Abstract 19521: Macrophages Infiltrating into the Heart Early After Pressure Overload Are Indispensable for the Transition to Chronic Heart Failure
The response to acute cardiac injury is characterized by tissue-resident (CCR2–) and infiltrating (CCR2+) macrophages that exhibit opposing reparative vis-à-vis pro-inflammatory functions. In contrast, pressure-overload (PO) heart failure (HF) is primarily considered a T-cell activated inflammatory state, and the importance of macrophages in PO cardiac remodeling is less clear. We recently demonstrated that acute pressure overload (PO) is accompanied by an early (within 1 w) increase in infiltrating cardiac CCR2+ macrophages, which are derived from circulating CCR2+ Ly6Chi monocytes. Given that macrophages are antigen-presenting cells that can activate effector T-cells, we tested the hypothesis that the early recruitment of CCR2+ macrophages to the heart after PO contributes to long-term T-cell activation and the late development of HF. After transverse aortic constriction (TAC), male C57BL/6 mice were treated with an anti-CCR2 monoclonal antibody (MC21), or IgG isotype control, for 3 d during the first week of PO, and cardiac remodeling was assessed 4 w post-TAC. As compared to isotype control-treated TAC mice, MC21-treated TAC mice exhibited significantly (p<0.05) improved systolic function (LVEF 47 ± 7 vs 39 ± 9%; and ESV 33.7 ± 10.3 vs 42.2 ± 11.9 uL). MC21 treatment also blunted LV hypertrophy (heart weight/tibia length 12.4 ± 2.6 vs 14.4 ± 2.3 mg/mm; LV posterior wall thickness 0.93 ± 0.08 vs 1.06 ± 0.14 mm), and suppressed interstitial cardiac fibrosis, as assessed by Masson’s trichrome staining (3.41 ± 0.28 vs 6.96 ± 1.5%). Moreover, cardiac infiltration of macrophages was diminished in MC21-treated TAC mice as compared with isotype controls. Lastly, to determine activation of the adaptive immune response, we analyzed T-cell populations in heart. Cardiac infiltration of CD4+ T-cells was blunted in MC21-treated TAC mice as compared to isotype control TAC mice (6051 ± 2525 vs 3541 ± 3000 cells/heart). We conclude that early infiltration of CCR2+ macrophages after PO is indispensable for the progression of adverse cardiac remodeling and long-term T-cell activation. Moreover, our results suggest that suppressing the cardiac infiltration of CCR2+ macrophages during the compensated phase of PO hypertrophy can delay or prevent the transition to HF.
Author Disclosures: B.D. Patel: None. S.S. Bansal: None. A. Ismahil: None. T. Hamid: None. S.D. Prabhu: None.
- © 2016 by American Heart Association, Inc.