Molecular imaging of inflammation crosstalk along the cardio-renal axis following acute myocardial infarction

Abstract

<b>Rationale:</b> Acute myocardial infarction (MI) triggers a systemic inflammatory response including crosstalk along the heart-kidney axis. We employed radionuclide-based inflammation-targeted whole-body molecular imaging to identify potential cardio-renal crosstalk after MI in a translational setup. <b>Methods:</b> Serial whole-body positron emission tomography (PET) with the specific CXCR4 ligand ⁶⁸Ga-Pentixafor was performed after MI in mice. Tracer retention in kidneys and heart was compared to hematopoietic organs to evaluate systemic inflammation, validated by <i>ex vivo</i> analysis and correlated with progressive contractile dysfunction. Additionally, 96 patients underwent ⁶⁸Ga-Pentixafor PET within the first week after MI, for systems-based image analysis and to determine prognostic value for adverse renal outcome. <b>Results:</b> In mice, transient myocardial CXCR4 upregulation occurred early after MI. Cardiac and renal PET signal directly correlated over the time course (r = 0.62, p < 0.0001), suggesting an inflammatory link between organs. <i>Ex-vivo</i> autoradiography (r = 0.9, p < 0.01) and CD68 immunostaining indicated signal localization to inflammatory cell content. Renal signal at 7d was inversely proportional to left ventricular ejection fraction at 6 weeks after MI (r = -0.79, p < 0.01). In patients, renal CXCR4 signal also correlated with signal from infarct (r = 0.25, p < 0.05) and remote myocardium (r = 0.39, p < 0.0001). Glomerular filtration rate (GFR) was available in 48/96 (50%) during follow-up. Worsening of renal function (GFR loss >5 mL/min/1.73m²), occurred a mean 80.5 days after MI in 16/48 (33.3%). Kaplan-Meier analysis revealed adverse renal outcome for patients with elevated remote myocardial CXCR4 signal (p < 0.05). Multivariate Cox analysis confirmed an independent predictive value (relative to baseline GFR, LVEF, infarct size; HR, 5.27). <b>Conclusion:</b> Systems-based CXCR4-targeted molecular imaging identifies inflammatory crosstalk along the cardio-renal axis early after MI.