IMAGING IMMUNITY – from Nanoscale to Macroscale | Insights from Biophysics
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Talks from Abstract Submissions

Session chair: Kim Cortenbach (Nijmegen, Netherlands)
 
Date: Wednesday, 15 January, 2020, 11:35 AM - 12:20 PM

Contents

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11:35 AM -01

Investigating the Cardiorenal Axis using CXCR4-directed Imaging (#11)

Rudolf A. Werner1, Annika Heß1, Tobias Koenig2, Johanna Diekmann1, Thorsten Derlin1, Hans-Jürgen Wester3, Anette Melk4, Johann Bauersachs2, James T. Thackeray1, Frank M. Bengel1

1 Hannover Medical School , Department of Nuclear Medicine, Hannover, Germany
2 Hannover Medical School , Department of Cardiology and Angiology, Hannover, Germany
3 Technical University Munich, Pharmaceutical Radiochemistry, Munich, Germany
4 Hannover Medical School , Department of Kidney, Liver and Metabolic Diseases, Children's Hospital, Hannover, Germany

Introduction

Cardiorenal syndrome comprises a spectrum of disorders involving bidirectional interaction between the failing heart and the kidney, wherein adaptive immune responses are a key pathophysiological mechanism. We aimed to obtain further insights into the cardiorenal crosstalk using systems-based whole-body chemokine receptor CXCR4-directed imaging to assess inflammation in the heart and kidney.

Methods

After permanent myocardial infarction (MI) or sham surgery, serial PET imaging with the CXCR4 specific ligand 68Ga-pentixafor was conducted in C57Bl6/N mice (n=80) at 1d, 3d, 7d, and 6wk after surgery. Contractile function was evaluated by cardiac magnetic resonance imaging. Additionally, 30 patients underwent CXCR4-directed PET imaging median 3.4 days after acute MI. Laboratory values of renal function (creatinine) were collected at baseline and after a median follow-up of 8 months.

Results/Discussion

MI mice demonstrated maximal cardiac CXCR4 upregulation at day 1 compared to sham, followed by a gradual decline (infarct/remote ratio: 1.40±0.12 at 1d*, 1.33±0.12 at 3d*, 1.11±0.07 at 7d*, 1.00±0.09 at 6wk, *P<0.05 vs. sham). Cardiac CXCR4 signal was paralleled by elevated splenic and renal CXCR4 signal (infarct/kidneys: 0.90±0.18 at d1*, 0.73±0.13 at 3d*, 0.49±0.14 at 7d, 0.43±0.09 at 6wk, *P<0.0001 vs. sham). Renal 68Ga-pentixafor uptake at 7d after MI in mice predicted left ventricular remodeling at 6wk (left ventricular ejection fraction, LVEF≤30%, R=-0.79, P<0.05 vs. LVEF>30%, R=-0.49, n.s.). Among MI patients, renal CXCR4 signal was independent of creatinine at baseline (R=-0.02, n.s.), but correlated with LVEF normalised to the infarct signal (R=-0.39, P<0.05). Early renal CXCR4 upregulation, however, showed a trend to correlate with late kidney function, which was more pronounced relative to the infarct signal (kidneys: R=0.42 vs. infarct: R=0.29, n.s., respectively).

Conclusions

Inflammatory crosstalk between failing heart and kidneys can be monitored non-invasively using CXCR4-directed PET imaging. Such systems-based whole-body imaging strategies may open avenues for further mechanistic insights into the cardiorenal axis and provide a foundation for future exploration of strategies pursuing imaging-guided multi-organ reparative therapies.

Acknowledgement

This work was funded by the German Research Foundation (DFG), through the Clinician-Scientist program PRACTIS (RAW) and the clinical research group KFO311 (FMB, JB). No potential conflicts of interests relevant to this article exist.

Investigating the cardiorenal axis using CXCR4-directed imaging in a translational approach.

Upper row: Serial short axis images of the myocardium and coronal images of the spleen and the kidneys in sham and after acute myocardial infarction (AMI) in mice (left). Renal CXCR4 signal predicted late left ventricular ejection fraction (LVEF) in mice at 7 days after MI (right). Lower row: In patients after AMI (left), renal CXCR4 signal predicted renal function derived by serum-creatinine during follow-up (right).

