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.

Dual-Contrast 19 F/ 1 H Magnetic Resonance Imaging to Characterize Myocardial Infarct Healing

“…In that study enhanced elastic structure of the injured myocardial extracellular matrix improved diastolic function, ameliorated ventricular dilation and preserved cardiac ejection fraction. In Ramos et al 3 the expression of elastin/tropoelastin was most prominent at 14- and 21-days post infarction using Gd-ESMA T1w imaging and mapping, which is consistent with the known pathological evolution of myocardial infarction repair 6 . While elastin replacement improves myocardial compliance and helps preserve ventricular ejection fraction, this metric alone did not predict changes in post infarction EDV.…”

“…MRI imaging techniques to noninvasively interrogate and characterize injured myocardium continue to evolve beyond viability or “scar imaging” 1, 2 . Ramos et al 3 present proof-of-concept data demonstrating a multi-nuclear ( 19 F/ 1 H) MRI imaging protocol intended to characterize myocardial inflammation and extracellular matrix remodeling following permanent coronary occlusion in mice. Dual contrast agents are employed to characterize macrophage accumulation within the inflamed myocardium (i.e., perfluorocarbon nanoparticles 4 ), and to assess extracellular matrix stabilization reflected by progressive elastin/tropoelastin content 5 .…”

<p>Perfluorocarbons-Based ¹⁹F Magnetic Resonance Imaging in Biomedicine</p>

“…In this study, they noninvasively assess and quantify cardiac inflammation extracellular matrix (ECM) remodeling of the myocardium at the molecular level. 129 Another study demonstrated the ability to use 19 F-MRI cell tracking to detect, quantify and track human mesenchymal stem cells (hMSC) labeled with Cell Sense in vivo on 3D images at 9.4 T after grafting. In this study they showed strong linear between the number of labeled cells implanted and the real cell number by 19 F-MRI.…”

“…Furthermore, a recent study using 19 F MRI to detect tumor-associated macrophages (TAM) 49 revealed that methods. 129 The commercially available PFC-based agents include Cell Sense and V-Sense (Celsense, Inc., Pittsburgh, USA) used for cell tracking in MRI. These types of labelling agents include fluorinated emulsions (CS-1000 and VS-1000H) and other fluorescently tagged formulations (CS-ATM DM Red, Green, NIR) for ex vivo and in situ cell labels.…”

“…180 HP gas MR also provides functional information about respiratory diseases, including chronic obstructive pulmonary disease, asthma, and cystic fibrosis. 181 Although 129 Xe is cheaper than 3 He, both 3 He and 129 Xe needs to prepare and process the gases. Thus, an attractive and economical alternative to HP gas MRI is functional MR imaging using inert fluorinated gases, such as sulfur hexafluoride (SF 6 ), hexafluoroethane (C 2 F 6 ), and perfluoropropane (PFP) (C 3 F 8 ), which are nontoxic and abundant.…”