Simultaneous Assessment of Cardiac Inflammation and Extracellular Matrix Remodeling after Myocardial Infarction

Isabel Ramos; Markus Olof Samuel Henningsson; Maryam Nezafat; Begona Lavin Plaza; Silvia Lorrio Gonzalez; Pierre Klaus Gebhardt; Andrea Protti; Thomas Roger Eykyn; Marcelo E Andia; Ulrich Flögel; Alkystis Phinikaridou; Ajay Manmohan Shah; Rene Michael Botnar

doi:10.1161/CIRCIMAGING.117.007453

Simultaneous Assessment of Cardiac Inflammation and Extracellular Matrix Remodeling after Myocardial Infarction

Isabel Ramos, Markus Olof Samuel Henningsson, Maryam Nezafat, Begona Lavin Plaza, Silvia Lorrio Gonzalez, Pierre Klaus Gebhardt, Andrea Protti, Thomas Roger Eykyn, Marcelo E Andia, Ulrich Flögel, Alkystis Phinikaridou, Ajay Manmohan Shah, Rene Michael Botnar

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Abstract

BACKGROUND: Optimal healing of the myocardium following myocardial infarction (MI) requires a suitable degree of inflammation and its timely resolution, together with a well-orchestrated deposition and degradation of extracellular matrix (ECM) proteins. METHODS AND RESULTS: MI and SHAM-operated animals were imaged at 3,7,14 and 21 days with 3T magnetic resonance imaging (MRI) using a 19F/1H surface coil. Mice were injected with 19F-perfluorocarbon (PFC) nanoparticles to study inflammatory cell recruitment, and with a gadolinium-based elastin-binding contrast agent (Gd-ESMA) to evaluate elastin content. 19F MRI signal co-localized with infarction areas, as confirmed by late-gadolinium enhancement, and was highest 7days post-MI, correlating with macrophage content (MAC-3 immunohistochemistry) (ρ=0.89,P<0.0001). 19F quantification with in vivo (MRI) and ex vivo nuclear magnetic resonance (NMR) spectroscopy correlated linearly (ρ=0.58,P=0.020). T1 mapping after Gd-ESMA injection showed increased relaxation rate (R1) in the infarcted regions and was significantly higher at 21days compared with 7days post-MI (R1[s-1]:21days=2.8 [IQR,2.69-3.30] vs 7days=2.3 [IQR,2.12-2.5], P<0.05), which agreed with an increased tropoelastin content (ρ=0.89, P<0.0001). The predictive value of each contrast agent for beneficial remodeling was evaluated in a longitudinal proof-of-principle study. Neither R1 nor 19F at day 7 were significant predictors for beneficial remodeling (P=0.68;P=0.062). However, the combination of both measurements (R1<2.34Hz and 0.55≤19F≤1.85) resulted in an odds ratio of 30.0 (CI95%:1.41-638.15;P=0.029) for favorable post-MI remodeling. CONCLUSIONS: Multinuclear 1H/19F MRI allows the simultaneous assessment of inflammation and elastin remodeling in a murine MI model. The interplay of these biological processes affects cardiac outcome and may have potential for improved diagnosis and personalized treatment.

Original language	English
Article number	e007453
Journal	Circulation-Cardiovascular imaging
Volume	11
Issue number	11
Early online date	15 Nov 2018
DOIs	https://doi.org/10.1161/CIRCIMAGING.117.007453
Publication status	Published - Nov 2018

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Simultaneous Assessment of Cardiac_RAMOS_Accepted4August2018_GOLD VoR (CC BY)Final published version, 3.19 MBLicence: CC BY

https://www.ahajournals.org/doi/full/10.1161/CIRCIMAGING.117.007453?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed

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Ramos, I., Henningsson, M. O. S., Nezafat, M., Lavin Plaza, B., Lorrio Gonzalez, S., Gebhardt, P. K., Protti, A., Eykyn, T. R., Andia, M. E., Flögel, U., Phinikaridou, A., Shah, A. M., & Botnar, R. M. (2018). Simultaneous Assessment of Cardiac Inflammation and Extracellular Matrix Remodeling after Myocardial Infarction. Circulation-Cardiovascular imaging, 11(11), Article e007453. https://doi.org/10.1161/CIRCIMAGING.117.007453