Keywords: PET, Nuclear Medicine, Molecular Imaging, Heart, Kidneys
11:55 AM -02

Molecular imaging of chemokine receptor CXCR4 early after myocardial infarction to assess inflammation and to guide therapy (#8)

Annika Hess1, Alexander Wittneben1, Hans-Jürgen Wester2, Tobias Ross1, Frank M. Bengel1, James T. Thackeray1

1 Hannover Medical School, Department of Nuclear Medicine, Hannover, Lower Saxony, Germany
2 Technical University of Munich, Chair of Radiopharmaceutical Chemistry, Garching, Bavaria, Germany

Introduction

Myocardial infarction (MI) induces tissue inflammation, which requires balance between pro- and anti-inflammatory components for effective cardiac repair. Targeted anti-inflammatory therapies are emerging, but patient selection remains challenging due to heterogeneity. We hypothesized that quantitative PET imaging of chemokine receptor CXCR4 and leukocyte infiltration after MI could predict acute and chronic outcome and subsequently guide CXCR4-targeted therapy.

Methods

C57Bl6/N mice underwent permanent ligation (n=149) or 60 min ischemia/reperfusion (n=9) of the left coronary artery, or sham surgery (n=13). Myocardial inflammation was assessed in subgroups of mice by serial CXCR4 PET (n=126) and ex vivo autoradiography (n=4) with 68Ga-pentixafor over 1wk post-MI. Perfusion SPECT defined infarct sizes, and cardiac magnetic resonance assessed left ventricular (LV) function. Targeted anti-inflammatory treatment with the CXCR4 antagonist AMD3100 (125µg) was administered at 1h (n=13), 3d (n=24), or 7d (n=16) post-MI, based on the CXCR4 PET signal intensity. Immunohistochemistry (n=4) and flow assisted cell sorting (FACS, n=40) assessed leukocyte accumulation in the heart on each PET imaging timepoint.

Results/Discussion

Infarct CXCR4 PET signal was highest at 1h post-MI versus sham (1.3±0.2%ID/g vs 0.6±0.1, p<0.001) and declined by 7d (0.6±0.1, p=0.9), confirmed by FACS and histology. Splenic CXCR4 signal was increased and proportional to the infarct signal (d1: r=0.56, p=0.001; d3: r=0.65, p<0.001), reflecting leukocyte activation. Persistent infarct CXCR4 upregulation at 3d post-MI predicted acute LV rupture compared to survivors (d3: 1.2±0.3 vs 0.9±0.2%ID/g, p<0.001). Among survivors, CXCR4 signal at 3d independently predicted ejection fraction at 6wks (36±15 vs 70±4%, p=0.001; rpartial=-0.4, p=0.04). Following the PET timecourse, selective CXCR4 blockade at 1h or 3d post-MI markedly lowered incidence of acute LV rupture compared to untreated MI (0% vs 8% vs 22%) and improved 6wk EF (+34% (1h), +24% (3d), p=0.01). FACS analysis revealed lower leukocyte content after CXCR4 blockade on d3 (p<0.04). CXCR4 blockade at MI+7d, outside PET-defined upregulation, did not improve survival or function.

Conclusions

PET imaging in mice identifies dynamic CXCR4 upregulation over the first week post-MI, which predicts early survival and late cardiac function. Image-guided blockade of CXCR4 at precise timepoints accelerates inflammatory resolution and improves acute and chronic cardiac outcome. This work provides the foundation for PET-guided CXCR4-targeted therapy after MI which should be further evaluated in the clinical setting.

PET imaging to guide CXCR4-targeted anti-inflammatory therapy

Figure. (A) Longitudinal short axis cardiac 68Ga-pentixafor PET images display CXCR4 upregulation (colorscale) in infarct territory defined by 18F-FDG (greyscale) at 1h and 3d but not 7d after MI. A single injection of CXCR4 blocker AMD3100 at timepoints corresponding to PET-defined CXCR4 upregulation (1h or 3d) but not off-peak (7d) evokes (B) lower incidence of acute left ventricular (LV) rupture within the first 7d post-MI, and (C) significantly improves chronic LV ejection fraction at 6wks compared to untreated MI.

Keywords: PET, MRI, Myocardial inflammation, Anti-inflammatory therapy