TY - JOUR
T1 - Molecular Imaging Visualizes Recruitment of Inflammatory Monocytes and Macrophages to the Injured Heart
AU - Heo, Gyu Seong
AU - Kopecky, Benjamin
AU - Sultan, Deborah
AU - Ou, Monica
AU - Feng, Guoshuai
AU - Bajpai, Geetika
AU - Zhang, Xiaohui
AU - Luehmann, Hannah
AU - Detering, Lisa
AU - Su, Yi
AU - Leuschner, Florian
AU - Combadière, Christophe
AU - Kreisel, Daniel
AU - Gropler, Robert J.
AU - Brody, Steven L.
AU - Liu, Yongjian
AU - Lavine, Kory J.
N1 - Funding Information:
K.J. Lavine is supported by the National Institutes of Health (NIH) K08 HL123519, R01 HL138466, and R01 HL139714, Burroughs Welcome Fund (1014782), Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (CH-II-2015–462 and CH-II-2017–628), and Foundation of Barnes-Jewish Hospital (8038–88). Y. Liu is supported by NIH R01 HL125655 and HL131908. D. Kreisel is supported by 1P01AI116501 and R01 HL094601, Veterans Administration Merit Review grant 1I01BX002730, and the Foundation for Barnes-Jewish Hospital. S.L. Brody is the Dorothy R. and Hubert C. Moog Professor of Pulmonary Medicine, awarded through the Barnes-Jewish Hospital Foundation.
Publisher Copyright:
© 2019 American Heart Association, Inc.
PY - 2019/3/15
Y1 - 2019/3/15
N2 - 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 (68Ga-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). 68Ga-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. 68Ga-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 68Ga-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 68Ga-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.
AB - 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 (68Ga-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). 68Ga-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. 68Ga-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 68Ga-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 68Ga-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.
KW - Macrophages
KW - Molecular imaging
KW - Monocytes
KW - Myocardial infarction
KW - Positron emission tomography
UR - http://www.scopus.com/inward/record.url?scp=85063006630&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.118.314030
DO - 10.1161/CIRCRESAHA.118.314030
M3 - Article
C2 - 30661445
AN - SCOPUS:85063006630
VL - 124
SP - 881
EP - 890
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 6
ER -