@article{260f6cbfaefa437d9b696f88c303d654,

title = "Simultaneous Assessment of Cardiac Inflammation and Extracellular Matrix Remodeling after Myocardial Infarction",

abstract = "BACKGROUND: Optimal healing of the myocardium following myocardial infarction (MI) requires a suitable degree of inflammation and its timely resolution, together with a well-orchestrated deposition and degradation of extracellular matrix (ECM) proteins. METHODS AND RESULTS: MI and SHAM-operated animals were imaged at 3,7,14 and 21 days with 3T magnetic resonance imaging (MRI) using a 19F/1H surface coil. Mice were injected with 19F-perfluorocarbon (PFC) nanoparticles to study inflammatory cell recruitment, and with a gadolinium-based elastin-binding contrast agent (Gd-ESMA) to evaluate elastin content. 19F MRI signal co-localized with infarction areas, as confirmed by late-gadolinium enhancement, and was highest 7days post-MI, correlating with macrophage content (MAC-3 immunohistochemistry) (ρ=0.89,P<0.0001). 19F quantification with in vivo (MRI) and ex vivo nuclear magnetic resonance (NMR) spectroscopy correlated linearly (ρ=0.58,P=0.020). T1 mapping after Gd-ESMA injection showed increased relaxation rate (R1) in the infarcted regions and was significantly higher at 21days compared with 7days post-MI (R1[s-1]:21days=2.8 [IQR,2.69-3.30] vs 7days=2.3 [IQR,2.12-2.5], P<0.05), which agreed with an increased tropoelastin content (ρ=0.89, P<0.0001). The predictive value of each contrast agent for beneficial remodeling was evaluated in a longitudinal proof-of-principle study. Neither R1 nor 19F at day 7 were significant predictors for beneficial remodeling (P=0.68;P=0.062). However, the combination of both measurements (R1<2.34Hz and 0.55≤19F≤1.85) resulted in an odds ratio of 30.0 (CI95%:1.41-638.15;P=0.029) for favorable post-MI remodeling. CONCLUSIONS: Multinuclear 1H/19F MRI allows the simultaneous assessment of inflammation and elastin remodeling in a murine MI model. The interplay of these biological processes affects cardiac outcome and may have potential for improved diagnosis and personalized treatment.",

author = "Isabel Ramos and Henningsson, {Markus Olof Samuel} and Maryam Nezafat and {Lavin Plaza}, Begona and {Lorrio Gonzalez}, Silvia and Gebhardt, {Pierre Klaus} and Andrea Protti and Eykyn, {Thomas Roger} and Andia, {Marcelo E} and Ulrich Fl{\"o}gel and Alkystis Phinikaridou and Shah, {Ajay Manmohan} and Botnar, {Rene Michael}",

year = "2018",

month = nov,

doi = "10.1161/CIRCIMAGING.117.007453",

language = "English",

volume = "11",

journal = "Circulation-Cardiovascular imaging",

issn = "1941-9651",

publisher = "Lippincott Williams and Wilkins",

number = "11",

}

Ramos, I , Henningsson, MOS , Nezafat, M , Lavin Plaza, B , Lorrio Gonzalez, S , Gebhardt, PK , Protti, A , Eykyn, TR, Andia, ME, Flögel, U, Phinikaridou, A , Shah, AM & Botnar, RM 2018, 'Simultaneous Assessment of Cardiac Inflammation and Extracellular Matrix Remodeling after Myocardial Infarction', Circulation-Cardiovascular imaging, vol. 11, no. 11, e007453. https://doi.org/10.1161/CIRCIMAGING.117.007453

TY - JOUR

T1 - Simultaneous Assessment of Cardiac Inflammation and Extracellular Matrix Remodeling after Myocardial Infarction

