Abstract 12043: Neutrophil Extracellular Traps in Heart Tissue Drive Cardiac Dysfunction and Adverse Outcomes in Dilated Cardiomyopathy

Abstract

Background: Neutrophil extracellular traps (NETs) have emerged as crucial contributors to cardiovascular diseases, but the significance of NETs in heart failure remains unclear. Aims: We aimed to clarify the relevance of NETs in myocardial tissue in heart failure. Methods and Results: We studied consecutive 62 patients with idiopathic dilated cardiomyopathy (DCM) who underwent endomyocardial biopsy. Using immunohistochemistry, NETs were identified in heart tissue by detecting the colocalization of citrullinated histone H3, neutrophil elastase, and DAPI. DCM patients had significantly higher numbers of NETs per tissue area and per neutrophil compared to control subjects without heart failure (n=11, Figure A ) (P < 0.05 and P < 0.05, respectively). When categorizing DCM patients based on the presence or absence of NETs, patients with NETs (n=32) had lower left ventricular ejection fraction and higher B-type natriuretic peptide levels than those without NETs (P < 0.05 and P < 0.05, respectively). Kaplan-Meier analysis revealed that NETs-positive DCM patients had lower event-free survival rates from the composite of cardiac events including cardiac deaths, decompensated heart failure, and left ventricular assist device implantation over a median 768-day follow-up ( Figure B ). In a multivariable Cox proportional hazard model, the presence of NETs independently associated with the risk of adverse cardiac events (hazard ratio, 5.96; P < 0.05). Ex vivo analysis revealed that NETs-containing conditioned medium from wild-type neutrophils impaired mitochondrial oxygen consumption in mouse adult cardiomyocytes (P < 0.05), while genetic ablation of peptidyl arginine deiminase 4, a molecule essential for NETs formation, abolished this effect. Conclusion: NETs in myocardial tissue contribute to cardiac dysfunction and adverse outcomes in DCM patients, potentially through mitochondrial dysfunction of cardiomyocytes.