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.

journal_name

Eur Heart J

journal_title

European heart journal

authors

Hess A,Derlin T,Koenig T,Diekmann J,Wittneben A,Wang Y,Wester HJ,Ross TL,Wollert KC,Bauersachs J,Bengel FM,Thackeray JT

doi

10.1093/eurheartj/ehaa598

subject

Has Abstract

pub_date

2020-10-01 00:00:00

pages

3564-3575

issue

37

eissn

0195-668X

issn

1522-9645

pii

5903166

journal_volume

41

pub_type

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