Abstract 20112: Molecular Imaging of Chemokine Receptor Type 4 (CXCR4) Upregulation Independently Predicts Subsequent Contractile Dysfunction After Cardiac Ischemia in Mice

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Abstract

Acute inflammation after myocardial infarction (MI) influences left ventricular (LV) remodeling and healing, and may be a target for novel therapy. Molecular imaging of chemokine receptor CXCR4 can detect inflammation, but its value to predict subsequent LV dysfunction has not been elucidated. We aimed to measure acute inflammation and monitor LV geometry and function over 6 weeks post-MI. C57Bl/6 mice underwent permanent coronary occlusion (n=14), 60min ischemia-reperfusion (n=10) or sham surgery (n=5). Perfusion defects covered 18.6±12.3% of the LV with variable transmurality. Positron emission tomography (PET) using 68Ga-pentixafor measured CXCR4 upregulation at 1, 3, and 7d post-MI, with magnetic resonance (MR) imaging for LV function. Cell uptake assays showed pentixafor uptake by leukocytes. CXCR4 was elevated at 1d and 3d post-MI compared to sham (% injected dose (ID)/g: d1, 1.0±0.2; d3, 0.8±0.2; sham, 0.5±0.1, p<0.001). Signal returned to baseline at 7d (0.5±0.1%ID/g, p=0.936). Flow cytometry confirmed elevated CD45+ leukocytes at 3d, declining by 7d (cells/LV 106: sham 0.05±0.01; d3 1.61±0.61, p=0.001; d7, 0.53±0.17, p=0.022). Ly6G+ granulocytes were dominant at 1d post-MI, whereas CD68+ macrophages were highest at 3d. Cardiac MR revealed LV dilatation over 6wks vs sham (systolic volume 94±26 vs 49±6 μL, p<0.001), and LV dysfunction (ejection fraction 46±16% vs 70±7, p=0.001). CXCR4 upregulation at 1d correlated with late LV function (r=-0.641, p=0.003). Multivariate analysis confirmed independent predictive value of 3d pentixafor uptake for LV function (rpartial=-0.50, p=0.03). Treatment with CXCR4 inhibitor AMD3100 (125μg, 1h post-MI) did not affect the acute CXCR4 PET signal (1.1±0.2%ID/g) but attenuated LV dysfunction at 6wks (LVEF 45±12%, p=0.05). Taken together, dynamic measurement of CXCR4 upregulation predicts LV remodeling after ischemia. Noninvasive imaging of CXCR4 may enable precise timing and targeting of novel therapy.

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