Direct thrombus imaging as a means to control the variability of mouse embolic infarct models: The role of optical molecular imaging

Dong Eog Kim, Jeong Yeon Kim, Matthias Nahrendorf, Su Kyoung Lee, Ju Hee Ryu, Kwang Meyung Kim, Ick Chan Kwon, Dawid Schellingerhout

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background and Purpose: High experimental variability in mouse embolic stroke models could mask the effects of experimental treatments. We hypothesized that imaging thrombus directly would allow this variability to be controlled. Methods: We optically labeled thrombi with a near-infrared fluorescent (NIRF) probe C15 that is covalently linked to fibrin by factor-XIIIa. Labeled thrombus was injected into the left distal internal carotid artery (ICA) of C57/BL6 mice (n=47), near its bifurcation, and laser-Doppler cerebral-blood-flow (CBF) was assessed for 30 minutes. NIRF thrombus imaging was done ex vivo at 24 hours. Results: CBF variably decreased to 43.9±17.3% at 5 minutes (rCBF; 11.2∼80.4%). NIRF thrombus imaging at 24 hours showed variability in distribution (ICA bifurcation, adjacent and/or remote areas) and burden (2279 ±1270 pixels; 0∼5940 pixels). Final infarct size was also variable (21.0± 10.3%; 4.7∼60.3% of the bihemispheric volume). Despite this heterogeneity, a strong thrombus-infarct correlation was maintained. The left hemispheric target infarct size (% of the hemisphere) correlated with thrombus burden, as a stronger predictor of infarct volume (P<0.001, r=0.50) than rCBF (P=0.02, r=-0.34). The infarct size was best predicted by a combination of thrombus imaging and CBF: left-hemispheric big-thrombi (>1865 pixels)/low-rCBF (≤42%) had an infarct volume of 56.9±10.4% (n=12), big-thrombi/high-rCBF had 45.9±23.5% (n=11), small-thrombi/low-rCBF 35.7±17.3% (n=11) and small-thrombi/high-rCBF 27.3±16.4% (n=12). Conclusions: This is the first study to demonstrate that the highly heterogeneous nature of the mouse embolic stroke model can be characterized and managed by using near-infrared fluorescent thrombus imaging combined with CBF monitoring to stratify animals into useful subgroups.

Original languageEnglish
Pages (from-to)3566-3573
Number of pages8
JournalStroke
Volume42
Issue number12
DOIs
Publication statusPublished - 2011 Dec 1
Externally publishedYes

Fingerprint

Molecular Imaging
Optical Imaging
Thrombosis
Cerebrovascular Circulation
Internal Carotid Artery
Stroke
Factor XIIIa
Masks
Fibrin
Fluorescent Dyes
Lasers

Keywords

  • Embolic cerebral infarction
  • Molecular imaging
  • Optical imaging
  • Thrombus imaging

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Advanced and Specialised Nursing

Cite this

Direct thrombus imaging as a means to control the variability of mouse embolic infarct models : The role of optical molecular imaging. / Kim, Dong Eog; Kim, Jeong Yeon; Nahrendorf, Matthias; Lee, Su Kyoung; Ryu, Ju Hee; Kim, Kwang Meyung; Kwon, Ick Chan; Schellingerhout, Dawid.

In: Stroke, Vol. 42, No. 12, 01.12.2011, p. 3566-3573.

Research output: Contribution to journalArticle

Kim, Dong Eog ; Kim, Jeong Yeon ; Nahrendorf, Matthias ; Lee, Su Kyoung ; Ryu, Ju Hee ; Kim, Kwang Meyung ; Kwon, Ick Chan ; Schellingerhout, Dawid. / Direct thrombus imaging as a means to control the variability of mouse embolic infarct models : The role of optical molecular imaging. In: Stroke. 2011 ; Vol. 42, No. 12. pp. 3566-3573.
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AU - Kim, Jeong Yeon

