Mononuclear Phagocytes Are Dispensable for Cardiac Remodeling in Established Pressure-Overload Heart Failure

Background Although cardiac and splenic mononuclear phagocytes (MPs), i.e., monocytes, macro- phages and dendritic cells (DCs), are key contributors to cardiac remodeling after myo- cardial infarction, their role in pressure-overload remodeling is unclear. Wetested the hypothesis that these immune cells are required for the progression of remodeling in pres- sure-overload heart failure (HF), and thatMPdepletion would ameliorate remodeling. Methods and Results C57BL/6 mice were subjected to transverse aortic constriction (TAC) or sham operation, and assessed for alterations in MPs. As compared with sham, TAC mice exhibited expan- sion of circulating LyC6hi monocytes and pro-inflammatory CD206− cardiac macrophages early (1 w) after pressure-overload, prior to significant hypertrophy and systolic dysfunction, with subsequent resolution during chronic HF. In contrast, classical DCs were expanded in the heart in a biphasic manner, with peaks both early, analogous to macrophages, and late (8 w), during established HF. There was no significant expansion of circulating DCs, or Ly6C+ monocytes and DCs in the spleen. Periodic systemicMPdepletion from 2 to 16 w after TAC in macrophage Fas-induced apoptosis (MaFIA) transgenic mice did not alter car- diac remodeling progression, nor did splenectomy in mice with established HF after TAC. Lastly, adoptive transfer of splenocytes from TAC HF mice into naïve recipients did not induce immediate or long-term cardiac dysfunction in recipient mice. Conclusions Mononuclear phagocytes populations expand in a phasic manner in the heart during pres- sure-overload. However, they are dispensable for the progression of remodeling and failure once significant hypertrophy is evident and blood monocytosis has normalized.