Coronary Neutrophil Extracellular Trap Burden and Deoxyribonuclease Activity in ST-Elevation Acute Coronary Syndrome Are Predictors of ST-Segment Resolution and Infarct Size

Abstract

Rationale: Mechanisms of coronary occlusion in ST-elevation acute coronary syndrome are poorly understood. We have previously reported that neutrophil (polymorphonuclear cells [PMNs]) accumulation in culprit lesion site (CLS) thrombus is a predictor of cardiovascular outcomes. Objective: The goal of this study was to characterize PMN activation at the CLS. We examined the relationships between CLS neutrophil extracellular traps (NETs), bacterial components as triggers of NETosis, activity of endogenous deoxyribonuclease, ST-segment resolution, and infarct size. Methods and Results: We analyzed coronary thrombectomies from 111 patients with ST-elevation acute coronary syndrome undergoing primary percutaneous coronary intervention. Thrombi were characterized by immunostaining, flow cytometry, bacterial profiling, and immunometric and enzymatic assays. Compared with femoral PMNs, CLS PMNs were highly activated and formed aggregates with platelets. Nucleosomes, double-stranded DNA, neutrophil elastase, myeloperoxidase, and myeloid-related protein 8/14 were increased in CLS plasma, and NETs contributed to the scaffolds of particulate coronary thrombi. Copy numbers of Streptococcus species correlated positively with dsDNA. Thrombus NET burden correlated positively with infarct size and negatively with ST-segment resolution, whereas CLS deoxyribonuclease activity correlated negatively with infarct size and positively with ST-segment resolution. Recombinant deoxyribonuclease accelerated the lysis of coronary thrombi ex vivo. Conclusions: PMNs are highly activated in ST-elevation acute coronary syndrome and undergo NETosis at the CLS. Coronary NET burden and deoxyribonuclease activity are predictors of ST-segment resolution and myocardial infarct size.

Propagation of thrombosis by neutrophils and extracellular nucleosome networks

“…The importance of these findings is underscored by the detection of NET in association with neutrophils in specimens of human coronary thrombi ( Figure 1) and at lesion sites of patients with acute myocardial infarction and stent thrombosis. 6,53,54 NET could only be detected in early stages of coronary thrombosis, but not in organized thrombi, which could be attributed to digestion of NET by plasma DNases or disruption of NET by heparin treatment applied during cardiac catheterization. 53 Increased NET burden in coronary thrombi correlated with infarct size, and DNase treatment (in particular together with tissue plasminogen activator) promoted resolution of coronary thrombi ex vivo, suggesting that a combination of established antithrombotic and NET-disrupting therapy might be beneficial in the therapy of acute coronary syndromes.…”

“…5 In parallel, it was shown that NET derived from neutrophils are present at sites of pathological thrombus formation in large arteries in experimental mouse models as well as in coronary thrombi of patients. 6 Notably, a substantial fraction of neutrophilderived extracellular nucleosomes did not exhibit the typical morphology of NET and were present in fragmented forms.…”

“…53 Increased NET burden in coronary thrombi correlated with infarct size, and DNase treatment (in particular together with tissue plasminogen activator) promoted resolution of coronary thrombi ex vivo, suggesting that a combination of established antithrombotic and NET-disrupting therapy might be beneficial in the therapy of acute coronary syndromes. 6 In addition, neutrophils are by far the most important innate leukocyte subtype in stent thrombosis. 54 Apart from neutrophils, eosinophils were present in all types of stent thrombosis, indicating a highly sensitive determinant that could induce thrombosis via eosinophil-associated TF.…”

Is the neutrophil extracellular trap-driven microvascular inflammation essential for diabetes vasculopathy?

“…Unfortunately, there is no consensus about the clinical significance of NETosis in diabetes beyond early atherosclerosis and CV complications (Freigang et al, 2013;Mangold et al, 2014). Although chronic lowgrading microvascular inflammation is considered a clue in the pathogenesis of atherosclerosis, the factors that trigger and sustain the inflammation remain elusive.…”

The Neutrophil Extracellular Traps: The Missed Link between Microvascular Inflammation and Diabetes?

“…Unfortunately, there is no consensus about the clinical significance of NETosis in diabetes beyond early atherosclerosis and CV complications [27,28]. Although chronic low-grading microvascular inflammation is considered a clue in the pathogenesis of atherosclerosis, the factors that trigger and sustain the inflammation remain elusive.…”