Double-Stranded DNA and NETs Components in Relation to Clinical Outcome After ST-Elevation Myocardial Infarction

Abstract

Neutrophil extracellular traps (NETs) have been implicated in atherothrombosis; however, their potential role as markers of risk is unclear. We investigated whether circulating NETs-related components associated with clinical outcome and hypercoagulability in St-elevation myocardial infarction (STEMI). In this observational cohort study, STEMI patients admitted for PCI (n = 956) were followed for median 4.6 years, recording 190 events (reinfarction, unscheduled revascularization, stroke, heart failure hospitalization, or death). Serum drawn median 18 hours post-PCI was used to quantify double-stranded DNA (dsDNA) and the more specific NETs markers myeloperoxidase-DNA and citrullinated histone 3. Levels of the NETs markers did not differ significantly between groups with/without a primary composite endpoint. However, patients who died (n = 76) had higher dsDNA compared to survivors (p < 0.001). Above-median dsDNA was associated with an increased number of deaths (54 vs. 22, p < 0.001). dsDNA in the upper quartiles (Q) was associated with increased mortality (Q3 vs. Q1 + 2 adjusted HR: 1.89 [95% CI 1.03 to 3.49], p = 0.041 and Q4 vs. Q1 + 2 adjusted HR: 2.28 [95% CI 1.19 to 4.36], p = 0.013). dsDNA was weakly correlated with D-dimer (r s = 0.17, p < 0.001). dsDNA levels associated with increased all-cause mortality, yet weakly with hypercoagulability in STEMI patients. The prognostic significance of potentially NETs-related markers requires further exploration. Acute coronary syndrome (ACS) often results from erosion or rupture of atherosclerotic plaques followed by thrombosis, ischemia, and myocardial injury. It has been suggested that the risk-stratification of ACS patients should be expanded to include new soluble biomarkers, which may help individualize treatment 1. Potential candidates include components of the innate immune response, widely accepted to be important in the immediate aftermath of ACS, yet still not completely understood. Neutrophil extracellular traps (NETs) were first described in 2004 by Brinkmann and colleagues, who documented the expulsion of extracellular webbed structures comprising deoxyribonucleic acid (DNA) and histones, studded with neutrophil granule proteins 2. The process of NETs release, or NETosis, is initiated by granular proteins such as myeloperoxidase (MPO), neutrophil elastase, and peptidylarginine deiminase 4 3. The latter mediates the citrullination of histone 3, inducing chromatin decondensation before extracellular release 3. Circulating NETs-associated components may contribute to endothelial dysfunction and plaque instability 4 , as well as coronary thrombus formation 5 by activating platelets, triggering the coagulation cascade, and trapping thrombus constituents 6,7. Nevertheless, it is not yet clear how NETs per se are implicated in the fine balance between beneficial and deleterious effects of inflammation after revascularization.

Linking Neutrophil Extracellular Traps and Platelet Activation: A Composite Biomarker Score for Predicting Outcomes after Acute Myocardial Infarction

“…Liu et al 16 demonstrated that neither cell-free DNA nor MPO-DNA complexes sampled from the periphery were predictive of in-hospital MACE post-STEMI. Similarly, Langseth et al 17 observed that circulating NET biomarkers (dsDNA, MPO-DNA, H3(cit)) were not predictive of MACE. However, increased circulating levels of dsDNA, but not MPO-DNA or H3 (cit), were associated with increased risk of long-term allcause death.…”

“…However, increased circulating levels of dsDNA, but not MPO-DNA or H3 (cit), were associated with increased risk of long-term allcause death. 17,18 While other studies have shown the utility of peripheral NET burden for predicting MACE in patients with CAD, 13,14 this does not seem to translate into a utility for predicting MACE following AMI. 16,17 However, this statement comes with a caveat: the study of NET biomarkers for MACE is in its infancy.…”

“…First, there is a need to define a set of specific markers for NETosis. For example, it is acknowledged by Langseth et al 14,17 that circulating dsDNA can be produced by other ischemia-related pathways such as apoptosis, but remains a reliable and easily standardizable biomarker to measure. Second, there is no gold-standard methodology for measuring these NET-specific markers, and methodological variations between research groups are likely to contribute to the lack of consensus about their prognostic utility in CVD.…”

“…Sampling peripheral blood is favorable in this respect, but peripheral NET-specific markers alone may not be sufficient for risk prediction post-AMI. 16,17 Coupled to this, wider clinical utility of these NET biomarkers is hampered by two outstanding issues. There is (1) no consensus on what constitutes a specific marker of NETosis and (2) little standardization of the protocol for measuring these markers.…”

De-escalation Antibiotic Therapy Alleviates Organ Injury through Modulation of NET Formation during Sepsis

“…The release of intracellular contents, which is called neutrophil extracellular traps, is critical for killing bacteria in infection and sepsis [3]. Current studies have shown that NETs and their elements can cause organ injury, coagulation disorders, autoimmune diseases, and thromboembolism [20]. Although NETs are a double-edged sword in sepsis, few studies have focused on their antibacterial function in the early stage of sepsis, during which NETs can trap pathogens and prevent bacterial dissemination [17,18,21].…”