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

Figure 1. (A) Representative 68Ga-Pentixafor PET images, fused with concomitant 18F-fluorodeoxyglucose images of the myocardium after myocardial infarction (MI) in mice (short-axis). 68Ga-Pentixafor PET images of the spleen (transaxial) and kidneys (coronal axis) are also displayed. (B) Quantitative assessment of myocardial 68Ga-Pentixafor %ID/g, (C) infarct to remote activity ratio and (D) renal 68Ga-Pentixafor %ID/g. In all animals, infarct-derived signal was directly correlated with (E) kidney and (F) splenic signal. The latter signal was also significantly associated with renal CXCR4 expression (G). (B-G: MI+1d, n = 23; MI+3d, n = 23; MI+7d, n = 24 and MI+6wk, n = 11). RV, right ventricle; LV, left ventricle; S, spleen; L, Left; R, Right; RK, right kidney; LK, left kidney. * p < 0.05, ** p < 0.001, *** p = 0.0001, **** p < 0.0001.

Figure 2. (A) Left: Upper rows: In mice after myocardial infarction (MI), in-vivo signal of CXCR4-directed PET declined over time in the infarct territory (1st row), which was confirmed by ex-vivo autoradiography (AUTORAD) of the heart (2nd row, short-axis). Lower rows: Findings were paralleled by the in- and ex-vivo signal of the kidneys (coronal axis). Right: Quantitative analysis demonstrated a strong correlation between ex-vivo AUTORAD sections of heart and kidneys. (B) Paralleled by the in-vivo CXCR4-directed PET signal, CD68 staining in the infarct territory and kidneys confirmed a decrease in monocyte content from day 3 post-MI (MI+3d) to MI+7d (red arrows; n = 2).

Figure 3. (A) Among mice that died of left ventricular rupture, renal and infarct-derived CXCR4 signal was strongly correlated (r = 0.80, p < 0.05, n=7). (B) In surviving animals with more severe contractile impairment (left ventricular ejection fraction (LVEF) < 30%)), CXCR4 signal intensity in the kidneys at 7 days after the infarct (MI+7d) was inversely proportional to cardiac function at 6 weeks after MI (MI+6wk; n = 10). (C) The association of the infarct-derived CXCR4 signal at MI+7d with later cardiac functional outcome (MI+6wk) was comparatively less pronounced (n = 11).

Figure 4. (A) Maximum intensity (MIP) projection of 68Ga-Pentixafor PET in a patient early after acute myocardial infarction, along with representative transaxial hybrid PET/CT slices. Spherical volumes of interest are placed in infarct and remote myocardium, spleen, and renal parenchyma. (B) CXCR4 signal derived from infarct territory correlated with uptake in renal parenchyma and spleen. SUVpeak = peak standardized uptake value (n = 96).

Figure 5. (A) Receiver-operating-characteristics (ROC) curve for the association between CXCR4 tracer signal in remote myocardium and worsening of renal function (WRF) occurrence. Optimal cutoff is defined by a red arrow. (B) Kaplan-Meier curves for WRF-free survival in patient groups with increased vs. decreased myocardial remote CXCR4 signal. WRF during follow-up occurred primarily in patients showing increased CXCR4 uptake in the remote myocardium, while in subjects with no further decline in renal function, no discernible radiotracer signal in the cardiac remote area was noted. (C) Transaxial computed tomography (CT), positron emission tomography (PET)/CT and PET images of patients after myocardial infarction with (left) and without worsening of renal function (WRF, right). Left patient showed increased CXCR4 signal in the remote myocardium and a loss of glomerular filtration rate (GFR) of 6.2 mL/min/1.73 m2 was noted during follow-up. Right patient had no decline in renal function (GFR loss, 0.6 mL/min/1.73 m2) and demonstrated no substantial elevated CXCR4 expression in the remote myocardium. SUVpeak = peak standardized uptake value. (n = 48).