AU - Nahrendorf, Matthias

AU - Lee, Su Kyoung

AU - Ryu, Ju Hee

AU - Kim, Kwang Meyung

AU - Kwon, Ick Chan

AU - Schellingerhout, Dawid

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N2 - Background and Purpose: High experimental variability in mouse embolic stroke models could mask the effects of experimental treatments. We hypothesized that imaging thrombus directly would allow this variability to be controlled. Methods: We optically labeled thrombi with a near-infrared fluorescent (NIRF) probe C15 that is covalently linked to fibrin by factor-XIIIa. Labeled thrombus was injected into the left distal internal carotid artery (ICA) of C57/BL6 mice (n=47), near its bifurcation, and laser-Doppler cerebral-blood-flow (CBF) was assessed for 30 minutes. NIRF thrombus imaging was done ex vivo at 24 hours. Results: CBF variably decreased to 43.9±17.3% at 5 minutes (rCBF; 11.2∼80.4%). NIRF thrombus imaging at 24 hours showed variability in distribution (ICA bifurcation, adjacent and/or remote areas) and burden (2279 ±1270 pixels; 0∼5940 pixels). Final infarct size was also variable (21.0± 10.3%; 4.7∼60.3% of the bihemispheric volume). Despite this heterogeneity, a strong thrombus-infarct correlation was maintained. The left hemispheric target infarct size (% of the hemisphere) correlated with thrombus burden, as a stronger predictor of infarct volume (P<0.001, r=0.50) than rCBF (P=0.02, r=-0.34). The infarct size was best predicted by a combination of thrombus imaging and CBF: left-hemispheric big-thrombi (>1865 pixels)/low-rCBF (≤42%) had an infarct volume of 56.9±10.4% (n=12), big-thrombi/high-rCBF had 45.9±23.5% (n=11), small-thrombi/low-rCBF 35.7±17.3% (n=11) and small-thrombi/high-rCBF 27.3±16.4% (n=12). Conclusions: This is the first study to demonstrate that the highly heterogeneous nature of the mouse embolic stroke model can be characterized and managed by using near-infrared fluorescent thrombus imaging combined with CBF monitoring to stratify animals into useful subgroups.

AB - Background and Purpose: High experimental variability in mouse embolic stroke models could mask the effects of experimental treatments. We hypothesized that imaging thrombus directly would allow this variability to be controlled. Methods: We optically labeled thrombi with a near-infrared fluorescent (NIRF) probe C15 that is covalently linked to fibrin by factor-XIIIa. Labeled thrombus was injected into the left distal internal carotid artery (ICA) of C57/BL6 mice (n=47), near its bifurcation, and laser-Doppler cerebral-blood-flow (CBF) was assessed for 30 minutes. NIRF thrombus imaging was done ex vivo at 24 hours. Results: CBF variably decreased to 43.9±17.3% at 5 minutes (rCBF; 11.2∼80.4%). NIRF thrombus imaging at 24 hours showed variability in distribution (ICA bifurcation, adjacent and/or remote areas) and burden (2279 ±1270 pixels; 0∼5940 pixels). Final infarct size was also variable (21.0± 10.3%; 4.7∼60.3% of the bihemispheric volume). Despite this heterogeneity, a strong thrombus-infarct correlation was maintained. The left hemispheric target infarct size (% of the hemisphere) correlated with thrombus burden, as a stronger predictor of infarct volume (P<0.001, r=0.50) than rCBF (P=0.02, r=-0.34). The infarct size was best predicted by a combination of thrombus imaging and CBF: left-hemispheric big-thrombi (>1865 pixels)/low-rCBF (≤42%) had an infarct volume of 56.9±10.4% (n=12), big-thrombi/high-rCBF had 45.9±23.5% (n=11), small-thrombi/low-rCBF 35.7±17.3% (n=11) and small-thrombi/high-rCBF 27.3±16.4% (n=12). Conclusions: This is the first study to demonstrate that the highly heterogeneous nature of the mouse embolic stroke model can be characterized and managed by using near-infrared fluorescent thrombus imaging combined with CBF monitoring to stratify animals into useful subgroups.

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KW - Molecular imaging

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