Ziel/Aim Macrophages are involved in cardiac repair following acute myocardial infarction (MI). We investigated effects of macrophage depletion on early inflammation and later functional outcome in two models of MI.
Methodik/Methods C57BL6 mice received clodronate-liposomes for macrophage depletion (n = 49) or control PBS-liposomes (n = 23) 24h prior to permanent (PO) or transient (I/R, 60min) coronary artery ligation or sham surgery. Inflammation was assessed on MI+1, 3, and 7d by CXCR4-targeted PET/CT using Ga-68-pentixafor. Tc-99m-sestamibi SPECT/CT and cardiac magnetic resonance (CMR) calculated infarct sizes and left ventricular (LV) function at 1 and 6wk. F-18-NaF PET/CT measured tissue microcalcification. Imaging signals were validated by ex vivo autoradiography and immunohistochemistry.
Ergebnisse/Results Macrophage depletion did not influence infarct size vs PBS, but PO generated significantly larger infarcts compared to I/R (%LV, 32 ± 11 vs 14 ± 10, p = 0.01). In both models, infarct CXCR4 expression was higher after macrophage depletion vs PBS (%injected dose (ID)/g; d3: PO: 1.4 ± 0.2 vs 0.9 ± 0.1; I/R: 1.4 ± 0.2 vs 1.0 ± 0.02; p < 0.05), confirmed by autoradiography. Immunostaining demonstrated fewer macrophages and higher neutrophil content. Acute LV rupture after PO was more frequent in clodronate than PBS mice (37 % vs 17 %). At 6wk, surviving PO mice showed a similarly impaired ejection fraction (EF) after macrophage depletion (%, 32 ± 9 vs 32 ± 11, p = 0.84). No acute LV rupture was observed after I/R, but macrophage depletion led to worse EF (%, 42 ± 11 vs 54 ± 3, p = 0.1). Macrophage-depleted mice exhibited a dense intracavity thrombus adherent to the infarct wall in CMR after PO or I/R. NaF PET identified active calcification at the thrombus at 4wk after PO or I/R, colocalized to CT opaque regions at 6wk.
Schlussfolgerungen/Conclusions Macrophage depletion impairs cardiac repair, including persistent neutrophil recruitment, thrombus formation and tissue calcification. This underscores the necessity of macrophages for effective healing and may explain adverse response to broad anti-inflammatory therapy in myocardial ischemia.
