Macrophages are required for adequate cardiac repair after acute myocardial infarction - A multiparametric molecular imaging analysis

Ziel/Aim After acute myocardial infarction (MI), tissue inflammation plays a crucial role mediating cardiac repair. Here, we investigated effects of macrophage depletion on early myocardial inflammation and later functional outcome.

Methodik/Methods C57Bl6 mice received clodronate-loaded liposomes for peripheral macrophage depletion (n = 12) or control liposomes (n = 6). After 24h, mice underwent permanent coronary artery ligation or sham. Inflammation was assessed on MI+1d, 3d, and 7d by chemokine receptor 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 MI+1wk and 6wks. F-18-NaF PET/CT determined tissue microcalcification. Imaging signals were validated by immunohistochemistry.

Ergebnisse/Results Infarct size was comparable between groups (%LV, clodronate 38±8 vs vehicle 32±8, p=0.3). Surprisingly, infarct CXCR4 expression was higher after macrophage depletion vs vehicle (%injected dose (ID)/g; d1: 1.6±0.2 vs 1.2±0.1; d3: 1.3±0.2 vs 1.0±0.2; d7: 1.1±0.4 vs 0.7±0.1; p<0.05). Immunostaining confirmed reduced macrophages but higher neutrophil content. Acute LV rupture rate was increased in clodronate over vehicle mice (42 % vs 16 %). Surviving mice exhibited LV dilatation (end systolic volume (µl), clodronate 97±50 vs vehicle 98±55, p=0.98) accompanied by impaired LV ejection fraction (%,32±8 vs 29±10, p=0.61). CMR revealed a dense intra-cavity thrombus adhering to the infarct wall from MI+7d. Fluoidrefe PET identified active calcification at the intraluminal thrombus at MI+4wk, which was absent in untreated MI and sham mice. Regional calcification was confirmed by CT at MI+6wk.

Schlussfolgerungen/Conclusions Macrophage depletion impairs infarct repair, including altered neutrophil-dominated inflammation, 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.