Culprit site extracellular DNA and microvascular obstruction in ST-elevation myocardial infarction

Abstract

Aims Extracellular chromatin and deoxyribonuclease (DNase) have been identified as important players of thrombosis, inflammation and homeostasis in a murine model. We previously demonstrated that activated neutrophils release neutrophil extracellular traps (NETs) at the culprit site in ST elevation myocardial infarction (STEMI), which significantly contribute to extracellular chromatin burden, and are associated with larger infarcts. To understand the correlation between neutrophil activation, extracellular chromatin and infarct size (IS), we investigated these parameters in a porcine myocardial infarction model, and at different time points and sites in a prospective STEMI trial with cardiac magnetic resonance (CMR) endpoints. Methods and Results In a prospective STEMI trial (NCT01777750), 101 STEMI patients were included and blood samples were obtained from first medical contact until 6 months after primary percutaneous coronary intervention (pPCI) including direct sampling from the culprit site. CMR was performed 4 ± 2 days and 6 months after pPCI. Neutrophil counts, markers of extracellular chromatin and inflammation were measured. Double-stranded DNA (dsDNA), citrullinated histone 3, nucleosomes, myeloperoxidase, neutrophil elastase and interleukin (IL)-6 were significantly increased, while DNase activity was significantly decreased at the culprit site in STEMI patients. High neutrophil counts and dsDNA levels at the culprit site correlated with high microvascular obstruction (MVO) and low ejection fraction (EF). High DNase activity at the culprit site correlated with low MVO and high EF. In correspondence, dsDNA correlated with IS in the porcine myocardial infarction model. In porcine infarcts, neutrophils and extracellular chromatin were detected in congested small arteries corresponding with MVO. Markers of neutrophil activation, extracellular chromatin, DNase activity and CMR measurements correlated with markers of systemic inflammation C-reactive protein and IL-6 in patients. Conclusions NETs and extracellular chromatin are important determinants of MVO in STEMI. Rapid degradation of extracellular chromatin by DNases appears to be crucial for microvascular patency and outcome. Translational Perspective We show that NETs and extracellular DNA obstruct microvessels in the porcine myocardial infarction model and is connected to increased infarct size. We are able to prove this observation in human STEMI patients. DNase is capable to counteract these effects. Extracellular DNA could be a new treatment target in STEMI.

Neutrophil extracellular traps regulate ischemic stroke brain injury

“…In the bloodstream, NETs can induce thrombus formation with the intention to prevent dissemination of infectious agents ( 33 ). However, excessive NET formation contributes to cardiovascular diseases by stabilizing blood clots ( 10 ), mediating microvascular thrombosis ( 34 ), and inducing endothelial cell death ( 35 , 36 ). Several studies have reported the presence of NETs in ischemic stroke thrombi, where they contribute to tissue-type plasminogen activator (t-PA) resistance ( 10 , 11 , 37 ).…”

“…Additionally, we detected reduced activity of DNase in stroke patient plasma compared with plasma from matched healthy donors. Reduced DNase activity has previously been linked to disease outcomes in systemic lupus erythematosus ( 38 , 39 ), thrombotic microangiopathies ( 40 , 41 ), and myocardial infarction ( 34 , 42 ). DNases are part of the endogenous system to degrade NETs, and they help to maintain tissue integrity during inflammation ( 43 ).…”

A fresh look at coronary microembolization

“…Notably, thrombi also contained high levels of neutrophil extracellular traps (NETs), which correlated with infarct size as determined by CK-MB levels and MRI 177 . Again, in patients undergoing PCI for STEMI, increased levels of double-stranded DNA (as a surrogate for NETs) and IL-6 were retrieved by thromboaspiration from the culprit site and correlated with coronary microvascular obstruction on MRI 4 ± 2 days later 178 .…”

Secretome of Stressed Peripheral Blood Mononuclear Cells Alters Transcriptome Signature in Heart, Liver, and Spleen after an Experimental Acute Myocardial Infarction: An In Silico Analysis

“…As a result, leukocytes are readily recruited to the border zone, contributing to the aggravation of local cardiotoxic effects [ 7 ]. In addition, neutrophils have been shown to infiltrate the infarcted area, augmenting tissue damage by releasing extracellular traps and, thereby, further obstructing the vasculature [ 8 , 9 , 10 ]. Eventually, an AMI results in tissue fibrosis and scarring, leading to compromised cardiac performance.…”