Abstract
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. 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. 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.
Highlights
Optimal healing of the myocardium after myocardial infarction (MI) requires a suitable degree of inflammation and its timely resolution, together with a well-orchestrated deposition and degradation of ECM proteins
Multinuclear 1H/19F magnetic resonance imaging allows the simultaneous assessment of inflammation and elastin remodeling in a murine MI model
Quantitative in vivo 19F Magnetic resonance imaging (MRI) showed a significant increase of 19F signal (SNR/scar volume) within the infarcted area at 7 days post-MI (SNR=1.27 [interquartile range (IQR), 0.84–1.58]) compared with SHAM-operated animals (SNR=0.19 [IQR, 0.13–0.20]; P
Summary
The DICOM MR images will be made available to other researchers for purposes of reproducing the results.[10 ] Animal Model. MI was induced in 10-week-old female C57BL/6J mice (n=71; 21% mortality rate; Charles River, United Kingdom) by permanent occlusion of the left anterior descending (LAD) coronary artery. The animals underwent endotracheal intubation before surgery using an animal ventilator (Hugo Sacks Elektronic, Germany). A left thoracotomy was performed in the fourth intercostal space, the pericardium removed, and the LAD was permanently ligated with an 8-0 nylon suture (Direct Medical Supplies, Alton, United Kingdom). Subcutaneous tissue and skin were closed in separate layers and the animal was weaned from the ventilator. Sham-operated animals underwent the same surgical procedure, without LAD ligation. 0.15 mg/kg buprenorphine (Vetergesic, Alstoe, United Kingdom) was administered for analgesia by intramuscular injection
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