Abstract 4362755: Macrophage Extracellular Traps In Myocardial Tissue Are Associated With Adverse Clinical Outcomes In Patients With Heart Failure

Abstract

Introduction: The immune system, particularly bone marrow-derived macrophages, leads to the development of pathological cardiac remodeling. Inflammatory leukocytes release extracellular traps, web-like structures composed of DNA and histones, which promote sterile inflammation and pathology. More recently, it has been reported that macrophages release extracellular traps, termed macrophage extracellular traps (METs). However, the clinical relevance of METs in heart failure remains to be elucidated. Research Questions: We hypothesized that METs in myocardial tissue contribute to the pathophysiology and clinical outcomes in patients with heart failure. Methods: Myocardial biopsy specimens from 69 patients with heart failure due to dilated cardiomyopathy (mean age 55.5 ± 13.0 years; 84.1% male) were analyzed by fluorescent immunostaining to detect and quantify METs, defined as structures positive for citrullinated histone H3, CD68, and DAPI. Clinical characteristics and outcome data were collected. Results: Representative images of METs and a histogram distribution of CD68 + macrophages, MET counts per myocardial tissue area and the ratio of METs to CD68 in heart failure patients are presented in Figure 1 . Myocardial MET counts were positively associated with left ventricular (LV) volume at both diastole and systole, and negatively associated with LV ejection fraction, suggesting a link between METs and adverse LV remodeling. When patients were stratified based on a threshold MET count (2.69 per mm 2 ), patients with high METs exhibited larger LV end-diastolic and -systolic volumes compared to those with low METs. Over a median period of 1594 days, Kaplan-Meier analysis revealed that patients with high METs had significantly lower cardiac event-free survival rates from the composite outcome of cardiac death, worsening heat failure, or LV assist device implantation, compared to those with low METs ( Figure 2 ). In the multivariable Cox proportional hazard analyses, high METs independently predicted increased risk of cardiac events (hazard ratio [HR] 7.62; 95% confidence interval [CI], 2.17-26.76; P<0.01). Furthermore, MET count as a continuous variable remained significantly associated with elevated risk (HR 1.10 per 1/mm 2 increase; 95% CI, 1.02-1.19; P=0.01). Conclusion: Myocardial METs are associated with adverse LV remodeling and poorer clinical outcomes in patients with heart failure. METs may represent a novel pathological mechanism and therapeutic target in this disease.