Neutrophil extracellular traps (NETs) are formed by decondensed chromatin, histones, and neutrophil granular proteins and have a role in entrapping microbial pathogens. NETs, however, have pro-thrombotic properties by stimulating fibrin deposition, and increased NET levels correlate with larger infarct size and predict major adverse cardiovascular (CV) events. NETs have been involved also in the pathogenesis of diabetes, as high glucose levels were found to induce NETosis. Accordingly, NETs have been described as drivers of diabetic complications, such as diabetic wound and diabetic retinopathy. Inflammasomes are macromolecular structures involved in the release of pro-inflammatory mediators, such as interleukin-1, which is a key mediator in CV diseases. A crosstalk between the inflammasome and NETs is known for some rheumatologic diseases, while this link is still under investigation and not completely understood in CV diseases. In this review, we summarized the most recent updates about the role of NETs in acute myocardial infarction and metabolic diseases and provided an overview on the relationship between NET and inflammasome activities in rheumatologic diseases, speculating a possible link between these two entities also in CV diseases.

The NLRP3 inflammasome has been implicated in the development and progression of heart failure. The aim of this study was to determine the safety of an oral inhibitor of the NLRP3 inflammasome, dapansutrile (OLT1177), in patients with heart failure and reduced ejection fraction (HFrEF). This was a phase 1B, randomized, double-blind, dose escalation, single-center, repeat dose safety and pharmacodynamics study of dapansutrile in stable patients with HFrEF (New York Heart Association Class II–III). Subjects were randomized to treatment with dapansutrile for up to 14 days at a ratio of 4:1 into 1 of 3 sequential ascending dose cohorts (500, 1000, or 2000 mg) each including 10 patients. Subjects underwent clinical assessment, biomarker determination, transthoracic echocardiogram, and maximal cardiopulmonary exercise testing at baseline, day 14, and day 28 to ascertain changes in clinical status. Placebo cases (N = 2 per cohort) were used as a decoy to reduce bias and not for statistical comparisons. Thirty participants (20 men) were treated for 13 (12–14) days. No serious adverse events during the study were recorded. All clinical or laboratory parameters at day 14 compared with baseline suggested clinical stability without significant within-group differences in the dapansutrile-pooled group or the 3 dapansutrile cohorts. Improvements in left ventricular EF [from 31.5% (27.5–39) to 36.5% (27.5–45), P = 0.039] and in exercise time [from 570 (399.5–627) to 616 (446.5–688) seconds, P = 0.039] were seen in the dapansutrile 2000 mg cohort. Treatment with dapansutrile for 14 days was safe and well tolerated in patients with stable HFrEF.

Neutrophils are the most abundant circulating leucocytes in healthy humans. These cells are central players during acute inflammatory responses, although a growing body of evidence supports a crucial role in chronic inflammation and chemokines and cytokines related to it as well. Thus, both humoral and cellular components are involved in the development of plaque formation and atherosclerosis. Accordingly, CANTOS trial using an interleukin-1 beta antibody confirmed that inflammatory cytokines contribute to the occurrence of myocardial infarction and cardiac death independent of changes in lipids. Recent data revealed that neutrophils are a heterogeneous population with different subsets and functional characteristics (i.e. CD177⁺ cells, OLFM4⁺ neutrophils, proangiogenic neutrophils, neutrophils undergoing reverse migration, and aged neutrophils). Importantly, neutrophils are able to synthesize de novo proteins. Neutrophil extracellular trap generation and NETosis have been considered as very important weapons in sterile inflammation. Neutrophil-derived microvesicles represent another mechanism by which neutrophils amplify inflammatory processes, being found at high levels both at the site of injury and in the bloodstream. Finally, neutrophil aging can influence their functions also in relation with host age. These recent acquisitions in the field of neutrophil biology might pave the way for new therapeutic targets to prevent or even treat patients experiencing cardiovascular (CV) diseases. Here, we discuss novel findings in neutrophil biology, their impact on CV and cerebrovascular diseases, and the potential implementation of these notions into daily clinical practice.