Background: Sex differences in the clinical characteristics and pathophysiology of heart failure (HF) have been extensively described in clinical studies, where females are more prone to HF with preserved ejection fraction (EF), while males are more towards HF with reduced EF. However, sex differences in animal models of HF were not always addressed and often only single sex was included in experimental studies, which could limit the potential for translational medicine. Thus, this study aims to determine the sex-specific differences in cardiac hypertrophy, fibrosis and immune cell phenotype in heart and circulating monocytes during angiotensin II (AngII)-induced cardiac remodeling. 

methods:Male and female age-matched 9-week-old C57BL/6J mice were subjected to vehicle (saline) or AngII infusion for 7 and 28 days. Leukocyte subsets were examined via flow cytometry in blood, heart, and lymphoid organs. Differentially expressed genes (DEGs) in sorted circulating Ly6C ^hi  and Ly6C ^lo  monocytes were assessed via bulk RNA sequencing  with a sequencing depth of 10 million reads per sample . Assessment of cardiac inflammation, fibrosis and hypertrophy were performed via qPCR and histology. 

Results: In steady state, we found that male mice have a higher number of cardiac macrophages compared to females.Following AngII infusion for 28 days, hypertrophic growth of the cardiomyocytes was observed in both treated groups as determined by histology to measure the cross-sectional area and qPCR of cardiac pro-hypertrophic markers ( Nppa, Nppb ). Although cardiac fibrosis was noted in both treated groups, female mice showed more pronounced interstitial fibrosis compared to males, at least at the early time point (7 days AngII). However, enhanced numbers of myofibroblasts, pro-fibrotic ( Ctgf ) and pro-inflammatory ( Il6, Ccl2 ) gene expression were detected in male compared to female hearts, accompanied by higher Col3  expression and decreased Col1-to-Col3 ratio.Transcriptomic profiling of circulating Ly6C ^hi  monocytes uncovered many DEGs between male and female per se , independent of AngII infusion. In particular, the male vehicle group showed an enrichment of DEGs related to monocyte activation and leukocyte migration compared to the female vehicle group, which is in line with the elevated myeloid cell counts observed in the heart of baseline male mice. The gene ontology enrichment analysis of circulating Ly6C ^lo  Monocytes showed that genes associated with antigen processing and presentation were more expressed in females compared to males subjected to AngII. 
Conclusion: We may speculate that Ly6C ^hi monocyte-derived macrophages in male mice more actively infiltrate the myocardium under homeostasis. A higher number of cardiac macrophages can trigger the AngII-induced expression of pro-fibrotic and pro-inflammatory factors, which may translate into more pronounced cardiac fibrosis in the long term. In the early stage, male mice showed milder interstitial fibrosis in addition to excess type III collagen production, promoting dilated left ventricular phenotype that is more commonly observed in males. In contrast, adaptive antigen-specific immune responses appear to be more important in female hearts.