Eosinophil deficiency promotes aberrant repair and adverse remodelling following acute myocardial infarction

Background Eosinophil count predicts outcome following myocardial infarction (MI) and eosinophils regulate tissue repair and regeneration in extra-cardiac settings. Objectives To investigate the role of eosinophils in regulating inflammation, repair and remodelling following MI. Methods Blood eosinophil count was assessed in 732 patients undergoing primary percutaneous coronary intervention for ST-segment elevation MI (STEMI). Experimental MI was induced in wild-type (WT) and eosinophil-depleted mice (ΔdblGATA or anti-Siglec F antibody treated). Cardiac function was characterised by high-resolution ultrasound and immune cell infiltration by flow cytometry of infarct digests. Results Blood eosinophil count declined in the hours following STEMI in patients and following MI induction in mice. Eosinophils were subsequently identified in the myocardium of patients and mice. Genetic eosinophil depletion in mice increased LV dilatation (end-systolic area: 29.0±2.2cm 2 v 21.6±1.6cm 2 ; p=0.02) and reduced ejection fraction (22.0±3.6% v 34.3±4.0% in p=0.04,) in ΔdblGATA v WT following MI (n=8-9/group), an outcome reproduced by pharmacological depletion. ΔdblGATA mice had increased scar size with disrupted collagen deposition and altered expression of the collagen cross-linking genes plod2 and lox . CD206 + pro-repair macrophages were less prevalent in the infarct zone of ΔdblGATA mice (27.0±2.3% v WT: 39.2.4±3.5%; p=0.01, n=9-11/group) but were restored by replenishment with bone marrow-derived eosinophils. Anti-inflammatory cytokine concentrations were reduced in ΔdblGATA mice and IL-4 complex administration 24h after MI rescued adverse remodelling. Conclusions Eosinophils are recruited to the heart following MI and are required for effective repair and to prevent adverse remodelling. IL-4 therapy has potential to limit detrimental outcomes when eosinophil availability is low. HIGHLIGHTS A drop in eosinophil blood count is associated with recruitment of eosinophils to the heart during repair following clinical and experimental myocardial infarction. Genetic & pharmacological eosinophil depletion leads to increased adverse remodelling in experimental MI. Eosinophils are required for aquisition of an anti-inflammatory macrophage phenotype and a shift to resolution of inflammation during infarct repair. Interleukin-4 therapy is able to rescue the adverse remodelling phenotype in conditions of eosinophil deficiency. Condensed abstract In ST-segment elevation myocardial infarction (STEMI) of both patients and mice, there was a decline in blood eosinophil count, with activated eosinophils recruited to the infarct zone. Eosinophil deficiency resulted in attenuated anti-inflammatory pro-repair macrophage polarization, enhanced myocardial inflammation, increased scar size and deterioration of myocardial structure and function. Adverse cardiac remodelling in the setting of eosinophil deficiency was prevented by IL-4 therapy.