Neutrophil Extracellular Trap Components Associate with Infarct Size, Ventricular Function, and Clinical Outcome in STEMI

Abstract

Background The relevance of neutrophil extracellular traps (NETs) in acute ST-elevation myocardial infarction (STEMI) is unclear. We explored the temporal profile of circulating NET markers and their associations to myocardial injury and function and to adverse clinical events in STEMI patients. Methods and Results In 259 patients, blood samples were drawn before and after PCI, on day 1, and after 4 months. Double-stranded deoxyribonucleic acid (dsDNA) and myeloperoxidase-DNA (MPO-DNA) were measured in serum by a nucleic acid stain and ELISA. Cardiac magnetic resonance imaging assessed microvascular obstruction (MVO), area at risk, infarct size, myocardial salvage index, left ventricular ejection fraction (LVEF), and change in indexed left ventricular end-diastolic volume (LVEDVi). Clinical events were registered after 12 months. dsDNA and MPO-DNA levels were highest before PCI, with reduced levels thereafter (all p ≤ 0.02). Patients with high vs. low day 1 dsDNA levels (>median; 366 ng/ml) more frequently had MVO, larger area at risk, larger infarct size acutely and after 4 months, and lower myocardial salvage index (all p < 0.03). Moreover, they had lower LVEF acutely and after 4 months, and larger change in LVEDVi (all p ≤ 0.014). High day 1 dsDNA levels also associated with risk of having a large infarct size (>75th percentile) and low LVEF (≤49%) after 4 months when adjusted for gender, time from symptoms to PCI, and infarct localization (OR 2.3 and 3.0, both p < 0.021), and patients with high day 1 dsDNA levels were more likely to experience an adverse clinical event, also when adjusting for peak troponin T (hazard ratio 5.1, p = 0.012). No such observations were encountered for MPO-DNA. Conclusions High day 1 dsDNA levels after STEMI were associated with myocardial infarct size, adverse left ventricular remodeling, and clinical outcome. Although the origin of dsDNA could be discussed, these observations indicate a potential role for dsDNA in acute myocardial ischemia. This trial is registered with S-08421d, 2008/10614 (Regional Committee for Medical Research Ethics in South-East Norway (2008)).

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

“…Nonetheless, the lack of a clear association with TnT may indicate that the measured dsDNA has not merely leaked from damaged cardiomyocytes. This is corroborated by our previous observation that dsDNA peaked prior to PCI, indicating the importance of temporality which this study could not assess 25 . Even though causality cannot be established from our observations, and there is incongruence between the NETs-specific components, multivariable analyses show that even after adjusting for variables related to myocardial injury and function such as TnT and NT-proBNP, dsDNA still confers an increased risk of death.…”

Neutrophil Extracellular Traps Induce MCP-1 at the Culprit Site in ST-Segment Elevation Myocardial Infarction

“…NETs dominate the acute inflammatory setting of STEMI ( Mangold et al, 2015 ; Helseth et al, 2019 ). We reported that besides their cytotoxic ( Saffarzadeh et al, 2012 ) and pro-thrombotic ( Fuchs et al, 2012 ) properties, the presence of NETs affects other cell types such as fibrocytes ( Hofbauer et al, 2019 ) and monocytes ( Mangold et al, 2019 ) that are recruited to the culprit site and the ischemic myocardium.…”

“…NET burden was associated with microvascular obstruction, myocardial salvage index, and left ventricular ejection fraction in STEMI patients (Helseth et al, 2019).…”

“…This meshwork of DNA and associated proteins was identified as a major constituent of coronary thrombi ( de Boer et al, 2013 ; Mangold et al, 2015 ). NET burden was associated with microvascular obstruction, myocardial salvage index, and left ventricular ejection fraction in STEMI patients ( Helseth et al, 2019 ).…”

Neutrophil extracellular trap components and myocardial recovery in post-ischemic acute heart failure

“…Aside from expulsion of reactive oxygen species and other proteins, neutrophils also release extracellular traps (NETs), appearing as extracellular clouds consisting of deoxyribonucleic acid (DNA), histones, and neutrophil granule proteins in response to stimuli such as activated platelets or IL-8 [ 7 ]. NETs have been shown to be cytotoxic, proinflammatory and prothrombotic, potentially augmenting myocardial injury [ 8 , 9 ], and have recently been suggested to affect both myocardial infarct size and post-MI left ventricular remodeling [ 10 , 11 ]. However, the contribution of NETs components with respect to AHF complicating MI has not previously been reported on.…”