Abstract
Magnetic resonance imaging (MRI) provides non-invasive, repetitive measures in the same individual, allowing the study of a physio-pathological event over time. In this study, we tested the performance of 7 Tesla multi-parametric MRI to monitor the dynamic changes of mouse skeletal muscle injury and regeneration upon acute ischemia induced by femoral artery dissection. T2-mapping (T2 relaxation time), diffusion-tensor imaging (Fractional Anisotropy) and perfusion by Dynamic Contrast-Enhanced MRI (K-trans) were measured and imaging results were correlated with histological morphometric analysis in both Gastrocnemius and Tibialis anterior muscles. We found that tissue damage positively correlated with T2-relaxation time, while myofiber regeneration and capillary density positively correlated with Fractional Anisotropy. Interestingly, K-trans positively correlated with capillary density. Accordingly, repeated MRI measurements between day 1 and day 28 after surgery in ischemic muscles showed that: 1) T2-relaxation time rapidly increased upon ischemia and then gradually declined, returning almost to basal level in the last phases of the regeneration process; 2) Fractional Anisotropy dropped upon ischemic damage induction and then recovered along with muscle regeneration and neoangiogenesis; 3) K-trans reached a minimum upon ischemia, then progressively recovered. Overall, Gastrocnemius and Tibialis anterior muscles displayed similar patterns of MRI parameters dynamic, with more marked responses and less variability in Tibialis anterior. We conclude that MRI provides quantitative information about both tissue damage after ischemia and the subsequent vascular and muscle regeneration, accounting for the differences between subjects and, within the same individual, between different muscles.
Highlights
Critical limb ischemia (CLI) is the most severe form of peripheral artery disease, is mostly caused by atherosclerosis, and is characterized by intractable pain, ulcers and gangrene which require a prompt treatment [1]
To validate multi-parametric Magnetic Resonance Imaging (MRI) as a tool to investigate the structural and functional changes caused by acute ischemia, MRI data were compared to morphometric analysis of histological sections
T2 relaxation time (T2-rt), FA and K-trans of Gastrocnemius and Tibialis anterior muscles of both posterior limbs were evaluated at each time point
Summary
Critical limb ischemia (CLI) is the most severe form of peripheral artery disease, is mostly caused by atherosclerosis, and is characterized by intractable pain, ulcers and gangrene which require a prompt treatment [1]. Mortality, and costs associated with CLI, optimal treatment to increase limb preservation, prevent death, and improve functional capacity in these patients is still a unmet need [3]. In this context, preclinical studies, designed to understand the mechanisms underpinning cellular and tissue response to ischemia or to test the efficacy of prospective therapeutic agents, could provide new therapeutic options. A rather high variability in the outcome of the ischemic injury has been observed between different mouse strains and between mice of the same strain, due to genetic and microvascular morphology differences [9, 10]. This inter-individual variability models the heterogeneity observed in humans; on the other side, it can complicate the analysis and increase number of mice necessary to obtain statistically solid data
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