Molecular imaging-guided repair after acute myocardial infarction by targeting the chemokine receptor CXCR4

Abstract

Aims Balance between inflammatory and reparative leucocytes allows optimal healing after myocardial infarction (MI). Interindividual heterogeneity evokes variable functional outcome complicating targeted therapy. We aimed to characterize infarct chemokine CXC-motif receptor 4 (CXCR4) expression using positron emission tomography (PET) and establish its relationship to cardiac outcome. We tested whether image-guided early CXCR4 directed therapy attenuates chronic dysfunction. Methods and results Mice (n = 180) underwent coronary ligation or sham surgery and serial PET imaging over 7 days. Infarct CXCR4 content was elevated over 3 days after MI compared with sham (%ID/g, Day 1:1.1 ± 0.2; Day 3:0.9 ± 0.2 vs. 0.6 ± 0.1, P < 0.001), confirmed by flow cytometry and histopathology. Mice that died of left ventricle (LV) rupture exhibited persistent inflammation at 3 days compared with survivors (1.2 ± 0.3 vs. 0.9 ± 0.2% ID/g, P < 0.001). Cardiac magnetic resonance measured cardiac function. Higher CXCR4 signal at 1 and 3 days independently predicted worse functional outcome at 6 weeks (rpartial = −0.4, P = 0.04). Mice were treated with CXCR4 blocker AMD3100 following the imaging timecourse. On-peak CXCR4 blockade at 3 days lowered LV rupture incidence vs. untreated MI (8% vs. 25%), and improved contractile function at 6 weeks (+24%, P = 0.01). Off-peak CXCR4 blockade at 7 days did not improve outcome. Flow cytometry analysis revealed lower LV neutrophil and Ly6Chigh monocyte content after on-peak treatment. Patients (n = 50) early after MI underwent CXCR4 PET imaging and functional assessment. Infarct CXCR4 expression in acute MI patients correlated with contractile function at time of PET and on follow-up. Conclusion Positron emission tomography imaging identifies early CXCR4 up-regulation which predicts acute rupture and chronic contractile dysfunction. Imaging-guided CXCR4 inhibition accelerates inflammatory resolution and improves outcome. This supports a molecular imaging-based theranostic approach to guide therapy after MI.

Imaging Inflammation with Positron Emission Tomography

“…However, besides the relatively small patient number, this study was limited by its varying imaging and follow-up time points as well as lacking data on CXCR4/CXCL12 levels to determine endpoints of molecular inflammation. Moreover, the findings of this study are in contradiction to two recently published studies suggesting beneficial effects of CXCR4 blockade in mice with MI [30,31]. The more recent one of these studies reported that the timing of CXCR4 blockade is important and that CXCR4-directed PET imaging can serve as a tool for therapeutic guidance to determine the right timing of treatment.…”

“…The more recent one of these studies reported that the timing of CXCR4 blockade is important and that CXCR4-directed PET imaging can serve as a tool for therapeutic guidance to determine the right timing of treatment. Hess and colleagues further showed a correlation of CXCR4 expression in acute MI patients with cardiac outcome and inflammation parameters suggesting prognostic value of 68 Ga-pentixafor PET [31].…”

“…Cancer [20], atherosclerosis [21][22][23][24][25], myocardial infarction [26][27][28][29][30][31], osteomyelitis [32], urinary tract infections [33] and others C-C motif chemokine receptor 2 (CCR2) 68 Ga/ 64 Cu-DOTA-ECL1i…”

Molecular Imaging Using Cardiac PET/CT: Opportunities to Harmonize Diagnosis and Therapy

“…The intensity of the PET imaging signal at 3 days after injury predicted the severity of ventricle remodeling and contractile dysfunction 6 weeks later, independent of the infarct size. Moreover, mice with prolonged upregulation of CXCR4 over 3 days after ischemic injury had a higher incidence of acute ventricle rupture [ 44 ••]. Patients after acute infarction exhibit variable CXCR4 signal [ 45 , 46 ], but the imaging signal obtained 4−6 days after reperfused myocardial infarction also correlates with contractile function 6−9 months later [ 44 ••].…”

Fantastic voyage: Catheter-based quantification of tracer distribution on a miniature scale

“…Regional inflammation could be directly treated by antiinflammatory agents, gene therapy to promote endogenous repair, or immunomodulatory therapy to target adverse remodeling processes. 13,14 Such approaches could overcome the hazards of systemic immunomodulation. Alternatively, prior studies have reported alignment of nuclear cardiac images to catheter-based measures of electrophysiology, where the site of inducibility of ventricular arrhythmia corresponded to lower retention of norepinephrine analogues.…”