<p>Heart failure (HF) after myocardial infarction (MI) involves adverse cardiac remodeling. Trem1 may be a potential therapeutic target for MI, but its role in the HF process remains unclear. Our work aimed to investigate the effect of Trem1 on myocardial remodeling in MI-induced HF and the downstream molecular mechanism. The HF mouse model was established by left anterior descending (LAD) ligation, and cardiac function, hypertrophy markers, and fibrosis were measured. Additionally, Mouse cardiac fibroblasts (MCFs) were stimulated with angiotensin II (Ang II), and cell phenotypes, including proliferation and fibrosis, were detected. The regulation of Trem1 on the Rap1 pathway was evaluated using bioinformatics and western blot. We found that Trem1 was upregulated in HF mice (mean fold-change at RNA level was 4.68 and at protein level was 4.43) and AngII-treated MCFs (mean fold-change at RNA level was 6.28 and at protein level was 4.01). Trem1 knockdown improved cardiac function, as indicated by an increase in left ventricular ejection fraction (LVEF) from 36.45% to 58.62% and left ventricular fractional shortening (LVFS) from 18.78% to 30.19%, reduced hypertrophy (heart weight/body weight fold reduced from 6.40 to 4.85 and ANP and BNP mRNA expression was downregulated), and reduced collagen volume fraction from 30.47% to 14.33% in vivo. In AngII-stimulated MCFs, Trem1 silencing decreased cell viability by 48.76%, reduced EdU-positive cells by 46.92%, and downregulated fibrosis-related marker expression. Mechanistically, silencing of Trem1 promoted Rap1 pathway activation, manifested as an increase of 3.79 folds in Epac1, 1.90 folds in active Pap1, and 5.56 folds in Rac1 protein levels. Inhibition of Rap1 caused by GGTI298 partly reversed the effects of Trem1 knockdown both in vivo and in vitro. In conclusion, Trem1 promotes myocardial remodeling in post-MI HF by suppressing the Rap1 pathway, suggesting Trem1 is a potential therapeutic target.</p>