 (H3Cit) were independently associated with angiographic no-reflow in the ELISA subcohort.

MPO-DNA: OR per SD log2, 1.88 (95% CI, 1.26–2.81; P = 0.002).
H3Cit: OR per SD log2, 2.01 (95% CI, 1.33–3.02; P < 0.001).
Double-stranded DNA association was weaker and did not reach significance after adjustment (P = 0.074).
Biomarkers were measured in a case-enriched nested ELISA biomarker subcohort.

Results

NET-IP was associated with multiple markers of myocardial injury and left ventricular dysfunction.

Higher NET-IP was associated with higher peak high-sensitivity cardiac troponin I.
Higher NET-IP was associated with higher peak creatine kinase-MB.
Higher NET-IP was associated with lower discharge left ventricular ejection fraction (LVEF).
NET-IP was associated with large myocardial injury and discharge LVEF < 50%.

Discussion

The authors note that the findings do not establish direct NET burden, causal mediation, or immediate clinical treatment guidance.

The study is observational and translational in design.
NET-IP is described as a 'clinically measurable immune phenotype' rather than a direct measure of NET burden.
The authors explicitly state the findings 'do not establish direct NET burden, causal mediation, or immediate clinical treatment guidance.'
The study was conducted at a single center, which may limit generalizability.

What This Means

This research suggests that when a heart attack patient's blood shows signs of a specific immune response involving neutrophil extracellular traps (NETs) — a process where immune cells release DNA and proteins that can promote clotting — those patients are more likely to experience 'no-reflow' after a coronary stenting procedure. No-reflow means that even after the blocked artery is physically opened, blood does not properly reach the heart muscle. The researchers created a scoring system called NET-IP using five routine blood test values measured on hospital admission, and found that patients with higher scores were roughly twice as likely to experience no-reflow. The study included 742 heart attack patients and also used specialized laboratory tests (ELISA) in a subset to directly measure NET proteins in the blood. These direct NET markers — MPO-DNA and citrullinated histone H3 — were also significantly linked to no-reflow, strengthening confidence that the NET-related biology is relevant. Patients with higher NET-IP scores also had more heart muscle damage overall, as measured by cardiac enzyme levels and heart pumping function at hospital discharge. This research suggests that measuring a patient's NET-associated immune activity at the time of hospital admission could help identify those at higher risk of poor outcomes after emergency heart procedures. However, because the study is observational, it cannot prove that NETs directly cause no-reflow or that treating this immune response would improve outcomes. Further studies would be needed to determine whether targeting this immune pathway could benefit patients.

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Citation

Sun Z, Zhang Z, Qiao G, Jia F. (2026). 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.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1926100

Key Findings

What This Means

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