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

Abstract

Background: 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 (extracellular matrix) proteins. Methods and Results: MI and SHAM-operated animals were imaged at 3, 7, 14, and 21 days with 3T magnetic resonance imaging using a 19F/1H surface coil. Mice were injected with 19F-perfluorocarbon nanoparticles to study inflammatory cell recruitment, and with a gadolinium-based elastin-binding contrast agent to evaluate elastin content. 19F magnetic resonance imaging signal colocalized with infarction areas, as confirmed by late gadolinium enhancement, and was highest 7 days post-MI, correlating with macrophage content (MAC-3 immunohistochemistry; ρ=0.89, P<0.0001). 19F quantification with in vivo (magnetic resonance imaging) and ex vivo nuclear magnetic resonance spectroscopy correlated linearly (ρ=0.58, P=0.020). T1 mapping after gadolinium-based elastin-binding contrast agent injection showed increased relaxation rate (R1) in the infarcted regions and was significantly higher at 21 days compared with 7 days post-MI (R1 [s−1]: 21 days=2.8 [interquartile range, 2.69–3.30] versus 7 days=2.3 [interquartile range, 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<2.34 Hz and 0.55≤19F≤1.85) resulted in an odds ratio of 30.0 (CI 95%, 1.41–638.15; P=0.029) for favorable post-MI remodeling. Conclusions: Multinuclear 1H/19F magnetic resonance imaging 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.