Neutrophils orchestrate early cardiac remodeling after cardiac pressure overload

Cardiac pressure overload is a chronic condition where the left ventricle undergoes pathological hypertrophy and fibrosis ultimately causing heart failure. Increased myocardial stretch in left ventricular pressure overload initiates activation of an inflammatory and fibrotic response within resident cells leading to infiltration of immune cells. Neutrophils and monocytes are among the first responders during cardiac injury. While the role of monocytes and macrophages in pressure overload has been somewhat elucidated by multiple groups, including our lab, the role of neutrophils in chronic cardiac injury such as pressure overload is still unclear. We hypothesized that, like acute ischemic injury, neutrophils infiltrate to the heart early in pressure overload and initiate an inflammatory cascade which worsens cardiac dysfunction after TAC and that depletion of neutrophils in the first week of TAC would improve cardiac function. Our published single cell RNAseq dataset of immune cells (CD45+) cells from sham and TAC heart at day (D) 7 shows a distinct clustering of neutrophils with S100a9 (34-fold) , S100a8 (31-fold) , Retnlg (9-fold) , Il1b (5-fold) , and Slpi (5-fold) as top 5 differentially expressed genes (DEGs). Geneset enrichment analysis of top 58 DEGs (≥1.5-folds), shows significant association with pathways such as innate immune system, neutrophil degranulation, and signaling by interleukins by Reactome 2022 pathway. Using a murine model of transaortic constriction (TAC) to induce left ventricular pressure overload, we evaluated cardiac neutrophil counts by flow cytometry over the first week of TAC at D 2, 4 and 7. We observed that neutrophils (CD45 + Ly6G + CD11b + ) numbers consistently increase until D4, with a 7-fold increase at D2 to a 17-fold increase at D4 before returning to sham levels by D7. Using antibody (Anti Gr-1, 4 ug/g) mediated depletion of neutrophils, we observed that neutrophil depletion showed a protective effect in females compared to isotype controls with decreased cardiac hypertrophy and improved ejection fraction; while in male mice no change was observed between isotype and antibody treated groups. In conclusion, our data show that neutrophils peak early in pressure overload and orchestrate early cardiac remodeling with a potential for a sexually dimorphic role. We acknowledge funding from National Institute of Health under the awards numbers HL155993 and HL160665. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.