Molecular MRI of collagen enables evaluation of fibrosis and therapeutic response in venous thrombosis:Molecular MRI of collagen in DVT

Background: Fibrosis, with accumulation of type I collagen, is a hallmark of post-thrombotic change after deep vein thrombosis (DVT), but tools for its direct detection are lacking. Here, we investigate whether molecular magnetic resonance imaging (MRI) using a collagen-specific gadolinium-based probe can detect and measure changes in collagen during thrombus resolution and in response to treatment in a mouse model of DVT.<br/>Methods: Venous thrombus was induced in the inferior vena cava (IVC) of BALB/c mice (n=45) and MRI was performed at day 2 (n=3) and weeks 1, 2, 3 post-surgery using the collagen-specific probe, EP-3533 (10μmol/kg, n=11-13/ group). A subgroup of mice with DVT (n=7) was treated with pravastatin in drinking water (40mg/kg/day) for 3 weeks post-DVT. Pre- and post-EP3533 MRI scans were performed. Magnetic resonance venography (MRV) was used to measure thrombus volume. Inversion recovery T1-weighted (IR-T1w) images and T1 maps, pre- and post-contrast, were used to calculate the percent change (%) in contrast-to-noise ratio (ΔCNR), signal-to-noise ratio (ΔSNR), and relaxation rate (ΔR1). Tissues were used for ex vivo analyses. <br/>Results: EP-3533 uptake increased during thrombus organization and resolution resulting in MRI signal enhancement, with % ΔCNR, % ΔSNR and % ΔR1 peaking at 3 weeks after DVT. MRI measurements of collagen accumulation quantified as an increase in % ΔCNR (rho=0.89, P=0.012) and % ΔR1 (rho=0.80, P=0.029) correlated positively with collagen histology. The spatial distribution of gadolinium in the tissue co-localized with collagen type I based on immunohistochemistry (rho=0.95, P&lt;0.001). Statin-treatment decreased both collagen accumulation and vein wall thickness, without affecting thrombus size.<br/>Conclusions: Molecular MRI using a collagen targeting probe made collagenous thrombus visible on MRI and detected changes in collagen content during thrombus resolution.<br/><br/><br/>