TREM-1 upregulation on myeloid cells links obesity with adverse outcome after experimental myocardial infarction

Methods and Results: Starting at an age of 8 weeks male and female C57BL6/J mice were either feed with a high (60 kJ %) fat diet to induce obesity (DIO) or a low fat (10 kJ %) diet. After 16 weeks feeding we found significantly higher body weight (male: 46.6 ± 0.8 g vs. 34.7 ± 0.7 g, female: 33.5 ± 1.9 g vs. 25.7 ± 0.5 g) and significantly increased myelopoiesis in the spleen and higher leukocyte counts in peripheral blood (male: 8,050 ± 570 vs. 5,275 ± 599/mm3, female: 13,100 ± 1,775 vs. 14,280 ± 12,296/mm3) in male obese mice.

Mice underwent a sham procedure or MI surgery by permanent ligation of the left coronary artery. Survival over 56 days after MI was significantly impaired in DIO mice compared to lean mice (87 vs. 58%). Echocardiographic analysis revealed no difference in LV function.

In DIO mice, we found significantly higher MI induced myelopoiesis in the spleen and higher granulocyte, monocyte and macrophage numbers in the myocardium. Moreover, RNA sequencing of left ventricular tissue and immunohistology revealed increased Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) expression within the infarcted myocardium of DIO compared with lean mice on day 5. DIO serum induced TREM1 protein expression in bone marrow myeloid cells in vitro.

Blockade of TREM1 lead to significantly better preservation of systolic function in DIO mice.

Summary

Although male mice develop a more pronounced obesity-like phenotype, after MI both sexes show enhanced myelopoiesis and impaired survival compared to lean mice. TREM1 blockade might be a promising target for preserving systolic function in obese MI patients.