Neutrophil extracellular traps in cardiac fibrosis and heart failure

Neutrophil extracellular traps (NETs) have led to a paradigm shift in studying thrombotic and inflammatory disease. NETs promote thrombus formation by providing a scaffold for platelet, red blood cell, and coagulation factor binding. We and others have recently described the contribution of NETs and the early NET inducer peptidylarginine deiminase 4 (PAD4) to cardiac fibrosis development during aging in mice. Strikingly, aged PAD4-/- mice maintained healthy heart function (systolic and diastolic) comparable to young mice. In an experimental model of pressure-overload injury, both PAD4-deficiency and DNase treatment, which degrades NETs, similarly protected mice from aberrant collagen deposition and decline in cardiac output. In patients, this type of decline in cardiac function is linked to progression to heart failure with poor prognosis, often due to an increase in cardiac fibrotic remodeling with unknown etiology. It is interesting to study NET formation in the context of heart failure development. Our research lines will be to study sterile cardiac injury leading to heart failure with a focus on NETs and protein citrullination. We should obtain valuable insight into the role of neutrophil NETs or PAD4 in the pathogenesis of heart failure in patients, which could be applied to future therapeutic approaches in the clinic.