AU - Ramos, Isabel

AU - Henningsson, Markus Olof Samuel

AU - Nezafat, Maryam

AU - Lavin Plaza, Begona

AU - Lorrio Gonzalez, Silvia

AU - Gebhardt, Pierre Klaus

AU - Protti, Andrea

AU - Eykyn, Thomas Roger

AU - Andia, Marcelo E

AU - Flögel, Ulrich

AU - Phinikaridou, Alkystis

AU - Shah, Ajay Manmohan

AU - Botnar, Rene Michael

PY - 2018/11

Y1 - 2018/11

N2 - BACKGROUND: Optimal healing of the myocardium following myocardial infarction (MI) requires a suitable degree of inflammation and its timely resolution, together with a well-orchestrated deposition and degradation of extracellular matrix (ECM) proteins. METHODS AND RESULTS: MI and SHAM-operated animals were imaged at 3,7,14 and 21 days with 3T magnetic resonance imaging (MRI) using a 19F/1H surface coil. Mice were injected with 19F-perfluorocarbon (PFC) nanoparticles to study inflammatory cell recruitment, and with a gadolinium-based elastin-binding contrast agent (Gd-ESMA) to evaluate elastin content. 19F MRI signal co-localized with infarction areas, as confirmed by late-gadolinium enhancement, and was highest 7days post-MI, correlating with macrophage content (MAC-3 immunohistochemistry) (ρ=0.89,P<0.0001). 19F quantification with in vivo (MRI) and ex vivo nuclear magnetic resonance (NMR) spectroscopy correlated linearly (ρ=0.58,P=0.020). T1 mapping after Gd-ESMA injection showed increased relaxation rate (R1) in the infarcted regions and was significantly higher at 21days compared with 7days post-MI (R1[s-1]:21days=2.8 [IQR,2.69-3.30] vs 7days=2.3 [IQR,2.12-2.5], P<0.05), which agreed with an increased tropoelastin content (ρ=0.89, P<0.0001). The predictive value of each contrast agent for beneficial remodeling was evaluated in a longitudinal proof-of-principle study. Neither R1 nor 19F at day 7 were significant predictors for beneficial remodeling (P=0.68;P=0.062). However, the combination of both measurements (R1<2.34Hz and 0.55≤19F≤1.85) resulted in an odds ratio of 30.0 (CI95%:1.41-638.15;P=0.029) for favorable post-MI remodeling. CONCLUSIONS: Multinuclear 1H/19F MRI allows the simultaneous assessment of inflammation and elastin remodeling in a murine MI model. The interplay of these biological processes affects cardiac outcome and may have potential for improved diagnosis and personalized treatment.

AB - BACKGROUND: Optimal healing of the myocardium following myocardial infarction (MI) requires a suitable degree of inflammation and its timely resolution, together with a well-orchestrated deposition and degradation of extracellular matrix (ECM) proteins. METHODS AND RESULTS: MI and SHAM-operated animals were imaged at 3,7,14 and 21 days with 3T magnetic resonance imaging (MRI) using a 19F/1H surface coil. Mice were injected with 19F-perfluorocarbon (PFC) nanoparticles to study inflammatory cell recruitment, and with a gadolinium-based elastin-binding contrast agent (Gd-ESMA) to evaluate elastin content. 19F MRI signal co-localized with infarction areas, as confirmed by late-gadolinium enhancement, and was highest 7days post-MI, correlating with macrophage content (MAC-3 immunohistochemistry) (ρ=0.89,P<0.0001). 19F quantification with in vivo (MRI) and ex vivo nuclear magnetic resonance (NMR) spectroscopy correlated linearly (ρ=0.58,P=0.020). T1 mapping after Gd-ESMA injection showed increased relaxation rate (R1) in the infarcted regions and was significantly higher at 21days compared with 7days post-MI (R1[s-1]:21days=2.8 [IQR,2.69-3.30] vs 7days=2.3 [IQR,2.12-2.5], P<0.05), which agreed with an increased tropoelastin content (ρ=0.89, P<0.0001). The predictive value of each contrast agent for beneficial remodeling was evaluated in a longitudinal proof-of-principle study. Neither R1 nor 19F at day 7 were significant predictors for beneficial remodeling (P=0.68;P=0.062). However, the combination of both measurements (R1<2.34Hz and 0.55≤19F≤1.85) resulted in an odds ratio of 30.0 (CI95%:1.41-638.15;P=0.029) for favorable post-MI remodeling. CONCLUSIONS: Multinuclear 1H/19F MRI allows the simultaneous assessment of inflammation and elastin remodeling in a murine MI model. The interplay of these biological processes affects cardiac outcome and may have potential for improved diagnosis and personalized treatment.

U2 - 10.1161/CIRCIMAGING.117.007453

DO - 10.1161/CIRCIMAGING.117.007453

M3 - Article

SN - 1941-9651

VL - 11

JO - Circulation-Cardiovascular imaging

JF - Circulation-Cardiovascular imaging

IS - 11

M1 - e007453

ER -

Simultaneous Assessment of Cardiac Inflammation and Extracellular Matrix Remodeling after Myocardial Infarction

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