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Article Dans Une Revue Circulation Research Année : 2019

Molecular Imaging Visualizes Recruitment of Inflammatory Monocytes and Macrophages to the Injured Heart

Gyu Seong Heo
  • Fonction : Auteur
Benjamin Kopecky
  • Fonction : Auteur
Deborah Sultan
  • Fonction : Auteur
Monica Ou
  • Fonction : Auteur
Guoshuai Feng
  • Fonction : Auteur
Geetika Bajpai
  • Fonction : Auteur
Xiaohui Zhang
  • Fonction : Auteur
Hannah Luehmann
  • Fonction : Auteur
Lisa Detering
  • Fonction : Auteur
Yi Su
  • Fonction : Auteur
Florian Leuschner
  • Fonction : Auteur
Daniel Kreisel
  • Fonction : Auteur
Robert Gropler
  • Fonction : Auteur
Steven Brody
  • Fonction : Auteur
Yongjian Liu
  • Fonction : Auteur
Kory Lavine
  • Fonction : Auteur

Résumé

Rationale: Paradigm shifting studies have revealed that the heart contains functionally diverse populations of macrophages derived from distinct embryonic and adult hematopoietic progenitors. Under steady-state conditions, the heart is largely populated by CCR2− (C-C chemokine receptor type 2) macrophages of embryonic descent. After tissue injury, a dramatic shift in macrophage composition occurs whereby CCR2+ monocytes are recruited to the heart and differentiate into inflammatory CCR2+ macrophages that contribute to heart failure progression. Currently, there are no techniques to noninvasively detect CCR2+ monocyte recruitment into the heart and thus identify patients who may be candidates for immunomodulatory therapy. Objective: To develop a noninvasive molecular imaging strategy with high sensitivity and specificity to visualize inflammatory monocyte and macrophage accumulation in the heart. Methods and Results: We synthesized and tested the performance of a positron emission tomography radiotracer ( 68 Ga-DOTA [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-ECL1i [extracellular loop 1 inverso]) that allosterically binds to CCR2. In naive mice, the radiotracer was quickly cleared from the blood and displayed minimal retention in major organs. In contrast, biodistribution and positron emission tomography demonstrated strong myocardial tracer uptake in 2 models of cardiac injury (diphtheria toxin induced cardiomyocyte ablation and reperfused myocardial infarction). 68 Ga-DOTA-ECL1i signal localized to sites of tissue injury and was independent of blood pool activity as assessed by quantitative positron emission tomography and ex vivo autoradiography. 68 Ga-DOTA-ECL1i uptake was associated with CCR2+ monocyte and CCR2+ macrophage infiltration into the heart and was abrogated in CCR2 −/ − mice, demonstrating target specificity. Autoradiography demonstrated that 68 Ga-DOTA-ECL1i specifically binds human heart failure specimens and with signal intensity associated with CCR2+ macrophage abundance. Conclusions: These findings demonstrate the sensitivity and specificity of 68 Ga-DOTA-ECL1i in the mouse heart and highlight the translational potential of this agent to noninvasively visualize CCR2+ monocyte recruitment and inflammatory macrophage accumulation in patients.

Dates et versions

hal-03815255 , version 1 (14-10-2022)

Identifiants

Citer

Gyu Seong Heo, Benjamin Kopecky, Deborah Sultan, Monica Ou, Guoshuai Feng, et al.. Molecular Imaging Visualizes Recruitment of Inflammatory Monocytes and Macrophages to the Injured Heart. Circulation Research, 2019, 124 (6), pp.881-890. ⟨10.1161/CIRCRESAHA.118.314030⟩. ⟨hal-03815255⟩
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